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Handbook of Pharmaceutical Excipients SIXTH EDITION

Edited by

Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MlnstP

Chief Scientist lntelligensys Ltd, Stokesley, North Yorkshire, UK

Paul J Sheskey BSc, RPh

Application Development Leader The Dow Chemical Company, Midland, M( USA

Marian E Quinn BSc, MSc

Development Editor Royal Pharmaceutical Society of Great Britain, London, UK

(l?P) London • Chicago Pharmaceutical Press

lwillingham

New Stamp

Published by the Pharmaceutical Press An imprint of RPS Publishing

1 Lambeth High Street, London SE 1 7JN, UK 100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA

and the American Pharmacists Association 2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA

© Pharmaceutical Press and American Pharmacists Association 2009

(RP) is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain

First published 1986 Second edition published 1994 Third edition published 2000 Fourth edition published 2003 Fifth edition published 2006 Sixth edition published 2009

Typeset by Data Standards Ltd, Frome, Somerset Printed in Italy by L.E.G.O. S.p.A.

ISBN 978 0 85369 792 3 (UK) ISBN 978 1 58212 135 2 (USA)

All rights reserved . No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder.

The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liabi lity for any errors or omissions that may be made.

A catalogue record for this book is available from the British Library

14 Safety Hydrogenated castor oil is used in oral and topical pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material.

Acute oral toxicity studies in animals have shown that hydrogenated castor oil is a relatively nontoxic material·. Irritation tests with rabbits show that hydrogenated castor oil causes mild, transient irritation to the eye.

LDso (rat, oral): > 10g/kg

15 , Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled.

16 Regulatory Status Accepted in the USA as an indirect food additive. Included in the FDA Inactive Ingredients Database (oral capsules, tablets, and sublingual tablets).

Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Castor oil; vegetable oil, hydrogenated.

18 Comments Various different grades of hydrogenated castor oil are commercially available, the composition of which may vary considerably.

Cellulose, Microcrystalline 129

Sterotex K (Karlshamns Lipid Specialities), for example, is a mixture of hydrogenated castor oil and hydrogenated cottonseed oil. See Vegetable Oil, hydrogenated for further information.

The EINECS number for hydrogenated castor oil is 232-292-2.

19 Specific References 1 Kline CH. Thixcin R-thixotrope. Drug Cosmet Ind 1964; 95(6): 895-

897. 2 Yonezawa Y et al. Release from or through a wax matrix system. III:

Basic properties of release through the wax matrix layer. Chem Pharm Bull (Tokyo) 2002; 50(6): 814-817.

3 Vergote GJ et al. An oral controlled release matrix pellet formulation containing microcrystalline ketoprofen. Int J Phann 2002; 219: 81-87.

4 Danish FQ, Parrott EL. Effect of concentration and size of lubricant on flow rate of granules. J Pharm Sci 1971; 60: 752- 754.

5 Holzer AW, Sjogren]. Evaluation of some lubricants by the comparison of friction coefficients and tablet properties. Acta Pharm Suec 1981; 18: 139-148.

20 General References

21 Author

RT Guest.

22 Date of Revision

11 February 2009.

Cellulose, Microcrystalline

1 Nonproprietary Names

BP: Microcrystalline Cellulose

JP: Microcrystalline Cellulose PhEur: ,Cellulose, Microcrystalline USP-NF: Microcrystalline Cellulose

2 Synonyms Avicel PH; Cellets; Celex; cellulose gel; hellulosum microcristallinum; Celphere; Ceolus KG; crystalline cellulose; E460; Emcocel; Ethispheres; Fibrocel; MCC Sanaq; Pharmacel; Tabulose; Vivapur.

3 Chemical Name and CAS Registry Number

Cellulose [9004-34-6]

4 Empirical Formula and Molecular Weight

(C6H10Os),, ~ 36 000 where n ~ 220.

···----.. ~· -- ·- ------· ---~· ~--·-· - --·

5 Structural Formula

HO

'------0

HO

,_ ___ o

OH

OH n/2

6 Functional Category Adsorbent; suspending agent; tablet and capsule diluent; tablet disintegrant.

130 Cel lulose , M ic roc rysta lli ne

, dv: Excipient: microcrysta lline cellulose; manufacturer: JRS Pharma LP; lot no. : 98662; magnification: 1 OO x .

!'!i~M 2: Excipient: microcrysta lline cellulose (Avicel PH- I O 1); manufacturer: FMC Biopolymer. magnification: 200 x ; voltage: 3 kV.

SEM 3: Excipient: microcrysta lline cellulose (Avicel PH- I 02); manufacturer: FMC Biopolymer. magnification: 200 x ; voltage: 3 kV.

'" , Excipient: microcrystalline ce llulose (Avicel PH-I 05); manufacturer: FMC Biopolymer. magn ification: 500 x ; voltage: 3 kV.

SEM 5: Excipient: microcrystalline cellulose (Avicel PH-200) ; manufacturer: FMC Biopolymer. magnification: 200 x ; voltage: 3 kV.

SEM 6: Excipient: microcrystalline cellulose {Avicel PH-302); manufacturer: FMC Biopolymer. magnification: 200x ; voltage: 3 kV.

7 Applications in Pharmaceutical Formulation or Technology

Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation and direct-compression processesY-7l In addition to its use as a binder/diluent, microcrystalline cellulose also has some lubricant( Bl and disintegrant properties that make it useful in tableting.

....

Microcrystalline cellulose is also used in cosmetics and food products; see Table I.

8 Description Microcrystalline cellulose is a purified, partially depolymerized cellulose that occurs as a white, odorless, tasteless, crystalline powder composed of porous particles. It is commercially available in different particle sizes and moisture grades that have different properties and applications.

Table I: Uses of microcrystalline cellulose.

Use Concentration (%)

Adsorbent Anti adherent Capsule binder/diluenl Tablet disintegrant Tablet binder/diluent

20- 90 5-20 20- 90 5- 15 20-90

-------------··--·--·--·-----·-------- - ----

9 Pharmacopeial Specifications See Table II. See also Section 18.

Tcibleli: Pharmacopeial specifications for microcrystalline cellulose. -- --Test JP XV PhEur 6.3 USP32- NF27

---· -···--·-·-·--Identification + Characters + pH 5.0-7.5 Bulk density + Loss on drying ~:;7.0% Residue on ignition ,;; 0.1 % Conductivii + Sulfated as Ether-soluble substances ,;; 0.05% Water-soluble substances + Heavy metals ,;; JO ppm Microbial limits +

Aerobic ,;; 103 cfu/g Molds and yeasts ,;; l02 cfu/g

Solubility Particle size distribution

- ---·- ----------

10 Typical Properties A ngle of repose

49° for Ceo/us KG; 34.4° for Emcocel 90M _( 9)

Density (bulk) 0.337 g/cm3

;

0.32g/cm3 for Avicel PH-101 ; (lOl

+ + + 5.0-7.5 5.0-7.5

+ ":;7.0% ,;; 7.0%

,;:; 0.1% + + ,;; 0.1 % ,;; 0.05% ,;; 0.05% ,;; 0.25% ,;; 0.25% ,;; lOppm ,;; 0.001 % + + ,;; 103 cfu/g ,;; l 02 cfu/g

,;; 103 cfu/g ,;; 102 cfu/g

+ + --- -----------

0.80 ± 5 g/cm3 for Cellets 100, 200, 350, 500, 700, 1000; 0.29 g/cm3 for Emcocel 90M;(9

l

0.26-0.31 g/cm3 for M CC Sanaq 101; 0.28-0.33 g/cm3 for MCC Sanaq 102;

0.29-0.36 g/cm3 for MCC Sanaq 200;

0.34-0.45 g/cm3 for MCC Sanaq 301; 0.35-0.46 g/cm3 for MCC Sanaq 302;

0.13-0.23 g/cm3 for M CC Sanaq UL-002; 0.29 g/cm3 for Vivapur 101 .

Density (tapped)

0.478g/cm3;

0.45g/cm3 for Avice/ PH-101; 0.35 g/cm3 for Erncocel 90M.(9 I

Density (true) 1.512- 1.668 g/cm3;


0) __Q

. ~ 0.0 l-'-"1-A,J--H+A-#11J\--J""-lnA-."r-f-+-l'---t-c-i=---I-H,,P'--I-I (!)

""D ""D

C

~ X

0 '

., , - .... ' 2483

8 _,,·-- ' 2273

9 - 7.0 ~~_,__----~-~~~_,__~----~~~_._ ...... - 0.2 1100 1300 1500 1700 1900 2100 2300 2500

Wavelength/nm

Figure 1: Near-infrared spectrum of cellulose, microcrysta lline measured by reflectance.

1.420- 1.460 g/cm3 for Avicel PH-102.<1 1)

Flowability 1.41 g/s for Emcocel 90M_(9)

Melting point Chars at 260-270°C. Moisture content Typically less than 5% w/w. However, different

grades may contain varyinf amounts of water. Microcrystalline cellulose is hygroscopic.<1 2 See Table III.

NIR spectra see Figure 1. Particle size distribution Typical mean particle size is 20- 200 µm.

Different grades may have a different nominal mean particle size; see Table Ill.

Solubility Slightly soluble in 5% w/v sodium hydroxide solution; practically insoluble in water, dilute acids, and most organic solvents .

Specific surf ace area

l.06-1.12 m2/g for Avicel PH-101;

l.21- l.30m2/g for Avicel PH-102;

0.78-1.18m2/g for Avicel PH-200.

11 Stability and Storage Conditions Microcrystalline cellulose is a stable though hygroscopic material. The bulk material should be stored in a well-closed container in a cool, dry place.

12 Incompatibilities Microcrystalline cellulose 1s incompatible with strong oxidizing agents.

13 Method of Manufacture Microcrystalline cellulose is manufactured by controlled hydrolysis with dilute mineral acid solutions of a-cellulose, obtained as a pulp from fibrous plant materials. Following hydrolysis, the hydrocellulose is purified by filtration and the aqueous slurry is spraydried to form dry, porous particles of a broad size distribution.

14 Safety Microcrystalline cellulose is widely used in oral pharmaceutical formulations and food products and is generally regarded as a relatively nontoxic and nonirritant material.

Microcrystalline cellulose is not absorbed systemically fo llowing oral administration and thus has little toxic potential. Consumption of large quantities of cellulose may have a laxative effect, although this is unlikely to be a problem when cellulose is used as an excipient in pharmaceutical formulations.

Deliberate abuse of formulations containing cellulose, either by inhalation or br injection, has resulted in the formation of cellulose gran ulomas.<1 3

132 Cellu lose , Mic rocrys tal l ine

Table Ill : Properties of selected commercially available grades of microcrystalline cellulose.

Grade Nominal Particle size analysis Moisture mean content (%) particle size (11m) ·-· ··----- .. -----

Mesh size Amount retained (%)

Avice/ PH-IO 1 (a) 50 60 ,,:; 1.0 ,,:; 5.0 200 ,,:; 30.0

Avice/ PH- I 02 (al 100 60 ,,:; 8.0 ,,:; 5 .0 200 ;;, 45.0

Avice/ PH-I 03 (a) 50 60 ,,:; 1.0 ,,:; 3.0 . 200 ,,:; 30.0

Avicel PH- I 05 101 20 400 ,,:; 1.0 ,,:; 5.0 Avice/ PH-112 (a) 100 60 ,,:; 8.0 ,,:; 1.5 Avice/ PH-113 (al 50 60 ,,:; 1.0 ,,:; 1.5

200 ,,:; 30.0 Avice/ PH-200 (a) 180 60 ;;, 10.0 ,,:; 5 .0

100 ;;, 50.0 Avice/ PH-30 1 (a) 50 60 ,,:; 1.0 ,,:; 5.0

200 ,,:; 30.0 Avice/ PH-302 (al 100 60 ,,:; 8.0 ,,:; 5.0

200 ;;, 45.0 Ce/ex I O I (bl 75 60 ,,:; 1.0 ,,:; 5.0

200 ;;, 30.0 Ceo/us KG-802 (cl 50 60 ,,:; 0 .5 ,,:; 6.0

200 ,,:; 30.0 Emcocel 50M (di 50 60 ,,:; 0.25 ,,:; 5.0

200 ,,:; 30.0 Emcocel 90M (di 91 60 ,,:; 8.0 ,,:; 5.0

200 ;;, 45.0 MCC Sanaq 50 60 ,,:; 1.0 ,,:; 6.0

1011•1

200 ,,:; 30.0 MCC Sanaq 100 60 ,,:; 8.0 ,,:; 6.0

1021•1 200 ;;, 45.0

MCC Sanaq 180 60 ;;, 10.0 ,,:; 6.0 2001•1

100 ;;, 50.0 MCC Sanaq 50 60 ,,:; 1.0 ,,:; 6.0

301 1•1

200 ;;, 30.0 MCC Sanaq 100 60 ,,:; 8.0 ,,:; 6.0

3021•) · 200 ;;, 45.0

MCC Sanaq UL- 50 60 <0.5 ,,:; 6.0 002!•)

100 <5 .0 200 <5.0-30.0

Vivapur IO 1 !di 50 60 ,,:; 1.0 ,,:; 5.0 200 ,,:; 30.0

Vivapur 1 02 (dJ 90 60 ,,:; 8.0 ,,:; 5 .0 200 ;;, 45.0

Vivapur 12 (di 160 38 ,,:; 1.0 ,,:; 5.0 94 ,,:; 50.0

Suppliers: (al FMC Biopolymer (bl International Specialty Products (cl Asahi Kasei Corporation (d) JRS Pharma (e) Pharmatrons Sanaq AG

15 Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Microcrystalline cellulose may be irritant to the eyes. Gloves, eye protection, and a dust mask a re recommended. In the UK, the workplace exposure limits -for cellulose have been set at 10 mr,m3 long-term (8-hour TWA) for ~otal inhalable dust and 4 mg/m for respirable dust; the short-term limit for total inhalable dust has been set at 20 mg/m3

. (l4

J

16 Regulatory Status

GRAS lis ted. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (inhalations; oral capsules, powders, suspensions, syrups, and tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.

17 Related Substances

Microcrystalline cellulose and carrageenan; microcrystalline cellulose and carboxymethylcellulose sodium; microcrystalline cellulose and guar gum; powdered cellulose; silicified microcrystalline cellulose.

Microcrystalline cellulose and carrageenan Synonyms Lustre Clear. Comments Lustre Clear (FMC Biopolymer) is an aqueous film

coating combining microcrystalline cellulose and carrageenan.

Microcrystalline cellulose and guar gum Synonyms Avicel CE-15. Comments Avicel CE-15 (FMC Biopolymer) is a coprocessed

mixture of microcrystalline cellulose and guar gum used in chewable tablet fo rmula tions.

18 Comments

Microcrystalline cellulose is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further informa tion see the General Information Chapter < 1196> in the USP32- NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JPXV.

Several different grades of microcrysta lline cellulose are commercially available that differ in their method of manufacture,!15

•16

>

particle size, moisture, flow, and other physical properties .<17-

29>

The larger-particle-size grades generally provide better flow properties in pharmaceutica l machinery. Low-moisture grades are used with moisture-sensitive materia ls. Higher-density grades have improved flowability.

Several coprocessed mixtures of microcrystalline cellulose with other excipients such as carrageenan, carboxymethylcellulose sodium, and guar gum are commercially available; see Section 17.

Celphere (Asahi Kasei Corporati on) is a pure spheronized microcrystalline cellulose avail able in several different particle size ranges. Balocel Sanaq (Pharmatrans Sanaq AG) is an excipient used mainly in the production of pellets and granulates in direct tableting, which contains lactose, microcrystalline cellulose, and sodiµm carboxymethylcellulose.

According to PhEur 6.3, microcrys talline cellulose has certain functionali ty related characteristics that are recognised as being relevant control parameters for one or more functions of the substance when used as an excipient. Non-mandatory testing procedures have been described for particle size distribution (2.9.31 or 2.9.38 ) and powder flow (2 .9.36).

A specification for microcrystalline cellulose is contained in the Food Chemica ls Codex (FCC).130

> The PubChem Compound ID (CID) for microcrystalline cellulose is 14055602.

19 Specific References 1 Enezian GM. [Direct compression of ta blets using microcrystalline

cellulose.] Pharm A cta He/v 1972; 47: 321-363[in French]. 2 Lerk CF, Bolhuis GK. Comparative evaluation of excipients for direct

compression I. Pharm .Weekb/ 1973; 108: 469-481. 3 Lerk CF et al. Compara tive evaluation of excipients for direct

compression II. Pharm Weekbl 1974; 109: 945- 955 . 4 Lamberson RF, Raynor GE. Tableting properties of microcrystalline

cellulose. M anuf Chem A erosol N ews 1976; 47(6): 55-61.

5 Lerk CF et al. Effect of microcrystalline cellulose on liquid penetration in and disintegration of directly compressed tablets. J Pharm Sci 1979; 68: 205-211.

6 Chilamkurti RN et al. Some studies on compression properties of tablet matrices using a computerized instrumented press. Drug Dev Ind Phann 1982; 8: 63-86.

7 Wallace JW et al. Performance of pharmaceutical filler/binders as related to methods of powder characterization. Pharm Technol 1983; 7(9): 94-104.

8 Omray A, Omray P. Evaluation of microcrystalline cellulose as a glidant. Indian J Pharm Sci 1986; 48: 20-22.

9 Celik M, Okutgen E. A feasibility study for the development of a prospective compaction functionality test and the establishment of a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309- 2334.

10 Parker MD et al. Binder-substrate interactions in wet granulation 3: the effect of excipient source variation. Int J Pharm 1992; 80: 179-190.

11 Sun CC. True density of microcrystalline cel lulose. J Pharm Sci 2005; 94(10): 2132- 2134.

12 Callahan JC et al. Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 8: 355-369.

13 Cooper CB et al. Cellulose granulomas in the lungs of a cocaine sniffer. Br Med J 1983; 286: 2021-2022.

14 Health and Safety Executive. EH40/2005: Workplace Ex posure Limits . Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ coshh/tablel.pdf (accessed 5 February 2009).

15 Jain JK et al. Preparation of microcrystalline cellulose from cereal straw and its evaluation as a tablet excipient. Indian J Pharm Sci 1983; 45: 83-85.

16 Singla AK et al. Evaluation of microcrysta lline cellulose prepared from absorbent cotton as a direct compression carrier. Drug Dev Ind Pharm 1988; 14: 1131- 1136.

17 Doelker E et al. Comparative tableting properties of sixteen microcrystalline celluloses. Drug Dev Ind Pharm 1987; 13: 1847-1875.

18 Bassam F et al. Effect of particle size and source on variability of Young's modulus of microcrystalline cellulose powders. J Pharm Pharmacol 1988; 40: 68P.

19 Dittgen M et al. Microcrystalline cellulose in direct tabletting. Manu( Chem 1993; 64(7): 17, 19, 21.

20 Landin M et al. Effect of country of origin on the properties of microcrystalline cellulose. Int J Pharm 1993; 91: 123- 131.

21 Landin M et al. Effect of batch variation and source of pulp on the properties of microcrystal line cellulose. Int J Pharm 1993; 91: 133-141.

22 Landin M et al. Influence of microcrysralline cellulose source and batch variation on tabletting behavior and stability of prcdnisone formula tions. Int] Pharin 1993; 91: 143- 149.

23 Podczeck F, Revesz P. Evaluation of the properties of microcrystalline and microfine cellulose powders. /11t J Pham, 1993; 91: 183-193.

24 Rowe RC et al. The effect of batch and source variation on the crystallinity of microcrystalline cellulose. /11t J Phann 1994; 101: 169-172.

------· - ---·-··-·-·


25 Hasegawa M. Direct compression: microcrystallinc cellulose grade 12 versus classic grade 102. Pharm Technol 2002; 26(5): 50, 52, 54, 56, 58, 60.

26 Kothari SH et al. Comparative evaluations of powder and mechanical properties of low crystallinity celluloses, microcrystalline celluloses, and powdered celluloses. Int J Pharm 2002; 232: 69-80.

27 Levis SR, Deasy PB. Production and evaluation of size-reduced grades of microcrystalline cellulose. int J Phann 2001; 213: 13-24.

28 Wu JS et al. A statistical design to evaluate the influence of manufacturing factors on the material properties and functionalities of microcrystalline cellulose. Eur J PharmSci 2001; 12: 417-425.

29 Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline cellulose on the compactability and dissolution of tablets. Eur J Pharm Biophann 1999; 47: 225-230.

30 · Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 187.

20 General References Asahi Kasei Corporation. Ceo/us KG, Celphere. http://www.ceolus.com

(accessed 6 November 2008). Doelker E. Comparative compaction properties of various microcrystalline

cellulose types and generic products. Drug Dev Ind Pharm 1993; 19: 2399-2471.

European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq: m.eu/site/-614.html (accessed 5 February 2009).

FMC Biopolymer. Problem Solver: Avicel PH, 2000. International Specialty Products. Material Safety data sheet: Ce/ex 101,

2003. JRS Pharma LP. Technical literature: Emcocel, 2003. Pharmatrans Sanaq AG. Product literature: Ce/lets. http://www.cellets.com

(accessed 6 November 2008). Pharmatrans Sanaq AG. Product literature: MCC Sanaq. http://www.phar

matrans-sanaq.com/prod.html (accessed 6 November 2008). Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. Boca

Raton, FL: CRC Press, 1992; 71-74. Staniforth JN et al. Effect of addition of water on the rheological and

mechanical properties of microcrystalline celluloses. Int J Phann 1988; 41: 231- 236.

21 Author

A Guy.

22 Date of Revision

5 February 2009.

It,

It has been shown that the increased force required to expel coconut oil from plastic syringes was due to uptake of the oil into the rubber plunger; this resulted in swelling of the rubber plunger and an increased resistance to movement down the syringe barrel. (ll)

13 Method of Manufacture Coconut oil is the fixed oil obtained from the seeds of Cocos nucifera Linn. (Palmae). This oil is then refined to produce refined coconut oil, which is referred to in the coconut industry as RBD (refined, bleached, and deodorized) coconut oil.

14 Safety When administered orally, coconut oil is essentially nontoxic, although ingestion of large amounts may cause digestive or gastrointestinal irritation or upset. Coconut oil can act as an irritant when applied to the skin and when in contact with the eyes; it may be absorbed through the skin. Inhalation of mist or vapor may cause respiratory tract irritation.

15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of the material handled. Coconut oil should be kept away from heat and sources of ignition, and contact with oxidizing agents, acids, and alkalis should be avoided.

If in the solid form, large spillages of coconut oil should be dealt with by shoveling the material into a waste disposa l container. For liquid spillages, the oil should be absorbed with an inert material before removal for disposal.

16 Regulatory Status Included in the FDA Inactive Ingredients Database (oral capsules and tablets; topical creams, solutions, and ointments). Included in scalp ointments and therapeutic shampoos licensed i:n the UK.

17 Related Substances Almond oil; canola oil; castor oil; castor oil, hydrogenated; corn oil; cottonseed oil; medium-chain triglycerides; olive oil; peanut oil; sesame oil; soybean oil; sunflower oil.

Colloidal Silicon Dioxide

1 Nonproprietary Names BP: Colloidal Anhydrous Silica JP: Light Anhydrous Silicic Acid

PhEur: Silica, Colloidal Anhydrous USP-NF: Colloidal Silicon Dioxide

2 Synonyms Aerosil; Cab-0-Sil; Cab-0-Sil M-SP; colloidal silica; fumed silica; fumed silicon dioxide; hochdisperses silicum dioxid; SAS; si lica colloidalis anhydrica; silica sol; silicic anhydride; silicon dioxide colloidal; silicon dioxide fumed; synthetic amorphous silica; Wacker HDK.

Colloidal Silicon Dioxide 185

18 Comments A specification for coconut oil (unhydrogenated) is contained in the Food Chemicals Codex (FCC)Y3

)

19 Specific References 1 Hung CF et al. The effect of oil components on the physicochemical

properties and drug delivery of emulsions: tocol emulsion versus lipid emulsion. Int J Pharm 2007; 335(1-2): 193-202.

2 Garti N, Arkad 0. Preparation of cloudy coconut oi l emulsions containing dispersed TiO2 using atomizer. J Dispersion Sci Technol 1986; 7(5): 513-523.

3 Fang JY et al. Lipid nano/submicron emulsions as delivery vehicles for topical flurbiprofen delivery. Drug De/iv 2004; 11(2): 97-105.

4 Nielsen HW et al. Intranasal administration of different liquid formu lations of bumetanide to rabbits. Int J Pharm 2000; 204(1-2): 35-41.

5 Tanabe K et al. Effect of different suppository bases on release of indomethacin. J Pharm Sci Technol Jpn 1984; 44: 115- 120.

6 Broda H et al. Preparation and testing of suppositories with cephradine - evaluation of pharmaceutical availability and biological availability. Farm Pol 1993; 49(11-12 ): 1-8.

7 Ogbolu DO et al. In vitro antimicrobial properties of of coconut oil on Candida species in Ibadan, Nigeria.] Med Food 2007; 10(2): 384-387.

8 Anonymous. Nitlotion. Pharm f 2000; 265: 345. 9 Pajoumand A et al. Survival following severe aluminium phosphide

poisoning. J Pharm Pract Res 2002; 32(4): 297-299. 10 Patel HR. Sales of coconut oil. Pharm J 1992; 249: 252. 11 Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn. London:

Pharmaceutical Press, 1979; 214. 12 Dexter MB, Shott MJ . The eva luation of the force to expel oily injection

vehicles from syringes. J Pharm Pharmacol 1979; 31: 497-500. 13 Food Chemicals Codex, 6th edn. Bethesda, MD: United States

Pharmacopiea, 2008; 222.


21 Author CG Cable.

22 Date of Revision 27 February 2009.


Silica (7631-86-9]


Si02 60.08

5 Structural Formula See Section 4.

6 Functional Category Adsorbent; anticaking agent; emulsion stabilizer; glidant; suspending agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent.

--------------------------------- - --- - .,.._.. .. _._ I

186 Collo idal Silicon Dioxide

7 Applications in Pharmaceutica l Formulation or Technology

Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and food products; see Table I. Its small particle size and large specific surface area give it desirable flow characteristics that are exploited to improve the flow properties of dry powders(l)

. in a number of processes such as tableting12--4) and capsule filling.

Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic thickening and suspending agent in gels and semisolid preparations. (S) With other ingredients of similar refractive index, transparent gels may be formed. The degree of viscosity increase depends on the polarity of the liquid (polar liquids generally require a greater concentration of colloidal silicon dioxide than nonpolar liquids). Viscosity is largely independent of temperature. However, changes to the pH of a system may affect the viscosity; see Section 11.

In aerosols, other than those for inhalation, colloidal silicon dioxide is used to promote particulate suspension, eliminate hard settling, and minimize the clogging of spray nozzles. Colloidal silicon dioxide is also used as a tablet disintegrant and as an adsorbent dispersing agent for liquids in powders.( 61 Coll oidal silicon dioxide is frequently added to suppository fo rmulations containing lipophilic excipients to increase viscosity, prevent sedimentation during molding, and decrease the release ra te.(7•

81

Colloidal silicon dioxide is also used as an adsorbent during the preparation of wax microspheres/ 9

) as a thickening agent for topica l preparations;(lOJ and has been used to aid the freeze-drying of nanocapsules and nanosphere suspensions.(1 1 l

Table I: Uses of collo idal silicon dioxide.

Use

Aerosols Emulsion stabi lizer Glidant Suspending and thickening agent

8 Description

Concentration (%)

0.5-2.0 1.0-5.0 0. 1- 1.0 2.0- 10.0

Colloidal silicon dioxide is a submicroscopic fumed silica with a particle size of about 15 nm. It is a light, loose, bluish-white-colored, odorless, tasteless, amorphous powder.

SEM 1: Excipient: colloidal silicon dioxide (Aerosil A-200); manufacturer: Evonik Degussa Corp. lot no.: 87 A-1 (04 l 69C); magni fication: 600x ; voltage: 20kV.

~.; Excipient: colloidal silicon dioxide (Aerosil A-200); manufacturer: Evonik Degussa Corp. lot no.: 87 A-1 (04 l 69C); magnification: 2400 x ; voltage: 20 kV.

9 Pharmacopeial Specifications

See Table II. Sl'e also Section 18.

Table II: Pharmacopeial specifications for colloidal si licon dioxide.

Test JP.XV PhEur 6.0 USP32-NF27

Identification + + + Characters + pH (4% w/v dispersion) 3.5-5.5 3.5-5.5 Arsenic .,:; 5ppm .,:; 8 µg/g Chloride .,:; 0.011 % .,:; 250ppm Heavy metals .,:; 40ppm .,:; 25ppm Aluminum + Calcium + Iron .,:; 500ppm Loss on drying .,:; 7 .0% .,:; 2.5% Loss on ignition .,:; 12.0% .,:; 5 .0% .,:; 2.0% Volume test (5 g sample) ~ 70mL Assay (on ignited sample) ~ 98.0% 99.0-100.5% 99.0-100.5%

10 Typical Properties Acidity/alkalinity pH= 3.8-4.2 (4% w/v aqueous dispersion) and

3.5-4.0 (10 % w/v aqueous dispersion) for Cab-O-Sil M-SP Density (bulk) 0.029-0.042 g/cm3

Density (tapped) see Tables Ill, IV, and V. Melting point 1600°C Moisture content see Figure 1Y2

•13l

Particle size distribution Primary particle size is 7- 16 nm. Aerosil forms loose agglomerates of 10-200 µm. See also Figure 2.

Refractive index 1.46 Solubility Practically insoluble in organic solvents, water, and

acids, except hydrofluoric acid; soluble in hot solutions of alkali hydroxide. Forms a colloidal dispersion with water. For Aerosil, solubility in water is 150 mg/L at 25°C (pH 7).

Specific gravity 2.2 Specific surface area

100-400 m2/g depending on grade. See also Tables III, IV,and V. Several grades of colloidal silicon dioxide are commercially

available, which are produced by modifying the manufacturing process. The modifications do not affect the silica content,

80

70 o Sorption • Desorption

~ 60 -

Q) .... 50 .2

<I)

·a E 40 E :::>

·.:: 30 ...0 -·5 0- 20 -

UJ

10

0o 10 20 30 40 50 60 70 80 90 100

Relative humidity (%)

figure 1: Sorption-desorption isotherm for colloidal si licon dioxide.

100 \

90 \

80

~ 70 Q) N 60 1

'iii .... Q)

50 -> 0

..:c 0) ,10

'<ii ~ 30

\ 20 -

10 -

0 ··~ ' 0 10 20 30 40 50 60 70 80 90 100

Particle size (~ m)

Figure 2: Particle size distribution of colloidal silicon dioxide (Aerosi/ A-200, Evonik Degussa Corp. ).

specific gravity, refractive index, color, or amorphous form. However, particle size, surface areas, and densities are affected. The physical properties of three commercially available colloidal silicon dioxides, Aerosil (Evonik Degussa Corp.), Cab-O-Sil (Cabot Corporation), and Wacker HDK (Wacker-Chemie GmbH) a re shown in Tables III, IV and V, respectively.

11 Stability and Storage Conditions Colloidal silicon dioxide is hygroscopic but adsorbs large quantities of water without liquefying. When used in aqueous systems at a pH 0-7.5, colloidal silicon dioxide is effective in increasing the viscosity of a system. H owever, at a pH greater than 7.5 the viscosityincreasing properties of co lloidal silicon dioxide are reduced; and at a pH grea ter than 10.7 this ability is lost entirely since the silicon dioxide dissolves to form silicates.'14

) Colloida l silicon dioxide powder should be stored in a well-closed container.

Colloidal Silicon Dioxide 187

Table Ill: Physical properties of Aerosil.

Grade

130 130v 200 200v 300 300 380. 380

(a) BET method.

Specific surface area101

(m2/ g)

130 ± 25 130 ± 25 200 ± 25 200 ± 25 300 ± 30 300 ± 30 380 ± 30 380 ± 30

Table IV: Physical properties of Cab-0-Si/.

Grade

LM-5 LM-50 M-5 H-5 EH-5 M-7D

(al BET method.

Specific surface area10l (m2/ g)

130 ± 25 150 ± 25 200 ± 25 325 ± 25 390 ± 40 200 ± 25

Table V: Physical properties of Wacker HOK.

Grade

S13 V15 N20 130 140 Hl5 H20 H30 H2000 H3004 H20 15 H2050

(al BET method.

Specific surface area 101

(m2/ g)

125 ± 15 150 ± 20 200 ± 30 300 ± 30 400 ± 40 120 ± 20 170 ± 30 250 ± 30 140 ± 30 2 10 ± 30 110 ± 30 110 ± 30

12 Incompatibilities

Density (tapped) (g/ cm3)

0.05 0.1 2 0.05 0.12 0.05 0.12 0.05 0. 12

Density (tapped) lg/ cm3)

0.04 0.04 0.04 0.04 0.04 0.10

Density (tapped) lg/ cm3)

0.05 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.22 0.08 0.20 0.20

Incompatible with diethylstilbestrol preparations. (lS)

13 Method of Manufacture

Colloidal silicon dioxide is prepared by the flame hydrolysis of chlorosilanes, such as silicon tetrachloride, at 1800°C using a hydrogen-oxygen flame. Rapid cooling from the molten state during manufacture causes the product to remain amorphous.

14 Safety

Colloidal silicon dioxide is widely used in oral and topical · pharmaceutical products and is generally regarded as an essentially nontoxic and nonirritant excipient. H owever, intraperitoneal and subcutaneous injection may produce local tissue reactions and/or granulomas. Colloidal silicon dioxide should therefore not be administered parentera lly.

LD50 (rat, IV): 0.015 g/kg' 16)

LD50 (rat, oral): 3.16 g/kg

V

l 88 Collo idal Si licon Dioxide

15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Considered a nuisance dust, precautions should be taken to avoid inhalation of colloidal silicon dioxide. In the absence of suitable containment facilities, a dust mask should be worn when handling small quantities of material. For larger quantities, a dust respirator is recommended.

Inhalation of colloidal silicon dioxide dust may cause irritation to the respiratory tract but it is not associated with fibrosis of the lungs (silicosis), which can occur upon exposure to crystalline silica.

16 Regulatory Acceptance GRAS listed. Included in the FDA Inactive Ingredients Database (oral capsules, suspensions, and tablets; transdermal, rectal, and vaginal preparations). Also approved by the FDA as a food additive and for food contact. Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.

17 Related Substances Hydrophobic colloidal si lica.

18 Comments Colloidal silicon dioxide is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General In formation Chapter < 1196 > in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JPXV.

The PhEur 6.0 also contains a specification for hydrated colloidal silicon dioxide. The incidence of microbial contamination of colloidal silicon dioxide is low'17 l due to the high production temperatures and inorganic precursor materials.

Note that porous silica gel particles may also be used as a glidant, thickener, dispersant and to adsorb moisture, which may be an advantage for some formu lations. Syloid 244FP meets the USPNF requirements for silicon dioxide, and Syloid 244 FP-BU meets the PhEur and JP requirements for silicon dioxide. (JS)

Another CAS number that is used for colloidal silicon dioxide is 112945-52-5.

The EINECS number for colloidal silicon dioxide is 231-545-4. The PubChem Compound ID (CID) for colloidal silicon dioxide is 24261.

19 Specific References York P. Application of powder fai lure testing equipment in assessing effect of glidants on flowability of cohesive pharmaceutical powders. J Pharm Sci 1975; 64: 121 6- 1221.

2 Lerk CF et al. Interaction of lubricants and colloidal silica during mixing with excipients I: its effect on tabletting. Pharm Acta I-lelv 1977; 52: 33-39.

3 Lerk CF, Bolhuis GK. Interaction of lubricants and colloidal silica during mixing with excipients II: its effect on wettability and dissolution velocity. Pharm A cta Helv 1977; 52: 39-44.

4 Jonat S et al. Influence of compacted hydrophobic and hydrophilic colloidal silicon dioxide on tabletting properties of pharmaceutical excipients. Drug Dev Ind Pharm 2005; 31: 687-696 .

5 Daniels R et al. The sta bility of drug absorba tes on silica. Drug Dev Ind Pharm 1986; 12: 2127-2156.

6 Sherriff M, Enever RP. Rheological and drug release properties of oil gels containing colloidal silicon dioxide. J Pharm Sci 1979; 68: 842-845.

7 Tukker JJ, De Blaey CJ. The addition of colloidal silicon dioxide to suspension suppositories II. The impact ori in vitro release and bioavailability. Acta Pharm Technol 1984; 30: 155-160.

8 Realdon N et al. Effects of silicium dioxide on drug release from suppositories. Drug Dev Ind Pharm 1997; 23: 1025-1041.

9 Mani N et al. Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure. II. Effects of adsorbents on microsphere properties. Drug Dev Ind Pharm 2004; 30(1): 83-93.

10 Gallagher SJ et al. Effects of membrane type and liquid/liquid phase boundary on in vitro release of ketoprofen from gel formulations. J Drug Target 2003; 11(6): 373-379.

11 Schaffazick SR et al. Freeze-drying polymeric colloidal suspensions: nanocapsules, nanospheres and nanodispersion. A comparative study. Eur J Pharm Biopharm 2003; 56(3): 501-505.

12 Ettlinger M et al. [Adsorption at the surface of fumed silica.] Arch Pharm 1987; 320: 1- 15[in German].

13 Callahan JC et al. Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 8: 355-369.

14 Cabot Corporation. Technical literature: Cab-O-Sil fumed silicas, the performance additives, 1995.

15 Johansen H, MIiler N. Solvent deposition of drugs on excipients II: interpretation of dissolution, adsorption and absorption characteristics of drugs. Arch Pharm Chem Sci Ed 1977; 5: 33-42.

16 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 3205.

17 Kienholz M. [The behaviour of bacteria in highly pure silicic acid.] Pharm Ind 1970; 32: 677- 679[in German].

18 WR Grace & Co. Technical literature: Sy/aid 244FP, 2002.

20 General References Cabot Corporation. Technical literature PDSl 71: Cab-O-Sil M-5P, 2006. Evonik Degu~sa Corp. Technical Bulletin Fine Particles No. 11 TB0011-1:

Basic characteristics of Aerosil fumed silica, 2006. Evonik Degussa Corp. Technical literature TI 1281-1: Aerosil colloidal

silicon dioxide for pharmaceuticals, 2006. · European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

Meyer K, Zimmermann I. Effect of glidants in binary powder mixtures. Powder Technol 2004; 139: 40-54.

Wacker-Chemie GmbH. Technical literature: Wacker HDK fumed silica, 1998.

Waddell WW. Silica amorphous.Kirk-Othmer Encyclopedia of Chemical Technology, 5th edn, vol. 22: New York: John Wiley & Sons, 2001; 380-406.

Wagner E, Brunner H. Aerosil: its preparation, properties and behaviour in organic liquids. Angew Chem 1960; 72: 744-750.

Yang KY et al. Effects of amorphoun ilicon dioxides on drug dissolution. J Pharm Sci 1979; 68: 560-565.

Zimmermann I et al. Nanomaterials as flow regulators in dry powders. Z Phys Chem 2004; 218: 51-102.

21 Author KP Hapgood.


208 Crospovidone

4 Shangraw R et al. A new era of tablet disintegrants. Pharm Technol 1980; 4(10): 49- 57.

5 Zhao N, Augsburger LL The influence of product brand-to-brand variability on superdisintegrant performance. A case study with croscarmellose sodium. Pharm Dev Technol 2006; 11(2): 179-185.

6 Zhao N, Augsburger LI. The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorthiazide from directly compressed tablets. AAPS Pharm Sci Tech 2005; 6(1): E120- E126.

7 Battu SK et al. Formulation and evaluation of rapidly disintegrating fenoverine tablets: effects of superdisintegrants. Drug Dev Ind Pharm 2007; 33(11): 1225-1232.

8 Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopicity on disintegrant efficiency in direct compression tablets in terms of dissolution. J Pharm Sci 1987;76: 907-909.

9 Gordon MS, Chowhan ZT. The effect of aging on disintegrant efficiency in direct compression tablets with varied solubility and hygroscopicity, in terms of dissolution. Drug D ev Ind Pharm 1990; 16: 437-447.

10 Johnson JR et al. Effect of formulation solubility and hygroscopicity on disintegrant efficiency in tablets prepared by wet granulation, in terms of dissolution. J Pharm Sci 1991; 80: 469--471.

11 Gordon MS et al. Effect of the mode of super disintegrant incorporation on dissolution in wet granulated tablets. J Pharm Sci 1993; 82(2): 220-226.

12 Khattab I et al. Effect of mode of incorporation of disintegrants on the characteristics of fluid-bed wet-granulated tablets. J Pharm Pharmacol 1993; 45(8): 687- 691.

t:Y. Crospovidone

1 Nonproprietary Names BP: Crospovidone

PhEur: Crospovidone

USP-NF: Crospovidone

2 Synonyms

Crospovidonum; Crospopharm; crosslinked povidone; E1202; Kollidon CL; Kollidon CL-M; Polyplasdone XL; Polyplasdone XL-1 O; polyvinylpolypyrrolidone; PVPP; 1-vinyl-2-pyrrolidinone homopolymer.


1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]


(C6H9NO)n > 1000000 The USP32- NF27 describes crospovidone as a water-insoluble

synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone. An exact determination of the molecular weight has not been established because of the insolubility of the material.


See Povidone.

6 Functional Category Tablet disintegrant.

13 Ferrero C et al. Disintegrating efficiency of croscannellose sodium in a direct compression formulation. Int J Pharm 1997; 147: 11-21.

14 FAO/WHO. Evaluation of certain food additives and contaminants. Thirty-fifth report of the joint FAO/WHO expert committee on food additives. World Health O rgan Tech Rep Ser 1990; No. 789.

20 General References DMV-Frontera Excipients. Product literature: Primellose and Primojel,

August 2008. European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 6 February 2009).

FMC Biopolymer. Material Safety Datasheet: A c-Di-Sol, May 2008. JRS Pharma. Product literature: Vivasol. http://www.jrspharma.de/Pharma/

wEnglisch/produktinfo/productinfo_vivasol.shtml (accessed 6 February 2009).

21 Author

RT Guest.

22 Date of Revision

6 February 2009.


Crospovidone is a water-insoluble tablet disintegrant and dissolution agent used at 2- 5% concentration in tablets prepared by directcompression or wet- and dry-granulation methodsY-6) It rapidly exhibits high capillary activity and pronounced hydration capacity, with little tendency to form gels. Studies suggest that the particle size of crospovidone strongly influences disintegration of analgesic tablets.m Larger particles provide a faster disintegration than smaller particles. Crospovidone can also be used as a solubility enhancer. With the technique of co-evaporation, crospovidone can be used to enhance the solubility of poorly soluble drugs. The drug is adsorbed on to crospovidone in the presence of a suitable solvent and the solvent is then evaporated. This technique results in faster dissolution rate.

8 Description

Crospovidone is a white to creamy-white, finely divided, freeflowing, practically tasteless, odorless or nearly odorless, hygroscopic powder.


See Table I. See also Section 18 .

10 Typical Properties Acidity/alkalinity _pH= 5.0- 8.0 (1 % w/v aqueous slurry) Density l .22 g/cm Density (bulk) see Table II. Density (tapped) see Table II.

sEM l : Excipient: crospovido_n_e (~olyplasdone XL-IO); manufacturer: ISP Corp.; lot no.: S8 103 1; magn1f1cahon: 400 x ; voltage: 10 kV.

... r ... .... • .,,, ' •,..i "- "" ...... t .,.

Table I: Pharmacopeial specifications for crospovidone.

Test PhEur 6.3

Identification + Characters + pH (1 % suspension) Water Residue on ignition ,;; 0.1 % Water-solu ble substa nces ,;; l .0% Peroxides ,;; 400 ppm Heavy metals ,;; l Oppm Vinylpyrrolid inone ,;; l Oppm Loss on drying ,;; 5.0% Nitrogen content (anhydrous basis) 11.0- 12 .8%

USP32- NF27

+

5.0- 8.0 ,;; 5.0% ,;; 0.4% ,;; 1.50%

,;; 0.001 % .;; O 1%

+

Table II: Density values of commercial grades of crospovidone.

Commercial grade

Kollidon CL Kollidon CL-M Polyplasdone XL ~}yplosdone XL-10

Density (bulk) (g/ cm3)

0.3- 0 .4 0 .15-0. 25 0.2 13 0.323

Density (tapped~{ cm3)

0 .4-0.5 0.3- 0.5 0 .273 0.46 1

Moisture content Maximum moisture sorption is approximately 60%.

NIR spectra see Figure 1. Particle size distribution Less than 400 µm for Polyplasdone X L;

less than 74 ~Lm for Polyplasdone X L-10. Approximately 50% greater than 50 µm and maximum of 3% greater than 250 µmin size for Kollidon CL. Minimum of 90% of particles are below 15 µm for Kollidon CL-M. The average particle size for Crospopharm type A is 100 µm and for Crospopharm type B it is 30 µm.

Solubility Practically insoluble in water and most common organic solvents.

Specific surface area see Table III.

11 Stability and Storage Conditions Since crospovidone is hygroscopic, it should be stored in an airtight container in a coo l, dry place.

Crospovidone 209

= 4.0 0. 2 Cl<'. 22 0 2312 ......._

1668 f 2353 0) 0

> cZ ·.:::: Q)

u 0.0 ......._

' .

u . ' ,. ' 0) C ._ 0 ~ ' ' 2367 X

, • • '2 148

0 -- 2262 .. ' ' 0 ' -. -- -' 0 ' ._

1692 2282 0 193 ~ - 5.0 -0. 2

1100 1300 1500 1700 1900 2 100 2300 2500

W avelength/nm

Figure 1: Near-infrared spectrum of crospovidone measured by reflecta nce.

Table Ill: Specific surface areas for commercial grades of crospovidone.

Commercial grade

Kollidon CL Kollidon CL-M Polyplasdone XL Polyplasdone XL-10


Surface area (m2 / g)

1.0 3.0-6.0 0.6-0 .8 1.2-1.4

Crospovidone is compatible with most organic and inorganic pharmaceutical ingredients. When exposed to a high water level, crospovidone may form molecular adducts with some materials; see Povidone.

13 Method of Manufacture Acetylene and forma ldehyde are reacted in the presence of a highly active catalyst to form butynediol, which is hydrogenated to butanediol and then cyclodehydrogenated to form butyrolactone. Pyrrolidone is produced by reacting butyrolactone with ammonia. This is followed by a vinylation reaction in which pyrrolidone and acetylene are reacted under pressure. The monomer vinylpyrroli done is then polymerized in solution, using a catalyst. Crospovidone is prepared by a 'popcorn polymerization' process.

14 Safety Crospovidone is used in oral pharmaceutical formul ations and is generally regarded as a nontoxic and nonirritant material. Shortterm animal toxicity studies have shown no adverse effects associated with crospovidone.(Sl However, owing to the lack of available data, an acceptable daily intake in humans has nor been specified by the WHO.l8l

LD50 (mouse, IP): 12 g/kg

15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask are recommended.

16 Regulatory Status Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (IM injections, oral capsules and tablets; topical, transdermal, and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

210 Cyclodextrins

17 Related Substances Copovidone; povidone.

18 Comments Crospovidone is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5 .8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Crospovidone has been studied as a superdisintegrant. The ability of the compound to swell has been examined directly using scanning electron microscopy. (9 l The impact of crospovidone on percolation has also been examined. (l O) The impact of crospovidone on dissolution of poorly soluble drugs in tablets has also been investigatedY l l Crospovidone has been shown to be effective with highly hygroscopic drugs. (lZJ It continues to be examined for its uses in a number of tablet formulations.

A specification for crospovidone is contained in the Food Chemicals Codex (FCC).'1 3l

The PubChern Compound ID (CID) for crospovidone is 6917.

19 Specific References Kornblum SS, Stoopak SB. A new tablet disintegrating agent: crosslinked polyvinylpyrrolidone. J Pharm Sci 1973; 62: 43-49.

2 Rudnic EM et al. Stud ies of the utility of cross linked polyvinylpolypyrrolidine as a tablet disintegrant. Drug Dev Ind Pharm 1980; 6: 291-309.

3 Gordon MS, Chowha n ZT. Effect of tablet solubility and hygroscopicity on disintegrant efficiency in direct compression tablets in terms of dissolu tion. J Phann Sci 1987; 76: 907-909.

4 Gordon MS et al. Effect of the mode of super disintegrant incorporation on dissolution in wet granulated tablets. J Pharm Sci 1993; 82: 220-226.

5 Tagawa M et al. Effect of various disintegrants on drug release behavior from tablets. J Pharm Sci Tech Yakuzaigaku 2003; 63 (4): 238-248.

6 Hipasawa N et al. Application of nilvadipine solid dispersion to tablet formu lation and manufacturing using crospovidone and methylcellulose on dispersion carriers. Chem Pharm Bu/12004; 52(2): 244-247.

. ·St; Cyclodextrins

1 Nonproprietary Names BP: Alfadex Betadex PhEur: Alfadex Betadex USP-NF: Alfadex Betadex

Gamma Cyclodextrin

2 Synonyms Cyclodextrin Cavitron; cyclic oligosaccharide; cycloamylose;

cycloglucan; Encapsin; Schardinger dextrin. <J.-Cyclodextrin alfadexum; alpha-cycloamylose; alpha-cyclodex

trin; alpha-dextrin; Cavamax W6 Pharma; cyclohexaamylose; cyclomaltohexose. ·

~-Cyclodextrin beta-cycloamylose; beta-dextrin; betadexum; Cavamax W7 Pharma; cycloheptaamylose; cycloheptaglucan; cyclomaltoheptose; Kleptose.

7 Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur J Pharm Sci 2002; 15(3): 295- 305.

8 FAO/WHO. Evaluation of certain food additives and contaminants. Twenty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1983; No. 696.

9 Thibert R, Hancock BC. Direct visualization of superdisintegrant hydration using environmental scanning electron microscopy. J Pharm Sci 1996; 85: 1255-1258.

10 Caraballo I et al. Influence of disintegrant on the drug percolation threshold in tablets. Drug Dev Ind Pharm 1997; 23(7): 665-669.

11 Yen SY et al. Investigation of dissolution enhancement of nifedipine by deposition on superdisintegrants. Drug Dev Ind Pharm 1997; 23(3): 313-317.

12 Hirai N et al. Improvement of the agitation granulation method to prepare granules containing a high content of a very hygroscopic drug. J Pharm Pharmacol 2006; 56: 1437-1441.

13 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 794.

20 General References Barabas ES; Adeyeye CM. Crospovidone. Brittain HG, ed. Analytical

Profiles of Drug Substances and Excipients., vol. 24: London: Academic Press, 1996; 87-163.

BASF. Technical litera ture: Insoluble Kollidon grades, 1996. European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21( 1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

ISP. Technical literature: Polyplasdone crospovidone NF, 1999. NP Pharm. Product data sheet: Crospopharm, 2008. Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int J Pharm

1989; 50: 147- 153.

21 Author

AH Kibbe.

22 Date of Revision

3 February 2009 .

y-Cyclodextrin Cavamax W8 Pharma; cyclooctaamylose; cyclomaltooctaose.

3 Chemical Name and CAS Registry Number <J.-Cyclodextrin (10016-20-3) ~-Cyclodextrin [7585-39-9]

· y-Cyclodextrin (1 7465-86-0]


<J.-Cyclodextrin C36H600 3o 972 ~-Cyclodextrin C42H700 35 1135 y-Cyclodextrin C4sH80040 1297

4 He L et al. A novel conrrolled porosity osmotic pump system for sodium ferulate. Pharmazie 2006; 61(12): 1022-1027.

20 General References Wilson AS. Plasticisers - Principles and Practice. London: Institute of

Materials, 1995.

Ex Dibutyl Sebacate


USP-NF: Dibutyl Sebacate

2 Synonyms Bis(n-butyl)sebacate; butyl sebacate; DBS; decanedioic acid, dibutyl ester; dibutyl decanedioate; dibutyl 1,8-octanedicarboxylate; Kodaflex DBS; Morflex DBS.

3 Chemical Name and CAS Registry Number Decanedioic acid, di-n-butyl ester (109-43-3]


C18H34O4 314.47 The USP32-NF27 describes dibutyl sebacate as consisting of the

esters of n-butyl alcohol and saturated dibasic acids, principally sebacic acid. ·

5 Structural Formula 0 0

II II H,C- (CH2l,-O- C- (CH2)8 - - C- O- (CH2J,-CH3

6 Functional Category

Plasticizer.


Dibutyl sebacate is used in oral pharmaceutical formulations as a plasticizer for film coatings on tablets, beads, and granules, at concentrations of 10- 30% by weight of polymer.(1 ,2) It is also used as a plasticizer in controlled-release tablets and microcapsule preparations. (3,4 I

Dibutyl sebacate is also used as a synthetic flavor and flavor adjuvant in food products;151 for example, up to 5 ppm is used in ice cream and nonalcoholic beverages.

8 Description Dibutyl sebacate is a clear, colorless, oily liquid with a bland to slight butyl odor.

9 Pharmacopeial Specifications See Tab le I.

21 Author RT Guest.

22 Date of Revision

5 February 2009.

Dibutyl Sebocote 227

Table I: Pharmacopeial specifications for dibutyl sebacote.

Test

Specific gravity Refractive index Acid value Saponification value Assay (of C1 aH3404)

10 Typical Properties Acid value 0.02

USP32- NF27

0.935-0.939 1 .429-1 .44 1 ,s;: 0.1 352-360 ;,: 92.0%

Boiling point 344-349°C; 180°C at 3 mmHg for Morflex DBS. Flash point 193°C; 178°C (OC) for Morflex DBS. Melting point -10°C Refractive index n t5 = 1.4401 Solubility Soluble in ethanol (95% ), ether, isopropanol, mineral

oil, and toluene; practically insoluble in water. Speci-fi.c gravity 0.937 at 20°c Vapor density (relative) 10.8 (air = 1) Vapor pressure 0.4kPa (3mmHg) at 180°C

11 Stability and Storage Conditions Dibutyl sebacate should be stored in a closed container in a coo l, dry location. Dibutyl sebacate is stable under the recommended storage conditions and as used in specified applications under most conditions of use. As an ester, dibutyl sebacate may hydrolyze in the presence of water at high or low pH conditions.

12 Incompatibilities Dibutyl sebacate is incompatible with strong oxidizing materials and strong alkalis.

13 Method of Manufacture Dibutyl sebacate is manufactured by the esterification of n-butanol and sebacic acid in the presence of a suitable catalyst, and by the distillation of sebacic acid with n-butanol in the presence of concentrated acid.

14 Safety Dibutyl sebacate is used in cosmetics, foods, and oral pharrnaceu- . tical formulations, and is generally regarded as a nontoxic and nonirritant material. Following oral administration, dibutyl sebacate is metabolized in the same way as fats. In humans, direct eye contact and prolonged or repeated contact with the skin may cause very mild irritation. Acute animal toxicity tests and long-term animal feeding studies have shown no serious adverse effects to be associated with orally administered dibutyl sebacate.

LD50 (rat, oral): 16 g/kg16)

_let,,, ____ ~--~---"··- ---- ·-··-·------------------ -------- ----------------

228 Diethanolamine

1 5 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. It is recommended that eye protection be used at all times. When heating this product, it is recommended to have a well-ventilated area, and the use of a respirator is advised.

16 Regulatory Status Included in the FDA Inactive Ingredients Database (oral capsules, granules, film-coated, sustained action, and tablets). Included in the C::anadian List of Acceptable Non-medicinal Ingredients.


18 Comments As dibutyl sebacate is an emollient ester, the personal care grade is recommended for use in cosmetics, hair products, lotions, and creams.

The EINECS number for dibutyl sebacate is 203-672-5. The PubChem Compound ID (CID) for dibutyl sebacate is 7986.

19 Specific References 1 Goodhart FW et al. An evaluation of aqueous film-forming dispersions

for controlled release. Pharm Technol 1984; 8(4): 64, 66, 68, 70, 71. 2 Iyer U et al. Comparative evaluation of three organic solvent and

dispersion-based ethylcellulose coating formulations. Pharm Technol 1990; 14(9): 68, 70, 72, 74, 76, 78, 80, 82, 84, 86.

Diethanolamine

1 Nonproprietary Names USP-NF: Diethanolamine

2 Synonyms

Bis(hydroxyethyl)amine; DEA; diethylolamine; 2,2 '-dihydroxydiethylamine; diolamine; 2 ,2' -iminodiethanol.

3 Chemical Name and CAS Registry Number 2,2' -Iminobisethanol [111 -42-2]

4 Empirical Formula and Molecular Weight C4H 11NO2 105.14


H

HO~N~OH


Alkalizing agent; emulsifying agent.

3 Lee BJ et al. Controlled release of dual drug loaded hydroxypropyl methylcellulose matrix tablet using drug containing polymeric coatings. Int J Pharm 1999; 188: 71-80.

4 Zhang ZY et al. Microencapsulation and characterization of tramadolresin complexes. J Control Release 2000; 66: 107-113.

5 FAO/WHO. Fifty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives. Dibutyl sebacate, 2002.


20 General References Appel LE, Zentner GM. Release from osmotic tablets coated with modified

Aquacoat lattices. Proc Int Symp Control Rel Bioact Mater 1990; 17: 335- 336.

Morflex Inc. Technical literature: Morflex DBS, March 2005. Ozturk AG et al. Mechanism of release from pellets coated with an

ethylf:ellulose-based film. J Control Release 1990; 14: 203-213. Rowe RC. Materials used in the film coating of oral dosage forms. Florence

AT, ed. Materials Used in Pharmaceutical Formulation: Critical Reports on Applied Chemistry., vol. 6: Oxford: Blackwell Scientific, 1984; 1- 36.

Wheatley TA, Steurnagel CR. Latex emulsions for controlled drug delivery. McGinity JC, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel Dekker, 1996; 13-41.

21 Author

T Farrell.

22 Date of Revision

14 January 2009.


Diethanolamine is primarily used in pharmaceutical formulations as a buffering agent, such as in the preparation of emulsions with fatty acids. In cosmetics and pharmaceuticals it is used as a pH adjuster and dispersant.

Diethanolamine has also been used to form the soluble salts of active compounds, such as iodinated organic acids that are used as contrast m edia. As a stabilizing agent, diethanolamine prevents the discoloration of aqueous formulations containing hexamethylenetetramine-1,3-dichloropropene salts.

Diethanolamine is also used in cosmetics.

8 Description

The USP32-NF27 describes diethanolamine as a mixture of ethanolamines consisting la rgely of diethanolamine. At about room temperature it is a white, deliquescent solid. Above room temperature diethanolamine is a clear, viscous liquid with a mildly ammoniacal odor.

9 Pharmacopeial Specifications See Table I.

---- --------- -·~''----,- ···

346 lsopropyl Alcohol

Ndindayino F etal. Direct compression properties of melt-extruded isomalt. Int J Pharm 2002; 235(1-2): 149-157.

Ndindayino F et al. Bioava ilability of hydrochlorothiazide from isomaltbased moulded tablets. Int J Pharm 2002; 246: 199-202.

O'Brien Nabors L, ed. Alternative Sweeteners: An Overview, 3rd ed n. New York: Marcel Dekker, 2001; 553.

lsopropyl Alcohol

1 Nonproprietary Names BP: Isopropyl Alcohol

JP: Isopropanol PhEur: Isopropyl Alcohol USP: Isopropyl Alcohol

2 Synonyms

Alcohol isopropylicus; dimethyl carbinol; IPA; isopropanol; petrohol; 2-propanol; sec-propyl alcohol; rubbing alcohol.


Propan-2-ol [67-63-0]


C3HsO 60.1


H3CYOH CH 3


Disinfectant; solvent.


Isopropyl alcohol (propan-2-ol) is used in cosmetics and pharmaceutical formulations, primarily as a solvent in topical formulationsYl It is not recommended for oral use owing to its toxicity; see Section 14.

Although it is used in lotions, the marked degreasing properties of isopropyl alcohol may limit its usefulness in preparations used repeatedly. Isopropyl alcohol is also used as a solvent both for tablet film-coating and for tablet granulation,(2l where the isopropyl alcohol is subsequently removed by evaporation. It has also been shown to significantly increase the skin permeability of nimesulide from carbomer 934_(3l

Isopropyl alcohol has some antimicrobial activity (see Section 10) and a 70% v/v aqueous solution is used as a topical disinfectant. Therapeutically, isopropyl alcohol has been investigated for the treatment of postoperative nausea or vomiting. (4 )

21 Authors B Fritzsching, 0 Luhn, A Schoch.

22 Date of Revision 16 January 2009.

8 Description Isopropyl alcohol is a clear, colorless, mobile, volatile, flammable liquid with a characteristic, spirituous odor resembling that of a mixture of ethanol and acetone; it has a slightly bitter taste.


See T1hk I.

Table I: Phormacopeiol specifico tions for isopropyl alcohol.

Test JP XV PhEur 6.0 USP 32 ·--·····- -·------ -"

Identification + + + Appearance of + +

solution Absorbance + Characters + Specific gravity 0.785-0.788 0.785-0.789 0.783- 0.787 Refractive index l .37 6-1 .379 1.37 6-1 .378 Acidity or alka linity + + + Water .,; 0.75% .,; 0.5% Nonvolatl le residue .,; 1.0mg .,; 20ppm .,; 0.005% Disti llation range 81-83°C Benzene + Peroxides + Assay ;, 99.0%

10 Typical Properties Antimicrobial activity Isopropyl alcohol is bactericidal; at con

centrations greater than 70% v/v it is a more effective antibacterial preservative than ethanol (95% ). The bactericidal effect of aqueous solutions increases steadily as the concentration approaches 100% v/v. Isopropyl alcohol is ineffective against bacterial spores.

Autoignition temperature 425°C Boiling point 82.4°C Dielectric constant D20 = 18.62 Explosive limits 2.5-12.0% v/v in air 'flammability Flammable. Flash point 11.7°C (closed cup); 13°C (open cup). The water

azeotrope has a flash point of l6°C. Freezing point - 89.5°C Melting point - 88.S°C Moisture content 0.1-13% w/w for commercial grades (13% w/w

corresponds to the water azeotrope). Refractive index

nf)0 = 1.3776;

nf:/ = 1.3749. Solubility Miscible with benzene, chloroform, ethanol (95%),

ether, glycerin, and water. Soluble in acetone; insoluble in salt

solutions. Forms an azeotrope with water, containing 87.4% w/w isopropyl alcohol (boiling point 80.37°C).

Specific gravity 0.786 Vapor density (relative) 2.07 (air= 1) Vapor pressure

133.3Pa (lmmHg) at - 26.1°C; 4.32kPa (32.4mmHg) at 20°C; 5.33kPa (40mmHg) at 23.8°C; 13.33 kPa (100 mrnHg) at 39.5°C.

Viscosity (dynamic) 2.43 mPa s (2.43 cP) at 20°C

11 Stability and Storage Conditions Isopropyl alcohol should be stored in an airtight container in a cool, dry place.

12 Incompatibilities Incompatible with oxidizing agents such as hydrogen peroxide and nitric acid, which cause decomposition. Isopropyl alcohol may be salted out from aqueous mixtures by the addition of sodium chloride, sodium sulfate, and other salts, or by the addition of sodium hydroxide.

13 Method of Manufacture Isopropyl alcohol may be prepared from propylene; by the catalytic reduction of acetone, or by fermentation of certain carbohydrates.

14 Safety Isopropyl alcohol is widely used in cosmetics and topical pharmaceutical formulations. It is readily absorbed from the gastrointestinal tract and may be slowly absorbed through intact skin. Prolonged direct exposure of isoproprl alcohol to the skin may result in cardiac and neurological deficits. 5l In neonates, isopropyl alcohol has been reported to cause chemical burns following topical application. '6•

7'

Isopropyl alcohol is metabolized more slowly than ethanol, primarily to acetone. Metabolites and unchanged isopropyl alcohol are mainly excreted in the urine.

Isopropyl alcohol is about twice as toxic as ethanol and should therefore not be administered ora lly; isopropyl alcohol also has an unpleasant taste. Symptoms of isopropyl alcohol toxicity are similar to those for ethanol except that isopropyl alcohol has no initial euphoric action, and gastritis and vomiting are more prominent; see Alcohol. Delta osmolality may be useful as ra pid screen test to identify patients at risk of complications from ingestion of isopropyl alcohol.rs, The lethal oral dose is estimated to be about 120-250 mL although toxic symptoms may be produced by 20 mL.

Adverse effects following parenteral administration of up to 20 mL of isopropyl alcohol diluted with water have included only a ~ensation of heat and a slight lowering of blood pressure. However, 1sopropyl alcohol is not commonly used in parenteral products.

Although inhalation can ca use irritation and coma, the inhalation of isopropyl alcohol has been investigated in therapeutic applications.'3' . Isopropyl alcohol is most frequently used in topical pharmaceu

tical formulations where it may act as a local irritant.<9> When

applied to the eye it can ca use corneal burns and eye damage.

LD50 (dog, oral): 4.80 g/kg'9'

LD50 (mouse, oral): 3.6 g/kg LD5o (mouse, IP): 4.48 g/kg LD50 (mouse, IV): 1.51 g/kg LD50 (rabbit, oral): 6.41 g/kg LD50 (rabbit, skin): 12.8 g/kg LD50 (rat, IP): 2.74 g/kg

lsopropyl Al cohol 347

LDso (rat, IV): 1.09 g/kg LD50 (rat, oral): 5.05 g/kg

1 5 Handling Precautions -,

Observe normal precautions appropriate to the circumstances and quantity of material handled. Isopropyl alcohol may be irritant to the skin, eyes, and mucous membranes upon inhalation. Eye protection and gloves are recommended. Isopropyl alcohol should be handled in a well-ventilated environment. In the UK, the longterm (8-hour TWA) workplace exposure limit for isopropyl alcohol is 999 mg/m3 (400 ppm); the short-term (15-minute) workplace exposure limit is 1250 mg/m3 (500 ppm). (lO) OSHA standards state that IPA 8-hour time weighted average airborne level in the workplace cannot exceed 400 ppm. Isopropyl alcohol is flammable and produces toxic fumes on combustion.

16 Regulatory Status Included in the FDA Inactive Ingredients Database (oral capsules, tablets, and topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Propan-"1-ol.

Propan- 1-ol Empirical formula C3HsO Molecular weight 60.1 CAS number [71-23-8] Synonyms Propanol; n-propanol; propyl alcohol; propylic alco-

hol. Autoignition temperature 540°C Boiling point 97.2°C · Dielectric constant D 25 = 22.20 Explosive limits 2.15-13.15% v/v in air Flash point 15°C (closed cup) Melting point -127°C Refractive index n io = 1.3862 Solubility Miscible with ethanol (95 % ), ether, and water. Specific gravity 0.8053 at 20°C Viscosity (dynamic) 2.3 mPa s (2.3 cP) at 20°C Comments Propan-1-ol is more toxic than isopropyl alcohol. In

the UK, the long-term (8-hour TWA) exposure limit for propan-1-ol is 500 mg/m3 (200 ~pm); the short-term (1 5-minute) exposure limit is 625 mg/m (250 ppm). (JO)

18 Comments A specification for isopropyl alcohol is contained in the Food Chemicals Codex (FCC).'1 n

The EINECS number for isopropyl alcohol is 200-661 -7. The PubChem Compound ID (CID) for isopropyl alcohol is 3776.

19 Specific References 1 Rafiee Tehrani H, Mehramizi A. In vitro release studies of piroxicam

from oil-in-water creams and hydroalcoholic gel topical formulations. Drug Dev Ind Pharm 2000; 26(4): 409--414.

2 Ruckmani K et al. Eudragit matrices for sustained release of ketorolac tromethamine: formulation and kinetics of release. Boll Chim Form 2000; 139: 205-208.

3 Guengoer S, Bergisadi N. Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin. Pharmazie 2004; 59: 39---41.

4 Merritt BA et al. Isopropyl alcohol inhalation: alternative trea tment of postoperative nausea and vomiting. Nurs Res 2002; 51(2): 125- 128.

5 Leeper SC et al. Topical absorption of isopropyl alcohol induced cardiac neurological deficits in an adult female with intact skin. Vet Hum Toxicol 2000; 42: 15- 17.

-··---- - ---------·-- ------- - -----~--~ -~~-,-=->I ''""' ··-::>"· -'~- ..

348 lso propyl Myristate

6 Schick JB, Milstein JM. Burn hazard of isopropyl alcohol in the neonate. Pediatrics 1981; 68: 587-588.

7 Weintraub Z, Iancu TC. Isopropyl alcohol burns. Pediatrics 1982; 69: 506.

8 Monaghan MS et al. Use of delta osmolality to predict serum isopropanol and acetone concentrations. Pharmacotherapy 1993; 13(1): 60-63.

9 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 2148-2149.

10 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ coshh/ta ble 1. pdf ( accessed 5 February 2009).


6_: lsopropyl Myristate

1 Nonproprietary Names BP: Isopropyl Myristate PhEur: Isopropyl Myristate USP-NF: Isopropyl Myristate

2 Synonyms Esto/ IPM; H al/Star IPM-NF; isopropyl ester of myristic acid; Isopropylm yristat; isopropylis myristas; Kessco IPM 95; Lexol IPM-NF; myristic acid isopropyl ester; Rita IPM; Stepan IPM; Super Refined Crodamol IPM; Tegosoft M; tetradecanoic acid, 1-methylethyl ester; Waglinol 601 4.

3 Chemical Name and CAS Registry Number 1-Methylethyl tetradecanoate [110-27-0]


C17H34O2 270.5


6 Functional Category Emollient; oleaginous vehicle; skin penetrant; solvent.


Isopropyl myristate is a nongreasy emollient that is absorbed readily by the skin. It is used as a component of semisolid bases and as a solvent for many substances applied topically. Applications in topical pharmaceutical and cosmetic formulations include bath oils; make-up; hair and nail care products; creams; lotions; lip products; shaving products; skin lubricants; deodorants; otic suspensions; and vaginal creams; see Table I. For example, isopropyl myristate is a self-emulsifying component of a proposed cold cream formula,'1> which is suitable for use as a vehicle for drugs or dermatological


21 Author

CP McCoy.

22 Date of Revision

5 February 2009.

actives; it is also used cosmetically in stable mixtures of water and glycerol. t2>

Isopropyl myristate is used as a penetration enhancer for transdermal formulations, and has been used in conjunction with therapeutic ultrasound and iontophoresis.'3> It has been used in a water-oil gel prolonged-release emulsion and in various microemulsions. Such microemulsions mar increase bioavailability in topical and transdermal applications.(4 Isopropyl myristate has also been used in microspheres, and significantli increased the release of drug from etoposide-loaded microspheres. 5>

Isopropyl myristate is used in soft adhesives for pressuresensitive adhesive tapes.(6

)

Table I: Uses of isopropyl myristote.

Use

Detergent Otic suspension Perfumes Microemulsions Soap Topical aerosols Topical creams and lotions

8 Description

Concentration (%)

0.003-0.03 0.024 0.5-2.0 <50 0.03-0.3 2.0-98.0 1.0-10.0

Isopropyl myristate is a clear, colorless, practically odorless liquid of low viscosity that congeals at about 5°C. It consists of esters of propan-2-ol and saturated high molecular weight fatty acids, principally myristic acid.

9 Pharmacopeial Specifications See Table II.

10 Typical Properties Boiling point 140.2°C at 266 Pa (2 mmHg) Flash point 153.5°C (closed cup) Freezing point ~s0 c Solubility Soluble in acetone, chloroform, ethanol (95%), ethyl

acetate, fats, fatty alcohols, fixed oils, liquid hydrocarbons, toluene, and waxes. Dissolves many waxes, cholesterol, or lanolin. Practically insoluble in glycerin, glycols, and water.

Viscosity (dynamic) 5-7 mPa s (5-7 cP) at 25°C

h

Table II: Pharmacopeial specifications for isopropyl myristale.

Test

Identification Characters Appearance of solution Relative density Refractive index Residue on ignition Acid value Saponification value iodine value Viscosity Water Assay (as C17H340 2)

PhEur 6.0

+ + + ::::, 0.853 l .434-1 .437 ~ 0.1 % ~ 1.0 202-212 ~ 1.0 5-6mPas ~ 0.1 % ~ 90.0%

11 Stability and Storage Conditions

USP32- NF27

+

0.846-0.854 l .432-1 .436 ~ 0.1% ~ l.O 202-212 ~ 1.0

~ 90.0%

Isopropyl myristate is resistant co oxidation and hydrolysis, and does not become rancid. It should be stored in a well-closed conta iner in a cool, dry place and protected from light.

12 Incompatibilities When isopropyl myristate comes into contact with rubber, there is a drop in viscosity with concomitant swelling and partial dissolution of the rubber; contact with plastics, e.g. nylon and polyethylene, res ults in swelling. Isopropyl myristate is incompatible with hard paraffin, producing a granular mixture. It is also incompatible with strong oxidizing agents.

13 Method of Manufacture Isopropyl myristate may be prepared either by the esterification of myristic acid with propan-2-ol or by the reaction of myristoyl chloride and propan-2-ol with the aid of a suitable dehydrochlorinating agent. A high-purity material is also commercially available, produced by enzymatic esterification at low temperature.

14 Safety Isopropyl myristate is widely used in cosmetics and topical pharmaceutical formulations, and is generally regarded as a nontoxic and nonirritant material. (7-9

)

LDso (mouse, oral): 49.7 g/kg(l O)

LD 50 (ra bbit, skin): 5 g/kg

15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity o f material handled.

16 Regulatory Status Included in the FDA Inactive Ingredients Database (otic, topical, transdermal, and vaginal preparations). Used in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Isopropyl palmitate.

lsopropyl Myristate 349

18 Comments

Isopropyl myristate has been used in microemulsion templates to produce nanoparticles as potential drug delivery vehicles for proteins and peptides. <11,

12)

Isopropyl myristate 50% has been shown to be an effective pediculicide for the control of head lice.<1 3

)

The EINECS number for isopropyl myristate is 203-751-4. The PubChem Compound ID (CID) for isopropyl myristate is 8042.

19 Specific References 1 Jimenez SMM et al. Proposal and pharmacotechnical study of a modern

dermo-pharmaceutical formulation for cold cream. Boll Chim Farm 1996; 135: 364-373.

2 Ayannides CA, Ktistis G. Stabili ty estimation of emulsions of isopropyl myristate in mixtures of water and glycero l. J Cosmet Sci 2002; 53(3): 165-173.

3 Fang JY et al. Transdermal iontopheresis of sodium nonivaride acetate III: combined effect of pretreatment by penetration enhancers. Int J Pharm 1997; 149: 183-195.

4 Kogan A, Garti N. Microemulsions as transdermal delivery vehicles. Adv Colloid Interface Sci 2006; 123- 126: 369-385.

5 Schaefer MJ, Singh J. Effect of isopropyl myristic acid ester on the physical characteristics and in vitro release of etoposide from PLGA microspheres. AAPS Pharm Sci Tech 2000; 1(4): 32.

6 Tokumura F et al. Properties of pressure-sensitive adhesive tapes with soft adhesives to human skin and thei r mechanism. Skin Res Technol 2007; 13(2): 211-216.

7 Stenback F, Shubik P. Lack of toxicity and carcinogenicity of some commonly used cutaneous agents. Toxicol Appl Pharmacol 1974; 30: 7-13.

8 Opdyke DL. Monographs on fragrance raw materials. Food Cosmet Toxicol 1976; 14(4): 307-338.

9 Guillot JP et al. Safety evaluation of cosmetic raw materials. J Soc Cosmet Chem 1977; 28: 377-393.


11 Graf A et al. Protein delivery using nanoparticles based on microemulsions with different structure types. Eur .I Pharm Sci 2008; 33(4-5): 434- 444.

12 Graf A et al. Microemulsions containing lecithin and sugar-based surfactant: nonparticle templates for delivery of proteins and peptides. Int J Phann 2008; 350(1-2 ): 351- 360.

13 Kaul N et al. North American efficacy and safety of a novel pediculicide rinse, isopropyl myristate 50% (results). J Cutan Med Surg 2007; 11(5): 161- 167.

20 General References Fitzgerald JE et al. Cutaneous and parenteral studies with vehicles

containing isopropyl myrista te and peanut oil. Toxicol Appl Phannacol 1968; 13: 448-453.

Nakhare S, Vyas SP. Prolonged release of rifampicin from internal phase of multiple w/o/w emulsion systems. Indian] Phann Sci 1995; 57: 71-77.

21 Author

AK Taylor.

22 Date of Revision

28 January 2009.

Lactose, Anhydrous

1 Nonproprietary Names BP: Anhydrous Lactose

JP: Anhydrous Lactose

PhEur: Lactose, Anhydrous

USP-NF: Anhydrous Lactose

2 Synonyms Anhydrous 60M; Anhydrous Direct Tableting (DT); Anhydrous DT High Velocity; Anhydrous Impalpable; Lactopress Anhydrous; Lactopress Anhydrous 250; lactosum anhydricum; lattosio; milk sugar; SuperTab 21AN; SuperTab 22AN; saccharum lactis.


O-P-D-Galactopyranosyl-( 1---->4 )-P-D-glucopyranose [ 63-42-3)


C12H220u 342 . .10


CH, OH ,,t~: ~O~ O~H ~ OH

OH

Anhydrous a-lactose

~ H

~O OH

OH

Anhydrous ~-lactose

The PhEur 6.5 and USP32-NF27 describe anhydrous lactose as OP-o-galactopyranosyl-(l - ->4)-P-o-glucopyranose; or a mixture of O-P-D-galactopyranosyl-( 1- ->4 )-a-D-glucopyranose and O-P-Dgalactopyranosyl-( 1--+4 )-P-D-glucopyranose. The JP XV describes anhydrous lactose as P-lactose or a mixture of P-lactose and a -lactose, and defines these as per the PhEur and USP- NF.


Directly compressible tablet excipient; dry powder inhaler carrier; lyophilization aid; tablet and capsule diluent; tablet and capsule filler.


Anhydrous lactose is widely used in direct compression ta bleting applications, and as a tablet and capsu le filler and binder. Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content. It may a lso be used in intravenous injections.

See also Lactose, Inhalation; Lactose, Monohydrate; Lactose, Spray-Dried.

8 Description

Anhydrous lactose occurs as white to off-white crystalline particles or powder. :Several different brands of anhydrous lactose are commercially available which contain anhydrous P-lactose and anhydrous a-lactose. Anhydrous lactose typically contains 70-80% anhydrous P-lactose and 20-30% an hydrous a-lactose.


See Table I. See also Section 18.

10 Typical Properties Brittle fracture index 0.0362 Bonding index 0.0049 (at compression pressure 177.8 MPa )<l ) Density (true) 1.589 g/cm3 for anhydrous P-lactose Density (bulk) 0. 71 g/cm3 for Super Tab 21 AN; 0.66 g/cm3 for

Super-Tab 22AN.

SEM 1: Excipient: Super Tab 21 AN; manufacturer: DMV-Fonterra Excipients; magnification: 200x ; voltage: 1.5 kV.

SEM 2: Excipient: Super Tab 22AN; manufacturer: DMV-Fonterra Excipients; magnification: 55 x ; voltage: 1.5 kV.

~.--.'.""'.tr--;'."""'_.,.="'----~

359

360 La ctose, Anhydrous

Table I: Pharmocopeiol specifications for lactose anhydrous.

Test JP XV PhEur 6.5 USP32-NF27

Identi fica ti on + + + Ahpearance/color of solution + + + C oracters + Optica l rotation +54.4° lo + 54.4° to + 54.4° to

+55.9° + 55 .9° + 55.9° Acid ity or a lka lini ty + + + Heavy meta ls ,;; 5ppm ,;; 5ppm ,;; 5 µg/g Protein and light absorbing + +

impurities/ substances Absorbance

2 10-220nm ..; 0 .25 ..; 0.25 ..; 0.25 270- 300nm ..; 0 .07 ..; 0.07 ..; 0.07 400nm ..; 0.04 ~ 0.04 ..; 0.04

Loss on drying ..; 0.5% + la) ..; 0 .5% Water ..; 1.0% ,;; 1.0% ~ l .0% Residue on ig nition ..; 0. 1% ~ 0.1 % Sulfa ted ash ..; 0.1 % Microbia l limit

Aerobic bacteri a ..; l00 cfu/g l02 cfu/g ~ l00cfu/g Fungi ond rost ,;; 50cfu/g ~ 50cfu/g Absence o Escherichia coli + + + Absence of Salmonella +

Isomer ra tio + +lo) +

(al Not o mandatory fest.

Density (tapped) 0.88 g/cm3 for SuperTab 21AN; 0. 78 g/cm3 for Super-Tab 22AN.

M elting point 223 .0°C for anhydrous ex-lactose;

252.2°C for anhydrous ~-lactose; 232.0°C (typical) for commercial anhydrous lactose.

NIR spectra see Figure 1. Particle size distribution see Table II. Permanent deformation pressure 521.0 MPa (at compression

pressure 177.8 MPai 1l Reduced modulus of elasticity 5315 (at compression pressure

177.8 MPa)11l Solubility Soluble in water; sparingly soluble in ethanol (95% )

and ether; 40 g/100 ml at 25°C for typical Sheffie ld Pharma Ingredients products.

Specific rotation [o:Jf,5 = 54.4° to 55.9° Tensile strenr;;h 2.577 MPa (at compression pressure

177.8 MPa)1 l Methods for characterizing the mechanical properties of compacts of pharmaceutical ingredients are specified in the Handbook of Pharmaceutical Excipients, 3rd ednYl

11 Stability and Storage Conditions M old growth may occur under humid conditions (80% RH and above). Lactose may develop a brown coloration on storage, the reaction being accelerated by warm, damp conditions; see Section

1.0 ~------------------, 0 .5

X 0 0 0

\ '2369 23 14

· 290 2264

o? .......__

0) 0

~ - l . 2 .__..__...,__....__.___,__....__. ____ ....._..___.__ ........ ....__.__. -0. 2 11 00 1300 1500 1700 1900 2 100 2300 2500

W avelength/ nm

Figure 1: Near-infrared spectrum of lactose a nhydrous measured by reflecta nce .

12. At 80°C and 80% RH, tablets containing anhydrous lactose have been shown to expand 1.2 times after one day.12)

Lactose anhydrous should be stored in a well-closed container in a cool, dry place.

12 Incompatibilities Lactose anhydrous is incompatible with strong oxidizers. When mixtures containing a hydrophobic leukotriene antagonist and anhydrous lactose or lactose monohydrate were stored for six weeks at 40°C and 75% RH, the mixture containing anhydrous lactose showed greater moisture uptake and drug degradation.13)

Studies have also shown that in blends of roxifiban acetate (DMP-7 54) and lactose anhydrous, the presence of lactose anhydrous accelerated the hydrolysis of the ester and amidine groups.14)

Lactose anhydrous is a reducing sugar with the potential to interact with primary<5l and secondary amines16l (Maillard reaction) when stored under conditions of high humidity for extended periods.

See Lactose, Monohydrate.

13 Method of Manufacture There are two anhyd rous fo rms of lactose: ex-lactose and P-lactose. The temperature of crystallization influences the ratio of o:- and ~lactose. The anhydrous forms that are commercially available may exhibit hygroscopicity at high rela tive humidities. Anhydrous lactose is produced by ro ller drying a solution of lactose above 93.5°C. The resulting product is then milled and sieved. Two anhydrous ex-lactoses can be prepared using special drying techniques: one is unstable and hygroscopic; the other exhibits good compaction properties.17) However, these materials are not commercially available.

Table II: Particle size distribution of selected commercially available anhydrous lactose. .,

Supplier/ grade Percentage less than stated size ------

<45µm <53µm < 150µm <250 µm

DMV-Fonterra Excipients Super Tab 2 1 AN ~ 20 40- 65 ;;. BO su

10erTab 22AN ~ 7 25-50 ;;. 65

Fries and Foods Domo Lactopress Anhydrous ..; 30 ;;. 80 Lactopress Anhydrous 250 ~ 20 40-65 ;;. 80

14 Safety Lactose is widely used in pharmaceutical formulations as a diluent and filler-binder in oral capsule and tablet formulations. It may also be used in intravenous injections. Adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactase, and is associated with oral ingestion of amounts well over those found in solid dosage forms.


15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of materials handled. Excessive generation of dust, or inhalation of dust, should be avoided.

16 Regulatory Status GRAS listed. Included in the FDA Inactive Ingredients Database (IM, IV: powder for injection solution; IV and sublingual preparations; oral: capsules and tablets; powder for inhalation; vaginal). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Lactose, inhalation; lactose, monohydrate; lactose, spray-dried.

18 Comments Lactose anhydrous is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5.8 in PhEur 6.5, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Lactose anhydrous has been used experimentally in hydrophilic matrix tablet formulations(S) and evaluated for dry powder inhalation applications.(9,I o) Partial hydration of anhydrous lactose increases the specific surface area and reduces the flow properties of powders but has no effect on compactibility.'1 1

) A specification for lactose is included in the Food Chemicals Codex (FCC(12

)); see Lactose, Monohydrate.

The EINECS number for lactose anhydrous is 200-559-2. The PubChem Compound ID (CID) for lactose anhydrous includes 6134 and 84571.

19 Specific References 1 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn.

London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association, 2000; 641- 643.

2 Du J, Hoag SW. The influence of excipienrs on the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose

Lactose, Anhydrous 361

monohydrate with tablets containing anhydrous lactose. Pharm Dev Technol 2001; 6(2): 159-166.

3 Jain R et al. Stability of a hydrophobic drug in presence of hydrous and anhydrous lactose. Eur J Pharm Biopharm 1998; 46: 177-182.

4 Badawy SI et al. Effect of different acids on solid state stability of an ester prodrug of a Ilb/II!a glycoprotein receptor antagonist. Pharm Dev Technol 1999;4: 325-331.

5 Castello RA, Mattocks AM. Discoloration of tablets containing amines and lactose. J Pharm Sci 1962; 51: 106-108.

6 Wirth DD et al. Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.] PharmSci 1998; 87: 31-39.

7 Lerk CF et al. Increased binding capacity and flowability of alphalactose monohydrate after dehydration. J Pharm Pharmacol 1983; 35(11): 747- 748.

8 Heng PW et al. Investigation of the influence of mean HPMC particle size and number of polymer particles on the release of aspirin from swellable hydrophilic matrix tablets. J Control Release 2001; 76(1-2): 39-49.

9 Larhrib H et al. The use of different grades of lactose as a carrier for aerosolized salbutamol sulphate. Int J Pharm 1999; 191(1): 1-14.

10 Vanderbist Fetal. Optimization of a dry powder inhaler formulation of nacystelyn, a new mucoactive agent. J Pharm Pharmacol 1999; 51 ( 11 ): 1229-1234.

11 Cal S et al. Effects of hydration on the properties of a roller-dried ~lactose for direct compression. Int J Pharm 1996; 129(1- 2): 253- 261.


20 General References Bolhuis GK, Chowhan ZT. Materials for direct compaction. Alderborn G,

Nystrom C, eds. Pharmaceutical Powder Compaction Technology. New York: Marcel Dekker, 1996; 469-473.

Bolhuis GK, Armstrong NA. Excipients for direct compaction: an update. Pharm Dev Technol 2006; 11: 111...:124.

DMV-Fonterra Excipients. Technical literature: SuperTab 21AN, SuperTab 22AN, 2008. http://www.dmv-fonterra-excipients.com (accessed 27 February 2009).

European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 27 February 2009).

Friesland Foods Domo. Technical literature: Lactopress Anhydrous, Lactopress Anhydrous 250, 2008 . http://www.domo.nl/pharma (accessed 27 February 2009).

Kirk JH et al. Lactose: a definite guide to polymorph determination. Int J Pharm 2007;334: 103-107.

Sheffield Pharma Ingredients. Technical literature: Anhydrous Lactose, 2008. http://www.sheffield-products.com/ (accessed 2 7 February 2009).

21 Authors

S Edge, AH Kibbe, J Shur.

22 Date of Revision

27 February 2009.

- · ----.;: . ... .r ____ _

Lactose, Inhalation


None adopted.

2 Synonyms

Inhalac; inhalation lactose; Lactohale; Respitose. For grades, see Tables I and IL


Inhalation lactose is lactose monohydrate, O-P-D-galactopyranosyl(l - t4 )-a-D-glucopyranose monohydrate [5989-81-1); [10039-26-6]; [64044-51-5] (see Lactose, Monohydrate), mhydrous lactose, O-P-D-galactopyranosyl-(l - t4 )-P-D-glucopyranose [ 63-42-3], or a mixture of O-P-D-galactopyranosyl-(l --t4 )-P-n-glucopyranose and O-P-D-galactopyranosyl-( 1---+4 )-a-D-glucopyranose (see Lactose, Anhydrous).

CAS numbers for lactose monohydrate are [5989-81-1] (lactose monohydrate); [10039-26-6] (lactose monohydrate, cyclic); [64044-51-5] (lactose monohydrate, open form).


C12H 22O11 342.30 (for anhydrous) C12H22O11 -H2O 360.31 (for monohydrate)


See Lactose, Anhydrous; Lactose, Monohydrate.

6 Functional Category Diluent; dry powder inhaler carrier.


Inhalation lactose is widely used as a carrier, diluent, and flow aid in dry powder inhalation formulations. Inhalation lactose of suitable particle size can also be used to prepare soft pellets of dry powder inhaler formulations.

See also Lactose, Anhydrous; Lactose, Monohydrate.

8 Description

Lactose occurs as white to off-white crystalline particles or powder. It is odorless and slightly sweet-tasting.


See Lactose, Anhydrous; Lactose, Monohydrate.

10 Typical Properties Density (bulk) see Table L Density (tapped) see Table L Loss on drying see Table L Particle size distribution see Table IL Surface area see Table I.


Inhalation lactose should be stored in a well-closed container in a cool, dry place.

362

, : , ; : Excipient: Respitose SV003; manufacturer: DMV-Fonterra Excipients; magnification: 200 x ; voltage: 5 kV.

SEM 2: Excipient: Respitose MLOO 1; manufacturer: DMV-Fonterra Excipients; magnification: 1 OOO x ; voltage: 5 kV.


Lactose is a reducing sugar. Typical reactions include the Maillard reaction with either primary(!) or secondary amines.(2

)



Inhalation lactose is manufactured by milling, sieving, air classifying, micronizing and/or blending pharmaceutical grade lactose, typically in dedicated facilities. Although off-the-shelf grades are available, the manufacturing processes can be tailored to produce lactose with properties for a specific application.

14 Safety

Lactose is widely used in pharmaceutical formulations as a diluent in oral capsule and tablet formulations, and has a history of being used in dry powder inhaler formulations.

Table I: Typical physical properties of selected commercially available inhalation lactose.

Supplier/ grade Surface Density Density Loss on area (bulk) (ta/cped) drying (m2/g) (g/cm3

) (g cm3) (%)

DMV·Fonterra Excipients Respitose SV003 0.4 0.63 0.78 Respitose SVO 10 0.2 0.69 0.83 Respitose MLO0 1 0.9 0.57 0.88 Respitose ML006 1.6 0.43 0.75 Ftesland Foods Domo L ctohale LH I 00 ,,; 0.2 Lactohale LH200 ,,;0.2 Lactohale LH300 ,,; 0.5 MeggleGmbH lnhalac 70 0.60 0.66 lnhalac 120 0.68 0.78 lnhalac 230 0.69 0.80 Sheffield Pharma Ingredients Monohydrate Inhalation 40M 0.1 Monohydrate Inhalation B0M 0.1 Monohydrate Inhalation I 20M - 0.1 Monohydrate Inhalation 120MS 0.1 Anhydrous Inhalation 120M 0.18 Anhydrous Inhalation I 20MS 0.18

Table II: Typical particle size distribution of selected commercially available inhalation lactose.

Supplier/ grade d10(µm) dso (µm) d90 (µm)

DMV·Fonterra Excipients Respitose SV0031°I 30 60 100 Respitose SV0 10161 50 105 175 Respitose MLO0 I ial 4 55 170 Respitose ML00616l 2 17 45 Friesland Foods Domo Lactohale LH I 0ol6l 45- 65 125- 145 200- 250 Lactohale LH200l6l 5-15 50- 100 120-160 Lactohale LH300l0 1 <5 ,,; 10 Meggle GmbH lnhalac 70 110 200 300 lnhalac 120 90 150 200 lnhalac 230 60 100 140

··-----··-·-"-(a) Malvern (wet) laser diffraction. (b) Sympatec laser diffraction.

Adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the enzyme lactase. Recently, the presence of milk proteins in lactose-containing dry powder inhalers, which can cause ana8hf laxis in cases of severe allergy to cow's milk, has been reported. ,4

In view of the route of administration, inhalation lactose should be tested to additional micobiological specifications, for example, endotoxins, as requested by the regulatory authorities. Inhalation lactose is typically supplied with an increased range of microbiological tests.


1 5 Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material being handled. Excessive generation of dust, or inhalation of dust, should be avoided.

16 Regulatory Status GRAS listed. Included in the FDA Inactive Ingredients Database (inhalation preparations). Included in nonparenteral and parenteral

Lactose, Inhalation 363

medicines licensed in the UK, which refer to lactose monohydrate in general.


17 Related Substances See Lactose, Anhydrous; Lactose, Monohydrate.

18 Comments

Lactose is one of a very small number of excipients that are used in marketed dry powder inhaler products. Specific grades of inhalation lactose can be produced from the readily available wide range of pharmaceutical lactose grades using standard pharmaceutical manufacturing processes. Lactose is found in capsule, blister, and reservoir-based dry powder inhaler products. The relatively low mass per dose of lactose used means that, compared with conventional oral solid dosage forms, the levels of inhalation lactose ingested during inhalation are relatively small.

In view of the importance of particle characteristics for powder blending and drug product performance(5-

12l, it has been suggested that pharmacopeial monograph acceptance criteria are not adequate for controlling key physicochemical characteristics for inhalation applications of this excipient. Accordingly, further material controls may be required to ensure consistent drug product pharinaceutical performance, such as control of surface properties.

The effect of modifying the surfaces of lactose particles by particle smoothing, crystallization, and co-processing with other excipients on the aerosolization performance has been reported.113-

191 .


19 Specific References 1 Castello RA, Mattocks AM. Discoloration of tablets containing amines

and lactose. J Phann Sci 1962; 51: 106-108. 2 Wirth DD et al. Maillard reaction of lactose and fluoxetine

hydrochloride, a secondary amine. J Phann Sci 1998; 87: 31- 39. 3 Nowak-Wegrzyn A et al. Contamination of dry powder inhalers for

asthma with milk proteins containing lactose. J Allergy Clin lmm unol 2004; 113: 558-560.

4 Morisset M et al. Allergy to cow milk proteins contaminating lactose, common excipient of dry powder inhalers for asthma. J Allergy Clin Immunol 2006; 117(Suppl. 1): 95.

5 Kawashima Y et al. Effect of surface morphology of carrier lactose on dry powder inhalation property of pralukast hydrate. Int J Pharm 1998; 172: 179- 188.

6 Steckel H et al. Functionality testing of inhalation grade lactose. Eur J Phann Biophann 2004; 57: 495-505 .

7 Telko MJ, Hickey AJ. Dry powder inhaler formulation. Respir Care 2005; 50: 1209-1227.

8 Jones MD, Price R. The influence of fine excipient particles on the performance of carrier-based dry powder inhalation formulations. Pharm Res 2006; 23: 1665- 1674.

9 Hickey AJ et al. Physical characterization of component particles included in dry powder inhalers. I. Strategy review and static characteristics. J Phann Sci 2007; 96: 1282-1301.

10 Hickey AJ et al. Physical characterization of component particles included in dry powder inhalers. IL Dynamic characteristics. J Pharm Sci 2007; 96: 1302-1319.

11 Shur J et al. The role of fines in the modification of the fluidization and dispersion mechanism within dry powder inhaler formulations. Phann Res 2008; 25: 1931- 1940.

12 Larhrib H et al. The use of different grades of lactose as a carrier fo r . aerosolised salbutamol sulfa te. Int J Phann 1999; 191: 1- 14.

13 Zeng XM et al. The influence of carrier morphology on drug delivery by dry powder inhalers. Int J Phann 2000; 200: 93- 106.

14 Zeng XM et al. The influence of crystallization conditions on the morphology of lactose intended for use as a carrier fo r dry powder aerosols. J Pharm Pharmacol 2004; 52: 633-643.

'1 5 Islam N et al. Lactose surface modification by decantation: Arc drngfin e lactose ratios the key to better dispersion of salmeterol xinofate from lactose interactive mixtures ? Phann Res 2004; 21: 492-499.

364 lactose, Mo no hydra te

16 Young PM et al. Characterisation of a surface modified dry powder inhalation carrier prepared by 'particle smoothing'. J Pharm Phannacol 2002;54: 1339-1344.

17 EI-Sa bawi D et al. Novel temperature controlled surface dissolution of excipient particles for carrier based dry powder inhaler formulations. D rug Dev Ind Pharm 2006; 32: 243-251.

18 Kuman M et al. Application and mechanism of inhalation profile improvement of DPI formulations by mechanofusion with magnesium stearate. Chem Pharm Bull (Tokyo) 2008; 56: 617-625.

19 Guchardi R et al. Influence of fine lactose and magnesium stearate on low dose dry powder inhaler formulations. Int J Pharm 2008; 348: 10-17.

20 General References CDER. Guidance for industry: M etered dose inhaler (MDI) and dry powder

inhaler (DPI) drug products (draft). Rockville, MD: United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; 1998 .

DMV-Fonterra Excipients. Technical litera ture: Respitose, 2008. http:// www.dmv-fonterra-excipients.com (accessed 27 February 2009).

Domo. Technical literature: Lactohale, 2008. http://www.domo.nl/pharma (accessed 27 February 2009).

8 Lactose, Monohydrate

Nonproprietary Names

BP: Lactose PhEur: Lactose Monohydrate JP: Lactose Hydrate USP-NF: Lactose Monohydrate

2 Synonyms CapsuLac; GranuLac; Lactochem; lactosum monohydricum; Monohydrate; Pharmatose; PrismaLac; SacheLac; SorboL(lc; SpheroLac; SuperTab 30GR; Tablettose.

For grades, see Tables II and III.

3 Chemical Name and CAS Registry Number O-~-D-Galactopyranosyl-( 1--+4 )-a-o-glucopyranose monohy-drate [5989-81-1]; [10039-26-6]; [64044-51-5]

CAS Registry numbers for lactose monohydrate are [5989-81-1] (lactose monohydrate), [10039-26-6] (lactose monohydrate, cyclic), and [64044-51-5] (lactose monohydrate, open form).


C12H2201!'f-120 .1 60.3 1

EMEA. Committee for Medicinal Products for Human Use. Guidance on the pharmaceutical quality of inhalation and nasal products. EMEA/CHMP/ QWP/493 13/2005 Corr. London; 12 June 2006.

Friesland Foods Domo. http://www.lactose.com/ (accessed 27 February 2009).

Kaerger JS et al. Carriers for DPis: formulation and regulatory challenges. Pharm Tech Eur 2006; 18(10): 25-30.

Kussendrager K et al. A new DSC method for the detection of very low amorphous contents in lactose carriers for dry powder inhalers. Proc AAPS Ann11al M eeting, 2005. http://www.aapsj .org/abstracts/ AM_2005/AAPS2005-001716.pdf (accessed 27 February 2009).

Meggie GmbH. Technica l literature: Inhalac, 2008. http://www.megglepharma.de (accessed 27 February 2009).

Sheffield Pharma Ingredients. Technical literature: Inhalation lactose, 2008. http://www.sheffield-products.com (accessed 27 February 2009).

21 Authors S Edge, JS Kaerger, J Shur.



CH, OH l'~: ~ O~0~H ~ OH . H2O

OH

a-Lactose monohydrate

The USP32-NF27 describes lactose monohydrate as a natural disaccharide, obtained from milk, which consists of one galactose and one glucose moiety. The PhEur 6.5 and JP XV describe lactose monohydrate as the monohydrate of O-~-D-galactopyranosyl(l --+4)-a -o-glucopyranose. It is stated in the USP32-NF27 that lactose monohydrate may be modified as to its physical characteristics, and may contain varying proportions of amorphous lactose.


Dry powder inhaler carrier; lyophilization aid; tablet binder; tablet and capsule diluent; tablet and capsule filler.


Lactose is widely used as a filler and diluent in tablets and capsules, and to a more limited extent in lyophilized products and infant formulas. (l -

9! Lactose is also used as a diluent in dry-powder inhalation; seeLactose, Inhalation. Various lactose grades are commercially available that have different physical properties such as particle size distribution and flow characteristics. This permits the selection of the most suitable material for a particular application; for example, the particle size range selected for capsules is often dependent on the type of encapsulating machine used.

Usually, fine grades of lactose are used in the preparation of tablets by the wet-granulation method or when milling during processing is carried out, since the fine size allows better mixing with other formulation ingredients and utilizes the binder more efficiently.

Other applications of lactose include use in lyophilized products, where lactose is added to freeze-dried solutions to increase plug size and aid cohesion. Lactose is also used in combination with sucrose (approximately 1 : 3) to prepare sugar-coating solutions. It may also be used in intravenous injections. -

Lactose is also used in the manufacture of dry powder formulations for use as aqueous film-coating solutions or suspensions.

Direct-compression grades of lactose monohydrate are available as granulated/agglomerated ct-lactose monohydrate, containing small amounts of anhydrous lactose.

Direct-compression grades are often used to carry lower quantities of drug and this permits tablets to be made without granulation.

Other directly compressible lactoses are spray-dried lactose and anhydrous lactose; see Lactose, Spray-Dried and Lactose, Anhydrous.

8 Description In the solid state, lactose appears as various isomeric forms, depending on the crystallization and drying conditions, i.e. ctlactose monohydrate, P-lactose anhydrous, and o:-lactose anhydrous. The stable crystalline forms of lactose are ct- lactose monohydrate, P-lactose anhydrous, and stable o:-lactose anhydrous.

Lactose occurs as white to off-white crystalline particles or powder. Lactose is odorless and slightly sweet-tasting; ct-lactose is approximately 20% as sweet as sucrose, while P-lactose is 40% as sweet.

9 Pharmacopeial Specifications See Table I. See also Section 18.

10 Typical Properties Brittle fracture index

0.0749 (at compression pressure 189.5 MPa); 0.0883 (at compression pressure 191.0MPa).001

Bonding index 0.0081 (at compression pressure 189.5 MPa); 0.0052 (at compression _pressure 191.0 MP a) .< toJ

Density (true) 1.545 g/cm (ct-lactose monohydrate) Density (bulk) see Table II.

SEM 1: Excipient: Pharmatose 125M; manufacturer: DMV-Fonterra Excipients; magnification: 1 OO x ; voltage: 1.5 kV.

Lac tose, Mo nohydrate 365

SEM 2: Excipient: Super Tab 30GR; manufacturer: DMV-Fonterra Excipients .

SEM 3: Excipient: Lactochem Crystals; manufacturer: Friesland Foods Domo; magnification: 200 x ; voltage: lOkV.

SEM 4: Excipient: Lactochem Crystals; manufacturer: Friesland Foods Domo; magnification: 700 x ; voltage: 10 kV.

Density (tapped) see Table II. Loss on drying Typically 0.2 % fo r Monohydrate 80M, Mono

hydrate Impalpable; and 0.1-0.2% for Meggie products. Melting point 201-202°C (for dehydrated ct- lactose monohy

drate) Moisture content Lactose monohydrate contains approximately

5% w/w water of crystallization and normally has a range of 4.5-5 .5 % w/w water content. See Table II.

NIR spectra see Figure 1.

366 Lactose , M o no hydrote

Table I: Pharmacopeial specifications for lactose, monohydrote.

Test JP XV PhEur 6.5

Identification + + Characters + + Appearance/color of + +

solution Acidt or alka li nity + + Speci ic optical rotation +54.4° to +54.4° to

+55.9° +55.9° Protein and li ght- +

absorbing impurities/ substances

Absorbonce at 210- 220 nm ,,; 0 .25 ,:;; 0 .25 at 270- 300 nm ,,; 0 .07 ,,; 0.07 at 400nm ,s: 0.04 ,s: 0.04

Heavy metals ,,; 5ppm ,,; 5ppm Water 4.5-5.5%101 4.5-5.5% Sulfated ash ,s: 0.1 % Residue on ignition ,s: 0.1 % Loss on drying ,s: 0 .5%161

Microbial limit Aerobic bacteria ,,; 1 00cfu/g 102 cfu/g Fungi and rast ,,; 50cfu/g Absence o + +

Escherichia coli Absence of +

Salmonella

(a) 4.0- 5.5% far granu lated powder. (b) For the granulated powder, not more than 1.0%. (c) Modified monohydrate form, not more than 1.0%.

Particle size distribution see Table III. Permanent deformation pressure

USP32-NF27

+

+

+ +54.4° to

+55.9° +

,s: 0.25 ,s: 0.07 ,:;; 0.04 ,,; 5 µg/g 4 .5-5.5%

,:;; 0.1 % ,:;;'. 0 .5%{c)

,:;; l00cfu/g ,s: 50 cfu/g +

370.0 MPa (at compression pressure 189.5 MPa);

485.0MPa (at compression pressure 191.0MPa).'10l

Reduced modulus of elasticity 1472 (at compression pressure 189.5 MPa );

5155 (at compression pressure 191.0 MPa).0°> Solubility see Table IV. Specific rotation [a] ti0 = + 54.4° to +55.9° as a 10% w/v solution.

Lactose exhibits mutarotation, and an equilibrium mixture containing 62% P-lactose and 38 % a-lactose is obtained instantly on the addition of a trace of ammonia.

Tensile strength 2.987 MPa (at compression pressure 189.5 MPa); 2.5 17 MPa (at compression pressure 191.0 MPa). 110l

Water content see Table IL M ethods for characterizing the mechanical properties of

compacts of pharmaceutical ingredients are s~ecified in the Handbook of Pharmaceutical Excipients, 3rd edn. 1 0>

Table IV: Solubility of lactose.

Solvent

Chloroform Ethanol Ether Water

- -- .

Solubility at 20UC unless otherwise stated

Practically insoluble Practically insoluble Practically insoluble 1 in 5.24 1 in 3.05 at 40°C 1 in 2.30 at 50°C 1 in 1 .71 at 60°C 1 in 0.96 at 80°C


Mold growth may occur under humid conditions (80% relative humidity and above). Lactose may develop a brown coloration on

Table II: Typical physical properties of selected commercially available lactose, monohydrate.

Supplier/ grade Density Density Water (bulk) (tafcped) content (%) (g/cm3) (g cm3)

-----·-·-· ·- --~---------·---·--------DMV·Fonterra Excipients Pharmatose SOM 0.70 0.82 Pharmatose 60M 0.80 0.98 Pharmatose 70M 0.81 1.02 Pharmatose 80M 0.75 0.92 Pharmatose 90M 0.72 0.90 Pharmatose 1 OOM 0.73 0.88 Pharmatose 1 1 OM 0.72 0.88 Pharmatose 125M 0.68 0.85 Pharmatose 130M 0.65 0.96 Pharmatose 150M 0.62 0.90 Pharmatose 200M 0.57 0.84 Pharmatose 350M 0.54 0.80 Pharmatose.450M 0.48 0.74 SuperTab 30GR 0 .53 0.66 Friesland Foods Domo Lactochem Coarse Crystals 0.75 0.88 Lactochem Crystals 0.74 0.86 Lactochem Fine Crystals 0.73 0.85 Lactochem Extra Fine Crystals 0.73 0.86 Lactochem Coarse Powder 0.71 0.95 Lactochem Regular Powder 0.62 0.92 Lactochem Powder 0.64 0.89 Lactochem Fine Powder 0 .61 0.84 Lactachem Extra Fine Powder 0.45 0.74 Lactochem Super Fine Powder 0.47 0.74 MeggleGmbH Capsulac 60 0 .59 0.70 5.2 Granulac 70 0.72 0.90 5.2 Granulac 140 0 .66 0.89 5.2 GranuLac 200 0.54 0.80 5.2 GranuLac 230 0.47 0.76 5.2 Prismolac 40 0.47 0.54 5.2 SacheLac 80 0.60 0.71 5.2 SorboLac 400 0.36 0.78 5.2 Spherolac 1 00 0.69 0.84 5.2 Tablettose 70 0.5 1 0.62 5.2 Tablettose 80 0.57 0.72 5.2 Tablettose 100 0.54 0.74 5.2 Sheffield Pharma Ingredients Monohydrate 80M 0.66 0.92 4 .8-5.2 Monohydrate Impalpable 0.53 0.81 4.8-5.2

storage, the reaction being accelerated by warm, damp conditions; see Section 12. The purities of different lactoses can vary and color evaluation may be important, particularly if white tablets are being formulated . The color stabilities of various lactoses also differ.

Solutions show mutarotation; see Section 10. Lactose should be stored in a well-closed container in a cool, dry

place.

12 Incompatibilities A Maillard-type condensation reaction is likely to occur between lactose and compounds with a primarr amine group to form brown, or yellow-brown-colored products. 111 The Maillard interaction has also been shown to occur between lactose and secondary amine. However, the reaction sequence stops with the formation of the imine, and no yellow-brown coloration developsY2> l

Lactose is also incompatible with amino acids, amfetamines,113

and lisinopril.'14)

13 Method of Manufacture Lactose is a natural disaccharide consisting of galactose and glucose, and is present in the milk of most mammals. Commercially, lactose is produced from the whey of cows' milk; whey being the

",,

Table Ill: Particle size distribution of selected commercially available lactose, monohydrote. ---- -- - -···--·--Supplier/ grade Typical particle size distribution (%)

<10µm <32µm <45µm <63µm <75µm <lOOµm <150µm <200µm <250µm <315µm <400µm <600µm <800µm

DMV-Fonterra Excipients Pharmatose 50M - - - - - - - ~20 - - ;;, 80 Pharmatose 60M - - - - ~5 - 10-20 - 40-65 - - ;;,98 Pharmatose 70M - - - - 5- 13 - 25-45 - 60- 80 - - ;;,,98 Pharmatose 80M - - - - - ,:;;20 - - 70- 90 ;;,,95 Pharmatose 90M - - - ,:;; 15 - 15-30 55- 90 - - 100 Pharmatose IOOM - - - ,:;; 15 - - 60- 80 - ;;,99 Pharmatos~ 1 1 OM - - - ,:;;20 - 30-60 75-90 - - 100 Pharmatose 125M - - ~40 40-70 - ;;,90 ;;,,97 -Pharmatose I 30M - - - - ,:;;50 - - 80-90101 Pharmatose 150M - - ~50 - - ;;,,70 ;;,,85 - - 100 Pharmatose 200M - - 50-65 - - ;;,90 ;;,,96 - ;;,99 Pharmatose 350M - - ;;,60 - - ;;,96 - - 100 Pharmatose 450M - - ;.-90 ;;,98 - - 100 - -Super Tab 30GR - - - - ,:;;30 - 40- 70 - - ;;,90lb) - 1oo{c) Friesland Foods Domo Lactochem Coarse Crystals - - - - - - 30- 80 - ;;,,65 - ;;,90ld) Lactochem Crystals - - - - 5- 30 - 55-95 - ;;,90 Lactochem Fine Crystals - - - - ,:;;30 - - -- ;;, 90 Lactochem Extra Fine Crystals - - - 10- 45 - - - ;;, 99 Lactochem Coarse Powder - - - - 15-50 - ;;,75 - ;;,, 98 Lactochem Regular Powder - - 20-421"1 - - - - ;;, 951~

Lactochem Powder - - - - 65- 80 ;;, 85191 ;;,95 Lactochem Fine Powder - 55-801•1 ;;,80 - ;;,,98 Lactochem Extra Fine Powder - - ;;;, 9o1•l - - - ;;, 99lh) Lactochem Super Fine Powder - - ;;, 95 Lactochem Microfine 90 M eggle GmbH

1001;) Capsulac 60 ·- - - - - 5 15 - 60 - 99 Granulac 70 - - - - - 50 - - - - 99.5 l00FI Granulac 140 - 30 - - - 90 100 Granulac 200 - 55 - - 96 Granulac 230 - 75 - 96 - 99.5 Prismalac 40 - - - - - - - 4 - - - 851;1 100 Sachelac 80 - - - - - 5 - - 63 - 100 Sorbolac 400 - 95 - 99.5 Spherolac 1 00 - - 9 - - · 78 98 99.5

1oolc) ,-

Tablettose 70 - - - l - - 25 56 - - 97 - 0

Tablettose 80 13 - 53(o) 93 l00Fl - (") - - - - - - 0 Tablettose 1 00 - - 12 - 22 42 - 77 - 98 1oolc) - V,

Sheffield Pharma Ingredients} _(l)

Monohydrate 80M - - - - 24- 65 69-85(9) - ;;;,99(o) - - - - - s: Monohydrate Impalpable - - 64-80 - ;;,94 ;;,99(9) - - - - - - - 0

::J

(a) < 180µm. 0 ::::r

(b) <355µm. -< 0....

(c) <500µm. 0 (d) <425 µm. ro (e) <53µm. 1n <2 12µm. (g) <1 06 µm. (h),:;; 125 µm. (,J

(i) <630 µm. 0-

"

________________ ... _ --;,._ 19,;,a4 J a

368

~

o2" ..........

0)

__Q

> ·.:: Cl)

-0 -0

C

~ X

0

1.0

0.0

Lac to se, Mo no hydrate

1915

' .. .. .... .. ~ t

g ___ __ ,,,

2243 2267

·,--' 2092

1934

; 2303

/ 2336

/ '

'

\~318/ 22782475

2256

L.

. ,

~ - 1 . 2 ,.___.__.___.____._..___.__.___..____._.__.._._..__.___. -0 . 2 1100 1300 1500 1700 1900 2100 2300 2500

Wavelength/ nm

Figure 1: Near-infrared spectrum of lactose monohydrate measured by reflectance.

residual liquid of the milk following cheese and casein production. Cows' milk contains 4.4-5.2% lactose; lactose constitutes 38% of the total solid content of milk.

a-Lactose monohydrate is prepared by crystallization from supersaturated solutions below 93.5°C. Various crystalline shapes are prism, pyramidal, and tomahawk; these are dependent on the method of precipitation and crystallization. Direct compression grades of et-lactose monohydrate are prepared by granulation/ agglomeration and spray-drying.

14 Safety

Lactose is widely used in pharmaceutical formulations as a filler and filler-binder in oral capsule and tablet formulations. It may also be used in intravenous injections. Adverse reactions to lactose are largely attributed to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactaseY5

-ts) This results in lactose being undigested and may lead to cramps, diarrhea , distension, and flatulence. In lactose-tolerant individuals, lactase hydrolyzes lactose in the small intestine to glucose and galactose, which are then absorbed. Lactase levels are normally high at birth, and levels decline rapidly in early childhood. Malabsorption of lactose (hypolactasia) may occur at an early age (4-8 years) and varies among different ethnic groups. Lactose is excreted unchanged when administered intravenously.

The symptoms of lactose intolerance are caused by the osmotic effect of the unabsorbed lactose, which increases water and sodium levels in the lumen. Unabsorbed lactose, upon reaching the colon, can be fermented by colonic flora, which produces gas, causing abdominal distension and discomfort. A lactose tolerance test has been developed based on the measurement of blood glucose level and the hydrogen level in the breath. However, its usefulness has been questioned as the test is based on a 50 g dose of lactose.

Approximately 10-20% of lactose-intolerant individuals, in two studies, showed clinical symptoms of intolerance after ingestion of 3-5 g of lactoseY5

•16

) In one of the studies,!15) 75% of the subjects

had symptoms with 12 g of lactose (equivalent to 250 mL of milk). In another,<16

) eight out of 13 individuals developed diarrhea after the administration of 20 g of lactose, and nine out of 13 after the administration of 25 g.

Lower doses of lactose produce fewer adverse effects, and lactose is better tolerated if taken with other foods. As a result, there is a significant population with lactose malabsorption who are still able to ingest normal amounts of lactose, such as that in milk, without the development of adverse side effectsY 7l

Most adults consume about 25 g of lactose per day (500 mL of milk) without symptomsY 8

•19

) When symptoms appear, they are usually mild and dose-related . The dose of lactose in most

pharmaceuticals seldom exceeds 2 g per day. It is unlikely that severe gastrointestinal symptoms can be attributed to the lactose in a conventional oral solid-dosage form, especially in adults who have not previously been diagnosed as severely lactose-intolerant. However, anecdotal reports of drug-induced diarrhea due to lactose intolerance have been made following administration of pharmaceutical preparations containing lactose.

It has also been suggested that lactose intolerance may have a role in irritable bowel syndrome, but this role is currently unclear. '20

)

In the past, there have been concerns over the transmissible spongiform encephalopathies (TSE) contamination of animalderived products. However, in the light of current scientific knowledge, and irrespective of geographical origin, milk and milk derivatives are reported as unlikely to present any risk of TSE contamination; TSE risk is neglif ible if the calf rennet is produced in accordance with regulations. (2 t

LD50 (rat, IP): > 10g/kg

LD 50 (rat, oral): > 10 g/kg

LD5o (rat, SC) : > 5 g/kg


Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive generation of dust, or inhalation of dust, should be avoided.

16 Regula tory Status

GRAS listed. Included in the FDA Inactive Ingredients Database (IM, IV, and SC: powder for injections; oral: capsules and tablets; inhalation preparations; vaginal preparations). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.


Lactose, anhydrous; lactose, inhalation; lactose, monohydrate and corn starch; lactose, monohydrate and microcrystalline cellulose; lactose, monohydrate and povidone; lactose, monohydrate and powdered cellulose; lactose, spray-dried.

18 Comments

Lactose monohydrate is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter 1196 in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

A number of different grades of lactose are commercially available that vary in their physical properties, and many studies have been reported in the literature comparing the behavior of these various materials in different formulations. (3';S,

9) A number of co

processed excipients which contain lactose are available for directcompression applications: co-processed lactose and starch (Starlac, Meggle/Roquette Freres), <22l lactose and microcrystalline cellulose (Microcelac, Meggle);<23) lactose and cellulose powder (Celli:lctose, Meggle),'24

•25

) lactose, Eovidone, and crospovidone (Ludipress, Ludipress LCE, BASF).< 6 l

Lactose may exhibit complex thermoanalytical transitions because of its several crystalline, as well as amorphous, forms. Differential scanning calorimetry (DSC) can be used effectively to characterize the composition.<27- 29) For example, et-lactose becomes anhydrous at approximately 120°C. a -Lactose monohydrate may also contain a small quantity of the ~-form.

A specification for lactose is included in the Food Chemicals Codex (FCq .<30 )

The EINECS number for lactose is 200-559-2. The PubChem compound ID (CID) for lactose monohydrate includes 62223 and 104938.

19 Specific References 1 Alpar O et al. The compression properties of lactose. J Pharm

Pharmacol 1970; Dec(Suppl.}: 1S-7S. 2 Vromans H et al. Studies on the tableting properties of lactose: the effect

of initial particle size on binding properties and dehydration characteristics of ()(-lactose monohydrate. Rubinstein MH, ed. Pharmaceutical Technology:Tableting Technology., vol. 1: Chichester: Ellis Horwood, 1987; 31-42.

3 Thwaites PM et al. An inves tigation of the effect of high speed mixing on the mechanical and physical properties of direct compression lactose. Drug Dev Ind Pharm 1991; 17: 503-517.

4 Riepma KA et al. The effect of moisture sorption on the strength and interna l surface area of lactose tablets. Int J Pharm 1992; 87: 149-159,

5 (:elik M, Okutgen E. A feas ibility study for the development of a prospective compaction functionality test and the establishment of a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309-2334.

6 Lerk CF. Consolidation and compaction of lactose. Drug Dev Ind Pharm 1993; 19: 2359-2398.

7 Otsuka M et al. Effect of humidity on solid-state isomerization of various kinds of lactose during grinding. J Pharm Pharmacol 1993; 45: 2-5.

8 Paronen P. Behaviour of some direct compression adjuvants during the tabletting process. STP Pharma 1986; 2: 682-688 .

9 Zuurman K et al. The relationship between bulk density and compactibility of lactose granulations. Int J Pharm 1994; 102: 1-9.

10 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association, 2000; 641-643.


12 Wirth DD et al. Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine. J Pharm Sci 1998; 87: 31-39.

13 Blaug SM, Huang W. Interaction of dextroamphetamine sulfate with spray-dried lactose. J Pharm Sci 1972; 61: 1770- 1775.

14 Eyjolfsson R. Lisinopril-lactose incompatibility. Drug Dev Ind Pharm 1998; 24: 797- 798.

15 Bedine MS, Bayless TM. Intolerance of small amounts of lactose by individuals with low lactase levels. Gastroenterology 1973; 65: 735-743.

16 Gudmand-Hoyer E, Simony K. Individual sensitivity to lactose in lactose ma la bso rption. Am] Dig Dis 1977; 22(3): 177- 181.

17 Lorner M C et al. Review article: lactose intolerance in clinical practice -myths and realities. Aliment Pharmacol Ther 2008; 27(2) : 93-103.

18 Suarez FL, Savaiano Dennis A. Diet, genetics, and lactose intolerance. Food Technol 1997; 51(3): 74-76.

19 Suarez FL et al. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported lactose intolerance. N Engl J Med 1995; 333: 1-4.

20 Spanier JA. A systemic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 2003; 163 (3): 265-274.

21 The European Agency for the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use. London, 9 D ec 2002: EMEAI 410/01 Rev. 2.

22 Hauschild K, Picker-Freyer KM. Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation. AAPS Pharm Sci Tech 2004; 6(2): e16.

Lactose, M o nohydrate 369

23 Michael A et al. Comparative evaluation of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Pharm Dev Technol 2002; 7(1): 79-87.

24 Casalderrey M et al. A comparison of drug loading capacity of cellactose with two ad hoc processed lactose-cellulose direct compression excipients. Chem Pharm Bull (Tokyo) 2004; 52(4): 398-401.

25 Arida AI, AI-Tabakha MM. Cellactose a co-processed excipient: a comparison study. Pharm Dev Technol 2008; 13: 165- 175.

26 Heinz R et al. Formulation and development of tablets based on Ludipress and scale-up from laboratory to production scale. Drug Dev Ind Pharm 2000; 26: 513-521.

27 Chidavaertzi OC et al. The use of thermal techniques to assess the impact of feed concentration on the amorphous content and polymorphic forms present in spray dried lactose. Int J Pharm 1997; 159: 67-74.

28 Hill VL et al. Characterisation of spray-dried lactose using modulated differential scanning calorimetry. Int J Pharm 1998; 161: 95-107.

29 Lerk CF et al. Alterations of ()(-lactose during differential scanning calorimetry. J Phann Sci 1984; 73: 856-857.

30 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008: 522.

20 General References BASF. Technical literature: · Ludipress, Ludipress L CE, 2008. http://

www.pharma-solutions.basf.com (accessed 10 March 2009). Bolhuis GK, Chowhan ZT. Materials for direct compaction. Alderborn G,

Nystrom.C, eds. Pharmaceutical Powder Compaction Technology. New York: Marcel Dekker, 1996; 459-469.

Bolhuis GK, Armstrong NA. Excipients for direct compaction: an update. Pharm Dev Technol 2006; 11: 111- 124.

DMV-Fonterra Excipients. Technical literature: Pharmatose, SuperTab 30GR, 2008. http://www.dmv-fonterra-excipients.com (accessed 10 March 2009).

European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 2 1(1): 142- 143.www.edqm.eu/ site/-614.html (accessed 10 March 2009).

Friesland Food Domo. Technical literature: Lactochem, 2008. http:// www.domo.nl/pharma (accessed 10 March 2009).

Kirk JH et al. Lactose: a definite guide to polymorph determination. Int J Pharm 2007; 334: 103-107.

Meggie GmbH. Technical literature: Lactose excipiellts, 2004 . http:// www.meggle-pharma.de (accessed 10 March 2009).

Rajah KK, Blenford DE, eds. The ALM Guide to Lactose Properties and Uses. The Hague: Association of Lactose Manufacturers, 1998 .

Roquette Freres. Technical literature: Starlac, 2008. http://www.roquettepharma.com (accessed 10 March 2009).

Sheffield Pharma Ingredients. Technical literature: Excipients, 2008. http:// www.sheffield-products.com (accessed 10 March 2009).

21 Authors S Edge, AH Kibbe, J Shur.

22 Date of. Revision 10 March 2009.

=----- ···--··---------~-- - - ----------- -------------

--------------- - -~~- -------· - ·----- --- - ----

6l Lactose, Monohydrate and Corn Starch


None adopted.

2 Synonyms

Star Lac.


See Section 8.


See Section 8.


See Section 8.

6 Functional Category Directly compressible tablet excipient; disintegrant; tablet and caps ule diluent.



Both lactose monohydrate and corn (maize) starch are listed as separate monographs in the JP, PhEur, and USP-NF, but the combination is not listed. See Lactose, Monohydrate, and Starch. See also Section 18.

10 Typical Properties Angle of repose :( 29° for Star Lac Density (bulk) 0.57glcm3 for StarLac Density (tapped) 0.68 g/cm3 for Star Lac Hausner ratio 1.19 for Star Lac Heavy metals 5 ppm for Star Lac Loss on drying :( 3.0% for Star Lac Microbial content Total viable aerobic count :( 100 cfu/g, molds

< 10cfu/g, yeasts < 10cfu/g (Escherichia coli and Salmonella species absent) for StarLac.

Particle size distribution :( 15% < 32 µm, 35-65% <160 µm , ;?: 80% < 250 ~ltn for Star Lac.

Sulfated ash :( 0.25 % for StarLac Solubility Partially soluble in cold water for StarLac.

11 Stability and Storage Conditions Store in well-closed conta iners under dry and odor-free conditions.

Lactose monohydrate and corn starch can be used in tablets to improve compressibility, flowability and disintegration proper- 12 Incompatibilities ties. (l) It is used in homeopathic and low-dose to mid-dose See Lactose, Monohydrate, and Starch. form ulations.

8 Description

a-Lactose monohydrate and corn starch occurs as a white or almost white odorless powder containing 82-88% of lactose monohydrate and 12- 18% of corn (maize) starch. It is a free-flowing powder owing to its spherical structure.

:'.' M 1: Excipient: Starlac; manufacturer: Roquette/Meggle; magnification: 200 x ; voltage: 2 kV.

370


Lactose monohydrate and corn starch is prepared by spray-drying a mixture of the two ingred ients.

14 Safety

See Lactose, Monohydrate, and Starch.


Observe normal precautions appropriate to the circumstances and quantity of material handled.


Lactose monohydrate and corn starch is a mixture of two materials both of which are generally regarded as nontoxic: Lactose monohydrate GRAS listed. Included in the FDA Inactive

Ingredients Database (IM, IV, and SC: powder for injections; oral: capsules and tablets; inhalation preparations; vaginal preparations). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Starch GRAS listed. Included in the FDA Inactive Ingredients Database (buccal tablets, ora l capsules, powders, suspensions and tablets; topical preparations; and vaginal tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.


Lactose, monohydrate; starch.

It

Lactose , Mono hydrate and Microcrystalli ne Ce llulose 371

18 Comments Lactose monohydrate and corn starch are two of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5 .8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

StarLac has been designed for direct compression, combining good flowability and compressibility with fast disintegration properties. Excipients or formulations containing a variety of drugs, namely ascorbic acid, paracetamol [acetaminophen] and theophylline monohydrate show it to be superior to a simple mixture of its components in terms of flowability, tablet strength, friability and disintegration time. '1•

2' Starch particles are embedded

in a matrix mainly consisting of crystalline lactose monohydrate, and very low quantities of amorphous lactose are detectable. Its balanced elastic and brittle properties make it suitable for roller compaction. Specific quantitative, analytical methods for the assay of starch and lactose in StarLac have been developed and validated. (3l

19 Specific References 1 Wagner KG, Dressler JA. A corn starch/alpha-lactose monohydrate

compound as a new directly compressible excipient. Pharm Ind 2002; 64( 9): 992-999.

2 Hauschild K, Picker KM. Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation. AAPS J 2004; 6(2) : 27-38.

3 Roquette/Meggle. Technical data sheet. Star Lac additional information, August 2007.

20 General References Deorkar N. High-functionality excipients: a review. Tablets and Capsules

2008: 22-26. http://www.tabletscapsules.com (accessed 3 March 2009). European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Phanneuropa 2009; 21(1): 142- 143 . http://www.edqm.eu/site/-614.html (accessed 3 February 2009) .

Gohel MC, Jogani PD. A review of co-processed directly compressible excipients.J Pharm Pharm Sci 2005; 8(1): 76- 93 .

Haeusler 0. A star is born. Pharmaceutical Formulation a11d Quality 2002; 54-57.

Meggie. Product literature: Lactose Excipients, September 2008 . Nachaegari SK, Bansal AK. Coprocessed excipients for so lid dosage forms.

Pharm Tech 2004; (Jan): 52-64. Roquette. Technical datasheet: Star Lac - lactose-starch compound for direct

compression, October 2005 .

21 Authors ME Quinn, RC Rowe.

22 Date of Revision 3 March 2009.

Lactose, Monohydrate and Microcrystalline Cellulose


None adopted.

2 Synonyms MicroceLac 100.


See Section 8.


See Section 8.

S Structural Formula

See Section 8.


Tablet and capsule diluent.


Lactose monohydrate and microcrysta lline cellu lose can be used in tablets for direct compression.

8 Description Lactose monohydrate and microcrystalline cellulose occurs as a white or almost white odorless powder containing 73-77% of lactose monohydrate and 23-27% of microcrystalline cellulose.


Both lactose monohydrate and microcrystalline cellulose are listed as separate monographs in the JP, PhEur, and USP-NF, bur the combination is not listed. See Lactose, M onohydrate, and Cellulose, Microcrystalline. See also Section 18.

10 Typical Properties Acidity/alkalinity pH = 4.0-7.0 for MicroceLac 100 Angle of repose 34 ° for MicroceLac 100 Density (bulk) 0.5 glcm3 for MicroceLac 100 Density (tapped) 0.61 g/cm3 for MicroceLac 100 Hausner ratio 1.16 for MicroceLac 1 00 Heavy metals ,;:; 5 ppm for MicroceLac 100 Loss on drying ,;:; 1.5% for MicroceLac 100 . Microbial content Total viable aerobic count ,;:; l00 cfu/g, molds

,;:; 10 cfu/g, yeasts ,;:; 10 cfu/g (Escherichia coli and Salmonella species absent) for MicroceLac 100

Particle size distribution ,;:; 15 % < 32~tm, 45- 70% < 160~tm, ;;,: 90% <250 µm for MicroceLac 100

Solubility Partially soluble in water fo r MicroceLac I 00 Sulfated ash ,s; 0.1 % for MicroceLac 100 Water content 4-6 % for MicroceLac 100

372 Lactose , Monohydra te and Microcrystallin e C ellulose

· Excipient: Microcelac 100; manufacturer: Meggie; magnification: 200 x ; voltage: 3 kV.

.}EM 2: Excipient: Microcelac 100; manufacturer: Meggie; magnification: 500x ; voltage: 3 kV. ----


Store at room temperature in well-closed containers under dry and odor-free conditions.


See Lactose, Monohydrate, and Cellulose, Microcrystalline.


Lactose monohydrate and microcrystalline cellulose is prepared by spray-drying a mixture of the two ingredients.

14 Safety See Lactose, Monohydrate, and Cellulose, Microcrystalline.

1 S Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

16 Regulatory Status Lactose monohydrate and microcrystalline cellulose is a mixture of two materials both of which are generally regarded as nontoxic: Lactose monohydrate GRAS listed. Included in the FDA Inactive

Ingredients Database (IM, IV, and SC: powder for injections; oral: capsules and tablets; inhalation preparations; vaginal preparations). Included in nonparenteral and parenteral medi-

cines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Microcrystalline cellulose GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (inhalations; oral capsules, powders, suspensions, syrups, and tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Cellulose, microcrystalline; lactose, monohydrate.

18 Comments

Lactose monohydrate and microcrystalline cellulose are two of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

MicroceLac 100 has been designed for formulating high-dose small tablets with a poorly flowable active ingredient. It showed superior flow and binding properties compared to simple mixtures of its components. CJ •21 Differences between MicroceLac 100 and Cellactose 80 have recently been evaluated. (3 I ·

A specification for lactose and microcrystalline cellulose spheres is contained in the Japanese Pharmaceutical Excipients (JPE);(4 l see Table I.

Table I: JPE specification for lactose and microcrystalline cellulose spheres.

Test

Description Identification Heavy metals Arsenic Loss on drying Water Residue on ignition Assay (dried basis)

Lactose Microcrystalline cellulose

19 Specific References

JPE 2004

+ + ,;:; 5ppm ,;:; 2ppm ,;:;5 .0% ,;:; 9.0% ,;:; 0.1%

60-80% 20-40%

-

1 Michael A et al. Comparative evaluation of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Pharm Dev Technol 2002; 7(1): 79- 87.

2 Goto K et al. Pharmaceutical evaluation of multipurpose excipients for direct compressed tablet manufacture: comparisons of the capabilities of multipurpose excipients with those in general use. Drug Dev Ind Pharm 1999; 25(8): 869- 878.

3 Muzikova J, Zvolankova J. A study of the properties of tablets from coprocessed dry binders composed of alpha-lactose monohydrate and different types of cellulose. Ceska Slav Farm 2007; 56(6): 269-275.

4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients 2004. Tokyo: Yakuji Nippo, 2004; 457-459.



(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

...

Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Pharm Sci 2005; 8(1): 76-93 .

Meggie GmbH. Product literature: Lactose excipients, September 2008 . Meggie GmbH. Product literature: MicroceLac 100, March 2006. Nachaegari SK, Bansal AK. Coprocessed excipients for solid dosage forms.

Pharm Tech 2004; 28: 52- 64.

Lactose, M onohyd rate and Povidone 373



r Lactose, Monohydrate and Povidone

Nonproprietary Names None adopted.

2 Synonyms

Ludipress LCE.


See Section 8.

4 Empirical Formula and Molecular Weight See Section 8.

s Structural Formula See Section 8.

6 Functional Category Tablet and capsule diluent.


Lactose monohydrate and povidone can be used to formulate chewable tablets, lozenges, effervescent tablets, and controlledrelease tablets by direct compressionYl It is su itable for low-dose drugs. 12)

8 Description Lactose monohydrate and povidone occurs as white free-flowing granules, odorless with a neutral taste, containing 96.5% ± 1.8% of lactose monohydrate and 3.5% ± 0.5% of povidone K30.

9 Pharmacopeial Specifications Both lactose monohydrate and povidone are listed as separate monographs in the JP, PhEur, and USP- NF, but the combination is not listed. See Lactose, Monohydrate, and Povidone. See also Section 18.

10 Typical Properties Angle of repose 29.5° for Ludip_ress LCE Density (bulk) 0.56 ± 0.6 glcm3 for Ludipress LCE Hausner ratio 1.20 ± 0.10 for Ludipress LCE Heavy metals ,;;;; 10 ppm for Ludipress L CE Loss on drying 5.75% for Ludipress LCE Microbial content Mesophilic aerobes ,:;;; 1000cfu/g, yeasts and

fungi ,:;;; l 00 cfu/g (Escherichia coli , Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella species absent), other Enterobacteriaceae ,:;;; 100 cfu/g) for Ludipress LCE

Particle size distribution ,;;;; 20% < 63 µm, 40-65 % <200 µm, ,:;;;20% <400 µm for Ludipress LCE

Solubility Soluble in water for Ludipress LCE Water content ,;;;; 6.0% for Ludipress LCE

11 Stability and Storage Conditions Store at room temperature iri tightly closed containers.

12 Incompatibilities See Lactose, Monohydrate, and Povidone.

13 Method of Manufacture Lactose monohydrate and povidone 1s manufactured by a proprietary agglomeration process.

14 Safety See Lactose, Monohydrate, and Povidone.

1 5 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled.

16 Regulatory Status Lactose monohydrate and povidone is a mixture of two materials both of which are generally regarded as nontoxic: Lactose monohydrate GRAS listed. Included in tl1e FDA Inactive


Povidone Accepted for use in Europe as a food additive. Included in the FDA Inactive Ingredients Database (IM and IV injections; ophthalmic preparations; oral capsules, drops, granules, suspensions, and tablets; sublingual tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.

17 Related Substances Lactose, monohydrate; povidone.

18 Comments Lactose monohydrate and povidone are two of the materia ls that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General

_________________ . .,. - · ,... .

37 4 lac tose, Mo no hydrate and Powde red Cellulose

Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Ludipress LCE has been shown to have compression characteristics superior to a simple physical mixture of its constituents.(3

,4l

Tablet strength has been shown to be independent of machine . speed(5 l and tablet geometry,(5l and does not increase on storage.(6

)

Disintegra tion time has been shown not to increase at high compression forces.(?)

19 Specific References 1 Kolter K, Fussnegger B. Development of tablet formulations using

Ludipress LCE as a direct compression excipient. BASF Product Literature, No. 1, November 1998.

2 Kolter K et al. Ludipress LCE. A new direct compression excipient. BASF Product Litera ture, No. 10, May 2003.

3 Schmidt PC, Rubensdorfer CJ. Evaluation of Ludipress as a multipurpose excipients for direct compression. Part 1. Powder characteristics and tableting properties. Drug Dev Ind Phann 1994; 20(18): 2899-2925.

4 Goto K et al. Pharmaceutical evaluation of multipurpose excipients for direct compressed tablet manufacture: comparisons of the capabilities o f multipurpose excipients with those in general use. Drug Dev Ind Phanll 1999; 25(8): 869-878.

5 H einz R et al. Formulation and development of tablets based on Ludipress and scale-up for laboratory to production scale. Drug Dev Ind Pharm 2000; 26(5): 513- 521.

6 Baykara T et al. Comparing the compressibility of Ludipress with the other direct tableting agents by using acetaminophen as an active ingredient. Drug Deu Ind Pharm 1991; 17(1 7) : 2359- 2371.

7 Schmidt PC, Rubensdorfer CJ. Evaluation of Ludipress as a multipurpose excipients fo r direct compression. Part 2. Interactive blending and tableting with micronized glibenclamide. Drug D ev Ind Pharrn 1994; 20( 18): 2927- 2952 .


2008: 22- 26. http://www.tabletscapsules.com (accessed 3 March 2009). European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009 ).

Gobel MC, Jogani PD. A review of co-processed directly compressible excipients. J Phann Pharm Sci 2005; 8(1): 76- 93 .

Nachaegari SK, Bansal AK. Coprocessed excipients fo r solid dosage forms. Pharm Tech 2004; 28 : 52- 64.

BASF. Technical literature: Ludipress LCE, May 1999.



Ex Lactose, Monohydrate and Powdered Cellulose


None adopted.

2 Synonyms

Cellactose 80.


Sec Section 8.


See Section 8.


See Section 8.

6 Functional Category Tablet and capsule diluent.


Lactose monohydrate and powdered cellulose can be used in tablets for direct compression to improve compressibility and mouthfeel. (l)

8 Description Lactose monohydrate and powdered cellulose occurs as a white or almost white odorless powder containing 73-77% of lactose monohydrate and 23- 27% of cellulose powder.

9 Pharmacopeial Specifications Both lactose monohydrate and powdered cellulose are listed as separate monographs in the JP, PhEur, and USP-NF, but the combination is not listed. See Lactose, Monohydrate, and Cellulose, Powdered. See also Section 18.

10 Typical Properties Acidity/alkalinity pH = 4.0-7.0 for Cellactose 80 Angle of repose 32- 35° for Cellactose 80 Density (bulk) 0.38 g/cm3 for Ce/lactose 80 Density (tapped) 0.5 glcm3 for Ce/lactose 80 Hausner ratio 1.24 for Cellactose 80 Heavy metals ,;;; 5 ppm for Cellactose 80 Loss on drying :;;; 3.5% for Cellactose 80 Microbial content Total viable aerobic count ,;;; 100 cfu/g, molds

~ 10 cfu/g, yeast ~ 10 cfu/g (Escherichia coli and Salmonella species absent) for Cellactose 80

Particle size distribution ,;;; 20% <32 µm , 35-65% < 160 µm, ~ 80% < 250 µm for Cellactose 80

Sulfated ash ~ 0.2 % for ,Cellactose 80 Solubility Partially soluble in water for Cellactose 80 Water content 4- 7% for Cellactose 80

11 Stability and Storage Conditions Store at room temperature in well-closed containers under dry and 0 dor-free conditions.

12 Incompatibilities Sec Lactose, Monohydrate, and Cellulose, Powdered.

13 Method of Manufacture Lactose monohydrate and powdered cellulose is prepared by spraydrying a mixture of the two ingredients.

14 Safety See Lactose, Monohydrate, and Cellulose, Powdered.

15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled.

16 Regulatory Status Lactose monohydrate and powdered cellulose is a mixture of two materials both of which are generally regarded as nontoxic: Lactose monohydrate GRAS listed. Included in the FDA Inactive


Powdered cellulose GRAS listed. Accepted for use as a food additive in Europe (except for infant food in the UK). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Lactose, monohydrate; cellulose, powdered.

18 Comments Lactose monohydrate and powdered cellulose are two of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Lactose, Monohydrate and Powdered Ce llulose 375

Ce/lactose 80 has been designed especially for direct compression. It has been shown to be superior to a simple mixture of its components in terms of dilution potential,<2

) compressibility,(3) tensile strength, <4,

5) lubricant susceptibility, <6•7) and subsequent

tablet properties for a range of drugs.<8)

19 Specific References 1 Nachaegari SK, Bansal AK. Coprocessed excipients for solid dosage

forms. Pharm Tech 2004; 28: 52-64. 2 Flores LE et al. Study of load capacity of Avicel PH-200 and Ce/lactose,

two direct-compression excipients, using experimental design. Drug Dev Ind Pharm 2000; 26(4) : 465-469.

3 Belda PM, Mielck JB. The tableting behavior of Cellactose compared with mixtures of celluloses with lactoses. Eur J Pharm Biopharm 1996; 42(5): 325-330.

4 Muzikova J, Zvolankova J. A study of the properties of tablets from coprocessed dry binders composed of alpha-lactose monohydrate and different types of cellulose. Ceska Slov Farm 2007; 56(6): 269-275.

5 Arida AI, Al-Tabakha MM. Ce/lactose a co-processed excipient: a comparison study. Pharm Dev Technol 2008; 13(2): 165-175 .

6 Konkel P, Mielck JB. Associations of parameters characterizing the time course of the tabletting process on a reciprocating and on a rotary tabletting machine for high-speed production. Eur J Phann Biopharm 1998; 45(2): 137-148.

7 Flores LE et al. Lubricant susceptibility of Cellactose and Avicel PH-200: a quantitative relationship. Drug Dev Ind Phann 2000; 26(3): 297-305.

8 Casalderrey M et al. A comparison of drug loading capacity of cellactose with two ad hoc processed lactose-cellulose direct compression excipients. Chem Phann Bull (Tokyo) 2004; 52(4): 398-401.



(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Phanneuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Phann Sci 2005; 8(1): 76-93 .

Meggie. Product literature: Lactose e~cipients, September 2008. Meggie. Technical literature: Cellactose 80, August 2006.



6~ Lactose, Spray-Dried

1 Nonproprietary Names None adopted.

2 Synonyms FlowLac 90; FlowLac 100; Lactopress Spray-Dried; Lactopress Spray-Dried 250; NF Lactose-315; NF Lactose-31 6 Fast Flo; SuperTab llSD; SuperTab 14SD.

3 Chemical Name and CAS Registry Number Spray-dried lactose is a mixture of amorphous lactose, which is a 1 : 1 mixture of ci:-and-P-lactose, and O-P-D-galactopyranosyl(l --t4 )-ci:-D-glucopyranose monohydrate [5989-81-1]; [10039-26-6]; [64044-51 -5].

CAS numbers for lactose monohydrate are [5989-81 -1) (lactose monohydrate); (10039-26-6) (lactose monohydrate, cyclic); [64044-51-5 ) (lactose monohydrate, open form).


C12I-I220 11 C12I-I22011" I-I20

342.30 (for amorphous) 360.31 (for monohydrate)

5 Structural Formula See Lactose, Anhydrous and Lactose, Monohydrate.

6 Functional Category Directly compressible tablet excipient; tablet and capsule diluent; tablet and capsule filler.


Spray-dried lactose is widely used as a binder, filler-binder, and flow aid in direct compression tableting.

See also Lactose, Monohydrate; Lactose, Anhydrous.

8 Description Lactose occurs as white to off-white crystalline particles or powder. It is odorless and slightly sweet-tasting. Spray-dried directcompression grades of lactose are generally composed of 80-90% specially prepared pure ci:-lactose monohydrate along with 10-20% of amorphous lactose.

9 Pharmacopeial Specifications See Section 18. See also Lactose, Monohydrate.

10 Typical Properties Angle of repose 29° for Flow Lac 90; 28° for Flow Lac 100. Bonding index 0.0044 for NF Lactose-3 15 (at compression

pressure 54.90 MPa}'1l Brittle fracture index 0.1671 for NF Lactose- 315 (at compres

sion pressure 54.90 MPa)(lJ Density bulk see Table I. Loss on drying 0.3% for NF Lactose-3 15; 0.6% for NF Lactose-

316. Particle size distribution see Table II. Reduced modulus of elasticity 5648 for NF Lactose-315 (at

compression pressure 54.90 MPa)(lJ Tensile strength 2.368 M Pa for NF Lactose- 315 (at compression

pressure 54.90 MPa)( l ) Water content see Table I.

376

---- - ---.-._..., .,,c-> •. - -· -- - · · -·· ....--·

!EM l: Excipient: Super Tab 11 SD; manufacturer: DMV-Fanterra Exc ipients; magnification: 300 x ; voltage: 5 kV.

!M '. :; Excipient: Lactopress Spray-Dried; manufacturer: Friesland Foods Domo; magnification: 500 x ; voltage: 3 kV.

SEM 3: Excipient: NF lactose--316 Fast Flo; manufacturer: Sheffield Pharma Ingredients; magnification: 500 x ; voltage: 3 kV.

lactose , Spray-Dried 3 77

Table I: Typical physical properties of selected commercially availoble spray-dried lactose.

Supplier/ grade Density (bulk) (g/ cm3) Density (tapped) (g/cm3) Water content (%)

DMV·Fonterra Excipients Super Tab 11 SD SuperTab 14SD MeggleGmbH Flowlac 90 Ffowlac 100 Sheffield Pharma Ingredients NF Laclose-3 15 NF Lactose-3 16 Fast Flo

0.60 0.62

0.57 0.62

0.67 0.58

0.71 0.72

0.67 0.73

0.78 0.67

4.8-5.2 4 .8-5.2

Table II: Particle size distribution of selected commercially available spray-dried lactose.

Supplier/ grade Percentage less than stated size

DMV·Fonterra Excipients Super Tab I I SD Super Tab I 4SD Friesland Foods Domo laclopress Spray-Dried laclopress Spray-Dried 250 MeggleGmbH Flowlac 90 Flowlac 100 Sheffield Pharma Ingredients NF Lactose-315 NF lactose-3 16 Fast Flo

(a) <106ttm.

<32µm

~ 5 ~ 10

<45~tm

~ 15 ~ 15

~ 25 ~ 15

Methods for characterizing the mechanical properties of compacts of pharmaceutical ingredients are 5rrecified in the Handbook of Pharmaceutical Excipients, 3rd edn. >

11 Stability and Storage Conditions Spray-dried lactose should be stored in a well-closed container in a cool, dry p lace.

12 Incompatibilities Lactose is a reducing sugar. The amorphous lactose, which is the most reactive form of lactose present in spray-dried lactose, will interact more readily than conventional crystalline gradesYl Typical reactions include the M aillard reaction with either primary131 or secondary14

> amines. See Lactose, Anhydrous and Lactose, M onohydrate.

13 Method of Manufacture A suspension of ix-lactose monohydrate crystals in a lactose solution is atomized and dried in a spray drier.15•6) Approximately 10-20% of the total amount of lactose is in solution and the remaining 80-90% is present in the crystalline form. The spray-drying process predominantly produces spherical particles. The compactibility of the material and its flow characteristics are a function of the primary particle size of the lactose monohydrate and the amount of amorphous lactose. I?)

14 Safety

Lactose is widely used in pharmaceutica l formulations as a diluent in oral capsule and ta blet formulations. It may also be used in intravenous injections.

Adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the enzyme lactase.


<75µm

~ 50

25- 45 20-40

< 100µm

30-60 30-60

30- 60101 30-60

25- 40 20-45

40-701°1 45-701°1

1 5 Handling Precautions

<200µm <250µm

~ 98 ~ 98

~ 65 ~ 98

~ 85 ~ 80

99.5- 100

Observe normal precautions appropriate to the circumstances and quantity of material being handled. Excessive generation of dust, or inhalation of dust, should be avoided.




Lactose, anhydrous; lactose, inhalation; lactose, monohydrate.

18 Comments Spray-dried lactose was one of the first direct-compression excipients. Spray-dried lactose typically comprises lactose monohydrate and amorphous lactose (see Section 8); see Lactose, Monohydrate for the relevant pharmacopeial information.

It has been shown that during the spray-drying process the effects of nozzle orifice diameter and atomization air flow control the droplet size during atomization; however, it has also been demonstrated that increasing feed concentration results in increased shell thickness of hollow particles that are formed. IS) The physical properties of spray-dried lactose produced from alcoholic media are directly affected by the ethanol-to-water ratio in the feed solution. Lactose spray-dried from pure ethanol was shown to be 100% crystalline, whereas lactose spray-dried from pure water was 100% amorphous. Furthermore, the surface area of the spraJ;-dried lactose . increased as a function of amorphous content.1 > Spray-dried lactoses exhibit good flow properties.< 10

>

Polyethylene glycol (PEG) 4000, when spray-dried with lactose, has been shown to accelerate the rate and extent of crystallization of lactose _(ll l It has also been shown that spray-dried lactose composite particles containing an ion complex of chitosan are su itable for the dry-coating of tablets_l1 2

) Spray-dried lactose and crysta llized spray-dried lactose have been evaluated for dry powder

-------- - ·---------- -----------------, 378 La no lin

inhalation application.!13,14 l Amorphous sriray-dried lactose has

also been studied in composites with pyp_(J l

See also Lactose, Anhyd rous, Lactose, Inhalation and Lactose, Monohydrate.

19 Specific References 1 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn.

London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association, 2000; 641-643 .

2 Blaug SM, Huang W. Interaction of dextro amphetamine sulfate with spray-dried lactose. J Pharm Sci 1972; 61: 1770-1775.


4 Wirth DD et al. Maillard reaction of lactose and fluoxetine hydrochloride: a secondary amine. J Pharm Sci 1998; 87: 31- 39.

5 Hutton JT et al. Lactose product and method. United States Patent No . 3,639,170; 1972.

6 Vromans H et al. Spray-dried lactose and process for preparing the same. United States Patent No. 4,802,926; 1989.

7 Vromans H et al. Studies on tableting properties of lactose. VII. The effect of variations in primary particle size and percentage of amorphous lactose in spray dried lactose products. Int J Phann 1987; 35(1-2): 29-37.

8 Elversson J et al. Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying. J Phann Sci 2003; 92(4): 900-910.

9 Harjunen PI et al. Effects of ethanol to water ratio in feed solution on the crystallinity of spray dried lactose. Drug Dev illd Pharm 2002; 28(8): 949-955.

10 Bhattachar SN et al. Evaluation of the vibratory feeder method for assessment of powder flow properties. Int I Phann 2004; 269: 385-392.

11 Corrigan DO et al. The effects of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties. Int J Pharm 2002; 235 (1- 2): 193-205.

12 Takeuchi H et al. Spray dried lactose composite particles containing an ion complex of alginate- chitosan for designing a dry coated ta blet having a time controlled releasing function. Pharm Res 2000; 17: 94-99.

13 Kawashima Y et al. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydra te. Int J Pharm 1998; 172: 179-188.

14 Harjunen P et al. Lactose modifications enhance its drug performance in the novel multiple dose Taifun (R) DPI. Eur J Pharm Sci 2002; 16(4- 5): 313- 321.

(y Lanolin

1 Nonproprietary Names BP: Wool Fat JP: Purified Lanolin PhEur: Wool Fat

USP: Lanolin

2 Synonyms

Adeps lanae; cera Janae; E913; lanolina; lanolin anhydrous; Protalan anhydrous; purified lanolin; refined wool fat.

3 Chemical Name and CAS Registry Number Anhydrous lanolin [8006-54-0)

15 Berggren J et al. Compression behaviour and tablet-forming ability of spray-dried amorphous composite particles. Eur J Pharm Sci 2004; 22: 191-200.

20 General References Bolhuis GK, Armstrong NA. Excipients for direct compaction: an update.

Pharm Dev Technol 2006; 11: 111-124. Bolhuis GK, Chowhan ZT. Materials for direct compaction. Alderborn G,

Nystrom C, eds. Pharmaceutical Powder Compaction Technology. New York: Marcel Dekker, 1996; 473-476.

Bolhuis G et al. New developments in spray-dried lactose. Pharm Tech 2004; June: 26-31.

DMV-Fonterra Excipients. Technical literature: SuperTab 11SD, SuperTab 14SD, 2008. http://www.dmv-fonterra-excipients.com (accessed 27 February 2009).

Friesland Foods Domo. Technical literature: Lactopress Spray-Dried, Lactopress Spray-Dried 250, 2008 . http://www.domo.nl/pharma (accessed 27 February 2009 ).

Fell JT, Newton JM. The characterization of the form of lactose in spraydried lactose. Pharm Acta Helv 1970; 45: 520-522.

Fell JT, Newton JM. The production and properties of spray-dried lactose, part 1: the construction of an experimental spray drier and the production of spray-dried lactose under various conditions of operation. Pharm Acta Helv 1971; 46: 226- 235.

Fell JT, Newton JM. The production and properties of spray-dried lactose, part 2: the physical properties of samples of spray-dried lactose produced on an experimental drier. Pharm Acta Helv 1971; 46: 425-430.

Meggie GmbH. Technical literature: Flow Lac 90, Flow Lac 100, 2008. http://www.meggle-pharma.de (accessed 27 February 2009).

Price R, Young PM. Visualisation of the crystallisation of lactose from the amorphous state. J Pharm Sci 2004; 93: 155- 164.

Sheffield Pharma Ingredients. Technical literature: NF Lactose-3 15, NF Lactose-3 16 Fast Flo, 2008 . http://www.sheffield-products.com (accessed 27 February 2009).

21 Authors

S Edge, AH Kibbe, J Shur.

22 Date of Revision 2 7 February 2009.

4 Empirical Formula and Molecular Weight The USP 32 describes lanolin as the purified wax-like substance obtained from the wool of the sheep, Ovis aries Linne (Fam. Bovidae), that has been cleaned, decolorized, and deodorized. It contains not more than 0.25% w/w of water and may contain up to 0.02 % w/w of a suitable antioxidant; the PhEur 6.0 specifies up to 200 ppm of butylated hydroxytoluene as an antioxidant.

See also Section 18.

S Structural Formula See Section4.

6 Functional Category Emulsifying agent; ointment base.

- - - - - . - - - -~------------ ----------- - ---- -------

Magnesium Stearate


BP: Magnesium Stearate JP: Magnesium Stearate PhEur: Magnesium Stearate USP-NF: Magnesium Stearate

2 Synonyms Dibasic magnesium stearate; magnesium distearate; magnesii stearas; magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt; Synpro 90.

3 Chemical Name and CAS Registry Number Octadecanoic acid magnesium salt [557-04-0]


C.,6H70MgO4 591.24 The USP32- NF27 describes magnesium stearate as a compound

of magnesium with a mixture of solid organic acids that consists chiefly of variable proportions of magnesium stearate and magnesium palmitate (C32H62MgO4 ). The PhEur 6.5 describes magnesium stearate as :1 mixture of solid organic acids consisting

SEM 1: Excipient: magnesium stearate; magnification: 600 x .

mainly of variable proportions of magnesium stearate and SEM 2: Excipient: magnesium stearate; magnification: 2400x _ magnesium palmitate obtained from sources of vegetable or animal ongm.


[CH3(CH2)16COO]iMg

6 Functional Category Tablet and capsule lubricant.


Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5 .0% w/w. It is also used in barrier creams. See also Section 18.

8 Description Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin.


10 Typical Properties Crystalline forms High-purity magnesium stearate has been

isolated as a trihydrate, a dihydrate, and an anhydrate. Densit:y (bulk) 0.159g/cm3

Densit:y (tapped) 0.286 g/cm3

Densit:y (true) 1.092 g/cm3

Flash point 250°C Flowabilit:y Poorly flowing, cohesive powder. Melting range

117- 150°C (commercial samples);

404

126-130°C (high purity magnesium stearate). NIR spectra see Figure 1. Solubilit:y Practically insoluble in ethanol, ethanol (95%), ethe~

and water; slightly soluble in warm benzene and warm ethano (95%).

Specific surface area 1.6-14.8 m2/g

11 Stability and Storage Conditions Magnesium stearate is stable and should be stored in a well-closed container in a cool, dry place.

Table I: Pharmacopeial specifications for magnesium stearate.

Test JPXV PhEur 6.5 USP32-NF27

lckrrlification + + + characters + Microbial li mits + + +

Aerobic microbes ~ lOOOcfu/g ~ 103 cfu/g ~ lOOOcfu/g Fungi and yeasts ~ 500cfu/g ~ 102 cfu/g ~ 500cfu/g

Acidity or a lkalinity + + + Acid value of the fatty 195-2 10

acid freezing point ;;, 53°C Nickel ~ 5ppm Cadmium ~ 3ppm Specific surface area + Loss on dryi ng ~ 6.0% ~ 6.0% ~ 6.0% Chloride ~ 0 .1% ,s; 0. 1% ~ 0. 1% Sulfate ~ 1.0% ,s; l .0% ,s; l .0% Lead ~ l Oppm ,s; 0 .001 % Heavy meta ls ~ 20ppm Relative stea ric/palmitic + + +

content Assay (dried, as Mg) 4.0-5 .0% 4 .0-5.0% 4 .0-5.0%


Incompatible with strong acids, alkalis, and im n salts. Avoid mixing with strong oxidizing materials. M agnesium stearate cannot be used in prod ucts containing aspirin, some vitamins, and most alkaloidal salts.

13 Method of Manufacture Magnesium stearate is prepared either by the interaction of aqueous solutions of magnesium chloride with sodium stearate or by the interaction of magnesium oxide, hydroxide, or carbonate with stearic acid at elevated temperatures.

14 Safety

Magnesium stearate is widely used as a pharmaceutical excipient and is genera lly regarded as being nontoxic fo llowing oral administra tion. However, oral consumption of large quantities may produce a laxative effect or mucosa! irrita tion.

No toxicity information is available relating to normal routes of occupational exposure. Limits for heavy metals in magnesium stearate have been evaluated in terms of magnesium stearate worstcase da ily intake and heavy metal composition.<t )

Toxicity assessments of magnesium stearate in rats have indi~a ted that it is not ~rritating to the skin, and is nontoxic when adm1111stered orally or mhaled.T2·3l

Magnesium stearate has not been shown to be carcinogenic when implanted into the bladder of mice.(4)

LDso (rat, inhalation): > 2 mg/L(2)

LDso (ra t, oral): > lO g/kg


Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Excessive inhalation of magnesium stearate dust tnay cause upper respira tory tract discomfort, coughing, and choking. Magnesium stearate should be handled in a well-ventilated r.nv_ironment; a respirator is recommended. In the USA, the OSHA 1tn.1t is 10 mg/m3 TWA for magnesium stearate.

l 6 Regulatory Acceptance

f RAS listed . Accepted as a foo d addi tive in the USA and UK. ncluded in the FDA Inactive Ingredients Database (oral capsules, Powders, and tablets; buccal and vaginal tablets; topical prepara-

Mag nes ium Stearate 405

1.5 23 25 0.2

cZ '-.._ 2295 2363

1747 '-CT)

0 0 .0

-~ cZ ,_ 12 14 I '-.._ Q) 1764 u I

u 1730 I CT) I

C ~ I ..2 ~ /1 .,

235 1 I J\ ~ -........ _ ... / X I "'' ...,' 0 I\ ", I ,, 0 I \ / ..... .... --0 _t ..__

23 11 ~ - 3 .0 - 0.2

11 00 1300 1500 1700 1900 2100 2300 2500

W avelength/nm

Figure 1: Near-infrared spectrum of magnesium stea rate measured by reflectance .

tions; intravitreal implants and injections). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. Listed on the US TSCA inventory.


Calcium stearate; magnesium aluminum silicate; stearic acid; zinc stearate.

18 Comments M agnesium stearate is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Magnesium stearate is hydrophobic and may retard the dissolution of a drug from a solid dosage form; the lowest possible concentration is therefore used in such formulations_(5- l0) Capsule dissolution is also sensi tive to both the amount of magnesium stearate in the formulation and the mixing time; higher levels of magnesium stearate and long mixing times can result in the formation of hydrophobic g owder beds that do not disperse after the capsule shell dissolves .< 1•

12)

An increase in the coefficient of variation of mixing and a decrease in the dissolution ra te have been observed fo llowing blending of magnesium stearate with a tablet granulation. Tablet dissolution rate and crushing strength decreased as the time of blending increased; and magnesium stearate may also increase tablet friabili ty. Blending times with magnesium stearate should therefore be carefully controlled.0 3-29

) A variety of online analytical techniques have been investi~a ted to monitor magnesium stearate in powder blends and tablets.( 0

-32

) Inverse gas chromatography has been used to examine the surface coverage of magnesium stearate on powder blends. (33l Magnesium stearate also affects the flow properties of blends.<34

l

The existence of various crystalline forms of magnesium stearate has been establishedP5

-3 9 l A trihlcdrate, a dihydra te, and an

anhydrate have been isolated,(5•37·38· O) and an amorphous form has ·

been observed. <41l While the hydrated forms are stable in the presence of moisture, the anhydrous form adsorbs moisture at relative humidity up to 50%, and at higher humidities rehydrates to form the trihydrate. The anhydrate can be formed by drying either of the hydrates a t 105°C.08)

It has not been conclusively established which form of pure magnesium stearate possesses the best lubricating propertiesY6•3 7•41-43l Commercial lots of magnesium stearate generally

406 M ag nes iu m Steara te

consist of mixtures of crystalline forms .P7•39

•41

•42

'44-

461 Because of the possibility of conversion of crystalline forms during heating, consideration should be given to the pretreatment conditions employed when determining physical 1,roperties of magnesium stearate powders such as surface area.(4

,4

Sl

Physical properties of magnesium stearate can vary among ba tches from different manufacturers'461 because the solid-state characteristics of the powder are influenced by manufacturing variables. '361 Variations in the physical properties of different lots of magnesium stearate from the same vendor have also been observed.'46

) Presumably because of these variations, it has not been possible to conclusively correlate the dissolution rate retarda tion with observed lubricity. (49

)

However, various physical properties of different batches of magnesium stearate, such as specific surface area, particle size, crystalline structure, moisture content, and fatt41 acid comriosition, have been correlated with lubricant efficacy.'37, t,45,46,50- 5 l Due to variations in the specific surface area, the labeling states that specific surface area and the method specified for its determination should be listed on the label. Reduction in dissolution caused by the effects of magnesium stearate in some cases can be overcome by including a highly swelling disintegrant in the formulation. (5 6 )

The impact of magnesium stea rate levels on tablet compaction properties and performance of ro ller compacted granulations has been examinedY7

-59l In other compaction studies performed with

granules, magnesium stearate has been shown to exert an influence on granule relaxation and may help to prevent capping. (GO)

There is evidence to suggest that the hydrophobic nature of magnesium stearate can vary from batch to batch owing to the presence of water-soluble, surface-active impurities such as sodium stearate. Batches containing very low concentrations of these impurities have been shown to retard the dissolution of a drug to a greater extent than when using batches that contain higher levels of impurities . (4 9

l One study related lubricity to the fatty acid composition (stearate : palmitate) of lubricant lots for tablet formulations based on compaction data and tablet material propertiesY4 l However, other studies have indicated that fatty acid composition has no influence on lubricant activity(37 l and highpurity magnesium stearate was as effective a lubricant as the commercial material.(JOJ Moisture sorption at different relative humidities can result in morphological changes in the magnesium stearate. '61

•62

)

Magnesium stearate has been investi~ated for use in inhalation powders to control their performance. (6 l

A specification for ma~nesium stearate is included in the Food Chemicals Codex (FCC). ( 4 l The EINECS number for magnesium stearate is 209-150-3.

19 Specific References 1 Chowhan ZT. Harmonization of excipient standards. Weiner ML,

Kotkoskie LA, eds. Excipient Toxicity and Safety. New York: Marcel Dekker, 2000; 321-354.

2 Anonymous. Final report of the safety assessment of lithium stearate, aluminum distearate, aluminum stearate, aluminum tristearate, ammonium stearate, calcium stearate, magnesium stearate, potassium steara te, sodium stearate, and zinc stearate. J A m Coll Toxicol 1982; 1: 143- 177.

3 Sondergaard D et al. Magnesium stearate given perorally to rats: a short term study. Toxicology 1980; 17: 51- 55.

4 Boyland E et al. Further experiments on implantation of materials into the urinary bladder of mice. Br J Cancer 1964; 18: 575-581.

5 Levy G, Gumtow RH. Effect of certain formulation factors on dissolution rate of the active ingredient III: tablet lubricants. J Pharm Sci 1963; 52: 1139-1144.

6 Ganderton D. The effect of distribution of magnesium stearate on the penetration of a tablet by water. J Phann Pharmacol 1969; 21(Suppl.): 9S-18S.

7 Caldwell HC. Dissolution of lithium and magnesium from lithium carbonate capsules containing magnesium stearate. J Phann Sci 1974; 63 : 770-773.

8 Chowhan ZT et al. Tablet-to-tablet dissolution variability and its relationship to the homogeneity of a water-soluble drug. Drug Dev Ind Pharm 1982; 8: 145- 168 .

9 Lerk CF et al. Interaction of tablet disintegrants and magnesium stearate during mixing II : effect on dissolution rate. Pharm Acta Helv 1982; 57: 282-286 .

10 Hussain MSH et al. Effect of commercial and high purity magnesium steara tes on in-vitro dissolution of paracetamol DC tablets. Int J Pharm 1992; 78: 203-207.

11 Samyn JC, Jung WY. In vitro dissolution from several experimental capsule formulations. J Pharm Sci 1970; 59: 169-175.

12 Murthy KS, Samyn JC. Effect of shear mixing on in vitro drug release of capsule formulations containing lubricants. J Pharm Sci 1977; 66: 1215-1219.

13 Ragnarsson G et al. The influence of mixing time and colloidal silica on the lubricating properties of magnesium stearate. Int J Pharm 1979; 3: 127-131.

14 Bolhuis GK et al. Mixing action and eva luation of tablet lubricants in direct compression. Drug Deu Ind Phann 1980; 6: 573-589.

15 Bossert J, Stamm A. Effect of mixing on the lubrication of crystalline lactose by magnesium stearate. Drug Dev Ind Pharm 1980; 6: 573-589.

16 Bolhuis GK et al. Interaction of ta blet disintegrants and magnesium steara te during mixing I: effect on ta blet dis integration. J Pharm Sci 198 1; 70: 1328- 1330.

17 Sheikh-Salem M, Fell JT. The influence of magnesium stearate on time dependent strength changes in tablets. Drug Dev Ind Pharm 1981; 7: 669- 674.

18 Stewart PJ. Influence of magnesium stearate on the homogeneity of a prednisone gran ule ordered mix. Drug Dev Ind Pharm 1981; 7: 485-495.

19 Jarosz PJ, Parrott EL. Effect of tablet lubricants on axial and radial work of fai lure. Drug Dev Ind Phann 1982; 8: 445- 453.

20 Mitrevej KT, Augsburger LL. Adhesion of tablets in a rotary ta blet press II: effects of blending time, running time, and lubricant concentration. Drug Dev Ind Pharm 1982; 8: 237-282.

21 Khan KA et al. The effect of mixing time of magnesium stearate on the tableting properties of dried microcrystalline cellulose. Phann Acta Helv 1983; 58: 109-111.

22 Johansson ME. Investigations of the mixing time dependence of the lubricating properties of granular and powdered magnesium stearate. A cta Phann Suec 1985; 22: 343- 350.

23 Johansson ME. Influence of the granulation technique and starting material properties on the lubricating effect of granular magnesium stearate. J Pharm Pharmacol 1985; 37: 68 1-685 .

24 Chowhan ZT, Chi LI-I. Drug- excipient interactions resulting from powder mixing III: solid state properties and their effect on drug dissolution. J Pharm Sci 1986; 75: 534-541.

25 Chowhan ZT, Chi LH. Drug-excipient interactions resulting from powder mixing IV: ro le of lubricants and their effect on in vitro dissolution. J Pharm Sci 1986; 75: 542- 545.

26 Johansson ME, Nicklasson M. Influence of mixing time, particle size and colloidal silica on the surface coverage and lubrication of magnesium stearate. Rubinstein MH, ed. Pharmaceutical Technology: Tableting Technology. Chichester: Ellis Horwood, 1987; 43- 50.

27 Wang LH, Chowhan ZT. Drug-excipient interactions resulting from powder mixing V: role of sodium lauryl sulfa te. Int J Pharm 1990; 60: 61-78 .

28 Muzikova J, Horacek J. The dry binders, Vivapur 102, Vivapur 12 and the effect of magnesium stearate on the strength of tablets containing these substances. Geske Slov Farm 2003; 52(4): 176-'180.

29 Muzikova J . Effect of magnesium stearate on the tensile strength of tablets made with the binder Prosolv SMCC 90. Ceska Slow Farm 2002; 51(1): 41-43 .

30 Aguirre-Mendez C, Romanach RJ. A Raman spectroscopic method to monitor magnesium stearate 'in blends and tablets. Pharmaceut Tech Eur 2007; 19(9): 53- 61.

31 St-Onge L et al. Rapid quantitative ana lysis of magnesium stearate in tablets using laser-induced breakdown spectroscopy. J Pharm Pharmaceut Sci 2005; 8(2): 272-288.

32 Duong N-H et al. A homogeneity study using NIR spectroscopy: tracking magnesium stearate in Bohle bin-blender. Drug Dev Ind Phamt 2003; 29(6): 679-687.

33 Swaminathan V et al. Measurement of the surface energy of lubricated pharmaceutical powders by inverse gas chromatography. Int. ]. Phamt 2006; 312(1- 2): 158- 165.

34 Faqih AM et al. Effect of moisture and magnesium stearate concentration on flow properties of cohesive granular materials. Int J Pharm 2007; 336(2): 338-345.

35 Muller BW. The pseudo-polymorphism of magnesium stearate. Zbl Pharm 1977; 116(12): 1261-1266.

36 Miller TA, York P. Physical and chemical characteristics of some high purity magnesium stearate and palmitate powders. Int J Pharm 1985; 23: 55-67.

37 Ertel KD, CarstensenJT. Chemical, physical, and lubricant properties of magnesium stearate. J Pharm Sci 1988; 77: 625-629.

38 Ertel KD, Carstensen JT. An examination of the physical properties of pure magnesium stearate. Int J Pharm 1988; 42: 171- 180.

39 Wada Y, Matsubara T. Pseudo-polymorphism and crystalline transition of magnesium stearate. Thermochim Acta 1992; 196: 63- 84.

40 Sharpe SA et al. Physical characterization of the polymorphic variations of magensium stearate and magnesium palmitate hydrate species. Struct Chem 1997; 8(1): 73- 84.

41 Leinonen UI et al. Physical and lubrication properties of magnesium stearate. J Pharm Sci 1992; 81(12): 1194-1198.

42 Muller BW. Polymorphism of magnesium stearate and the influence of the crystal structure on the lubricating behavior of excipients. Acta Pharm Suec 1981; 18: 74- 75.

43 Okoye P, Wu S.H. Lubrication of direct-compressible blends with magnesium stearate monohydrate and dihydrate. Pharm Technol 2007; 31(9): 116-129.

44 Brittain HG. Raw materials. Drug Dev Ind Pharm 1989; 15(13): 2083-2103.

45 Dansereau R, Peck GE. The effect of the variability in the physical and chemical properties of magnesium stearate on the properties of compressed tablets. Drug Dev Ind Pharm 1987; 13: 975-999.

46 Barra J, Somma R. Influence of the physicochemical variability of magnesium stearate on its lubricant properties: possible solutions. Drug Dev Ind Pharm 1996; 22(11): 1105- 1120.

47 Phadke DS, Collier JL. Effect of degassing temperature on the specific surface area and other physical properties of magnesium stearate. Drug Dev Ind Pharm 1994; 20(5): 853- 858.

48 Koivisto M et al. Effect of temperature and humidity on vegetable grade magnesium stearate. Powder Technol 2004; 147(1- 3): 79- 85.

49 Billany MR, Richards JH. Batch variation of magnesium stearate and its effect on the dissolution rate of salicylic acid from solid dosage forms. Drug Dev Ind Phann 1982; 8: 497- 511.

50 Frattini C, Simioni L. Should magnesium stearate be assessed in the formulation of solid dosage forms by weight or by surface area ? Drug Dev Ind Pharm 1984; 10: 1117- 1130. ·

51 Bos CE et al. Lubricant sensitivity in relation to bulk density for granulations based on starch or cellulose. lnt J Pharm 1991; 67: 39- 49.

52 Phadke DS, Eichorst JL. Evaluation of particle size distribution and specific surface area of magnesium stearate. Drug D_ev Ind Pharm 1991; 17: 901-906.

53 Steffens KJ, Koglin J. The magnesium steara te problem. Manuf Chem 1993; 64(12): 16-19.

54 Marwaha SB, Rubinstein MH. Structure-lubricity evaluation of magnesium stearate. Int J Pharm 1988; 43(3): 249- 255.

55 Rao KP et al. Impact of solid-state properties on lubrication efficacy of magnesium stearate. Pharm Dev Technol 2005; 10(3): 423--437.

56 Desai DS et al. Physical interactions of magnesium stearate with starchderived disintegrants and their effects on capsule and tablet dissolution. Int J Pharm 1993; 91(2- 3): 21 7- 226.

Magnesium Stearate 407

57 Wurster DE et al. The influence of magnesium stearate on the hiestand tableting indices and other related mechanical properties of maltodextrins. Pharm Dev Technol 2005; 10(4): 461--466.

58 Likitlersuang S et al. The effect of binary mixture composition and magnesium stearate concentration on the hiestand tableting indices and other related mechanical properties. Pharm Dev Technol 2007; 12(5): 533-541.

59 He X et al. Mechanistic study of the effect of roller compaction and lubricant on tablet mechanical strength. J Pharm Sci 2007; 96(5): 1342-1355.

60 Ebba F et al. Stress relaxation studies of granules as a function of different lubricants. Eur J Pharm Biopharm 2001; 52(2): 211-220.

61 Swaminathan V, Kildisig DO. An examination of the moisture sorption characteristics of commercial magnesium stearate. AAPS Pharm Sci Tech 2001; 2(4): 28.

62 Bracconi P et al. Structural properties of magnesium stearate pseudopolymorphs: effect of temperature. Int J Pharm 2003; 262(1-2): 109-124.

63 Guchardi R et al. Influence of fine lactose and magnesium stearate on low dose dry powder inhaler formulations. Int J Pharm 2008; 348( 1-2): 10-17.


20 General References Bohidar NR et al. Selecting key pharmaceutical formulation factors by

regression anaysis. Drug Dev Ind Pharm 1979; 5: 175-216. Butcher AE, Jones TM. Some physical characteristics of magnesium stearate.

J Pharm Pharmacol 1972; 24: 1P-9P. European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmoaisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

Ford JL, Rubinstein MH. An investigation into some pharmaceutical interactions by differential scanning calorimetry. Drug Dev Ind Pharm 1981; 7: 675-682.

Johansson ME. Granular magnesium stearate as a lubricant in tablet formulations. Int J Pharm 1984; 21: 307- 315.

Jones TM. The effect of glidant addition on the flowability of bulk particulate solids. J Soc Cosmet Chem 1970; 21: 483-500.

Pilpel N. Metal stearates in pharmaceuticals and cosmetics. Manuf Chem Aerosol N ews 1971; 42(10): 37--40.

York P. Tablet lubricants. Florence AT, ed. Materials Used in Pharmaceutical Formulation. London: Society of Chemical Industry, 1984; 37-70.

Zanowiak P. Lubrication in solid dosage form design and manufacture. Swarbick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Teclmology., vol. 9: New York: Marcel Dekker, 1990; 87-112.

21 Authors

LV Allen Jr, PE Luner.

22 Date of Revision

3 February 2009.

______________ _.,.,.-~ae~~----·-- ----------------

424 M a nnito l

gloves, and a dust respirator are recommended. When heated to decomposition, maltose emits acrid smoke and irritating fumes.

16 Regulatory Status In the USA, maltose is considered as a food by the FDA and is . therefore not subject to food additive and GRAS regulations. Included in the FDA Inactive Ingredients Database (oral solutions). Included in the Canadian List of Acceptable Non-medicinal Ingredients. Included in parenteral products available in a number of countries worldwide.


Glucose, liquid.

18 Comments

Crystalline maltose, e.g. Advantose 100 (SPI Pharma Group), is spray-dried to produce spherical particles with good flow properties. The material is also nonhygroscopic and is highly compressible.

A specification for maltose syrup powder is contained in the Japanese Pharmaceutical Excipients (JPE).(7) The EINECS number fo r ma ltose is 200-716-5. The PubChem Compound ID (CID) for maltose includes 6255 and 23724983.

E.t Mannitol


BP: M annitol

JP: D-Mannitol PhEur: Mannitol USP: Mannitol

2 Synonyms Cordycepic acid; c •·PharmMannidex; E421; Emprove; manna sugar; D-mannite; mannite; mannitolum; Mannogem; Pearlitol.


D-Mannitol (69-65-8]


C6H14O6 182.17


OH OH

HO OH

OH OH

19 Specific References 1 SP! Pharma Group. Technical literature: Advantose 100 maltose, 2004. 2 Bowe KE et al. Crystalline maltose: a direct compression pharmaceu

tical excipient. Pharm Technol Eur 1998; 10(5): 40. 3 Mulderrig KB. Placebo eva luation of selected sugar-based excipients in

pharmaceutical and nutraceutical tableting. Pharm. Technol 2000; 24(5): 34, 36, 38, 40, 42, 44 .

4 Palevsky PM et al. Maltose-induced hyponatremia. Ann Intern Med 1993; 118(7): 526-528.

5 Mundt S, Wedzicha BL. Role of glucose in the Maillard browning of maltose and glycine: a radiochemical approach. J Agric Food Chem 2005;53: 6798-6803.

6 Lewis RJ, ed . Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 2275.

7 Japan Pharmaceutical Excipients Council. Japan Pharmaceutical Excipients, 2004. Tokyo, Yakuji Nippo: 2004; 516-518.


21 Author CK Tye.



Diluent; plasticizer; sweetening agent; tablet and capsule diluent; therapeutic agent; tonicity agent.


Mannitol is widely used in pharmaceutical formulations and food products. In pharmaceutical preparations it is primarily used as a diluent (10- 90 % w/w) in tablet formulations, where it is of particular value since it is not hygroscopic and may thus be used with moisture-sensitive active ingredientsY•2

)

Mannitol may be used in direct-compression tablet applications,,3,4l for which the granular and spray-dried forms are availa ble, or in wet granulations.<5,6l Granulations containing mannitol have the advantage of being dried easily. Specific tablet applications include antacid preparations, glyceryl trinitrate tablets, and vitamin prepara tions. Mannitol is commonly used as an excipient in the manufacture of chewable tablet formulations because of its negative heat of solution, sweetness, and 'mouth feel'.' 6'7)

In lyophilized preparations, mannitol (20-90% w/w) has been included as a carrier to produce a stiff, homogeneous cake that improves the appearance of the lyophilized plug in a vial.(8

-10l A

pyrogen-free form is available specifically for this use. Mannitol has also been used to prevent thickening in aqueous

antacid suspensions of aluminum hydroxide ( < 7% w/v). It has been suggested as a plas ticizer in soft-gelatin capsules, as a component of sustained-release tablet formulations,' 11

) and as a carrier in dry powder inhalers.' 12

,13) It is also used as a diluent in rapidly

dispersing oral dosage forms_(l 4,l

5 l It is used in food applications as a bulking agent.

Therapeutically, mannitol administered parenterally is used as an osmotic diuretic, as a diagnostic agent for kidney function, as an adjunct in the treatment of acute renal failure, and as an agent to reduce intracranial pressure, treat cerebral edema, and reduce intraocular pressure. Given orally, mannitol is not absorbed significantly from the gastrointestinal tract, but in large doses it can cause osmotic diarrhea; see Section 14.

8 Description Mannitol is D-mannitol. It is a hexahydric alcohol related to mannose and is isomeric with sorbitol.

Mannitol occurs as a white, odorless, crystalline powder, or freeflowing granules. It has a sweet taste, approximately as sweet as glucose and half as sweet as sucrose, and imparts a cooling sensation in the mouth. Microscopically, it appears as orthorhombic needles when crystallized from alcohol. Mannitol shows polymorphism. (l

6)


SEM 1: Excipient: mannitol; manufacturer: Merck; magnification: 50 x ; voltage: 3.5 kV.

SEM 2: Excipient: mannitol; manufacturer: Merck; magnification: 500 x ; voltage: 3.5 kV.

Mannitol 425

SEM 3: Excipient: niannitol powder; manufacturer: SPI Polyols Inc.; lot no: 3140GB; magnification: 1 OO x .

SEM 4: Excipient: mannitol granular; manufacturer: SPI Polyols Inc.; lot no: 2034F8; magnification: 1 OO x .

10 Typical Properties Compressibility see Figure 1. Density (bulk)

0.430 g/cm3 for powder; 0.7 g/cm3 for granules.

Density (tapped) 0.734 g/cm3 for powder; 0.8 g/cm3 for granules.

Density (true) 1.514 g/cm3

Dissociation constant pKa = 13.5 at l 8°C Flash point < 150°C Flowability Powder is cohesive, granules are free flowing. Heat of combustion 16.57 kJ/g (3.96 kcal/g) Heat of solution - 120.9 Jig (- 28 .9 cal/g) at 25°C Melting point 166-168°C Moisture content see Figure 2. NIR spectra see Figure 3. Osmolarity A 5.07% w/v aqueous solution is isoosmotic with

serum. Particle size distribution

Pearlitol 300 DC: maximum of 0.1 % greater than 500 µm and minimum of 90% greater than 200 ~tm in size;

426 Mann itol

Table I: Pharmacopeial specifications for mannitol.

Test JP XV PhEur 6.4 USP 32 --·--·--Identification + + + Characters + Appearance of + +

solution Melting range 166-169°C 165- 170°C 164-169°C Specific rototion + 137° to + 145° + 23° to +25° + 137° to + 145° Conductivity ~ 20µS-cm- 1

Acidity + + Loss on drying ~ 0.3% ~ 0.5% ~ 0.3% Chloride ~ 0.007% ~ 0.007% Sulfate ~ 0.01 % ~ 0.01 % Arsenic ~ 1.3 ppm ~ 1 ppm Lead ~ 0.5 ppm Nickel + ~ 1 ppm Heavy metals ~ 5ppm Reducing sugars + ~ 0.2% + Residue on ~ 0.10%

ignition Related +

substances Bacterial ~ 4 IU/glbJ

endotoxinsl0 l ~ 2.5IU/g!cJ

Microbial ~ lOOcfu/g contamination

Assay (dried ;;, 98.0% 98 .0- 102.0% 96.0- 101.5% basis)

(al Test applied only ii the monnitol is ta be used in the manufacture of parenteral dosage forms. (bl For parenteral preparations having a concentration of l 00 g/L or less of mannitol. (cl For parental preparations having a concentration of more than l 00 g/L of monnitol.

Pear/ital 400 D C: maximum of 20 % greater than 500 µm and minimum of 85% greater than 100 µmin size;

Pear/ital 500 D C: maximum of 0.5% greater than 841 µm and minimum of 90% greater than 150 µmin size.

Average particle diameter is 250 µm for Pearlitol 300 DC, 360 ~Lm for Pearlitol 400 D C and 520 µm for Pearlitol 500 DCY7l See also Figure 4.

Refractive index n5° = 1.333 Solubility see Table IL Specific surface area 0.37-0.39 m2/g

Table II: Solubility of mannitol.

Solvent

Alkalis Ethanol (95%) Ether Glycerin Propan-2-ol Water

Solubility at 20°C

Soluble 1 in 83 Practically insoluble 1 in 18 1 in 100 1 in 5 .5

11 Stability and Storage Conditions Mannitol is stable in the dry state and in aqueous solutions. Solutions may be sterilized by filtration or by autoclaving and if necessary may be autoclaved repeatedly with no adverse physical or chemical effects. !lBJ In solution, mannitol is not attacked by cold, dilute acids or alkalis, nor by atmospheric oxygen in the absence of catalysts. Mannitol does not undergo Maillard reactions.

The bulk material should be stored in a well-closed container in a cool, dry place.

100 £.::-

90 - {° '\

z 80 ,l u

_c 70 - Li.'/ CT,) /,lj µ C l ,I Q) 60 -l= V)

I\ )(/ 0) 50 C

_c V)

40 I 2 u Q) 30 0 PeaniloJ 300DC

....0 lJ Pe.arlitol 400DC ~ 20 £> eorlito.J 500DC

10

00 10 20 30 40 50 60 70 80 90 100

Compression force (kN)

figul·,. I; Compression characteristics of granular mannitol (Pearlitol, Roquette Freres). .

Tablet diameter: 20 mm. Lubricant: magnesium stearate 0.7% w/w for Pearlitol 400 DC and Pearlitol 500 DC; magnesium stearole 1 % w/w for Pearlitol 300 DC.

, 12 ,-------------------,

~

c 2 C 0 u Q) L...

.2 V)

·o ~

• Sorption equilibrium moisture

10 + Desorption equi librium moisture

8 -

6

4

2 -

-------..---33 43 52 57 67


Figure 2: Sorption-desorption isotherm for mannitol.


75 100

Mannitol solutions, 20% w/v or stronger, may be salted out by potassium chloride or sodium chloride.T1 91 Precipitation has been reported to occur when a 25% w/v mannitol solution was allowed to contact plastic. <20J Sodium cephapirin at 2 mg/mL and 30 mg/mL concentration is incompatible with 20% w/v aqueous mannitol solution. Mannitol is incompatible with xylitol infusion and may form complexes with some metals such as aluminum, copper, and iron. Reducing sugar impurities in mannitol have been implicated in the oxidative degradation of a peptide in a lyophilized formation.<21l Mannitol was found to reduce the oral bioavailability of cimetidine compared to sucrose. 122l

~ 1.5 ...-------------------.0.6 o2" '--0)

_Q

> "i:

2245

1674

~ 0.0 !Ll'.l,...ltlj,,.JM-1-.t-lH ff.-+-tl.f-rnrllfl~I-J-'l,,Jl,ol.....lH-l-ltf\l -0

C:

~ X

0 • ' 0 ' 0 .• ,,. .... .. _ .. , 2082 226 1

0) 0

~ - 1.5 .__....._........__.__._ ......... _..__._.__....._ ......... _.__.__,_____. - 0 .2 1100 1300 1500 1700 1900 2100 2300 2500

Wavelength/nm

Figure 3: Near-infrared spectrum of mannitol measured by reflectance.

100~---------------~

80 -

~ (I)

.!::! 60 -V)

~ 0

.1: 40 0)

~ 20

40

\

It

80 100

Particle diameter (f.lm)

I I) 111_1 jJ

160

, igure 4: Particle size distribution of mannitol powder.


1)

200

Mannitol may be extracted from the dried sap of manna and other natural sources by means of hot alcohol or other selective so lvents. It is commercially produced by the catalytic or electrolytic reduction of monosaccharides such as mannose and glucose.

14 Safety

Mannitol is a naturally occurring sugar alcohol fo un~ in animals and plants; it is present in small quantities in almost all vegetables. Laxative effects may occur if mannitol is consumed orally in large quantitiesY3

) If it is used in foods as a bodying agent and daily ingestion of over 20 g is foreseeable, the product label should bear the statement 'excessive consumption may have .a laxative effect'. After intravenous injection, mannitol is not metabolized to any appreciable extent and is minimally reabsorbed by the renal tubule, about 80% of a dose being excreted in the urine in 3 hours.(24

)

A number of adverse reactions to mannitol have been reported, primarily following the therapeutic use of 20% w/v aqueous intravenous infusions.(25

) The quantity of mannitol used as an excipient is considerably less than that used therapeutically and is consequently associated with a lower incidence of adverse reactions. However, allergic, hypersensitive-type reactions may occur when mannitol is used as an excipient.

Mannito l 427

An acceptable daily intake of mannitol has not been specified by the WHO since the amount consumed as a sweetening agent was not considered to represent a hazard to health. (26

)

LD5o (mouse, IP): 14 g/kg(27)

LD5o (mouse, IV): 7.47 g/kg LD5o (mouse, oral): 22 g/kg

LDso (rat, IV): 9.69 g/kg LD50 (rat, oral): 13.5 g/kg


Observe normal precautions appropriate to the circumstances and quantity of material handled. Mannitol may be irritant to the eyes; eye protection is recommended.


GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (IP, IM, IV, and SC injections; infusions; buccal, oral and sublingual tablets, powders and capsules; ophthalmic preparations; topical solutions). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Mon-medicinal Ingredients.


Sorbitol.

18 Comments

Mannitol is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur 'EDQM website, and also the General Information Chapter 8 in the JP XV.

Mannitol is an isomer of sorbitol, the difference between the two polyols occurring in the planar orientation of the OH group on the second carbon atom. Each isomer is characterized by its own individual set of properties, the most important difference being the response to moisture. Sorbitol is hygroscopic, while mannitol resists moisture sorption, even at high relative humidities.

Granular mannitol flows well and imparts improved fl ow properties to other materials. However, it usually cannot be used with concentrations of other materials exceeding 25% by weight. Recommended levels of lubricant are 1 % w/w calcium stearate or 1-2% w/w magnesium stearate. Suitable binders for preparing granulations of powdered mannitol are gelatin, methylcellulose 400, starch paste, povidone, and sorbitol. Usually, 3-6 times as much magnesium stearate or 1.5-3 times as much calcium stearate is needed fo r lubrication of mannitol granulations than is needed for other excipients.

A study has examined the influence of common excipients such as sucrose and trehalose, on the crystallization of rnannitol in freezedrying. (2 S)

Mannitol has been reported to sublime at 130°CY91

Ludiflash (BASF) is a coprocessed excipient used as a tablet filler, binder, and disintegrant, and contains mainly mannitol, and also crospovidone and polyvinyl acetate.

A specification for mannitol is contained in the Food Chemicals Codex (FCC).(30)

The EINECS number for mannitol is 200-711-8. The PubChem · Compound ID (CID) for mannitol includes 6251 and 453.

19 Specific References 1 Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharrn

Compound 2000; 4(4): 306- 310324- 325 .

----------------.---- --

428 Mannitol

2 Yoshinari T et al. Improved compaction properties of rnannitol after a moisture induced polymorphic transition. Int J Pharm 2003; 258(1-2): 121-131.

3 Debord B et al. Study of different crystalline forms of mannitol: comparative behaviour under compression. Drug Dev Ind Pharm 1987; 13: 1533-1546.

4 Molokhia AM et al. Aging of tablets prepared by direct compression of bases with different moisture content. Drug Dev Ind Pharm 1987; 13: 1933-1946.

5 Mendes RW et al. Wet granulation: a comparison of Manni-Tab and mannitol. Drug Cosmet Ind 1978; 122(3 ): 36, 38, 40, 44, 87-88.

6 Bouffard J et al. Influence of processing variables and physicochemical properties on the granulation mechanisms of mannitol in a fluid bed top spray granulator. Drug Dev Ind Pharm 2005; 31: 923-933.

7 Daoust RG, Lynch MJ. Mannitol in chewable tablets. Drug Cosmet Ind 1963; 93(1): 26-2888, 92, 128-129.

8 Cavatur RK et al. Crystall ization behavior of mannitol in frozen aqueous solutions. Pharm Res 2002; 19: 894-900.

9 Liao XM et al. Influence of processing conditions on the physical state of mannitol - implications in freeze drying. Pharm Res 2007; 24: 370-376.

10 Pyne A et al. Crystall ization of mannitol below Tg' during freeze-drying in binary and ternary aqueous systems. Pharm Res 2002; 19: 901-908.

11 Parah PV et al. Sustained release from Precirol (glycerol palmitostearate) matrix. Effect of mannitol and hydroxypropyl methylccllulose on the release of theophylline. Drug Dev Ind Pharm 1986; 12: 1309-1327.

12 Tee SK et al. Use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate. Int J Pharm 2000; 208: 111-123.

13 Steckel H, Bolzen N. Alternative sugars as potential carriers for dry powder inhalers. Int J Pharm 2004; 270(1-2): 297- 306.

14 Lee KJ et al. Evaluation of critical formulation factors in the development of a rapidly dispersing captopril oral dosage form. Drug D ev Ind Pharm 2003; 29(9): 967- 979.

15 Seager H. Drug development products and the Zydis fast dissolving dosage form . J Pharm Pharmacol 1998; 50: 375-382.

16 Bauer H et al. Investigations on polymorphism of mannitol/sorbitol mixtures after spray drying using differential scanning calorimetry, xray diffraction and near infrared spectroscopy. Pharm Ind 2000; 62(3) : 23 1-235.

17 Roquette Freres. Technical literature: Pearlitol, 2004. 18 Murty -BSR, Kapoor JN. Properties of mannitol injection (25% ) after

repeated autoclavings. Am J Hosp Pharm 1975; 32: 826- 827, 19 Jacobs J. Factors influencing drug stability in intravenous infusions. J

Hosp Pharm 1969; 27: 341-347. 20 Epperson E. Mannitol crystallization in plastic containers [letter]. Am J

Hosp Pharm 1978; 35: 1337.

21 Dubost DC et al. Characterization of a solid state reaction product frn1n a lyophilized formulation of a cyclic heptapeptide. A novel example 1;f an excipient-induced oxidation. Phann Res 1996; 13: 1811-1814.

22 Adkin DA et al. The effect of mannitol on the ora l bioavailability ,,f cimetidine. J Phann Sci 1995; 84: 1405-1409.

23 Anonymous. Flatulence, diarrhoea, and polyol sweeteners. Lan,~t 1983; ii: 1321.

24 Porter GA et al. Mannitol hemodilution-perfusion: the kinetics of mannitol distribution and excretion during cardiopulmonary bypass_ J Surg Res 1967; 7: 447-456.

25 McNeill IY. Hypersensitivity reaction to mannitol. Drug Inte/1 Cli,1

Pharm 1985; 19: 552- 553. 26 FAO/WHO. Evaluation of certain food additives and contaminanis_

Thirtieth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1987; No. 751.

2 7 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, l I th edn. New York: Wiley, 2004; 1944-1945.

28 Schneid S et al. Influence of common excipients on the crystall i 11~

modification of freeze-dried mannitol. Pharmaceutical Technology 2008; 32: 178-184.

29 Weast RC, ed. Handbook of Chemistry and Physics, 60th edn. Boe, Raton: CRC Press, 1979; c-369.

30 Food Chemicals Codex, 6th edn. Bethesda, MD: United Sta ~ Pharmacopeia, 2008; 583.

20 General References Armstrong NA. Tablet manufacture. Diluents. Swarbrick J, Boylan JC, eds.

Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3: Ne \' York: Marcel Dekke1; 2002; 2713-2732.

BASF. Product literature: Ludiflash, 2004. http://www.pharma-solutions.• basf.com (accessed 3 February 2009).

Bolhuis GK, Armstrong NA. Excipients for direct compression - an update. Phann Tech Technol 2006; 11: 111-124.

European Directorate for the Quality of Medicines and Healthcal1! (EDQM). European Pharmacopoeia - State Of Work Of Internation~l Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.ed.:i· m.eu/site/-614.html (accessed 3 February 2009) .

Pikal MJ. Freeze drying. Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 2: New York: Marcel Dekker, 2002; 1299-1326.

21 Author NA Armstrong.


6.c Polymethacrylates

1 Nonproprietary Names BP: Ammonio Methacrylate Copolymer (Type A)

Ammonio Methacrylate Copolymer (Type B) Basic Butylated Methacrylate Copolymer Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) Dispersion 30 per cent Methacrylic Acid-Methyl Methacrylate Copolymer (1: 1) Methacrylic Acid-Methyl Methacrylate Copolymer (1: 2) Polyacrylate Dispersion (30 per cent)

PhEur: Ammonio Methacrylate Copolymer (Type A) Ammonio Methacrylate Copolymer (Type B) Basic Butylated Methacrylate Copolymer Methacrylic Acid- Ethyl Acrylate Copolymer (1: 1) Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) Dispersion 30 per cent Methacrylic Acid-Methyl Methacrylate Copolymer (1: 1) Methacrylic Acid-Methyl Methacrylate Copolymer (1: 2) Polyacrylate Dispersion 30 per cent

USP-NF: Amino Methacrylate Copolymer Ammonio Methacrylate Copolymer Ammonio Methacrylate Copolymer Dispersion Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion Methacrylic Acid Copolymer Methacrylic Acid Copolymer Dispersion

Note that six separate monographs applicable to polymethacrylates are contained in the USP32-NF27. Several different types of material are defined in the same monographs. The PhEur (6.0, 6.2, and 6.3) contains eight separate monographs applicable to polymethacrylates. See also Section 9.

2 Synonyms

Acryl-EZE; acidi methacrylici et ethylis acrylatis polymerisatum; acidi methacrylici et methylis methacrylatis polymerisatum; ammonio methacrylatis copolymerum; copolymerum methacrylatis butylati basicum; Eastacryl; Eudragit; Kollicoat MAE; polyacrylatis dispersio 30 per centum; polymeric methacrylates. See also Table I.

3 Chemical Name and CAS Registry Number See Table I.


The PhEur 6.2 describes methacrylic acid-ethyl acrylate copolymer (1 : 1) as a copolymer of methacrylic acid and ethyl acrylate having a mean relative molecular mass of about 250 000. The ratio of carboxylic groups to ester groups is about 1 : 1. It may contain suitable surfactants such as sodium dodecyl sulfate or polysorbate 80. An aqueous 30% w/v dispersion of this material is also defined in a separate monograph. Methacrylic acid-methyl methacrylate copolymer (1: 1) is described in the PhEur 6.0 as a copolymer of methacrylic acid and methyl methacrylate having a mean relative molecular mass of about 135 000. The ratio of carboxylic acid to ester groups is about 1 : 1. A further monograph in the PhEur 6.0 describes methacrylic acid- methyl methacrylate copolymer (1: 2), where the ratio of carboxylic acid to ester groups is about 1 : 2. The PhEur 6.0 describes basic butylated methyacrylate copolymer as a copolymer of (2-dimethylaminoethyl) methacrylate, butyl methyacrylate, and methyl methacrylate having a mean relative molecular

mass of about 150 000. The ratio of (2-dimethylaminoethyl) methacrylate groups to butyl methyacrylate and methyl methacrylate groups is about 2: 1: 1. The PhEur 6.0 describes ammonio methyacrylate copolymer as a poly(ethyl propenoate-co-methyl 2-methylpropenoate-co-2-(trimethylammonio)ethyl 2-methylpropenoate) chloride having a mean relative molecular mass of about 150 000. The ratio of ethyl propenoate to methyl 2-methylpropenoate to 2-(trimethylammonio)ethyl 2-methylpropenoate . is about 1: 2: 0.2 for Type A and 1: 2: 0.1 for Type B. Polyacrylate dispersion (30 per cent) is described in the PhEur 6.3 as a dispersion in water of a copolymer of ethyl acrylate and methyl methacrylate having a mean relative molecular mass of about 800 000. It may contain a suitable emulsifier.

The USP32-NF27 describes methacrylic acid copolymer as a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester. Three types of copolymers, namely Type A, Type B, and Type C, are defined in the monograph. They vary in their methacrylic acid content and solution viscosity. Type C may contain suitable surface-active agents. Ammonio methacrylate copolymers Type A and Type B, consisting of fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, are also described in the USP32-NF27. They vary in their ammonio methacrylate units. The USP32-NF27 also describes amino methacrylate copolymer as a fully polymerized copolymer of 2-dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. See Sections 9 and 18. Further monographs for aqueous dispersions of Type C methacrylic acid copolymer, ammonio methacrylate copolymer, and also ethyl acrylate and methyl methacrylate copolymer are also defined; see Section 9.

Typically, the molecular weight of the polymer is ;:;, 100 000.

S Structural Formula

R1 R3 R1 R3

I I I I - -1--c-cH, - C- CH, - C-CH,- C-CH,-+--

I I I I c= o c= o c= o c= o I I I I 0 0 0 0

l, l. l, l.

For Eudragit E: R1,R3 =CH3 R2 = CH2CH2N(CH3)i R4 = CH3, C4H9 For Eudragit L and Eudragit S: R1,R3 =CH3 R2 =H R4 = CH3 For Eudragit PS: R1 = H R2 =H,CH3 R3 = CH3

R4 = CH3 For Eudragit RL and Eudragit RS: R1 = H, CH3

R 2 = CH3, C2Hs R3 = CH3

n

525

526 Po lymethac ry la tes

Table I: Chemical name and CAS Registry Number of polymethacrylates.

Chemical name Trade name Company name CAS number -- --- ·--·-·--·------- . Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 : 2 : 1 Eudrogit E I 00 Evonik Industries [24938-J~j

Eudragit E 12.5 Evonik Industries Eudrogit E PO Evonik Industries

Poly(ethyl acrylate, methyl methacrylate) 2: 1 Eudragit NE 30 D Evonik Industries [9010-88-2] Eudragit NE 40 D Evonik Industries Eudragit NM 30 D Evonik Industries

Poly(methacrylic acid, methyl methacrylate) 1 : 1 Eudragil L I 00 Evonik Industries [25806-15-1] Eudragit L 12.5 Evonik Industries

Poly(methacrylic acid, ethyl acrylate) 1 : 1 Eudragit L 12.5 P Evonik Industries Acryl-EZE Colorcon [25212-88-8] Acryl-EZE 93A Colorcon Ac;r,.,'-EZE MP Colorcon Eu ragit L 30 0-55 Evonik Industries Eudragit L I 00-55 Evonik Industries Eastocryl 300 Eastman

Chemical Kollicoot MAE BASF Fine

30 DP Chemicals Kollicoot MAE BASF Fine

IO0P Chemicals Poly(methacrylic acid, methyl methacrylate) 1 : 2 Eudragit S I 00 Evonik Industries [25086-15-1]

Eudrogit S 12.5 Evonik Industries Eudrogit S 12.5 P Evonik Industries Eudrogit FS 300 Evonik Industries Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3: 1

Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2: 0.2 Eudrogit RL I 00 Evonik Industries [26936-24-3] [3343 4-24-1]

Eudrogit RL PO Evonik Industries Eudrogit RL 30 D Evonik Industries Eudrogit RL 12.5 Evonik Industries

Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2: 0. 1 Eudrogit RS I 00 Evonik Industries [33434-24-1]

R4 = CH2CH2N(CH3)J +ci-For Eudragit NE 30 D and Eudragit NE 40 D: R1, R3 = H, CH3 R2, R4

= CH3, C2Hs For Acryl-EZE and A cryl-EZE MP; Eudragit L 30 D-55 and

Eudragit L 100-55, Eastacryl 30 D, Kollicoat MAE 100 P, and Kollicoat MAE 30 DP:

R. 1, R.1 = H, CH3

R2 = H R 4 = CH3, C2Hs


Film-forming agent; tablet binder; tablet diluent.


Polymethacrylates are primarily used in oral capsule and tablet formulations as film-coating agentsY-2 1

) Depending on the type of polymer used, films of different solubility characteristics can be produced; see Table II.

Eudragit E is used as a plain or insulating film former. It is soluble in gastric fluid below pH 5. In contrast, Eudragit L, Sand FS types are used as enteric coating agents because they are resistant to gastric fluid. Different types of enteric coatings are soluble at different pH values: e.g. Eudragit L is soluble at pH > 6 whereas Eudragit S and FS are soluble at pH > 7. The S grade is generally used for coating tablets, while the flexible FS 30 D dispersion is preferred for coating particles.

Eudragit RL, RS, NE 30 D, NE 40 D, and NM 30 Dare used to form water-insoluble film coats for sustained-release products. Eudragit RL films are more permeable than those of Eudragit RS, and films of varying permeability can be obtained by mixing the two types together. The neutral Eudragit NE/NM grades do not have

Eudrogit RS PO Evonik Industries Eudrogit RS 30 D Evonik Industries Eudrogit RS 12.5 Evonik Industries

functional ionic groups. They swell in aqueous media independently of pH without dissolving.

Eudragit L 30 D-55 is used as an enteric coating film former for solid-dosage form~. The coating is resistant to gastric juice but dissolves readily at above pH 5.5.

Eudragit L 100-55 is an alternative to Eudragit L 30 D-55. It is commercially available as a redispersible powder.

Kollicoat MAE 100 P, Acryl-EZE and Acryl-EZE MP are also commercially available as redispersible powder forms, which are designed for enteric coating of tablets or beads.

Eastacryl 30 D and Kollicoat MAE 30 DP are aqueous dispersions of methacrylic acid-ethyl acrylate copolymers. They are also used as enteric coatings for solidcdosage forms.

Polymethacrylates are also used as binders in both aqueous and organic wet-granulation processes. Larger quantities (5-20%) of dry polymer are used to control the release of an active substance from a tablet matrix. Solid polymers may be used in directcompression processes in quantities of 10-50%.

Polymethacrylate polymers may additionally be used to form the matrix layers of transdermal delivery systems and have also been used to prepare novel gel formulations for rectal administration.1221


8 Description Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several different types are commercially available and may be obtained as the dry powder, as an aqueous dispersion, or as an organic solution. A (60: 40) mixture of acetone and propan-2-ol is most commonly used as the organic solvent. See Tables I and Ill.

Eudragit E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters. It is soluble in gastric fluid as well as in weakly acidic buffer solutions (up to pH

Po lymeth ac ryl ates 527

Table II : Summary of properties and uses of commercia lly available polymethacrylates.

Grade Supply form Polymer dry weight Recommended solvents Solubility/ permeability Applications content or diluents

Eudragit E 12.5 Organic solution 12.5% Acetone, alcohols Soluble in gastric fluid to Film coating

Eudragit E 100 Granules .98% Acetone, alcohols ILH 5

So uble in gastric fluid to Film coating H 5 '

Eudragit E PO Powder 98% Acetone, alcohols Soluble in gastric fluid to Film coating

ILH 5 Eudragif L 12.5 P Organic solution 12.5% Acetone, alcohols So uble in intestinal fluid Enteric coatings

from pH 6 Eudragit L 12.5 Organic solution 12.5% Acetone, alcohols Soluble in intestinal flu id Enteric coatings

Eudragit L 100 Powder Acetone, alcohols from pH 6

95% Soluble in intestinal flu id Enteric coatings

Eudragit L 100-55 from pH 6

Powder 95% Acetone, alcohols Soluble in intesti na l flui d Enteric coatings from p H 5 .5

Eudragif L 30 D-55 Aqueous dispersion 30% Water Soluble in intestinal fluid Enteric coatings

Eudragif S 12.5 P Organ ic solution Acetone, alcohols from pH 5.5

12.5% Soluble in intestinal fluid Enteric coa tings from pH 7

Eudragif S 12.5 O rganic solu tion 12.5% Acetone, a lcohols Soluble in intestinal flui d Enteric coatings

Eudragif S 100 Acetone, a lcohols from pH 7

Powder 95% Soluble in intestina l fluid Enteric coa tings from pH 7

Eudragit FS 30 D Aqueous dispersion 30% Water Soluble in intestinal fluid Enteric coa tings

Eudragit RL 12.5 Organic solution Acetone, a lcohols from pH 7

12.5% High permeabi li ty Susta ined release Eudragif RL 100 Granules 9 7% Acetone, a lcohols High permeability Sustained relea se Eudragif RL PO Powder 97% Acetone, alcohols High permeabi lity Sustained release Eudragit RL 30 D Aqueous dispersion 30% Water High permeability Susla ined release Eudragit RS 12.5 Organic solution 12.5% Acetone, alcohols l ow permeability Sustained release Eudragif RS 100 Granules 97% Acetone, alcohols low permeability Sustained release Eudragit RS PO Powder 97% Acetone, a lcohols low permeability Sustained release Eudragit RS 30 D Aqueous dispersion 30% Water l ow permeability Sustained release Eudragit NE 30 D Aqueous dispersion 30% Water Swellable, permeable Sustained release, tablet

matrix Eudragit NE 40 D Aqueous dispersion 40% Water Swellable, permeable Sustained release, tablet

matri x Eudragit NM 30 D Aqueous di spersion 30% Water Swellable, permeable Sustained release, tablet

matri x Eostacry/30 D Aqueous dispersion 30% Water Soluble in intestinal fluid

from pH 5.5 Enteric coa tings

Kollicoat MAE 30 DP Aqueous dispersion 30% Water Soluble in intestina l fluid Enter ic coa tings from pH 5 .5

Kollicoaf MAE 100 P Powder 95% Acetone, a lcohols Soluble in intestinal fluid Enteric coa tings from pH 5.5

Acryl-EZE Powder 95% Acetone, a lcohols Soluble in intestinal fl uid Enteric coa tings

Acetone, alcohols from pH 5.5

Acryl-EZE 93 A Powder 95% Soluble in intestina l fluid Enter ic coatings from pH 5.5

Acryl-EZE MP Powder 95% Acetone, alcohols Soluble in intestinal fluid Enteric coatings from pH 5.5

Note: Recommended plasticizers for the above polymers include di butyl phthalate, polyethylene glycols, triethyl citrate, triacetin, and l ,2-propylene glycol. The recommended concentration of the plasticizer is approximately l 0-25% plasticizer (based on the dry polymer weight). A plasticizer is not necessary with Eudragit E 12.5, Eudragit E I 00 and Eudragit NE 30 D.

~ 5). Eudragit E is availa ble as a 12.5% ready-to-use solution in propan-2-ol-acetone (60 : 40 ). It is light yellow in color with the characteristic odor of the solvents. Solvent-free granules contain ~98% dried weight content of Eudragit E. Eudragit E PO is a white free-flowing powder with at least 95% of dry polymer.

Eudragit L and S, also referred to as methacrylic acid copolymers in the USP32-NF27 monograph, are anionic copolymerization products of methacrylic acid and methyl methacrylate. The ratio of free carboxyl groups to the ester is approximately 1: 1 in Eudragit L (Type A) and approximately 1: 2 in Eudragit S (Type B). Both po lymers are readi ly soluble in neutral to weakly alkaline conditions (pH 6-7) and form salts with alkalis, thus affording film coats that are resistant to gastric media but soluble in intestinal fluid. They are available as a 12.5% so lution in propan-2-ol without plasticizer (Eudragit L 12.5 and S 12.5); and as a 12.5 %

ready-to-use solution in propan-2-ol with 1.25% dibutyl phthalate as plasticizer (Eudragit L 12.5 P and S 12.5 P). Solutions are colorless, with the characteristic odor of the solvent. Eudragit L -100 and Eudragit S-100 are white free-flowing powders with at least 95% of dry polymers .

Eudragit FS 30 D is the aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid. The ratio of free carboxyl groups to ester groups is approximately 1: 10. It is a highly flexible polymer, designed fo r use in enteric-coated solid-dosage forms, and dissolves in aqueous systems at pH > 7.

Eudragit RL and Eudragit RS, also referred to as ammonia methacrylate copolymers in the USP32- NF27 monograph, are copolymers synthesized from acrylic acid and methacrylic acid esters, with Eudragit RL (Type A) having 10% of fun ctional

---------------- - ----------------------- - -

528 Polyme thac ry la tes

Table Ill: Solubility of C?mmerciany available polymethacrylates in various solvents.

Grade Solvent

Acetone and Dichloromethane alcohols la)

--------·---

. Eudragit E 12.5 M M Eudragit E 100 s s Eudragit L 12.5 P M M Eudragit L 12.5 M M Eudragit L 100-55 s I Eudragit L 100 s I Eudragit L 30 D-551bl Mic! Eudragit 5 12.5 P M M Eudragit 5 12.5 M M Eudragit 5 100 s I Eudragit RL 12.5 M M Eudragit RL 100 s s Eudragit RL PO s s Eudragit RL 30 D161 Mic! M Eudragit RS 12 .5 M M Eudragit RS 100 s s Eudragit RS PO s s Eudragit RS 30 olbJ Mic! M Eastacryl 30 olb) MicJ Kol/icoat MAE 30 op.bl Mlcl Kollicoat MAE 100 P MlcJ Acryl-EZE s ~'!yl-EZE MP s (o) Alcohols including ethanol (95%), methanol, ond propon-2-ol. (b) Supplied os o mi lky-white aqueous dispersion. (c) A l : 5 mixture forms o clear, viscous, solution.

Ethyl acetate

----·--·-

M s M M I I

M M I M s s M M s s M

1 N HCI

M

M

1 N NaOH

M M s s

M M s

I I M M M s s

Petroleum Water ether

-----------·-· M I I p p p p I I I I M p p p p I I p M I I I I I M p M I I I I I M

M M M I I

S = soluble; M = miscible; I = insoluble or immiscible; P = precipitates. l port of Eudrogit RL 30 Dor of Eudragit RS 30 D dissolves completely in 5 ports acetone, ethanol (95%), or propon-2-ol lo form a clear or slightly turbid solution. However, when mixed in o ratio of 1 : 5 with methanol, Eudragif RL 30 D dissolves completely, whereas Eudragit RS 30 D dissolves only partially.

quaternary ammonium groups and Eudragit RS (Type B) having 5% of functional quaternary ammonium groups. The ammonium groups are present as salts and give rise to pH-independent permea bility of the polymers. Both polymers are water-insoluble, and films prepared from Eudragit RL are freely permeable to water, whereas, films prepared from Eudragit RS are only slightly permeable to water. They are available as 12.5% ready-to-use solutions in propan-2-ol-acetone ( 60: 40). Solutions are colorless or slightly yellow in color, and may be clear or slightly turbid; they have an odor characteristic of the solvents. Solvent-free granules (Eudragit RL 100 and Eudragit RS 100) contain :;,,: 97% of the dried weight content of the polymer.

Eudragit RL PO and Eudragit RS PO are fine, white powders with a slight amine-like odor. They are characteristically the same polymers as Eudragit RL and RS. They contain :;,,: 97% of dry polymer.

Eudragit RL 30 D and Eudragit RS 30 D are aqueous dispersions of copolymers of acrylic acid and methacrylic acid esters with a low content of quaternary ammonium groups. The dispersions contain 30% polymer. The quaternary groups occur as salts and are responsible for the permeability of films made from these polymers. Films prepared from Eudragit RL 30 Dare readily permeable to water and to dissolved active substances, whereas films prepared from Eudragit RS 30 Dare less permeable to water. Film coatings prepared from both polymers give pH-independent release of active substance. Plasticizers are usually added to improve film properties.

Eudragit NE 30 D and Eudragit NE 40 D are aqueous dispersions of a neutral copolymer consisting of polymethacrylic acid esters. The dispersions are milky-white liquids of low viscosity and have a weak aromatic odor. Films prepared from the lacquer swell in water, to which they become permeable. Thus, films

produced are insoluble in water, but give pH-independent drug release.

Eudragit NM 30 D is an aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate, and is of identical monomer composition to Eudragit NE 30 D.

Eudragit L 30 D-55 is an aqueous dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate. The copolymer corresponds to USP32-NF2 7 methacrylic acid copolymer, Type C. The ratio of free-carboxyl groups to ester groups is 1: 1. Films prepared from the copolymers dissolve above pH 5.5, forming salts with alkalis, thus affording coatings that are insoluble in gastric media but soluble in the small intestine.

Eastacryl 30D and Kollicoat MAE 30 DP are also aqueous dispersions of the anionic copolymer based on methacrylic acid and ethyl acrylate. The copolymer also corresponds to USP32- NF27 methacrylic acid copolymer, Type C. The ratio of free-carboxyl groups to ester groups is 1 : 1. Films prepared from the copolymers dissolve above pH 5.5, forming salts with alkalis, thus affording coatings that are insoluble in gastric media but soluble in the small intestine.

Eudragit L 100-55 (prepared by spray-drying Eudragit L 30 D-55) is a white, free-flowing powder that is redispersible in water to form a latex that has properties similar to those of Eudragit L 30 D-55.

Acryl-EZE and Acryl-EZE MP are also commercially available as redispersible powder forms, which are designed for enteric coating of tablets and beads, respectively.

9 Pharmacopeial Specifications Specifications for polymethacrylates from PhEur 6.0, 6.2, and 6.3 are shown in Table IV, and those from the USP32-NF27 in Table V. See also Section 18.

Table IV: Specifications from PhEur 6.0, 6.2, and 6.3.

Test Ammonia methacrylate copolymer10l (PhEur 6.0)

Identification + Characters + Appearance of o film + Relative density Apparent viscosity Absorbance at 420 nm

,;;1 5mPas

Particulate matter -Limit of monomers Ethyl acrylate and

methacrylic acid ,;; l00ppm

Methyl methacrylate and ,;; 50ppm methacrylic acid

Residue on evaporation -Loss on drying ,;; 3.0% Methanol + Heavy metals ,s;20ppm Su lfated ash -

Type A -Type B -

Microbial contamination -Assay Ammonia methacrylate

units +

Type A 8.9- 12.3% Type B 4.5- 7.0%

(a) Corresponds lo Eudragil RL/RS. (b) Corresponds 10 Eudragit L 100.55. (c) Corresponds 1o Eudragit L 30 0-55. (d) Corresponds lo Eudragit L. (e) Corresponds to Eudragit S. (f) Corresponds to Eudragit E. ,., (g) Corresponds to Eudragit NE 30 D.

Methacrylic acid-ethyl acrylate copolymer (1 : l Jib! (PhEur 6.2)

+ + -

,_

-

,;;0.1 %

-,;;5.0%

+ 0.4% 0.5- 3.0% -Methacrylic acid

units + 46.0- 50.6% 43.0- 48.0%

-------Methacrylic acid-ethyl acrylate copolymer (1: 1) dispersion 30%(cl (PhEur 6.3)

+ + +

,;; 15 mPa s

,;;1 .0%

,;; 0 .1%

28.5- 31.5%

,;; 0.2%

,;; 103 cfu/ g Methacrylic acid

units 46.0- 50.6%

Methacrylic acid- methyl methacrylate copolymer (1 : lJ1dJ (PhEur 6.0)

Methacrylic acid-methyl methac1ate copolymer (1 : 2J!el PhEur 6.0)

+ + + + + +

50- 200mPas 50- 200mPas

,;; 0.1 % ,;;0.1%

- -,;; 5.0% ,;;5.0% - -

,;; 0 .1% ,;;0.1 % - -- -

Methacrylic acid Methacrylic acid units units

46.0-50.6% 27.6- 30.7%

Basic butylated methacrylate copolymer1~ (PhEur 6.0)

+ + +

3-6 mPas ,;; 0 .3 -,;; 0.3% -

-,;; 2.0% -,;; 20ppm ,;;0.1% --Dimethylaminoethyl

units 20.8-25 .5%

Polyacrylate dispersion 30%191 (PhEur 6.3)

+ + + 1.037- 1.047 ,;;50 mPa s

,;;0.5% ,;; l00ppm -

28.5- 31 .5%

-,;; 20ppm ,;;0.4% --,;; 103 cfu/g Residue on

evaporation 28.5%- 31 .5%

" 0 --< 3 (D

5'-0 n

-< 0 ro u,

(JI

"' ,0

Table V: Specifications from USP32-NF27.

Test

Identification Color of solution Viscosity

Type A Type B Type C

Loss on drying Type A Type B TypeC

Residue on ignition Type A Type B TypeC

Heavy metals Limit of total monomers Limit of methyl methacrylate Limit of butyl methacrylate Limit of 2-dimethylaminoethyl

methacrylate Lim it of ethyl acrylate Coagulum content Microbial contamination

Aerobic bacteria Yeast and mold

pH Assay (dried basis)

Type A Type B Type C

(al Corresponds to Eudrogit E 100.

Amino methacrylate copolymer101

+ + 3.6 mPa s --~2.0% --

~0.1% --

--~0.1% ~0.1% ~0.1%

--

-

Dimethylaminoethyl units20.8- 25.5%

(b) Corresponds to Eudrogit RL and RS. (c) Corresponds to Eudragit RL 30 D and RS 30 D. (d) Corresponds to Eudragit NE 30 D. (e) Corresponds to Eudragit L, Sand L 100-55. (f) Corresponds to Eudrogit L 30 0-55. (g) Calculated based on undried dispersion basis.

Ammonio methacrylate copolymerlbJ

+

~ 15 mPas ~ 15 mPas

~3.0% ~3 .0%

~0.1 % ~0.1%

~ 0.002% + ~0.005%

~0.025% -

-Ammonia methacrylate units

8.85- 11 .96% 4.48-6.77%

Ammonio methacrylate copolymer dispersion1<J

+

~ lOOmPas ~ lOOmPas

68.5- 71 .5%191 68.5-71.5%191

~0.5% ~0.5%

~0.002%

~0.008% ~ l.0%I9)

Ammonia methacrylate units

10.18- 13.73% 6.11-8.26%

Ethyl acrylate and methyl methacrylate copolymer dispersionldJ

+ -~50 mPa s

68.5- 71.5%19)

~0.4%

~0.01%

~l.0%I9)

103 cfu/ g l02 cfu/ g 5.5-8.6

Methacrylic acid copolymer1•1

Methacrylic acid c opolymer dispersion1~

+ + - -

50-200mPas -50-200 mPa s -l 00-200 mPa s ~ 15 mPas

~ 5.0% -~ 5.0% -~5.0% 68.5-71.5%191

~0.1 % ~0.1% ~0.4% ~0.2%19) ~0.002% ~0.002%191

~0.05% ~0.01%

~1%19)

2.0-3.0 Methacrylic acid Methacrylic acid units

units 46.0- 50.6% 27.6- 30.7% 46.0-50.6% 46.0-50.6%

u, w 0

u 0 -< 3 ~ ::, 0 n

-< 0 ro V>

10 Typical Properties Acid value

300-330 for Eudragit L 12.5, L 12.5 P, L 100, L 30 D-55, L 100-55, Eastacryl 30 D, Kollicoat MAE 100 P, and Kollicoat MAE30 DP;

180-200 for Eudragit S 12.5, S 12.5 P, and S 100. Alkali value

162-198 for Eudragit E 12.5 and E 100;

23.9-32.3 for Eudragit RL 12.5, RL 100, and RL PO;

27.5-31.7 for Eudragit RL 30 D; 12.1-18.3 for Eudragit RS 12.5, RS 100, and RS PO;

16.5-22.3 for Eudragit RS 30 D. Density (bulk) 0.390 g/cm3

Density (tapped) 0.424 g/cm3

Density (true)

0.811-0.821 g/cm3 for Eudragit E;

0.83-0.85 g/cm3 for Eudragit L, S 12.5 and 12.5 P;

1.058-1.068 g/cm3 for Eudragit FS 30 D; 0.831-0.852g/cm3 for Eudragit L, S 100;

l.062-l.072g/cm3 for Eudragit L 30 D-55;

0.821-0.841g/cm3 for Eudragit L 100-55;

0.816-0.836g/cm3 for Eudragit RL and RS 12.5;

· 0.816- 0.836 g/crn3 for Eudragit RL and RS PO;

1.047-1.057 g/cm3 for Eudragit RL and RS 30 D; 1.037-1.047 g/cm3 for Eudragit NE 30 D; 1.062- 1.072 g/cm3 for Eastacryl 30 D; 1.062-1.072 g/cm3 for Kollicoat MAE 100 P and Kollicoat

MAE 30 DP. NIR spectra see Figures 1, 2, 3, 4, 5, 6, and 7. Refractive index

nt0 = 1.38-1.385 for Eudragit E;

nt0 = 1.39- 1.395 for Eudragit Land S; nt0 = 1.387-1.392 for Eudragit L 100-55;

nt0 = 1.38- 1.385 for Eudragit RL and RS. Solubility see Table III. Viscosity (dynamic)

3-12 mPa s for Eudragit E;

;;;; 50mPas for Eudragit NE 30 D; 50-200 mPa s for Eudragit L and S; ;;;; 20 111Pa s for Eudragit PS 30 D; ;;;; 15mPas for Eudragit L 30 D-55; 100-200mPas for Eudragit L 100-55;

;;;; 15 mPa s for Eudragit RL and RS;

;;;; 200 111Pa s for Eudragit RL and RS 30 D; ;;;; 15 mPa s for Kollicoat MAE 100 P and Kollicoat MAE 30 DP;

145 mPas for Eastacryl 30D.

11 Stability and Storage Conditions Dry powder polymer forms are stable at temperatures less than 30°C. Above this temperature, powders tend to form clumps, although this does not affect the quality of the substance and the clumps can be readily broken up. Dry powders are stable for at least 3 years if stored in a tightly closed container at less than 30°C.

Dispersions are sensitive to extreme temperatures and phase separation occurs below 0°C. Dispersions should therefore be stored at temperatures between 5 and 25°C and are stable for at least 18 months after shipping from the manufacturer's warehouse if stored in a tightly closed container at the above conditions.

0) 0

> ·;::

Polymethacry lates

l.5.--------------------, 1649

1_331 ,··----

I ,,, 1224 :,r:R'J

/

~ 0.O1-'-t--+t-f--1~1-1\fv--"'-V-:t-JhrRN"+Hf-lF-+M''-+.;;wA...,,,.-J 7J

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.2.

.- -1.5 ..._.._...__.___,___._.___.._...__.___,___,__.___..____, 0. l 11 00 1300 1500 1700 1900 2100 2300 2500

Wavelength/nm

Figure 1: N ear-infrared spectrum of polymethacrylates (Eudragit E 100) measured by reflectance.

~ 5.0 0.2 ciZ" '--. 23 16

0) 22 16 -2 165 1

-~ 1711 1931 ' IY.

(I) , _ 7J 0. 0 7J U)

C 0 ~ 118/

X 1910 , , -

0 I \ ' ~ 12136 ,\ , ... , ~----0 I\ ,-,, I 1729 , 0 I '--.._I ,.._ _ _... l 680 2282' 0 224 ~ .- - 5. 0 ..._..___.__~_._~~-----------..__...__...___.___.__. - 0 . 2

1100 1300 1500 1700 1900 2100 2300 2500 Wavelength/ nm

Figure 2: Near-infrared spectrum of polymethacrylates (Eudragil E PO) measured by reflectance.

~ 1.0 ~--------------~ 0.5 ciZ" '--.

0) 0

. ~ 0 ,0 l¼-rP-""'-1,j -h,,_;:,.-q (I)

-cJ 11 74 -cJ

C

~ X

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2282

2250

a-:: ....___

rn I )

.- - 1.5 .__,__,___.___.___.___,___,___,__--'--'----'-----'---'--' 0.2 1500 1700 1900 2100 2300 2500 1100 1300

Wavelength/ nm

Figure 3: Near-infrared spectrum of polymethacrylates (Eudragit L 100) measured by reflectance.

12 Incompatibilities Incompatibilities occur with certain polymethacrylate dispersions depending upon the ionic and physical properties of the polymer and solvent. For example, coagulation may be caused by soluble electrolytes, pH changes, some organic solvents, and extremes of temperature; see Table II. For example, dispersions of Eudragit L 30 D, RL 30 D, L 100-55, and RS 30 D are incompatible with magnesium stearate. Eastacryl 30 D, Kollicoat MAE 100 P, and Kollicoat MAE 30 DP are also incompatible with magnesium stearate.

5 3 2 Polymeth acrylates

&""" ......__

0)

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24ot I -~ 2442

2255

~ - 1 . 5 .___,___.__,___,_..___.__,____._..__...__.____..___,..__. -0. 2 1100 1300 1500 1700 1900 2100 2300 2500

Wavelength/nm

Figure 4: Near-infrared spectrum of polymethocrylates (Eudragit RL PO) measured by reflectance.

1.5 .------- ---- --- ---~ 1. 2 &""" ......__

0) _Q

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.. .. . .. -

~ - 1. 5 '----'---'--'-----'--....L..-'--'-----'----'------'------'---"'--'---' 8 2 1100 1300 1500 1700 1900 2100 2300 250 .

Wavelength/ nm

tflur . ,i: Near-infrared spectrum of polymethacrylates (Eudragit RS 100) measured by reflectance.

~ 0.7 ...-----------------, 0.4 &""" 227 1 2320 '--- 1M6 U~

X 0 0 0

I J l I

~ 1908 ,1,./ \ / \ ,. I \

240~ I 2442

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0) _Q

~ - l . 5 .__..___.__.___.___._..__...___....,__.____..__..__...._..,____, -0. 2 1100 1300 1500 1700 1900 2100 2300 2500

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Figure 6: Near-infrared spectrum of polymethacrylates (Eudragit RS PO) measured by reflectance.

Interactions between polymethacrylates and some drugs can occur, although solid polymethacrylates and organic solutions are generally more compatible than aqueous dispersions.


Prepared by the polymerization of acrylic and methacrylic acids or their esters, e.g. butyl ester or dimethylaminoethyl ester.

----------------c---··········--- ----------

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Figure 7: Near-infrared spectrum of polymethacrylates (Eudragit S 100) measured by reflectance.

14 Safety

Polymethacrylate copolymers are widely used as film-coating materials in oral pharmaceutical formul ations. They are also used in topica l formulations and are generally regarded as nontoxic and nonirritant materials.

Based on relevant chronic oral toxicity studies in rats and conventionally ca lculated with a safety factor of 100, a daily intake of 2- 200 mg/kg body-weight depending on the grade of Eudragit may be regarded as essentially safe in humans.



Observe normal precautions appropriate to the circumstances and quantity of material handled . Additional measures should be taken when handling organic solutions of polymethacrylates. Eye protection, gloves, and a dust mask or respirator are recommended. Polymethacrylates should be handled in a well-ventilated environment and measures should be taken to prevent dust formation.

Acute and chronic adverse effects have been observed in workers handling the related substances methyl methacrylate and poly(methyl methacrylate) (PMMA).'23

l In the UK, the workplace exposure limit for methyl methacrylate has been set at 208 mg/m3

(50 ppm) long-term (8-hour TWA), and 416 mg/m3 (100 ppm) short-term. <24r



Included in the FDA Inactive Ingredients Database (oral capsules and ta blets) . Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.


Methyl methacrylate; poly(methyl methacrylate).

Methyl methacrylate Empirical fonnula C5Hs02 Molecular weight 100.13 CAS number (80-62-6] Synonyms Methacrylic acid, methyl ester; methyl 2-methacrylate;

methyl 2-methylpropenoate; MME. Safety

LD50 (dog, SC): 4.5 g/kg

LDso (mouse, IP): 1 g/kg

LD so (mouse, oral): 5 .2 g/kg LD50 (mouse, SC): 6.3 g/kg

LD50 (rat, IP): 1.33 g/kg LD5o (rat, SC): 7.5 g/kg

Comments Methyl methacrylate forms the basis of acrylic bone cements used in orthopedic surgery.

Poly(methyl methacrylate) Empirical formula (CsHs02)n Synonyms Methyl methacrylate polymer; PMMA. Comments Poly(methyl methacrylate) has been used as a material

for intraocular lenses, for denture bases, and as a cement for dental prostheses.

18 Comments A number of different polymethacrylates are commercially available that have different applications and properties; see Table II.

For spray coating, polymer solutions and dispersions should be diluted with suitable solvents. Some products need the addition of a plasticizer such as dibutyl sebacate, dibutyl phthalate, glyceryl triacetate, or polyethylene glycol. Different types of plasticizer may be mixed to optimize the polymer properties for special requirements.

The Japanese Pharmaceutical Excipients (JPE) 2004 includes specifications for aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer E, dried methacrylic acid copolymer LD, ethyl acrylate and methyl methacrylate copolymer dispersion, methacrylii:: acid copolymer L, methacrylic acid copolymer S, and methacrylic acid copolymer LD.

19 Specific References 1 Akhgari A et al. Combination of time-dependent and pH-dependent

polymethacrylates as a single coating formulation for colonic delivery of indomethacin pellets. Int J Pharm 2006; 320(1-2): 137-142.

2 Arno EA et al. Eudragit NE30D based metformin/gliclazide extended release tablets: formulation, characterisation and in vitro release studies. Chem Pharm Bull (Tokyo) 2002; 50(11): 1495-1498.

3 Ceballos A et al. Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets. Farmaco 2005; 60(11 -12): 913- 8.

4 Cerea M et al. A novel powder coating process for attaining taste masking and moisture protective films applied to tablets. Int J Pharm 2004; 279(1-2): 127-139.

5 Cheng G et al. Time- and pH-dependent colon-specific drug delivery for orally administered diclofenac sodium and 5-aminosalicylic acid. World ]Gastroenterol2004; 10(12): 1769-1774.

6 Cole ET et al. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int J Phann 2002; 231(1): 83-95.

7 Dittgen M et al. Acrylic polymers: a review of pharmaceutical applications. STP Pharma Sciences 1997; 7(6): 403--43 7.

8 Felton L, McGinity J. Enteric film coating of soft gelatin capsules. Drug De/iv Technol 2003; 3(6): 46-51.

9 Gao Y et al. Preparation of roxithromycin-polymeric microspheres by the emulsion solvent diffusion method for taste masking. Int J Pharm 2006; 318(1-2): 62-69.

10 Hamed E, Sakr A. Effect of curing conditions and plasticizer level on the release of highly lipophilic drug from coated mu!tiparticulate drug delivery system. Pharm Dev Technol 2003; 8(4): 397- 407.

Polymethacrylates 533

11 Ibekwe VC et al. A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery. Int J Pharm 2006; 308(1- 2): 52-60.

12 Kidokoro M et al. Properties of tablets containing granulations of ibuprofen and an acrylic copolymer prepared by thermal processes. Pharm Dev Technol 2001; 6(2): 263-275.

13 Lorenzo-Lamosa M et al. Development of a microencapsulated form of cefuroxime axetil using pH-sensitive acrylic polymers. J Microencapsul 1997; 14(5): 607-616.

14 Nisar ur R et al. Drug-polymer mixed coating: a new approach for controlling drug release rates in pellets. Pharm Dev Technol 2006; 11(1): 71- 77.

15 Rahman N, Yuen K. Eudragit NE40-drug mixed coating system for controlling drug release of core pellets. Drug Dev Ind Pharm 2005; 31(4-5): 339- 347.

16 Rao VM et al. Design of pH-independent controlled release matrix tablets for acidic drugs. Int J Pharm 2003; 252(1- 2 ): 81- 86.

17 Saravanan M et al. The effect of tablet formulation and hardness on in vitro release of cephalexin from Eudragit LlO0 based extended release tablets. Biol Pharm Bull 2002; 25(4): 541-545.

18 Signorino C et al. The use of acrylic resins for improved aqueous enteric coating. Pharm Technol Excipients Solid Dosage Forms 2004; (Suppl.): 32- 39.

19 Sohi H et al. Taste masking technologies in oral pharmaceuticals: recent developments and approaches. Drug Dev Ind Pharm 2004; 30(5): 429-448.

20 Zheng W et al. Influence of hydroxyethylceHulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D. Eur j Pharm Biopharm 2005; 59(1): 147- 154.

21 Zhu Y et al. Influence of thermal processing on the properties of chlorpheniramine maleate tablets containing an acrylic polymer. Pharm Dev Technol 2002; 7(4): 481--489.

22 Umejima H et al. Preparation and evaluation of Eudragit gels VI: in vivo evaluation of Eudispert rectal hydrogel and xerogel containing salicylamide. J Pharm Sci 1993; 82: 195- 199.

23 Routledge R. Possible hazard of contact lens manufacture [letter]. Br Med J 1973; 1: 487--488.

24 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ coshh/tablel.pdf (accessed 5 February 2009).

20 General References Evonik Industries. Eudragit. http://www.pharma-polymers.com/pharmapo

lymers/en/eudragit/ (accessed 4 March 2009). Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Exci

pients 2004. Tokyo: Yakuji Nippo, 2004. McGinity JW. Aqueous Polymeric Coatings for Pharmaceutical Dosage

Forms, 2nd edn. New York: Marcel Dekker, 1997. Petereit HU et al. Eudragit Application Guidelines, 10th edn. Darmst,1dr,

Germany: Evonik Industries AG, 2008 .

21 Authors

RK Chang, Y Peng, N Trivedi, AJ Shukla.

22 Date of Revision

4 March 2009.


20 General References Smolinske SC, ed. Handbook of Food, Drug, and Cosmetic Excipients. Boca

Raton, FL: CRC Press, 1992; 363-367. Sofas ]N, Busta FF. Sorbates. Branen AL, Davidson PM, eds. Antimicrobials

in Foods. New York: Marcel Dekker, 1983; 141-175. Walker R. Toxicology ofsoi:bic acid and sorbates. Food Add Contam 1990;

7(5): 671-676.

-------~

Povidone

1 Nonproprietary Names BP: Povidone

JP: Povidone PhEur: Povidone USP: Povidone

2 Synonyms E1201; Kollidon; Plasdone; poly[l-(2-oxo-1-pyrrolidinyl)ethyle~e]; polyvidone; polyvinylpyrrolidone; povidonum; Povipharm; PVP; 1-vinyl-2-pyrrolidinone polymer.

3 Chemical Name and CAS Registry Number 1-Ethenyl-2-pyrrolidinone homopolymer (9003-39-8]


(C6H 9NO)n 2500-3 000 000 The USP 32 describes povidone as a synthetic polymer consisting

essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of va rious molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the range 10-120. The K-value is calculated using Fikentscher's equation:(l)

log z= c --- +k [ 75k

1 l 1 + 1.5kc

where z is the relative viscosity of the solution of concentration c (in % w/v) , and k is the K-value ; 10-3

• Alternatively, the K-value may be determined from the following equation: ·

K-va lue = 300c log z (c + 1.5c log d + 1.5

O.lSc + 0.003c2

where z is the relative viscosity of the solution of concentration c (in % w/v). Approximate molecular weights for different povidone grades are shown in Table I.

21 Authors

ME Quinn, PJ Sheskey.


Povido ne 581

Table I: Approximate molecular weights for different grades of povidone.

K-value Approximate molecular weight

12 15 17 25 30 60 90 120

2500 8000 10000 30000 50000 400000 1000000 3000000

See also Section 8.



n

Disintegrant; dissolution enhancer; suspending agent; tablet binder.


Although povidone is used in a variety of pharmaceutical formulations; it is primarily used in solid-dosage forms. In tableting, povidone solutions are used as binders in wet-granulation processes.(2,3) Povidone is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol, or hydroalcoholic solutions. Povidone is used as a solubilizer in oral and parenteral formulations, and has been shown to enhance dissolution of poorly soluble drugs from solid-dosage forms . (4-

6)

Povidone solutions may also be used as coating agents or as binders when coating active pharmaceutical ingredients on a support such as sugar beads.

Povidone is additionally used as a suspending, stabilizing, or viscosity-increasing agent in a number of topical and oral suspensions and solutions. The solubility of a number of poorly

582 Povidone

soluble active drugs may be increased by mixing with povidone. See Table II.

Special grades of pyrogen-free povidone are available and have been used in parenteral formulations; see Section 14.

_.!able II: Uses of povid<:me.

Use

Carrier for drugs Dispersing agent Eye drops Suspending agent Tablet binder, tablet diluent, or

coating agent

8 Description

Concentration (%)

10-25 Up to 5 2- 10 Up to 5 0.5-5

Povidone occurs as a fine, white to creamy-white colored, odorless or almost odorless, hygroscopic powder. Povidones with K-values equal to or lower than 30 are manufactured by spray-drying and occur as spheres. Povidone K-90 and higher K-value povidones are manufactured by drum drying and occur as plates.

9 Pharmacopeial Specifications See Table III. See also Section 18.

10 Typical Properties Acidity/alkalinity pH = 3.0-7.0 (5% w/v aqueous solution); pH =

4.0-7.0 (5 % w/v aqueous solution) for Povipharm K90. Density (bulk) 0.29-0.39 g/cm3 for Plasdone. Density (tapped) 0.39-0.54 g/cm3 for Plasdone. Density (true) 1.180g/cm3

Flowability 20g/s for povidone K-15; 16 g/s for povidone K-29/32.

Melting point Softens at 150°C. Moisture content Povidone is very hygroscopic, significant

amounts of moisture being absorbed at low relative humidities. See Figures 1 and 2.

NIR spectra see Figure 3 . .

SEM 1: Excipient: povidone K-15 (Plosdone K-15); manufacturer: ISP; lot no.: 82A-1; magnification: 60 x ; voltage: 5 kV.

· Excipient: povidone K-15 (Plosdone K- 15); manufacturer: ISP; lot no.: 82A-1; magnification: 600 x ; voltage: 5 kV.

SEM 3: Excipient: povidone K-26/28 (Plosdone K-26/28); manufacturer: ISP; lot no.: 82A-2; magnification: 60 x; voltage: 5 kV.

Particle size distribution Kollidon 25/30: 90% >50 µm, 50% > 100 µm, 5% > 200 µm; Kollidon 90: 90% >200 µm, 95 % > 250 ~lm.m

Solubility Freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and water; practically insoluble in ether, hydrocarbons, and mineral oil. In water, the concentration of a solution is limited only by the viscosity of the resulting solution, which is a function of the K-value.

Viscosity (dynamic) The viscosity of aqueous povidone solution} depends on both the concentration and the molecular weight 0

the polymer employed. See Tables IV and v.m

11 Stability and Storage Conditions Povidone darkens to· some extent on heating at 150°C, with a reduction in aqueous solubility. It is stable to a short cycle of heat exposure around 110-130°C; steam sterilization of an aqueous solution , does not alter its properties. Aqueous solutions are

SEM 4: Excipient: povidone K-26/28 (Plasdone K-26/28); manufacturer: ISP; lot no.: 82A-2; magnification: 600 x ; voltage: 10 kV.

.. M 5: Excipient: povidone K-30 (Plasdone K-30); manufacturer: ISP; lot no.: 82A-4; magnification: 60 x ; voltage: l O kV.

susceptible to mold growth and consequently require the addition of suitable preservatives.

Povidone may be stored under ordinary conditions without undergoing decomposition or degradation. However, since the powder is hygroscopic, it should be stored in an airtight container in a cool, dry place.

12 Incompatibilities Povidone is compatible in solution with a wide range of inorganic salts, natura l and synthetic resins, and other chemica ls. It forms molecular add ucts in solution with sulfathiazole, sodium sa licylate, sa licylic acid, phenoharbital, tannin, and other compounds; see Section 18. The efficacy of some preservatives, e.g. thimerosal, may be adversely affected by the forma tion of complexes with povidone.

Povidone 583

5EM 6: Excipient: povidone K-30 (Plasdone K-30); manufacturer: ISP; lot na.: 82A-4; magnification: 600 x ; voltage: 10 kV.

SEM 7: Excipient: povidone K-29 /32 (Plasdone K-29 /32); manufacturer: ISP; lot no.: 82A-3; magnification: 60 x ; voltage: 5 kV.

~

13 Method of Manufacture Povidone is manufactured by the Reppe process. Acetylene and formaldehyde are reacted in the presence of a highly active copper acetylide catalyst to form butynediol, which is hydrogenated to butanediol and then cyclodehydrogenated to form butyrolactone. Pyrrolidone is produced by reacting butyrolactone with ammonia. This is followed by a vinylation reaction in which pyrrolidone and acetylene are reacted under pressure. The monomer, vinylpyrrolidone, is then polymerized in the presence of a combination of catalysts to produce povidone.

14 Safety Povidone has been used in pharmaceutica l formulations for many years, being first used in the 1940s as a plasma expander, although it has now been superseded for this purpose by dextran. 18 l

-------------->=-------------------------------------------------

584 Povidon e

, , , .. : Excipient: povidone K-29 /32 (Plasdone K-29 /32); man ufacturer: ISP; lot no.: 82A-3; magnification: 600 x ; voltage: l 0 kV.

Table Ill: Pharmacopeial specifications for povidone.

Test JP XV PhEur 6.5

identification + + Characters + pH + +

K ~ 30 3 .0-5.0 3.0- 5 .0 K > 30 4 .0-7.0 4 .0-7.0

Appearance of solution + + Viscosity + Water ~ 5 .0% ~ 5.0% Res idue on ignition Lead

~ 0.1% ~ 0. 1%

Aldehydes ~ 500ppm101 ~ 500ppm(a} Formic acid + Hydrazine ~ 1 ppm ~ l ppm Vinylpyrrol idinone ,:::; l0ppm ~ l0ppm Pyrro lidone ~ 3.0% Peroxides ~ 400ppm161 ~ 400ppm161

K-va lue 25-90 ~ 15 90.0-108.0% 85.0-115 .0% > 15 90.0-108.0% 90.0-108.0%

Heavy metals ~ l0ppm ~ l0ppm Assay (nitrogen content) 11.5- 12 .8% 11.5- 12.8%

(a) Expressed as acetaldehyde. (b) Expressed as hydrogen peroxide.

USP 32

+

3.0-7.0

~ 5.0% ~ 0.1% ~ lOppm ~ 0 .05%

~ lppm ~ 0 .001 %

85 .0-115.0% 90.0-108.0%

11 ,5-12.8%

Table IV: Dynamic viscosity of 10% w/v aqueous povidone (Kollidon) solutions at 20°C. 171

Grade

K- 11/14 K-16/ 18 K-24/27 K-28/32 K-85/95

Dynamic viscosity (mPa s)

1.3-2.3 1.5-3 .5 3.5- 5.5 5.5-8 .5 300-700

Povidone is widely used as an excipient, particularly in oral tablets and solutions. When consumed orally, povidone may be regarded as essentially nontoxic since it is not absorbed from the gastrointestinal tract or mucous membranes. 181 Povidone additionally has no irritant effect on the skin and causes no sensitization.

--- ·--- - - -

50 ....--------------------,

~ L 40 u 0

~ N -0

Q) '-.2 <I)

·o E E ::,

·;:: ...0

·-::, U'

LJ.J

30 -

20

10 -

00

/) d)G

cf) / ,,

l_)

~ I__,,»·,. ( .,,.,,.a o" I

10 20 30 .40 50 60 70 80 90 100


Hgure 1: Sorption- desorption isotherm of povidone K-15 (P/asdone K-15, ISP).

~

u 0

~ N

0 Q) '-.2 <I)

·o E E ::,

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40

30

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10 -

0o 10 20 30 40 50 60. 70 80 90 100


Figure 2: Sorption- desorption isotherm of povidone K-29 /32 (Plasdone K-29/32, ISP) .

Table V: Dynamic viscosity of 5% w/v Bovidone (Kollidon) solutions in ethanol (95%) and propan-2-ol at 25°C. I

Grade

K-12PF K-17PF K,25 K-30 K-90

Dynamic viscosity (mPa s)

Ethanol (95%)

1.4 1.9 2.7 3.4 53.0

Propan-2-ol

2.7 3.1 4.7 5.8 90.0

Reports of adverse reactions to povidone primarily conce~n thf formation of subcutaneous granulomas at the injection site 0

intramuscular injections formulated with povidone.191 Evidence also

0) 0

-~

1669 " 2239 : \, ,, .. .. .. /· -

2353

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1734 2148

I 2261 2282

1692 1932

0) q

~ - 1.0 ~~~~-~-~~-~~~-~~-0. 2 1100 1300 1500 1700 1900 2100 2300 2500

Wavelength/nm

Figure 3: Near-infrared spectrum of povidone measured by reflectance.

exists that povidone may accumulate in the organs of the body following intramuscular injection. (to)

A temporary acceptable daily intake for povidone has been set by the WHO at up to 25 mg/kg body-weight.'11

'

LD50 (mouse, IP): 12 g/kg(12l

15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material h:wdled. Eye protection, gloves, and a dust mask are recommended.

16 Regulatory Status Accepted for use in Europe as a food additive. Included in the FDA Inactive Ingredients Database (IM and IV injections; ophthalmic preparations; oral capsules, drops, granules, suspensions, and tablets; sublingual tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Crospovidone.

18 Comments Povidone is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32- NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

The molecular adduct formation properties of povidone may be used advantageously in solutions, slow-release solid-dosage forms, and parenteral formulations. Perhaps the best-known example of povidone complex formation is povidone- iodine, which is used as a topical disinfectant.

For accurate standardization of solutions, the water content of the solid povidone must be determined before use and taken into account for any calculations. Many excipients such as povidone may contain peroxides as trace contaminants. These can lead to degradation of ari active pharmaceutical ingredient that is sensitive to oxidation.

A specification for povidone is contained in the Food Chemicals Codex (FCq .<13l

19 Specific References 1 Fikentscher H, Herrle K. Polyvinylpyrrolidone. M odern Plastics 1945;

23 (3): 157- 161212, 214,216, 218.

Povidone 585

2 Becker D et al. Effectiveness of binders in wet granulation: comparison using model formulations of different tabletability. Drug Dev Ind Pharm 1997; 23(8): 791-808.

3 Stubberud L et al. Water-solid interactions. Part 3. Effect of glass transition temperature, Tg and processing on tensile strength of compacts of_ lactose and lactose/polyvinyl pyrrolidone. Pharm Dev Technol 1996; 1(2 ): 195-204.

4 Iwata M, Ueda H. Dissolution properties of glibenclamide in combinations with polyvinylpyrrolidone. Drug Dev Ind Phann 1996; 22: 11 61- 1165.

5 Lu WG et al. Development of nifedipine (NE) pellets with a high bioavailability. Chin Phann J Z hongguo Yaoxue Z azhi 1995; 30: 24-26.

6 Chowdary KP, Ramesh KV. Microencapsulation of solid dispersions of nifedipine - novel approach for controlling drug release. Indian D rugs 1995; 32(Oct): 477-483.

7 BASF Corporation. Technical literature: Soluble Kollidon Grades, Soluble Polyvinylpyrrolidone for the Pharmaceutical Industry, 1997.

8 Wessel W et al. Polyvinylpyrrolidone (PVP), its diagnostic, therapeutic and technical application and consequences thereof. Arzneimittelforschung 1971; 21: 1468-1482.

9 Hizawa K et al. Subcutaneous pseudosarcomatous polyvinylpyrrolidone granuloma. Am J Surg Pathol 1984; 8: 393-398.

10 Christensen M et al. Storage of polyvinylpyrrolidone (PVP) in tissues following long-term treatment with a PVP containing vasopressin preparation. Acta Med Scand 1978; 204: 295- 298.

11 FAO/WHO. Evaluation of certain food additives and contaminants . Twenty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1983; No. 696.

12 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 3016- 3017.


20 General References Adeyeye CM, Barabas E. Povidone. Brittain HG, ed. Analytical Profiles of

Drug Substances and Excipients., vol. 22: London: Academic Press, 1993;555-685.

European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

Genovesi A et al. Binder evaluation in tab letting. Manuf Chem 2004; 17 5 ( 6): 29-30 . \

Horn D, Ditter W. Chromatographic study of interactions between polyvinylpyrrolidone and drugs. J Pharm Sci 1982; 71: 1021- 1026.

Hsiao CH et al. Fluorescent probe study of sulfonamide binding to povidone. J Pharm Sci 1977; 66: 1157- 1159.

ISP. Technical literature: Plasdone povidone USP, 1999. Jager KF, Bauer KH. Polymer blends from PVP as a means to optimize

properties of fluidized bed granulates and tablets, Acta Phann Technol 1984; 30(1): 85- 92.

NP Pharm. Product data sheet: Povipharm, 2008. Plaizier-Vercammen JA, DeNeve RE. Interaction of povidone with aromatic

compounds III: thermodynamics of the binding equilibria and interaction . forces in buffer solutions at varying pH values and varying dielectric

constant. J Pharm Sci 1982; 71: 552-556. Robinson BV et al. PVP: A Critical Review of the Kinetics and Toxicology of

Polyvinylpyrrolidone (Povidone). Chelsea, MI: Lewis Publishers, 1990. Shefter E, Cheng KC. Drug- polyvinylpyrrolidone (PVP) dispersions. A

differential scanning calorimetric study. Int J Phann 1980; 6: 179-182. Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. Boca

Raton, FL: CRC Press, 1992; 303- 305. Wasylaschuk WR et al. Evaluation of hydroperoxides in common

pharmaceutical excipients. J Pharm Sci 2007; 96: 106-116.

21 Author AH Kibbe.


-------- ----- · ---- --

The therapeutic use of sodium propionate in topical antifungal preparations has largely been superseded by a new generation of antifungal drugs.

A specification for sodium propionate is contained in the Food Chemicals Codex (FCC).(6

>

The EINECS number for sodium propionate is 205-290-4. The PubChem Compound ID (CID) for sodium propionate is 23663426.

19 Specific References 1 Bishop Y, ed. The · Veterinary Formulary, 6th edn. London:

Pharmaceutical Press, 2005; 419-420. 2 Heseltine WW. A note on sodium propionate. J Pharm Pharmacol

1952; 4: 120- 122. 3 Graham WD et al. Chronic toxicity of bread additives to rats. J Pharm

Pharmacol 1954; 6: 534-545. 4 Lewis RJ, ed. Sax's Dangerous Properties of Industrial M aterials, 11th

edn. New York: Wiley, 2004; 3276.

~ Sodium Starch Glycolate


BP: Sodium Starch Glycolate

PhEur: Sodium Starch Glycolate USP-NF: Sodium Starch Glycolate

2 Synonyms

Carboxymethyl starch, sodium salt; carboxymethylamylum natricum; Ex plosol; Explotab; Glycolys; Primojel; starch carboxymethyl ether, sodium salt; Tabla; Vivastar P.


Sodium carboxymethyl starch [9063-38-1]


The USP32-NF27 describes two types of sodium starch glycolate, Type A .and Type B, and states that sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch or of a crosslinked carboxymethyl ether of starch.

The PhEur 6.0 describes three types of material: Type A and Type B are described as the sodium salt of a crosslinked partly Ocarboxymethylated potato starch. Type C is described as the sodium salt of a · partly O-carboxymethylated starch, crosslinked by physical dehydration. Types A, B, and C are differentiated by their pH, sodium, and sodium chloride content.

The PhEur and USP-NF monographs have been harmonized for Type A and Type B variants.

Sodium sta rch glycolate may be characterized by the degree of substitution and crosslinking. The molecular weight is typically 5 x 105-1 X 106

•

Sodium Starch Glycolate 663

5 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ coshh/tablel.pdf (accessed 5 February 2009).


20 General References Doores S. Organic acids. Branen AL, Davidson PM, eds. Antimicrobials in

Foods. New York: Marcel Dekker, 1983; 85-87. Furia TE, ed. CR C Handbook of Food Additives. Cleveland, OH: CRC

Press, 1972; 13 7-141.

21 Author

T Sakurai.

22 Date of Revision

5 February 2009.


0

OH


Tablet and capsule disintegrant.

0

OH OH

n


Sodium starch glycolate is widely used in oral pharmaceuticals as a disintegrant in capsule'1- 6

> and tablet formulations.(7- lO) It is

commonly· used in tablets prepared by either direct-compression(ll- l J) or wet-granulation processes.'1 4- 16

> The usual concentration employed in a formulation is between 2% and 8%, with the optimum concentration about 4 %, although in many cases 2% is sufficient. Disintegration occurs by ra~id uptake of water followed by rapid and enormous swelling. (l

7-

2 > ·

Although the effectiveness of many disintegrants is affected by the presence of hydrophobic excipients such as lubricants, the disintegrant efficiency of sodium starch glycolate is unimpaired. Increasing _the tablet compression pressure also appears to have no effect on d1smtegrat1on tune. ( 10

-12

Y

Sodium starch glycolate has also been investigated for use as a suspending vehicle.'21

>

664 Sodiu m Starch G lycolate

8 Description Sodium starch glycolate is a white or almost white free-flowing very hygroscopic powder. The PhEur 6.0 states that when examined under a microscope it is seen to consist of: granules, irregularly shaped, ovoid or pear-shaped, 30-100 ~1111 in size, or rounded, 10- 35 ~1m in size; compound granules consisting of 2-4 components occur occasionally; the granules have an eccentric hilum and clearly visible concentric striations. Between crossed nicol prisms, the granules show a distinct black cross intersecting at the hilum; small crystals are visible at the surface of the granules. The granules show considerable swelling in contact with water.


10 Typical Properties Acidity/alkalinity See Section 9. Density (bulk)

Sf!M 1: Excipient: sodium starch glycolate (Explotab); manufacturer: JRS Pharma; magnification: 300 x ; voltage: 5 kV.

T

- :;~ 2: Excipient: sodium starch glycolate (G/yco/ys}; manufacturer: Roquettes Freres.

0.756 g/cm3 for Glycolys; 0.81 g/cm' for Primojel; 0.67 g/cm3 for Tabla.

Density (tapped) 0.945 g/cm3 for Glycolys; 0.98 g/cm3 for Primojel; 0.83 g/cm3 for Tab la.

Density (true) 1.56 g/cm3 for Primojel; 1.49 g/cm3 for Tabla.

Melting point Does not melt, but chars at approximately 200°C. NIR spectra see Figure 1. Particle size distribution 100% of particles less than 106 µmin

size. Average particle size (d50) is 38 µm and 42 µm for Primoje/ by microscopy and sieving, respectively.

Solubility Practically insoluble in methylene chloride. It gives a translucent suspension in water.

Specific surface area

0.24 m2/f for Glycolys; 0.185 m lg for Primojel; 0.335 m2/g for Tabla.

SEM 3 : Excipient: sodium starch glycolate (Primoiet manufacturer: DMVFonterra Excipients; magnification: 200 x ; voltage: 1.5 kV.

~EM 4: Excipient: sodium starch glycolate (Vivastar f1); manufacturer: JRS Pharma; magnification: 300 x ; voltage: 5 kV.

Table I: Pharmacopeial specifications for sodium starch glycolate.

Test PhEur 6.0 USP32-NF27

Identification + + Characters + Appearance of solution + pH + +

Type A 5.5-7.5 5.5-7.5 Type B 3.0-5.0 3.0-5.b Type C 5.5-7.5

Heavy metals ~ 20ppm ~ 0.002% Iron ~ 20ppm ~ 0.002% Loss on drying + ~ 10%

Type A ~ 10.0% Type B ~ 10.0% TypeC

Microbial limits ~ 7.0% +la) +la)

Sodium chloride + ~ 7.0% Type A ~ 7.0% Type B ,;:; 7.0% Type C ~ l.0%

Sodium glycolote + ~ 2.0% Type A ~ 2.0% Type B ~ 2.0% TypeC ~ 2.0%

Assay (of No) + + Type A 2.8-4.2% 2.8-4.2% Type B 2.0-3.4% 2.0-3.4% Type C 2.8-5.0%

(a) Complies with tests for Salmonella and Escherichia coli.

Swelling capacity In water, sodium starch glycolate swells to up to 300 times its volume.

Viscosity (dynamic) ,;;; 200 mPa s (200 cP) for a 4% w/v aqueous dispersion; viscosity is 4.26 mPa s for a 2 % w/v aqueous dispersion (depending on source and grade).


Tablets prefared with sodium starch glycolate have good storage properties .< 2-

24> Sodium starch glycolate is stable although very

hygroscopic, and should be stored in a well-closed container in order to protect it from wide variations of humidity and temperature, which may cause caking.

The physical properties of sodium starch glycolate remain unchanged for up to 3 years if it is stored at moderate temperatures and humidity.

12 Incompatibilities Sodium starch glycolate is incompatible with ascorbic acid. 1251

13 Method of Manufacture Sodium starch glycolate is a substituted derivative of potato starch. Typically, commercial products are also crosslinked using either sodium trimetaphosphate (Types A and B) or dehydration (Type C).(26 )

Starch is carboxymethylated by reacting it with sodium chloroacetate in an alkaline, nonaqueous medium, typically denatured ethanol or methanol, followed by neutralization with citric acid, acetic acid, or some other acid . Vivastar P is manufactured in methanolic medium, and Explotab in ethanolic medium.

14 Safety Sodium starch glycolate is widely used in oral pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material. However, oral ingestion of large quantities may be harmful.

Sod ium Starch G lyco late 665

:::=: 3.0 .----------------=,~--, 0.5 o<: 1406 1888 -·n39 '-..

2011 0)

...Q

> -~ 0.0 1-"..-+V-+t-+-.f-\c-r---Hl\---+-t---t~-r"hrff-lltt-----11-1 -0 -0

C

~ X

0 0 0

1201

' , '• .

/ ·- . , 1433

2325

1923 2282

0)

..2

~ -4. 0 ,.._..,___._ ................ __.___..___.,__..,__....___.__ ........ __._L......I - 0. 2 1100 1300 1500 1700 1900 2100 2300 2500

Wavelength/ nm

Figure 1: Near-infrared spectrum of sodium starch glycolote measured by reflectance.

15 Hcmdling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium starch glycolate may be irritant to the eyes; eye protection and gloves are recommended. A dust mask or respirator is recommended for processes that genera te a large quantity of dust.

16 Regulatory Acceptance Included in the FDA Inactive Ingredients Database (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal 'Ingredients.

17 Related Substances Prege'fatinized starch; starch.

18 Comments Sodium starch glycolate is one of the materials that have 'been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32-NF27, the General Chapter 5 .8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

The physical properties of sodium starch glycolate, and hence its effectiveness as a disintegrant, are affected by the de~ree of crosslinkage, extent of carboxyrriethylation, and purity.<27

•2 1

Sodium starch glycolate has been reported to interact with glycopeptide antibiotics, 129•301 basic drugs, and increase the photostability 'of norfloxacin. 1311 The solubility of the formulation matrix and mode of incorporation in wet granulation can affect the disintegration time; djsintegration times can be slower in tablets containing high levels of soluble excipients.<321

Commercially, sodium starch glycolate is available in a number of speciality grades, e.g. low pH (Explotab L ow pH, Glycolys Low pH); low viscosity (Explotab CLV, Glycolys LV); low solvent (Vivastar PSF); and low moisture Glycolys LM.

A specification for sodium starch glycolare is included in the Japanese Pharmaceutical Excipients (JPE) .< 33

>

19 Specific References Newton JM, Razzo FN. Interaction of formulation factors and dissolution fluid and the in vitro release of drug from hard gela tin capsules. J Pharm Pharmacol 1975; 27: 78P.

666 Sodium Starch G lycolate

2 Stewart AG et al. The release of a model low-dose drug (riboflavine) from hard gelatin capsule formulations. J Pharm Pharmacol 1979; 31: 1-6.

3 Chowhan ZT, Chi L-H. Drug-excipient interactions resulting from powder mixing III: solid state properties and their effect on drug dissolution. J Pharm Sci 1986; 75: 534-541.

4 Botzolakis JE, Augsburger LL. Disintegrating agents in hard gelatin capsules part 1: mechanism of action. Drug Dev Ind Pharm 1988; 14(1): 29-41. .·

5 Hannula A-M et al. Release of ibuprofen from hard gelatin capsule formulations: effect of modern disintegrants. Acta Pharm Fenn 1989; 98: 189- 196.

6 Marvola M et al. Effect of sodium bicarbonate and sodium starch glycolate on the in vivo disintegration of hard gelatin capsules - a radiological study in the dog. Acta Pharm Nord 1989; 1: 355- 362.

7 Khan KA, Rooke DJ. Effect of disintegrant type upon the relationship between compressional pressure and dissolution efficiency. J Pharm Pharmacol1 976;28: 633-636.

8 Rubinstein MH, Price EJ. In vivo evaluation of the effect of five disintegrants on the bioavailability of frusemide from 40 mg tablets. J Pharm Pharmacol 1977; 29: SP.

9 Caramella C et al. The influence of disintegrants on the characteristics of coated acetylsalicylic acid tablets. Farmaco (Prat) 1978; 33: 498-507.

10 Gebre Mariam T et al. Evaluation of the disintegration efficiency of a sodium starch glycolate prepared from enset starch in compressed tablets. Eur J Pharm Biopharm 1996; 42(2): 124-132.

:t 1 Cid E, Jaminet F. [Influence of adjuvants on the dissolution rate and stability of acetylsalicylic acid in compressed tablets.] J Phann Belg 1971; 26: 38-48[in French].

12 Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopicity on disintegrant efficiency in direct compression tablets in terms of dissolution. J Pharm Sci 1987; 76: 907-909.

13 Cordoba-Diaz M et al. Influence of pharmacotechnical design on the interaction and availability of norfloxacin in directly compressed tablets with certain antacids. Drug Dev Ind Pharm 2000; 26: 159- 166.

14 Sekulovic D et al. The investigation of the influence of Explotab on the disintegration of tablets. Pharmazie 1986; 41: 153- 154.

15 Bolhius GK et al. Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant. Part 2. Choice of super disintegrants and effect of granulation. Eur J Pharm Sci 1997; 5(2): 63-69 .

16 Gordon MS et al. Effect of the mode of super disinregrant incorpora tion on dissolution in wet granulated tablets. J Phann Sci 1993; 82: 220-226.

17 Khan KA, Rhodes CT. Disintegration properties of calcium phosphate dibasic dihydrate tablets. J Pharm Sci 1975; 64: 166- 168.

18 Khan KA, Rhodes CT. Water-sorption properties of tablet disintegrants. J Pharm Sci 1975; 64: 447- 451.

19 Wan LSC, Prasad KPP. Uptake of water by excipients in ta blets. Tut J Pharm 1989; 50: 147-153.

20 Thibert R, Hancock BC. Direct visualiza tion of superdisintegrant hydration using environmental scanning electron microscopy. J Pharm Sci 1996; 85: 1255- 1258.

21 Danckwerts MP et al. Pharmaceutical formulation of a fixed-dose antituberculosis combination. Int J Tuberc Lung D 2003; 7: 289-297.

22 Horhota ST et al. Effect of storage at specified temperature and humidity on properties of three directly compressible tablet fo rmulations. J Pharm Sci 1976; 65: 1746- 1749.

23 Sheen P-C, Kim S-I. Comparative study of disintegrating agents in tiaramide hydrochlor ide tablets. Drug Dev Ind Pharm 1989; 15(3): 401-414.

24 Gordon MS, Chowhan ZT. The effect of aging on disintegrant efficiency in direct compression tablets with va ried solubility and hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 16(3): 437-447.

25 Botha SA et al. DSC screening fo r drug-excipient and excipientexcipient interactions in polypharmaceuticals intended fo r the allevia-

tion of the symptoms of colds and flu. III. Drug Dev Ind Phann. 1987, 13(7): 1197-1215. · '

26 Bolhuis GK et al. On the similarity of sodium starch glycolate from different sources. Drug Dev Ind Pharm 1986; 12(4): 621-630.

27 Rudnic EM et al. Effect of molecular structure variation on the disintegrant action of sodium starch glycolate. J Pharm Sci 1985; 74: 647-650.

28 Bolhuis GK et al. Effect of variation of degree of substitution crosslinking and purity on the disintegrant efficiency of sodium starch glycolate. Acta Pharm Technol 1984; 30: 24- 32.

29 Claudius JS, Neau SH. Kinetic and equilibrium characterization of interactions between glycopeptide antibiotics and sodium carboxymethyl starch. Int J Pharm 1996; 144: 71- 79.

30 Claudius JS, Neau SH. The solution stability of vancomycin in the presence and absence of sodium carboxymethyl starch. Int J Pharm 1998; 168: 41-48.

31 Cordoba-Borrego M et al. Validation of a high performance liquid chromatographic method for the determination of norfloxacin and its application to stability studies {photostability study of norfloxacin). J Pharm Biomed Anal 1999; 18: 919-926.

32 Gordon MS et al. Effect of the mode of super disintegrant incorporation on dissolution in wet granulated tablets. J Pharm Sci 1993; 82: 220-226.

33 Japanese Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients 2004. Tokyo: Yakuji Nippo, 2004; 77~.

20 General References Augsburger LL et al. Superdisintegrants: characterisation and function.

Swarbrick J, ed. Encyclopedia of Pharmaceutical Technology, 3rd edn. London: lnforma Healthcare, 2007; 2553-2567.

Blanver. Technical literature: Tabla, Explosol, 2008. DMV-Fonterra Excipients. Technical-literature: Primojel, 2008. European Directorate for the Quality of Medicines and Healthcare

(EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. '.Pharmeuropa 2009; 21(1): 142-143. http://www.edqm.eu/site/-614.html (accessed 3 February 2009).

Edge S et al. Chemical characterisation of sodium starch glycolate particles. Int J Pharm 2002; 240: 67-78.

Edge S et al. Powder compaction properties of sodium starch glycolate disintegrants. Drug Dev Ind Pharm 2002; 28(8): 989-999.

JRS Pharma. Technical literature: Explotab, Vivastar P, 2004. Khan KA, Rhodes CT. Further studies of the effect of compaction pressure

on the dissolution efficiency of direct compression systems. Pharm Acta Helv 1974; 49: 258- 261.

Mantovani F et al. A combination of vapor sorptlon and dynamic laser light scattering methods for the determination of the Flory parameter chi and the crosslink density of a powdered polymeric gel. Fluid Phase Equilib 2000; 167(1): 63- 81.

Mendell E. An evaluation of carboxymethyl starch as a· tablet disintegrant. Pharm Acta Helv 1974; 49: 248-250.

Roquette Freres. Technical literature: Glycolys, 2008. Shah U, Augsburger L. Multiple sources of sodium starch glycolate NF:

evaluation of functional equivalence and development of standard performance tests. Pharm Dev Tech 2002; 7(3): 345-359.

Young PM et al. Interaction of moisture with sodium starch glycolate. Pharm Dev Tech 2007; 12: 211-216.

Young PM et al. The effect of moisture on the compressibility and compactability of sodium starch glycolates. Pharm Dev Tech 2007; 12: 217- 222.

21 Author

PM Young.

22 Date of Revision

3 February 2009.

_ ___________ __ rfl

728 Talc

Synonyms Jyxo-2-Hexulose

L·Tagatose Empirical formula C6H1 2 0 6

CAS number [17598-82-2] Melting point 134-135°C Specific rotation cxf)6 = + 1 ° (2 % aqueous solution) Comments Sweetening agent for pharmaceutical and personal aid

products.

18 Comments The EINECS number for tagatose is 201-772-3. The PubChem Compound ID (CID) for tagatose is 92092.

19 Specific References 1 Levin GV. Tagatose, the new GRAS sweetener and health product. J

M ed Food 2002; 5: 23-36. 2 Lu Y. Humectancies of d-tagatose and d-sorbitol. Int J Cosmet Sci 2001;

23: 175-181.

Talc

1 Nonproprietary Names BP: Purified Talc

JP: Talc PhEur: Talc USP: Talc

2 Synonyms Altaic; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate; Imperial; Luzenac Pharma; magnesium hydrogen metasilicate; Magsil Osmanthus; Magsil Star; powdered talc; purified French chalk; Purtalc; soapstone; steatite; Superiore; talcum.

3 Chemical Name and CAS Registry Number Talc [14807-96-6]

4 Empirical Formula and Molecular Weight Talc is a purified, hydrated, magnesium silicate, approximating to the formula Mg6(Si20 5 )4(0Hk It may contain small, variable amounts of aluminum silicate and iron.

5 Structural Formula See Section 4.

6 Functional Category Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant.


Talc was once widely used in oral solid dosage formulations as a lubricant and diluent, see Table I, (l-

3) although today it is less

commonly used. However, it is widely used as a dissolution retardant in the development of controlled-release products.(4

-6

)

3 FAO/WHO. Joint FAO/WHO Expert Committee on Food Additives. Chemical and Technical Assessment, 2003: 61.

4 Freimund S et al. Convenient chemo-enzymatic synthesis of D-tagatose. J Carbohydr Chem 1996; 15(1): 115-120.

5 Que L, Gray GR. 13C Nuclear magnetic resonance spectra and the tautomeric equilibria of ketohexoses in solution. Biochemistry 1974; 13(1): 146-153.


21 Author GE Amidon.

22 Date of Revision

28 February 2009.

Talc is also used as a lubricant in tablet formulations;'7' in a novel powder coating for extended-release pellets;(B) and as an adsorbant. (9 )

In topical preparations, talc is used as a dusting powder, although it should not be used to dust surgical gloves; see Section 14. Talc is a natural material; it may therefore frequently contain microorganisms and should be sterilized when used as a dusting powder; see Section 11 .

Talc is additionally used to clarify liquids and is also used in cosmetics and food products, mainly for its lubricant properties.

Table I: Uses of talc.

Use

Dusti ng powder Glidant and tablet lubricant Tablet and capsule diluent

8 Description

Concentration (%)

90.0-99.0 1.Q:.-10.0 5 .0-30.0

Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness.

9 Pharmacopeial Specifications See Table II. See also Section 18.

10 Typical Properties Acidity/alkalinity pH= 7-10 for a 20% w/v aqueous dispersion. Hardness (Mohs) 1.0-1.5 Moisture content Talc absorbs insignificant amounts of water at

25.°C and relative humidities up to about 90%. NIR spectra see Figure 1. Particle size distribution Varies with the source and grade of

material. Two typical grades are ;,: 99% through a 74 µm (#200 mesh) or ;,: 99% through a 44 µm _(#325 mesh) .

SEM 1: Excipient: talc (Purtalc); manufacturer: Charles B Chrystal Co., Inc.; lot no.: l 102A-2; magnification: 1200x ; voltage: lOkV.

SEM 2: Excipient: talc; magnification: l 000 x; voltage: 3 kV.

t !

Refractive index n5° = 1.54- 1.59 Solubility Practically insoluble in dilute acids and alkalis, organic

solvents, and water. Specific gravity 2.7- 2.8 Specific surface area 2.41- 2.42 m 2/g

Talc 729

Table II: Pharmacopeial specifications for talc.

Test

Identification Characters Acid-soluble substances Acidity or alkalinity Production pH Water-soluble substances Aluminum Calcium Iron. Lead Magnesium Loss on ignition Microbial contamination

Aerobic bacteria

Fungi

Acid and alkali-soluble substances

Water-soluble iron Arsenic Heavy metals Absence of asbestos

JPXV

+ + ~ 2.0%

,;:; 5.0%

,;:; 4.0mg

+ ,;:; 4ppm

(a) If intended for topical administration. (b) If intended for oral administration.

PhEur 6.3

+ +

+ +

~ 0.2% ~2.0% ~ 0 .9% ~ 0 .25% ~ lOppm 17.0-19.5% ~ 7.0% + ,;:; l02 cfu/g

~ 102 cfu/g

USP 32

+

,;:; 2.0% +

,;:; 0.1 % 2.0% 0.9% 0.25% ,;:; 0.001% 17.0- 19.5% ,;:;7.0% ~ 500cfu/g l 02 du/ glaf 103 cfu/glbJ 50cfu/gTa) 102cfu/g161

,;:; 2.0%

,;:; 3 ppm ,;:; 0.004% +

3 .0 .----------------, 0. 2 o2" "-.

0) _Q

> ·.: Q)

""'O ""'O

C

~ X

0 0 0

0.0

1379 1405

,1392 ,, ,, ,, ,, ,, - ... 4 ....... ,;' .. ........ .. .. - - .. .. .... .... .. ............ .. 23 12

0) _Q

- 5 . 0 ,_...__...,__._____.____._..._...__.....__._____.____._.___.___. -0. 2 1100 1300 1500 1700 1900 2100 2300 2500

. Wavelength/nm

Figure 1: Near-infrared spectrum of talc measured by reflectance.

11 Stability and Storage Conditions Talc is a stable material and may be sterilized by heating at 160°C for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation.!1 °1

Talc should be stored in a well-closed container in a cool, dry place.

12 Incompatibilities Incompatible with quaternary ammonium compounds.

13 Method of Manufacture Talc is a naturally occurring hydropolysilicate mineral found in many parts of the world including Australia, China, Italy, India, France, and the USA.1111

The purity of talc varies depending on the country of origin. For example, Italian types are reported to contain calcium silicate as the contaminant; Indian types contain aluminum and iron oxides; French types contain aluminum oxide; and American types contain calcium carbonate (California), iron oxide (Montana), aluminum

730 Talc

and iron oxides (North Carolina), or aluminum oxide (Alabama).'12>

Naturally occurring talc is mined and pulverized before being subjected to flotation processes to remove various impurities such as asbestos (tremolite); carbon; dolomite; iron oxide; and various other magnesium and carbonate minerals. Following this process, the talc is finely powdered, treated with dilute hydrochloric acid, washed with water, and then dried. The processing variables of agglomerated talc strongly influence its physical characteris-tics.<13- 15> ·

14 Safety Talc is used mainly in tablet and capsule formulations. Talc is not absorbed systemically following oral ingestion and is therefore regarded as an essentially nontoxic material. However, intranasal or intravenous abuse of products containing talc can cause granulomas in body tissues, particularly the lungs.'16

-18) Contamination of

wounds or body cavities with talc may also cause granulomas; · therefore, it should not be used to dust surgical gloves. Inhalation of talc causes irritation and may cause severe respiratory distress in infants;09) see also Section 15.

Although talc has been extensively investigated for its carcinogenic potential, and it has been suggested that there is an increased risk of ovarian cancer in women using talc, the evidence is inconclusive. '20•21 ) However, talc contaminated with asbestos has been proved to be carcinogenic in humans, and asbestos-free grades should therefore be used in pharmaceutical produccs. '22>

Also, long-term toxic effects of talc contaminated with large quantities of hexachlorophene caused serious irreversible neurotoxicity in infants accidentally exposed to the substance.<23>

1 5 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. Talc is irritant if inhaled and prolonged excessive exposure may cause pneumoconiosis.

In the UK, the workplace exposure limit for talc is 1 mg/m3 of respirable dust long-term (8-hour TWA).'24> Eye protection, gloves, and a respirator are recommended.

16 Regulatory Status Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (buccal tablets; oral capsules and tablets; rectal and topical preparations). Included in nonparentera l medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances Bentonite; magnesium aluminum silicate; magnesium silicate; magnesium trisilicate.

18 Comments Talc is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Various grades of talc are commercially available that vary in their chemical composition depending upon their source and method of preparation.<1 1·25·26>

Talc derived from deposits that are known to contain associated asbestos is not suitable for pharmaceutica l use. Tests for amphiboles and serpentines should be carried out to ensure that the product is free of as bestos.

A specifica tion for talc is contained in the Food Chemicals Codex (FCC).<27>

The EINECS number for talc is 238-877-9. The PubChem Compound ID (CID) for talc includes 26924, 443754 and 16211421.

19 Specific References 1 Dawoodbhai S, Rhodes CT. Pharmaceutical and cosmetic uses of talc.

Drug Dev Ind Phann 1990; 16: 2409-2429. 2 Dawoodbhai S et al. Optimization of tablet formulations containing

talc. Drug Dev Ind Phann 1991; 17: 1343-1371. 3 Wang DP et al. Formulation development of oral controlled release

pellets of diclofenac sodium. Drug Dev Ind Phann 1997; 23: 1013-101 7.

4 Fassihi RA et al. Potential use of magnesium stearate and talc as dissolution retardants in the development of controlled release drug delivery systems. Pharm Ind 1994; 56: 579-583.

5 Fassihi R et al. Application of response surface methodology to design optimization in formulation of a typical controlled release system. Drugs Made Ger 1996; 39(Oct-Dec): 122-126.

6 Schultz P et al. New multiparticulate delayed release system. Part 2. Coating fo rmulation and properties of free films. J Control Release 1997;47: 191- 199.

7 Oetari RA et al. Formulation of PGV-O a new antiinflammatory agent as a tablet dosage form. Indonesian J Pharm 2003; 14(4): 160-168.

8 Pearnchob N, Bodmeier R. Dry powder coating of pellets with micronized Eudragil (R) RS for extended drug release. Pharm Res 2003; 20(12): 1970-1 976.

9 Mani N et al. Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure: II. Effects of adsorbents on microsphere properties. Drug Dev Ind Pharm 2004; 30(1): 83- 93.

10 Bubik JS. Preparation of sterile talc for treatment of pleural effusion [letter]. Am J Hosp Pharm 1992; 49: 562-563.

11 Grexa RW, Parmentier CJ. Cosmetic talc properties and specifications. Cosmet Toilet 1979; 94(2): 29-33.

12 H oepfner EM et al, ed. Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th edn, vol. II: Aulendorf: Editio Cantor Verlag, 2002; 1556-1559.

13 Lin K, Peck GE. Development of agglomerated talc. Part 1. Evaluation of fluidized bed granulation parameters on the physical properties of agglomerated talc. Drug Dev Ind Pharm 1995; 21: 447-460.

14 Lin K, Peck GE. Development o f agglomerated talc. Part 2. Optimization of the processing parameters for the preparation of granulated talc. Drug Dev Ind Pharm 1995; 21: 159-173.

15 Lin K, Peck GE. Development of agglomerated talc. Part 3. Comparisons of the physical properties of the agglomerated talc prepared by three different processing methods. Drug Dev Ind Pharm 1996; 22: 383-392.

16 Schwartz IS, Bosken C. Pulmonary vascular talc granulomatosis . J Am Med Assoc 1986; 256: 2584.

17 Johnson DC et al. Foreign body pulmonary granulomas in an abuser of nasally inhaled drugs. Pediatrics 1991; 88: 159- 161.

18 Sparrow SA, H allam LA. Talc granulomas [letter). Br Med] 1991; 303: 58.

19 Pairaudeau PW et al. Inha lation of baby powder: an unappreciated hazard. Br Med] 1991; 302: 1200- 1201.

20 Longo DL, Young RC. Cosmetic talc and ovarian cancer. Lancet 1979; ii: 349- 351.

21 Phillipson IM. Talc quality [letter). Lancet 1980; i: 48. 22 International Agency for Research on Cancer/World Health Organizaf

tion. Silica and Some Silicates: !ARC Monographs on the Evaluation° the Carcinogenic Risk of Chem icals to Humans. Geneva: WHO, 1987: 42.

23 Anonymous. Long-term sequelae of hexachlorophene poisoning, Prescrire Int 1992; 1: 168.

24 Health and Safety Executive. EH40/2005: Workplace Ex posure LirniW Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.u coshh/ta hlel.pdf (accessed 3 February 2009).

25 Phadke DS et al. Evaluation of batch-to-batch and manufacturer-tomanufacturer variability in the physica l properties of talc and steanc acid. Drug Dev Ind Pharm 1994; 20: 859- 871.

26 Lin K, Peck GE. Characterization of talc samples from different sources. Drug Dev fod Phann 1994; 20: 2993- 3003.

27 Food Chemicals Codex , 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 943.

20 General References European Directorate for the Quality of Medicines and Healthcare


Gold G, Campbell JA. Effects of selected USP talcs on acetylsalicylic acid stability in tablets. J Pharm Sci 1964; 53: 52-54.

Leterne P et al. Influence of the morphogranulometry and hydrophobicity of talc on its antisticking power in the production of tablets. Int J Pharm 2005;289: 109-115.

& Tartaric Acid

1 Nonproprietary Names BP: Tartaric Acid

JP: Tartaric Acid

PhEur: Tartar ic Acid

USP-NF: Tartaric Acid

2 Synonyms

Acid um tartaricum; L-( + )-2,3-dihydroxybutanedioic acid; (2R,3R)-2,3-dihydroxybutane-1,4-dioic acid; 2,3-dihydroxysuccinic acid; E334; d-tartaric acid; L-( + )-tartaric acid.


[R-(R * ,R *))-2,3-Dihydroxybutanedioic acid (87-69-4]


C4H60 6 150.09



Acidifying agent; flavoring agent; sequestering agent.


Tartaric acid is used in beverages, confectionery, food products, and pharmaceutica l formulations as an acidulant. It may also be used as a sequestering agent and as an antioxidant synergist. In pharmaceutical formulations, it is widely used in combination with bicarbonates, as the acid component of effervescent granules, powders, and tablets.

Tartaric acid is also used to form molecula r compounds (salts and cocrystals) with active pharmaceutical ingredients to improve physicochemical properties such as dissolution rate and solubilityY •2)

_L _________ -- -

Tartaric Acid 731

21 Author

AH Kibbe.

22 Date of Revision

3 February 2009.

8 Description Tartaric acid occurs as colorless monoclinic crystals, or a white or almost white crystalline powder. It is odorless, with an extremely tart taste.

9 Pharmacopeial Specifications See Table I.

Table I: Pharmacopeial specifications for tartaric acid.

Test JPXV PhEur 6.0 USP32-NF27

Identification + + + Characters + Appearance of solution + Specific rotation + 12.0° to + 12.0° 10

+ 12.8° + 13.0° Loss on drying ~ 0.5% ~ 0.2% ~ 0.5% Sulfated ash .;;0.1% Residue on igni tion ~ 0.05% ~ 0 .1 % Chloride ~ JOO ppm Oxalic acid ~ 350ppm Oxalate + + Sulfate ~ 0.048% ~ 150ppm + Calcium + ~ 200ppm Heavy metals ~ lOppm ~ l Oppm ~ 0.001 % Arsenic ~ l ppm Assay !dried basis) ;,, 99.7% 99.5-101.0% 99.7- 100.5%

10 Typical Properties Acidity/alkalinity pH= 2.2 (1.5% w/v aqueous solution) Density l.76 g/cm Dissociation constant

pK. 1 = 2.93 at 25°C;

pK.2 = 4.23 at 25°C. Heat of combustion 1151 kJ/mol (275. 1 kcal/mo!) Melting point 168-170°C NIR spectra see Figure l. Osmolarity A 3.9% w/v aqueous solution 1s isoosmotic with

serum. Solubility see Table II. Specific heat 1.20 JI§ (0.28 8 cal/g) at 20°C. Specific rotation [a]0°=+12.0° (20% w/v aqueous solution) .

--

w ~ Water


BP: Purified Water JP: Purified Water PhEur: Water, Purified

USP: Purified Water See also Sections 8 and 17.

2 Synonyms Aqua; aqua purificata; hydrogen oxide.

3 Chemical Name and CAS 'Registry Number

Water [7732-18-5]


H2O 18.02


See Section 4.


Solvent.


Water is widely used as a raw material, ingredient and solvent in the processing, formulation and manufacture of pharmaceutical products, active pharmaceutical ingredients ·(API) and intermediates, and analytical reagents. Specific gi'ades of water are used for particular applications in concentrations up to 100%; see Table I.

Table I: Typical applications of specific grades of water.

Type

Bacteriostatic water for in jection

Potable water

Purified water

Sterile water for inhalation

Sterile water for injection Sterile water for irrigation

Water for injections in bulk

8 Description

Use

Diluent for ophthalmic and multipledose injections.

Public supply suitable for drinking, the purity of which is unlikely to be suitable for use in the manufacture of pharmaceuticals.

Vehicle and solvent for the manufacture of drug products and pharmaceutical preparations; not suitable for use in the manufacture of parenteral products.

Diluent for inhalation therapy products.

Diluent for injections. Diluent for internal irrigation therapy

products , Water for the bulk preparation of

medicines for parenteral administration.

The term 'water' is used to describe potable water that is freshly drawn direct from the public supply and is suita ble fo r drinking. Water used in the pharmaceutical industry and related disciplines is classified as either drinking (potable) water, purified water, sterile

766

purified water, water for injection (WFI), sterile water for injection bacteriostatic water for injection; sterile water for irrigation, 0 ;

sterile water for inhalation. Validation is required for all systems producing the water indicated, with the exception of potable water.

The chemical composition of potable water is variable, and the nature and concentrations of the impurities in it depend upon the source from which it is drawn. Water classified as potable water for applications such as some initial rinsing and API manufacturing operations, must meet the US Environmental Protection Agency's National Primary Drinking Water Regulations, or comparable regulations of the EU or Japan. For most pharmaceutica l applications, potable water is purified by distillation, ion exchange treatment, reverse osmosis (RO), or some other suitable process to produce 'purified water'. For certain applications, water with pharmacopeial specifications differing from those of purified water should be used, e.g. WFI; see Sections 9 and 18.

Water is a clear, colorless, odorless, and tasteless liquid.


See Table IL See also Section 17.

10 Typical Properties Boiling point l 00°C Critical pressure 22.l MPa (218.3 atm) Critical temperature 374.2°C Dielectric constant D 25 = 78.54 Dipole moment

1.76 in benzene at 25°C;

1.86 in dioxane at 25°C. Ionization constant 1.008 x 10- 14 at 25°C. Latent heat of fusion 6 kJ/mol (1.436 kcal/mo!) Latent heat of vaporization 40.7 kJ/mol (9.71 7 kcal/mo!) Melting point 0°C Refractive index ni0 = 1.3330 Solubility Miscible with most polar solvents. Specific gravity 0.9971 at 25°C. Specific heat (liquid) 4.1 84 J/g/°C (1.00 cal/gl°C) at 14°C. Surface tension 71.97 mN/m (71.97 dynes/cm) at 25°C. Vapor pressure 3.17 kPa (23.76 mmHg) at 25°C. Viscosity (dynamic) 0.89 mPa s (0. 89 cP) at 25°C.

11 Stability and Storage Conditions Water is chemically stable in all physical states (ice, liquid, and vapor). Water leaving the pharmaceutical purification system and entering the storage tank must meet specific requirements. The go~! when designing and operating the storage and distribution system is to keep the water from exceeding allowable limits during storage·. In particular, the storage and distribution system must ensure that water is protected against ionic and organic contamination, which would lead to an increase in conductivity and total organic carbon, respectively. The system must also be protected against physical entry of foreign particles and microorganisms so that microbial growth is prevented or minimized. Water for specific pu rposes should be stored in appropriate containers; see Table Ill.

r Table 11, Phmmocopeiol specificotioos of=•>< foe diff<mt phocmoce'"col opplicotiocs --... --- -- --- ·-

Test Water Purified Purified Purified Purified Water, Sterile Baderiastatic Sterile Sterile Sterile Water for Water for Water for Sterile Sterile JP XI/ water water in waler in water high~ water for water for water for water for purified injection101 injection injection water for purified

JP XI/ bulk containers USP 32 purified injection injection inhalation irrigation water JP XI/ USP 32 (in bulk) injection water PhEur 6.3 PhEur 6.3 PhEur 6.3 USP 32 USP 32 USP 32 USP 32 USP 32 PhEur 6.3 PhEur 6.3 JP XI/

Identification Product ion - - + - + Characters - + ..... ·- · + - - - - - - - + Appearance of solution - + - - - - - - - - - - - - + Odor a nd taste - + - - - - - - - - - - - + pH - - - - - - 5 .0-7.0 4 .5-7 .0 Acid or a lkali - + + - - - - - - - + - - + + Cadmium

Chloride - + - + - - + - - - - - + - + + Cyanide Copper Sulfate - + + - - + - - - - + - + + Ammonium ,;; 0.05 mg/ l ,;; 0.05mg/ l - ,;; 0 .2 ppm - - + - - - - + - - ,;; 0.2ppm ,;; 0 .05 mg/ l Iron

Calcium - - + - + + - - - - - - + lead

Magnesium - - + - - - - - - - - - - + Aluminum - - ,;; ]0ppb - - ,;; l0ppb - - - - - - - ,;;l 0ppb ,;;] 0ppb Nitrate - - ,;; 0.2 ppm - - <; 0.2 ppm - - - - - - - ,;; 0.2 ppm <; 0.2 ppm + Nitrogen from nitrate - + - - - - - - - - + - - - + Nitrogen from nitrite - + - - - - - + - - - + Carbon dioxide - - - - + + Heavy metals - + <; 0.1 ppm - - - - - - - - + - - - + Oxidizable substances - - + + - - + - + + + - - - + Potassium - + - - - - - - - - - + - - - +

permanganate-reducing substances

Residue-on evaporation - ;!f l .O mg - :!f 0.001 % - - - - - + - - • ~ l.Omg Total organic carbon - - + - + ,;;0.5 mg / l - - - - +!bl + ,;; 0.5 mg/l Tota l hardness - - - - - - - - - - - -Conductivity - - + - - + - - ,;; 25 µS/cm for ,;;25 µS/ cm for · ,;; 25 µS/cm - + + ,;; 25 µS/ cm for

containers containers for containers containers ,;; l0ml, ,;; l 0ml, ,;; l0ml, ,;; l 0ml, ,;; 5 µS/ cm ,;; 5 µS / cm ,; 5 µS / cm for ,;; 5 µS/ cm for containers for containers containers for containers ;, 10ml ;, 10 ml ;, 10ml ;, 10 ml

Anionic surfactants Antimicrobial agents - - - - - - - + Steril ity - - - - - - + + + + + T - - + + Extractable volume - - - - - - - - - - - + Particulate matter - - - - - + + - - - - + Microbial contamination - - - ~ 102 du/ ml Bacterial endotoxins - - ,;; 0.25 1U/ml - - ,; 0 .25 1U/ml ,; 0 .25EU/ ml <0.5 EU/ ml <0.5 ~U/ ml ,;;0.25 EU/ ml - ,;; 0.25EU/ml ,; 0.25 EU/ ml ,;; 0 .25tU/ ml <0.251U/ ml

(a) For water for injection preserved in containers and sterilized, the JP XV provides separate tests for ocid or alkal i, chloride, ammonium, ond residue on evaporation within the monograph. (b) For woter for injection prepared by reverse osmosis-u ltrofiltrotion.

~ 0 co

"" 0,.

""

768 W a te r

Table Ill: Storage requirements for differen t grades of water.

Type

Bacteriostatic water for injection

Potable water Purified water

Sterile water for inhalation

Sterile water for injection

Water for injection Water for injections in bulk

----Storage requirements10J

Preserve in single-dose and multipledose containers, preferably of Type I or Type II glass, not larger than 30 ml in size.

Preserve in tightly sealed containers. Preserve in tightly sealed containers.

If it is stored in bulk, the conditions of storage should be designed to limit the growth of microorganisms and avoid any other contamination.

Preserve in single-dose containers, preferably of Type I or Type II glass.

Preserve in -~ingle-dose containers, preferably of Type I or Type II glass, not more than 1000 ml in size.

Preserve in tightly sealed containers. Collect and store in conditions

designed to prevent growth of microorganisms and avoid any other contamination.

(a) To prevent evaporation and to maintain quality.

12 Incompatibilities In pharmaceutical formulations, water can react with drugs and other excipients that are susceptible to hydrolysis (decomposition in the presence of water or moisture) at ambient and elevated temperatures.

Water can react violently with alkali metals and rapidly with alkaline metals and their oxides, such as calcium oxide and magnesium oxide. Water also reacts with anhydrous salts to form hydrates of various compositions, and with certain organic materials and ca lcium carbide.

13 Method of Manufacture Unlike other excipients, water is not purchased from outside suppliers but is manufactured in-house by pharmaceutical companies. As naturally occurring water has a variety of contaminants, many treatment processes have been developed to remove these. A typical pharmaceutical water purification system contains several unit 'operations designed to remove various components. The selection of the most appropriate system and its overall design are crucial factors in ensuring that water of the correct quality is produced. 11•21

To produce potable or drinking water, insoluble matter is first removed from a water supply by coagulation, settling (clarification), and filtering processes. Pathogenic microorganisms present are then destroyed by aeration, chlorination, or some other means. Water may also be rendered free of viable pathogenic microorganisms by active boiling for 15-20 minutes. Activated carbon filters are employed to remove chlorine and many dissolved organic materials found in water, although they may become a breeding ground for microorganisms. The palatability of the water is improved by aeration and charcoal filtration.

Purified water suitable for use in pharmaceutical formulations is usually prepared by purifying potable water by one of several processes, such as distillation, deionization, or R0. 11 ,3-s>

The quality attributes of WFI are stricter than those for purified water. Consequently, the preparation methods typically vary in the last stage to ensure good control of WFI quality. Methods for the production of WFI arc the subject of current debate. The PhEur 6.3 indicates that only distillation would give assurance of consistent supply of the appropriate quality, but permits distillation, ion

exchange, RO or any other suitable method that complies with regulations on water intended for human consumption laid down by the competent authority. The USP 32 and the JP XV permit the use of RO in additioq to distillation and ultrafiltration. In the past 10-15 years, RO has become the most common way to produce pharmaceutical purified water, either as a final treatment step or as a pretreatment step for the distillation stills. Distillation Distillation is a process that involves the evaporation

of water followed by the condensation of the resulting steam. While expensive, it allows removal of almost all organic and inorganic impurities and achieves very high quality water. It is also considered the safest method to avoid microbial and endotoxin contamination. To improve energy efficiency, distillation is usually conducted in multiple-effects stills designed to recover most of the energy spent on evaporating the water. A typical design consists of an evaporator, vapor separator, and compressor. The distilland (raw feed water) is heated in the evaporator to boiling and the vapor produced is separated from entrained distilland in the separator. The vapor then enters a compressor where the temperature of the vapors is raised to 107°C. Superheated vapors are then condensed on the outer surface of the tubes of the evaporator containing cool distilland circulating within.

Vapor compression stills of various sizes are commercially available and can be used to produce water of high purity when properly constructed. A high-quality distillate, such as WFI, can be obtained if the water is first deionized. The best stills are constructed from types 304 or 316 stainless steel and coated with pure tin, or are made from chemical-resistant glass.

Deionization An ionic exchange process is bas~d on the ability of certain synthetic resins to selectively adsorb either cations or anions, and to release (exchange) other ions based on their relative activity. Cationic and anionic ion exchange resins are used to purify potable water by removing any dissolved ions. Dissolved gases are also removed, while chlorine, in the concentrations generally found in potable water, is destroyed by the resin itself. Some organics and colloidal particles are removed by adsorption and filtration. Resin beds may, however, foster microbial life and produce pyrogenic effluent unless adequate precautions are taken to prevent contamination. Another disadvantage is the type of chemicals required for resin regeneration. A continuous deionizacion system, which represents a combination of ion exchange and membrane separation technologies, uses an electrical current to continuously regenerate the ion exchange resin simultaneously with the water treatment process, eliminating the need to handle powerful chemicals. Ion exchange units are normally used today to treat raw feed water prior to distillation or RO processing.

Reverse osmosis Water is forced through a semipermeable membrane in the opposite direction to norm,al osmotic diffusion. Typically, membranes range between 1-10 A and reject not only organic compounds, bacteria and viruses, but also 90-99 % of all ions. It is common to use double-pass RO systems with two filtration stages connected in series . Such systems meet requirements for USP purified water and WFI. However, EU regulations do not allow RO to be used as a final treatment step for the production of WFI.

Membrane filtration Membrane filters are surface-type filters, which stop particles larger than the pore size at the upstream surface of the polymeric membrane. Microfiltration uses membranes with pores in the 0.1- 1.0 µm range, which can fil ter out particles of dust, activated carbon, ion exchange resin fin es, and most microorganisms. Ultrafiltration uses membra nes that reject not only solid particles but also dissolved matter with a high molecular weight. The 'molecular weight cut-off' point of such membranes varies in the range 10 000- 100 000 Da, and bacteria, endotoxins, colloidal contaminants, and large organic molecules can be removed.

14 Safety

Water is the base for many biological life forms, and its safety in pharmaceutical formulations is un~uestioned provided it meets standards of quality for potability( l and microbial content; see Sections 9 and 18. Plain water is considered slightly more toxic upon injection into laboratory animals than physiological salt solutions such as normal saline or Ringer's solution.

Ingestion of excessive quantities of water can lead to water intoxication, with disturbances of the electrolyte balance.

WFI should be free from pyrogens. ·

LDso (mouse, IP): 25 g/kg(lO)


Observe normal precautions appropriate to the circumstances and quantity of material handled. ·


Included in nonparenteral and parenteral medicines licensed in the UK and USA.


Bacteriostatic water for injection; carbon dioxide-free water; deaerated water; hard water; soft water; sterile water for inhalation; sterile water for injection; sterile water for irrigation; water for injection (WFI).

Bacteriostatic water for injection Comments The USP 32 describes bacteriostatic water for injection

as sterile water for injection that contains one or more suitable antimicrobial agents.

Carbon dioxide-free w ater Comments Purified water that has been boiled vigorously for 5

minutes and allowed to cool while protecting it from absorption of atmospheric carbon dioxide.

De-aerated water Comments Purified water that has been boiled vigorously for 5

minutes and cooled to reduce the air (oxygen) content.

Hard water Comments Water containing the equivalent of not less than

120 mg/L and not more than 180 mg/L of calcium carbonate.

Soft water Comments Water containing the equivalent of not more than

60 mg/L of calcium carbonate.

Sterile water for inhalation Comments The USP 32 describes sterile water for inhalation as

WFI sterilized and suitably packaged. It contains no antimicrobial agents or other added substances, except where used in humidifiers or other similar devices, and where liable to contamination over a period of time.

Sterile water for injection Comments The USP 32 describes sterile water for injection as WFI

sterilized and suitably packaged. It contains no antimicrobial agents or other substances.

Sterile water for injection in containers is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the General Chapter 5. 8 in PhEur 6.0, a long with the 'Sta te of Work' document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV.

Water 769

Sterile w ater for irrigation Comments The USP 32 describes sterile water for irrigation as

WFI sterilized and suitably packaged. It contains no antimicrobial agents or other substances.

Water for injection (WFI) Comments The USP 32 describes WFI as water purified by

distillation or RO. It contains no added substances. The PhEur 6.3 title is 'water for injections' and comprises two parts: 'water for injections in bulk' and 'sterilized water for injection'. The PhEur 6.3 states that water for injections is produced by distillation.

18 Comments In most pharmacopeias, the term 'water' now refers to purified or distilled water.

Without further purification, 'water' may be unsuitable for certain pharmaceutical applications; for example, the presence of calcium in water affects the viscosity and gel strength of algins and pectin dispersions, while the use of potable water affects the clarity and quality of cough mixtures, and the stability of antibiotic liquid preparations.

Water commonly contains ·. salts of aluminum, calcium, iron, magnesium, potassium, sodium, and zinc. Toxic substances such as arsenic, barium, cadmium, chromium, cyanide, lead, mercury, and selenium may constitute a danger to health if present in excessive amounts. Ingestion of water containing high amounts of calcium and nitrate is also contraindicated. National standards generally specify the maximum limits for these inorganic substances in potable water. Limits have also been placed on microorganisms, detergents, phenolics, chlorinated phenolics, and other organic substances. The WHO(ll) and national bodies have issued guidelines for water quality, although many countries have their own standards for water quality embodied in specific legislation.'12

) See Table IV.

Table IV: Limits for inorganic substances in potable water (mg/L).

Contominant

Aluminum Ammonium Antimony Arsenic Barium Beryllium Boron Cadmium Calcium Chloride Chromium Copper Cyanide Fluoride Iron Lead Magnesium Manganese Mercury Nickel Nitrate (as N) Nitrate (as N03) Nitrite (as N02) Phosphorus Potassium Selenium Silver Sodium Sulfate Zinc

---------~----

UK (mg/L)

0.2 0.5 0.01 0.05 1.0

2.0 0.005 250 400 0.05 3.0 0.05 1.5 0.2 0.05 50 0.05 0.001 0.05

50 0.1 2.2 12 0.01 0.01 150 250 5.0

WHO (mg/L)

0.2

0.05 No limit No limit

0.005

250 0.05 1.0 0.1 1.5 0.3 0.05

0.1 0.001 No limit 10

0.01 No limit 200 400 5.0

----

-~----..-..l

770 Wax, Anionic Emulsifying

Control of microbiological contamination is critical for waters used in preparation of pharmaceuticals, as proliferation of microorganisms can potentially occur during all stages of manufacture, storage, or distribution. Suitable control is achieved by ensuring that the water system is well designed and well maintained. Purified water that is produced, stored, and circulated at ambient temperatures is susceptible to the establishment of biofilms; therefore, frequent monitoring, high usage, correct flow rate, and appropriate sanitization are all factors that require consideration to ensure that water is satisfactory.<13

)

5 Cross J. Steam sterilisa ble ultrafiltration membranes, Manuf Chern 1989; 60(3): 25-27.

6 Horry JM, Cross JR. Purifying water for ophthalmic and injectable preparations. Pharm ] 1989; 242: 169- 171,

7 Smith VC. Pure water. Manuf Chem 1990; 61(3): 22-24. 8 Burrows WD, Nelson JH. IV fluidmakers: preparation of sterile water

for injection in a field setting. J Parenter Sci Technol 1993; 47(3): 124-129.

9 Walker A. Drinking water - doubts about quality. Br Med] 1992; 304: 175- 178.

10 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 3692. Monitoring of the whole system is essential in order to

demonstrate that correct microbiological quality is achieved. For . 11 WFI, the recommended methodology is membrane filtration'. (0.45 µm) as a large sample size (100-300 mL) is required. For purified water, membrane filtration or plate count methods are typically used depending on the quality requirements of the system.

World Health Organiza tion. Guidelines for Drinking-water Quality, vol. 1: Recommendations. Geneva: WHO, 1984.

12 Statutory Instrument 114 7. The water supply (water quality) regulations 1989. London: HMSO, 1989. http://www.opsi.gov.uk/ (accessed 27 February 2009).

It is important to set appropriate target, alert, and action limits to serve as an indication of action required to bring the quality of water back under control. It is recognized that limits are not intended as pass/fail criteria for water or product batches; however an investigation regarding the implications should be conducted. (l

4l Validation is conducted to provide a high level of assurance that

the water production and distribution system will consistently produce water conforming to a defined quality specification. The validation process serves to qualify the design (DQ), installation (IQ), operation (OQ), and performance (PQ) of the system. The extent of monitoring data required should be defined, with consideration given to whether validation to FDA guidelines is required.< 14

) It is also important to have an ongoing control program with respect to maintenance, and periodic reviews of the performance of the water system.

The PubChem Compound ID (CID) for water is 962.

19 Specific References 1 Thomas WH, Harvey H. Achieving purity in pharmaceutical water.

13 Riedewald F. Biofilms in pharmaceutica l waters. Pharm Eng 1997; Nov/Dec: 8- 18. ·

14 Food and Drug Administration. Guide to Inspections of High Purity Water Systems. Washington, DC: FDA, 1993. http://www.fda.gov/ora/ inspect_ref/igs/high.html (accessed 27 February 2009).

20 General References Collentro WV, ed. Pharmaceutical Water: System Design, Operation and

Validation. Buffalo Grove, IL: interpharm Press, 1999. European Directorate for the Quality of Medicines and Healthcare


Rossler R. Water and air, two important media in the manufacture of sterile pharmaceuticals, with regard to the GMP. Drµgs Made Ger 1976; 19: 130- 136. .

Santoro M, Maini C. Which water fo r pharmaceutical use? Eur J Parenter Pharm Sci 2003; 8: 15- 20.

Manuf Chem Aerosol N ews 1976; 47(10): 32, 36, 39, 40. 21 Authors 2 McWilliam AJ. High purity water distribution systems. Pharm Eng

1995; Sept/Oct: 54-71. D Dubash, U Shah. 3 Honeyman T. Purified water for pharmaceuticals. Manuf Chem 1987;

58(3): 53, 54, 57, 59. 22 Date of Revision 4 Cross J. Treating waters for the pharmaceutical industry. Manuf Chem

1988; 59(3): 34- 35. 27 February 2. UWJ.

& Wax, Anionic Emulsifying

1 Nonproprietary Names BP: Emulsifying Wax

PhEur: Cetostearyl Alcohol (Type A), Emulsifying

PhEur: Cetostearyl Alcohol (Type B), Emulsifying

2 Synony ms

Collone HV; Crodex A; Cyclonette Wax; Lanette SX; Lanette W.

3 Chemical Name and CAS Registry Number Anionic emulsifying wax [8014-38-8]

4 Empirical Formula a nd Molecular Weight The PhEur 6.2 specifies that cetostearyl alcohol (type A), emulsifying contains a minimum of 80% cetostearyl alcohol and 7 % sodium cetostearyl sulfate. Cetostearyl alcohol (type B), emulsifying contains a minimum of 80% cetostearyl alcohol and 7% sodium lauryl sulfate. A suitable buffer can be added to both.

The BP 2009 describes anionic emulsifying wax as containing cetostearyl alcohol, purified water, and either sodium lauryl sulfa te or a sodium salt of a similar sulfated higher primary aliphatic alcohol. See also Section 18.

The BP 2009 specifies tha t the formula o f anionic emulsifying wax 1s:

Cetostea ryl alcohol Sodium lauryl sulfate Purified water

90g lOg 4 ml

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