QualitySupply safetyGlobal commitment.BASF – Yourpartner for thefuture.

No. 3, November 1999

Excipients & Actives for Pharma

New PharmaceuticalExcipients page 1

Calendar page 1

KollicoatY

SR 30 D page 2–3

Copovidone page 4

LutrolY F 68 page 5–6

SolutolY HS 15 page 7

Ibuprofen page 8–11

Product Launch page 11

Preview page 12

New Media page 12

Contact page 12

New PharmaceuticalExcipientsDear reader,You have probably heard A. T. Florence’s well-knownquestion, “Where are the new pharmaceuticalexcipients?” The background to this question is thatthere have been no major advances in the field ofpharmaceutical excipients in recent years. This isto change, as BASF AG has greatly increasedresearch and development for excipients. We aredeveloping entirely new innovative excipients forwhich comprehensive toxicological studies will benecessary, and this is entailing high developmentcosts. BASF AG is well placed to carry out this work,as it has both extensive experience in the manu-factures of polymers and great expertise in their usein pharmaceutical formulations. These new productswill make BASF one of the most innovativemanufacturers of excipients.

The new products will be in the fields of solid as wellas liquid dosage forms. They will have considerableadvantages and will make life easier for formulators ofpharmaceutical preparations.

BASF already has a wide range of modern excipientsfor a great diversity of pharmaceutical applications.With the new excipients we will even more be able tooffer complete system solutions from a single source.

This issue of ExAct presents Kollicoat SR 30 D,a polyvinyl acetate dispersion with excellent technicalproperties for controlled-release coatings.

Take the opportunity to improve your pharmaceuticaldevelopment and manufacture.

Yours sincerely,

BASF AktiengesellschaftProduct DevelopmentHealth and Nutrition

Dr. Kolter

Publisher:

BASF Aktiengesellschaft

Editorial staff:

Dr. Volker Bühler, Dr. Hubertus Folttmann,

Dr. Karl Kolter, Dr. Siegfried Lang,

Birgit Wesche

Concept/Layout:

MLW KommunikationsForm

GmbH Werbeagentur, Mannheim

Print:

Frotscher Druck, Darmstadt

Imprint

7th to 10th December, 1999

Pharmaindustria ’99 (Exhibition on raw

materials, semi-finished drugs and medicines

in bulk to the Russian market)

Moscow, Russia

28th to 30th March, 2000

Latin American Pharmaceutical Show 2000

Buenos Aires*, Argentina

3rd to 6th April, 2000

3rd World Meeting on Pharmaceutics,

Biopharmaceutics and Pharmaceutical

Technology

Berlin*, Germany

11th to 13th April, 2000

19th Pharmaceutical Technology

Conference and Exhibition

Baveno-Stresa, Italy

16th to 20th April, 2000

Millennial World Congress of

Pharmaceutical Sciences

San Francisco*, USA

* BASF will be represented.

Calendar

BASF – Expertise in Health and Nutrition

BASF ExAct page 2 – No. 3, November 1999

Elongation ofKollicoat SR 30 Dfilms in relation toplasticizerconcentration.(Figure 1)

Introduction

Sustained release products are gaining interestdue to a long lasting drug action with low sideeffects and a better compliance related toimmediate release dosage forms. However, for themanufacturing of coated sustained releasedosage forms only three polymers can be used:ethylcellulose (EC), ethyl acrylate-methylmethacrylate copolymer (EMM) and ammoniomethacrylate copolymer.Each of these polymers has certain disadvantages.Ethylcellulose shows curing effects and needs a highamount of plasticizer for a sufficient film formation.The plasticizer migration within the film and betweenthe film and the core, often causes a change in thedissolution profile [1]. As an aqueous dispersionethylcellulose is a very expensive coating material.The cationic character of ammonio methacrylatecopolymer is responsible for the interaction withanionic drugs or the counterion of cationic drugs.This can strongly change the permeation of the drugthrough the film and therefore the release rate [2].Based on the weaknesses of the established productsthere is a strong demand for a new coating polymerin this application field.

ObjectiveThe objective of this study was to evaluate thephysicochemical properties of the new productKollicoat SR 30 D and its suitability for sustainedrelease coating.

Materials and MethodsMaterials

Kollicoat SR 30 D (BASF AG),Spherofillin 0.8 –1.3 mm (Knoll AG).Kollicoat SR 30 D is polyvinyl acetate dispersionstabilised with polyvinylpyrrolidone and sodiumlauryl sulfate.Composition:Polyvinyl acetate 27%, polyvinylpyrrolidone 2.7%,sodium lauryl sulfate 0.3% (solids 30% [w/w])

Methods

Particle size, Malvern Autosizer 2 C (Malvern);minimum film forming temperature, Thermostair(Coesfeld); dissolution, Pharmatest PTW S (Pharma-test); viscosity, Brookfield RVT (Brookfield); Shearstability test: the dispersion was treated with a stirrerequipped with 8 pins at a speed of 2 000 rpm for 15minutes. Afterwards, the coagulate was determined bypassing the dispersion through a sieve of 125 µm.The residue was dried, weighed and calculated inpercent of the total polymer mass.

KollicoatY SR 30 DA new sustained release excipient.K. Kolter and F. Ruchatz

%

Polymer dispersionKollicoat SR 30 D 50.0 (=15.0 solids)Water 35.0

Pigment dispersionTalc 3.5Titanium dioxide 0.5Sicovit¤ Red 30 0.5Kollidon¤ 30 0.5Water 10.0

Inlet air temperature 50°COutlet air temperature 31°CAtomizing pressure 1.0 barSpraying rate 11.0g/minDrying 50°C/5 minCoating level 0.5/1.0/2.0 mg/cm2

mean particle size 160 nmpH 4.5minimum film formingtemperature (MFT) 18°Cwith 5% propylene glycol 16°Cwith 10% propylene glycol 14°Cwith 5% triethyl citrate 8°Cwith 10% triethyl citrate 1°Ccoagulate in the shearstability test 0°Cviscosity 54 mPasThe pigment dispersion was homogenized using a

corundum mill and added slowly to the polymerdispersion while stirring.

Coating processThe coating suspension was applied in a fluidized bedcoater (Aeromatic Strea 1, Aeromatic AG) on 0.5 kgtheophylline pellets under the following conditions:

Results and DiscussionPolyvinyl acetate possesses lipophilic character.Therefore it is insoluble but slightly swellable in water

500%

400%

300%

200%

100%

0%

450%

350%

250%

150%

50%

10% 15%

■ triethyl citrate■ propylene glycol

plasticizer

elo

ngat

ion

5%

Composition andpreparation of thespray suspension.

Physicochemical properties of KollicoatSR 30 D.

creating a permeation barrier. Polyvinylpyrrolidoneacts as a protective colloid to stabilize the polyvinylacetate dispersion.

The physicochemical properties of two-phasesystems (i. e. aqueous dispersions) are of greatimportance. The small particle size of 160 nm is aprerequisite for the stability of the dispersion.Therefore, Kollicoat SR 30 D passes the shear stabilitytest, where a stirrer with pins rotates generating a highshear force. No coagulate was found after thistreatment.The low viscosity of the dispersion (approx. 50 mPas)enables an easy handling and an atomization into finedroplets during the spraying process. The dispersiondoes not necessarily require a plasticizer, since theminimum film forming temperature is at 18°C. Theaddition of a small amount of plasticizer decreases theMFT and strongly increases the flexibility of the film.With 5% triethyl citrate or 10% propylene glycol theelongation of the film was improved up to 250%.

page 3 – No. 3, November 1999 BASF ExAct

time [h]

0

dru

g r

elea

se [

%]

120

100

80

60

40

20

0

2 4 6 8 10 12 14 16 18 20 22 24

Influence of coatingmass on thedissolution oftheophylline pelletscoated withKollicoat SR 30 D.Dissolution method:0–2h 0.08 N–HCI2–24h intestinalfluid pH 6.8.(Figure 2)

▲ 2.0 mg/cm2 polymer ◆ 0.5 mg/cm2 polymer■ 1.0 mg/cm2 polymer

Influence of pH onthe dissolution oftheophylline pelletscoated withKollicoat SR 30 D.(Figure 3)

time [h]

0

dru

g r

elea

se [

%]

80

70

60

50

40

30

20

10

0

2 4 6 8 10 12 14 16 18 20 22 24

■ 0.08 N–HCI ◆ pH-change

Influence of curingon the dissolution oftheophylline pelletscoated withKollicoat SR 30 D.Dissolution method:0–2h 0.08 N–HCI2–24h intestinalfluid pH 6.8(Figure 4)

time [h]

0

dru

g r

elea

se [

%]

70

60

50

40

30

20

10

0

2 4 6 8 10 12 14 16 18 20 22 24

■ curing 24 h/60°C ◆ without curing

To investigate the coating performance of Kollicoat SR30 D, theophylline pellets were coated with increasingamounts of polymer. As expected, drug dissolutionslows down with increasing film thickness. The coatinglevel of 2 mg/cm2 corresponds to an increase inweight of approx. 10%. During the coating process noagglomeration or stickiness of the pellets occurred.

Comparing the dissolution profiles in 0.08 N–HCl and0.08 N–HCl followed by a pH-change, it can beconcluded, that the new coating delivers drugs withoutany influence of the pH. This is mainly caused by theabsence of ionizable groups in the polymer.

Curing effects are negligible, since storing the coatedpellets under stress conditions (60°C/24 h) reducedthe dissolution only slightly. This coating was appliedwithout any plasticizer. Curing effects should be lesspronounced if a small amount of plasticizer is added,due to the greater difference between producttemperature /outlet air temperature and MFT, resultingin a completely homogeneous film.

Conclusions Kollicoat SR 30 D has demonstrated to be astable aqueous dispersion with good handling properties for coating and a strong sustained release activity. The drug release rate is independent of the dissolution medium’s pH. The excellent film forming properties result ina negligible curing effect and a high stabilityof the drug release rate after storage. Kollicoat SR 30 D films exhibit an enormous flexibility, particularly with small amounts of plasticizer.

References[1] B. K. Sutter, Aqueous EC-dispersions for the manufacturing of microcapsules, PhD thesis, Düsseldorf 1987[2] R. Bodmeier and X. Guo, Eur. J. Phar. Sci 2No. 1–2 (1994) 109.

H––––––CH–CH2––––

––––CH–CH2––––––H

NO

BASF ExAct page 4 – No. 3, November 1999

Copovidone is a copolymer of 1-vinyl-2-pyrroli-done and vinyl acetate in the mass proportion of3:2. The nominal K-value of Copovidone as statedin the labeling is not less than 90.0 percent andnot more than 110.0 percent.

Packaging and storagePreserve in tight containers, protected from moisture.

USP Reference standards (11)USP Copovidone RS.

LabelingLabel it to indicate its nominal K-value.

Clarity and color of solutionDissolve 1.0 g in 10 ml of water: the solution is clearor slightly opalescent and colorless to pale yellow orpale red.

Identification A: Infrared Absorption (197K). B: To 5 ml of a solution (1 in 50) add a few drops

of iodine TS: a deep red color is produced.

Loss on drying (731)Dry it at 105°C for 3 hours: it loses not more than5.0% of its weight.

Residue on ignition (281)Not more than 0.1%.

Limit of aldehydesEnzymatic method see Povidone monograph ofUSP 23. Not more than 0.05% is found.

Limit of hydrazineTLC method see Povidone monograph of USP 23.Not more than 1 µg per g is found.

Limit of peroxidesSpecific method see Povidone monograph of USP 23.Not more than 0.04%, expressed as hydrogenperoxide.

Limit of monomersDissolve the equivalent of 5.0 g of dried Copovidonein 20 ml of methanol, and slowly add 20.0 ml ofiodobromide TS. Allow to stand for 30 minutes,protected from light, with repeated shaking. Add 5 mlof potassium iodide solution (1 in 10), and titrate theliberated iodine with 0.1 N sodium thiosulfate VS until

(Figure 1)

Description and solubilityAdd the following:Copovidone: White to yellowish-white powder orflakes. Is hygroscopic. Freely soluble in water, inalcohol, and in methylene chloride; practicallyinsoluble in ether. NF category: Tablet binder;coating agent.

Our comment to this draft monograph:1. This draft monograph is almost completely harmonized with the Ph. Eur. monograph “Copovidone”.2. Kollidon VA64 meets all requirements of this monograph.3. For the determination of the monomers theUSP. Commission asked us for a HPLC methodto substitute the titration method. We proposedthe limit of †10 ppm for vinylpyrrolidone and† 20 ppm for vinyl acetate applying our HPLC method sent to USP. Kollidon VA64 meets alsothese requirements.

(C6H9NO)n + (C4H6O2)m

CH3

C

H––––––CH–CH2–––––––CH–CH2––––––H

N O O

n m

O

(n ¯ 1,2 m)

CopovidoneSummary of the USP-NF draft monograph “Copovidone” publishedin US Pharmacopoeial Forum, Vol. 24, No. 4, page 6456 to 6459.V. Bühler

the solution is yellow. Continue the titration dropwiseuntil the solution is colorless. Perform a blank deter-mination (see Residual Titrations under Titrimetry(541)): the difference between the volumes of 0.1 Nsodium thiosulfate consumed in the blank and thespecimen titrations is not more than 0.9 ml,corresponding to not more than 0.1% of monomerscalculated as vinylpyrrolidone.

K-valueMethod see Povidone monograph of USP 23.The K-value is not less than 90.0% and not morethan 110.0% of the K-value stated on the label.

Content of copolymerized vinyl acetateDetermine the saponification value as directed forSaponification Value under Fats and Fixed Oils (401).Calculate the percentage of copolymerized vinylacetate in the Copovidone taken by the formula:0.1(86.09/56.11)(S), in which 86.09 and 56.11 arethe molecular weights of vinyl acetate and potassiumhydroxide, respectively, and S is the saponificationvalue: not less than 35.3% and not more than41.4% of the copolymerized vinyl acetate component,calculated on the dried basis, is found.

NitrogenSpecific method see Povidone monograph ofUSP 23. The Nitrogen content, on the dried basis,is not less than 7.0% and not more than 8.0%.

(11) USP Reference StandardsAdd the following:USP Copovidone RS – dry portion at 105°C for3 hours before using. Keep container tightly closed.

H––––––CH–CH2––––

––––CH–CH2––––––H

page 5 – No. 3, November 1999 BASF ExAct

Liquid Paste Solid

101

122 123 124

105

181 182 183 184

202

221

272

331

401 402 403

333 334 335

224 225

205

185

407

338

278

228227

207

188

108

Percentage EO-part [%]

Mo

lecu

lar

wei

ght

of

Po

-par

t

4000

3625

3250

2750

2250

2050

1800

1450

1200

950

0% 10% 20% 30% 40% 50% 60% 70% 80%

IntroductionThe poloxamers are a group of surface activecompounds widely used in the pharmaceuticalindustry. As newly developed active drugs are oftenwater insoluble substances, their formulation togetherwith the interest to design new drug dosage forms inorder to increase the effectiveness of already existingformulations, promoted a variety of delivery vehiclessuch as controlled or sustained release systems, gels,microemulsions and nanoparticles. These dosageforms support the claim for enhanced solubility andbioavailability, for lengthened contact at specificlyselected sites in the body, combined with thereduction in quantity of applied drug [1]. All theseaspects could optimize systemic and minimize sideeffects of active drugs.

StructureThese products are described as block polymers ofthe type ABA, consisting of a central, hydrophobicblock of polypropylene oxide, which is edged by twohydrophilic blocks of polyethylene oxide. The poly-mers are derived from the sequential polymerizationof propylene oxide and ethylene oxide. A generalformula is shown in figure 1.

Due to the possibility to combine blocks of differentmolecular weights, the properties of the resultingpolymers vary in a wide range. The poloxamer grid

Poloxamers (1)LutrolY F 68 (Poloxamer 188).B. Fussnegger

(see figure 2) demonstrates the spectrum of themolecular weight, the different appearance (liquid,paste and solid) and variations in the hydrophilic orhydrophobic character of the individual compounds.

Lutrol F 68 has an average molecular weight of about8600. The polyoxyethylene units represent about 81%of the molecular weight whereas that one of polyoxy-propylene stands for about 19%. Due to thecomposition Lutrol F 68 is readily water soluble.

Pharmacopoeial situationUp to now the products for pharmaceutical use havebeen characterized on one hand in the familiy-mono-graph 'Poloxamers' in the USP/NF, on the other handin individual monographs cited in JPE (JapanesePharmaceutical Excipients, 1993). In the 'Third (2000)Supplement' to the ‘Third (1997) edition of theEuropean Pharmacopoeia‘ a family-monograph on'Poloxamers' was published. In contrast to the USP/NFeight different products are listed there [2].

Applications of Lutrol F 68Lutrol F 68 is primarily applied as an emulsifier,solubilizer, and suspension stabilizer in liquid oral,topical and parenteral dosage forms. In solidpreparations it acts as wetting agent, plasticizer, and toenhance the solubility and bioavailability of sparinglywater soluble active drugs.

Lutrol F 68 in solid pharmaceutical dosage formsSince the mid 70s Lutrol F 68 has been appliedto improve the dissolution behaviour and intestinalabsorption of hardly water soluble substances.Digitoxin, digoxin, sulfadiazine, sulfisoxazole, phenyl-butazone, spironolactone, diazepam and griseofulvinwere among the first actives tested. Improvement ofdissolution of solid dispersions was attributed to eithermodifications of the crystallinity or the facilitation ofwetting through lowering the surface tension informulations with increased surface. In coprecipitatesof Spironolacton and Diazepam the solubility of bothactives was significantly increased. Differentialthermograms and infra red spectra gave no indicationof polymorphs during the preparation. [3].After administration to volunteers solidified melts of20% griseofulvin in Lutrol F 68 showed a 62% higherurinary excretion of the metabolite 6-demethyl-griseo-fulvin than micronized griseofulvin, compared to 33%of a physical blend of the same composition. X-raydiffraction experiments revealed that directly afterpreparation the active is partially present as amorphousmaterial. However during time recrystallization tookplace [4]. Similar findings on the enhancement ofdissolution of nifedipine from solid dispersionsprepared using a fluidized bed for solvent evaporationwere recently published. In this case, DSC measure-ment did not reveal the formation of amorphousnifedipine in the solid dispersion [5].

Lutrol F 68 in liquid pharmaceuticaldosage formsDue to its low toxicity, Lutrol F 68 proved to be a veryuseful excipient, even for parenteral applications. Inaddition to standard tests intravenous administrationstudies in dogs revealed, in contrast to other widelyused surfactants, least distinctive side effects such ashistamine release and hypotension [6]. Solid-lipidnanoparticles (SLN) or nanosuspension formulatedwith Poloxamer 188 were investigated intensively andfound their way into various patents. A nanosus-pension of N-benzoylstaurosporine, a protein kinaseC inhibitor and antitumor agent for intravenous appli-cation, is described (7,8). The diameters of the resul-ting microparticles range from 5–20 nm. The SLNsystem (Compritol-Poloxamer 188) was examined[9] and demonstrated excellent long-term stabilityand was autoclavable under optimized conditions.Controlled drug delivery could be achieved by varyingthe composition of the formulation and the productionparameters. Dexniguldipin microemulsion for intra-venous injection are patented in [10]. The micro-emulsion comprises dexniguldipin, poloxamer 188,lecithin, a liquid triglyceride, PVP, propylene glycol orpolyethylene glycol, and water.

a b aHO–––CH2–CH2–O–––––CH2–CH–O–––––CH2–CH2–O–––H

CH3

Poloxamer grid.

(Figure 2)

(Figure 1)

BASF ExAct page 6 – No. 3, November 1999

Temperature [¡C]

0

Vis

cosi

ty [

Pas

]

7

6

5

4

3

2

1

0

10 20 30 40 50 60 70 80 90

Temperature [¡C]

0

Vis

cosi

ty [

Pas

]

7

6

5

4

3

2

1

0

10 20 30 40 50 60 70 80 90

Lutrol F 68 in contrast mediaIn recent years numerous patents and papers havebeen published on the application of poloxamer 188in the stabilization of contrast media preparations fororal or retrograde x-ray examination of the gastro-intes-tinal tract, for imaging the blood pool and lymphaticsystem, for computed tomography (CT) or magneticresonance (MR) and as phase shift colloids in ultra-sound contrast examination. The formulations havebeen formulated either in liquid or lyophilized form.The first group comprises e.g. nanoparticles of abarium salt which is formulated with 5% of Poloxamer188 [11]. The latter one, for example, is based on anaqueous microdispersion of perfluorocarbons [12].An echographic contrast agent composition is descri-bed in [13]. A solution of 30.0 g Poloxamer 188 and54.0 g mannitol in 800 ml water was added withvigorous stirring to a solution of 30.0 g phosphatidyl-glycerol and 20.0 g cholesterol in 100.0 g petroleumether. Water for injection was added to 1 l, and theliquid was homogenized until the particle size reached< 4 µm. The emulsion was dispensed into vials andlyophilized. These lyophilizates are characterized by aremarkable storage stability. When reconstituted withwater, they produce microbubble-containing echo-graphic contrast agents characterized by microbub-bles having a very small diameter and a surprisinglyhigh stability.

Lutrol F 68 for taste-maskingThe unpleasant taste or smell of actives such as inde-loxazine-HCl, Aceclofenac or Albendazole can bemasked by either using polymeric film formers or LutrolF 68 alone or by combining it with hydrophobic com-pounds. An example is given in [14] for rapid-releasecoated pharmaceuticals. The above given example ofAceclofenac instant granules is excerpted from thecompilation of “Generic Drug Formulations” of BASF.

Dependence of

viscosity and sol-

gel-transition

temperature of

Lutrol F 127/F 68

formulations.

(Figure 4)

Dependence of

viscosity and sol-

gel-transition

temperature of

Lutrol F 127/F 68

formulations.

(Figure 3)

1. FormulationI. Aceclofenac 1.3 g

Orange flavour 4.3 gSorbitol, crystalline 85.6 g

II. Lutrol F 68 [1] 4.4 gCremophor RH 40 [1] 4.4 gWater about 50.0 g

2. ManufacturingGranulate mixture I with solution II, passthrough a 0.8 mm screen, dry and sieve again.3.9 g of the granules correspond to 50 mgaceclofenac.

Formulation and manufacturing ofthe granules is as follows:

Lutrol F 68 in combination withgel-forming poloxamersThe development of liquid formulations, thermogellingat the administered site, is of increasing interest.This includes e.g. drug delivery systems for parenteraluse. When injected i.m. the formulation forms a depotfor the controlled release of drug by gelling at bodytemperature [15]. In such combinations Lutrol F 68strongly influences the thermorheological propertiesof F 127 preparations.In contrast to the effect of commonly used salts(e.g. NaCl) the addition of Lutrol F 68 to Lutrol F 127formulations resulted in an increase of the sol-gel-transition temperature, probably due to the formationof mixed micelles as shown in figure 3 and 4 fordifferent Lutrol F 68 concentrations. At constantamounts of Lutrol F 127 the viscosity and the thermo-reversible gelling temperature are functions of theLutrol F 68 concentration. The latter one can be ad-justed in a range of about 25°C by varying the quantityof Lutrol F 68 to a maximum of 20%. At this concen-tration the gelling temperature is within a very narrowrange. A strong increase in viscosity can be observedcoincidently.

References:[1] R. Schmolka; Polymer Controlled DrugDelivery (1991), 189–214, CRC, USA[2] European Pharmacopoeia, 3rd edition, 1997,Third Supplement 2000, p 1083–85[3] A.S. Geneidi, H.Hamacher; Pharm. Ind. 42 (3),1980, 315–319[4] K. Heyer, K.H. Frömming; Dtsch. Apoth. Ztg.,123 (1983), 859–861.[5] Chia-Nan Chen, Hsiu-O Ho, Ming-Thau Sheu;Proc. Int. Symp. Controlled Release Bioact. Mater.(1996), 23rd, 565–566[6] W. Lorenz, A. Schmal, H. Schult, S. Lang,Ch. Ohmann, D. Weber. B. Kapp, L. Lüben,A. Doenicke; Histamine release and hypotensivereaction in dogs by solubilizing agents and fattyacids: Analysis of various compounds in Cremo-phor ÉL and development of a compound withreduced toxicity; Agents and Actions, 1/2 (12),1982, 64–80[7] EP 733358 A2, Ciba-Geigy A.-G., Switzerland[8] EP 733372 A2, Ciba-Geigy A.-G., Switzerland.;Vesifact Ag[9] R.H. Mueller, A. zur Mühlen, C. Freitas,W. Mehnert; Proc. Int. Symp. Controlled ReleaseBioact. Mater. (1996), 23rd, 184–185[10] DE 4220616 A1, Byk Gulden LombergChemische Fabrik GmbH, Germany[11] WO 9624382 A1, Nanosystems L.L.C., USA.[12] WO 9532005, IMARx Pharmaceutical, USA.[13] WO 9401140 A1, BYK Gulden LombergChemische Fabrik GmbH, Germany.[14] WO 9209275 A1, Yamanouchi Pharma-ceutical Co., Ltd., Japan[15] F. Ruchatz, S. Lang, H. Reich, B. Fussnegger;The combination of Pluronic F 127 and Pluronic F68 – A new perspective for thermogelling drugdelivery formulations; Poster session CRS, 1998.

■ 20% F 127 ▲ 20% F 127 + 10% F68◆ 20% F 127 + 5% F68 ● 20% F 127 + 20% F68

■ 15% F 127 ▲ 15% F 127 + 10% F68◆ 15% F 127 + 5% F68 ● 15% F 127 + 20% F68

page 7 – No. 3, November 1999 BASF ExAct

Concentration of Solutol HS 15 [%]

0

So

lub

ilize

d D

rug

[%

]

1.2

1.0

0.8

0.6

0.4

0.2

0

5 10 15 20 25 30

G. Thaysen

IntroductionThe solubilizer Solutol HS 15 (polyethylenglycol 660 –12-hydroxystearate) is a non-ionic surfactant used forpharmaceutical purposes produced from 1 mol 12-hy-droxystearic acid and 15 mol ethylene oxide. The productis very efficient in solubilizing substances like fat-solublevitamins, and active ingredients of hydrophobic nature.

ApplicationThe solubilizing capacity for some tested drugs(Clotrimazole, Carbamazepine, 17ß-Estradiole, Sul-fathiazole, and Piroxicame) increased almost linearlywith enlarging concentration of solubilizing agent(fig. 1) due to the formation of spherical micelles evenat high concentrations of Solutol HS 15. Tests haverevealed that the viscosity increased with increasingamount of solubilizer, but the amount of solubilizeddrugs did not have any additional influence on thekinematic viscosity (fig. 2). In contrast to Solutol HS 15the viscosity of PS 80 strongly increased at higherconcentrations, whereas the viscosity of Solutol HS 15remained fairly low. Therefore an uncomplicatedadministration of a 30% solution of Solutol HS 15 ispossible. Many drugs are manufactured under asepticconditions but this can be avoided, because steamsterilization (121°C/20 min) of pure Solutol HS 15 ispossible. Tests did not reveal any changes of propertiesindicating that no considerable hydrolyzation processtook place. The sterilization process performed withsolubilizates of 20% Solutol HS 15 in demineralizedwater and a drug loading of 7.5% tocopherol acetatedid not influence the properties of the solubilizate excepta minor change of the pH-value. After the sterilizationprocess a phase separation occurred which can beovercome by shaking the solutions moderately duringcooling. Also the micelle diameter remained unchanged.

Regulatory status/toxicologyThe commission of the German Pharmacopoeia hasdecided to include polyoxyl 15 hydroxystearic acid asmonograph in the next edition of the DAB. BASF hasapplied for the monographs in the USP and the Ph.Eur. Solutol HS 15 is approved by the HPB (Canada)for human application. Active ingredient is vitamin K1.The reason to have a deeper look in Solutol HS 15 isthe improved tolerance after parenteral application.Based on the toxicity studies it can be concluded, thati. e. histamine release in dogs is roughly 10 times lowercompared to Cremophor EL.

ConclusionSolutol HS 15 meets the requirements of an effectivemodern solubilizer for parenteral use. Combined arethe high solubilizing capacity and low toxicity ofSolutol HS 15.

Applications of SolutolY HS 15

Influence of a

sterilization process

on solubilizates

of Solutol HS 15.

(Table 1)

Untreated 20 min/121°C

20 min/121°C

Untreated

20% Solutol HS 15+ 7.5% Tocoph.-acetate

20% Solutol HS 15

Acid V. [mg/g KOH] 0.1 0.1 0.1 0.1Saponif. V.[mg/g KOH] 13.0 13.2 21.0 21.0pH-value 6.0 5.5 5.75 5.63Micelle dm [nm] 13.0 13.0 24.6 24.1Turbidity [FTU] 5.1 5.0 26.0 26.0

Influence of

concentration of

solubilizer and

drug loading on the

kinematic viscosity.

(Figure 2)

Solubilizing capa-

city of Solutol

HS 15 for different

drugs.(Figure 1)

Concentration of solubilizer [%]

Kin

emat

ic V

isco

sity

[P

as]

35

30

25

20

15

10

5

0

5 10 15 20 25 30

■ Solutol HS 15 ■ Solutol HS 15 with clotrimazole▲ Polysorbate 80 ▲ Polysorbate 80 with clotrimazole

■ Clotrimazole ■ 17ß-Estradiole▲ Carbamazepine ● Sulfathiazole ◆ Piroxicame

BASF ExAct page 8 – No. 3, November 1999

Knoll Pharma Active Ingredients

Ibuprofen, more than30 years killing pain.

M. Black

Ibuprofen (I) is a chiral propionic acid derivativebelonging to the class of non-steroidal antiinflam-matory drugs (NSAIDs), having a range ofanalgesic, antipyretic and anti-inflammatory actions.Racemic Ibuprofen was originally developed byBoots as one of the first NSAIDs with the potencyof aspirin but with an improved side effect profile,particularly with regard to gastro-intestinal toxicity.Boots launched the first tablet form as Brufen in theUK in 1969. Following the release of Ibuprofen toOTC status it was established as one of the majorproducts in the analgesic market, competingagainst aspirin and paracetamol. In 1995 BASFPharma acquired of the bulk Ibuprofen businessand the Brufen prescription product through thefusion with the Boots Pharmaceutical division.

BASF Manufacturing ProcessCrude Ibuprofen is manufactured at BASF Bishop,in Texas, USA. Final purification and crystallization isthen carried out in Bishop and in Beeston, UK.A computer-controlled crystallization process isemployed at both plants to ensure that standardgrades have identical physical parameters and cha-racteristics. Products from both sites are controlledto ensure they comply with the United States,European and Japanese Pharmacopoeias.The Bishop facility has been recognized for environ-mental excellence. The technology utilizes a three-step catalytic synthesis (II) involving acetoacetyla-tion of Isobutylbenzene using HF as solvent, followedby a catalytic reduction to the alcohol which thenundergoes a palladium – facilitated carbonyl-insertion affording the racemic propionic acidderivative (Ibuprofen).The process has a high atom utilization ratio andearned recognition from “Chemical Engineering”as the 1993 winner of the Kirkpatrick ChemicalEngineering Achievement Award. This award ispresented biannually for the most notable chemicalengineering technology commercialized in thepreceding two years. Similarly, in June 1997, thisprocess received the US Presidential GreenChemistry Challenge Award.

(Figure 3)

Therapeutic ActivityIbuprofen is used in the treatment of painful andinflammatory conditions such as rheumatoid arthritis.Osteo-arthritis, ankylosing spondytis, mild to moderatepain, dysmennorhoea, vascular headache and alsofor the reduction of fever.It is characterized by its rapid absorption in thestomach with relatively little associated gastric disturb-ances and by its rapid onset of pharmacological action.

Ibuprofen’s mode of action in man is believed toinvolve the reversible inhibition of the enzyme systemresponsible for the biosynthesis of prostaglandinsfrom arachidonic acid in the cellular membrane.This system is called Cyclooxygenase (Cox), thereforeIbuprofen and related NSAIDs are also known as Cox-Inhibitors.

Prostaglandins (PGs) are naturally occuring fattyacid derivatives distributed in the tissues, and have,among other properties, a powerful effect upon thesmooth muscle. PGs appear to be synthesized lo-cally in increased amounts in response to an inflam-matory stimulus or to a blood flow disturbance.Evidence supports the view that PGs then sensitizethe tissues to the action of other agents such ashistamine and kinins thereby resulting in pain andinflammation (III).

The inhibitory action of NSAIDs on PG synthesis isthe most probable cause of the gastro-intestinal sideeffects generally associated with this class of drug.However over 30 years of clinical data reveal that incomparison to related products, Ibuprofen has thelowest incidence of serious gastro-intestinal reactions.

III

CO2H

MeMeMe

I

(Figure 2)

II

CO2H

Me

OH

Me

O

Me

O

H

OO

O

H

HO

HO OH

Cyclooxygenase

Arachidonic acid Prostaglandin e.g. PGF 2 alpha

VasodilationCapilliary Permeability

Fever Pain ReceptorSensibility

page 9 – No. 3, November 1999 BASF ExAct

PharmacologyIbuprofen, in the absence of food, is readily absorb-ed by the gastro-intestinal tract. In pain treatment itseffects can be felt within 30 minutes (from tabletform) and last between 4 to 6 hours. In the treatmentof arthritis the analgesic effect is apparent within afew days but relief of inflammatory symptoms maytake up to one week.

Ibuprofen has an extensive protein binding capacity(99%) and can achieve a plasma concentration of22 to 27 µg/ml in 1.2 to 2.1 hours following an oraldose of 200 mg. Having a half life of around 2 hours,Ibuprofen is readily metabolized and 100%eliminated in the urine within 24 hours.

Activity is known to reside exclusively in the S (+)-enantiomer of the racemic mixture: However, theR (-)-enantiomer is converted irreversibly to S-ibu-profen in vivo (IV), so there is no apparent thera-peutic advantage. Therefore interest in marketingS-ibuprofen has been very limited.

DosageDosage level is indication-dependent; for example, asantirheumatic for adults, 1.2 to 3.2 g orally per day in3 or 4 divided doses are normal. Generally, higherdoses are required for rheumatoid arthritis than forosteo-arthritis. As analgesic for adults 200 to 400 mgare taken every 4 to 6 hours as required. When ad-ministered as anti-pyretic for children over 6 months,5 to 10 mg per kg of body weight are indicated.

Available dosage forms vary by market, however 200,400, 600 and 800 mg tablets are generally available.Sustained release tablets for once-daily administrationhave proven to be highly popular.

Other formulations include capsules, oralsuspension, syrup, granules, suppositories as wellas topical gels and creams.

Ibuprofen GradesEach of the formulations above ideally requiresIbuprofen in a specific mean particle size andparticle size distribution. Such specifications areachieved by controlled crystallization at BASF, withmicronisation being an alternative means.

New pre-formulated grades have now been developedby BASF Pharma and will be discussed in the followingsection.

MeCO2HH

MeHO2C H

in vivo

R (-) S (+)

IV

Ibuprofen, break-through in formulationtechnology.

H. Einig

BASF Pharma is a major manufacturer of theanalgesic drug substance ibuprofen.The characteristics of an active drug substanceare determined not only by pharmacologicalattributes but also by the pharmaceutical formu-lation of the drug.It is commonly observed that different formulationsof the same drug substance can show widevariances in bioavability. Therefore, in recent yearsdevelopers have concentrated both on improvingthe physical properties of active ingredients and theoptimization of pharmaceutical formulations.Although ibuprofen is most frequentlyadministered in the form of tablets, it is notparticularly suitable for tabletting processes.

Its compressibility is poor, and therefore it is notpossible to manufacture tablets by the cost-savingdirect tabletting process. A more cost-intensivepretreatment such as granulation or compaction isgenerally necessary. However, none of the knowngranulation processes is suitable for producing verysmall dosage forms containing extremely high con-centrations of the active ingredient. Such small dosageforms are advantageous in terms of cost reductionand increased user-friendless. An investigation of ibu-profen tablets marketed in the USA showed that suchtablets have a maximum active ingredient content ofslightly more than 60%. Another drawback ofibuprofen is its slow dissolution rate in digestive juices.For these reasons ibuprofen is regarded as a difficultactive ingredient in the pharmaceutical industry.Intensive pharmaceutical work on this substance haseliminated these unfavourable properties andprovided the pharmaceutical industry for the first timewith intermediate formulations and finished prepara-tions which permit economic and simple manufactureof new ibuprofen tablets and which no longer exhibitany of the well-known disadvantages of ibuprofen.

The following 3 new types of ibuprofenwill be available in future:■ Ibuprofen DTP■ Ibuprofen DC 80■ Ibuprofen DC 92

1. Ibuprofen DTPThe poor compression characteristics of theactive ingredient ibuprofen were successfullyremedied by means of a special coating process.This led to the development of an intermediateformulation of the active ingredient, known asIbuprofen DTP, with very good direct tablettingproperties. The abbreviation DTP stands for DirectTabletting Preparation. Ibuprofen DTP has anactive ingredient content of 97 ±1%. Only smallamounts of filler, disintegrant, flow-conditioningagent and lubricant need to be added to theactive DTP ingredient and then the mixture ishomogenized. Tablets characterized by theirhardness, rapid disintegration and favourablerelease of the active ingredient can be manufac-tured using a low compression force.

The table shows therange of standardgrades produced byBASF Pharma and therecommended usesin each case.

Ibuprofen Grade Recommended Use

25 micron Oral liquid suspensions

Topical creams and ointments

Liquid gels

Micro-encapsulation

38 micron Wet granulation tablet and capsule products

50 micron As component of solid doseformulations

50 FF (free flowing), As component of solid dosecontaining 0.2% Aerosil formulations

XL Ibuprofen (large crystal) As component of solid doseformulations

BASF ExAct page 10 – No. 3, November 1999

This is illustrated in Table 1:

Ibuprofen DTP is especially suitable for the devel-opment of combination preparations, whereasIbuprofen DC 80 and DC 92 (described below) aremainly suitable for monopreparations with a rapidrelease. The advantages of Ibuprofen DTP for themanufacture of combination preparations aredemonstrated in Table 2, taking ibuprofen DTP incombination with caffeine as an example.

■ Table 2.Combination preparation consisting of200 mg ibuprofen and 65 mg caffeineComposition Ibuprofen DTP 206.0 mg = Ibuprofen 200.0 mg

Caffeine 65.0 mgLactose (Tablettose¤) 20.0 mgAcDiSol¤ 14.0 mgAvicel PH 200¤ 10.0 mgHydroxypropylmethyl

cellulose 6 cp 2.5 mgMagnesium stearate 1.25 mgAerosil 200¤ 1.25 mg

Content of activeingredients per tablet 82.8 %

Compression force: Tablet hardness:A = 3.8 kN A = 73.4 NB = 7.7 kN B = 128.4 NC = 11.4 k C = 162.7 N

Please note: When formulating combination

products of ibuprofen and caffeine, pay attention

to existing patents, especially patent No. US 4,

587, 249.

As in the ibuprofen monotablet, ibuprofen is quanti-tatively dissolved after 10–15 minutes. In addition to

■ Table 1. Example of a 200 mg ibuprofen tabletComposition Ibuprofen DTP 206 mg

= Ibuprofen 200 mgAcDiSol¤ 12 mgAvicel PH 200¤ 6 mgMagnesium stearate 1 mgAerosil 200¤ 1 mg

Compression force A = 4.2 kN Tablet hardness A = 79.1 NB = 8.2 kN B = 104.7 NC = 11.6 kN C = 104.8 N

Release (in accordance with USP XXIII) Sample B: 5 min 39.4 % 10 min 76.9 %

15 min 95.5 % 30 min 100.6 %

tablets with an active ingredient content of 200 mg,all other common doses (400 mg, 600 mg and800 mg) can also be produced in this way.

The use of ibuprofen DTP is especially favourable forsustained-release preparations (SR) in conjunctionwith highly viscous hydroxypropylmethyl celluloses orthe new excipient developed by BASF, Kollidon¤ SR,which is used as excipient to control the rate of release.In this way SR preparations of ibuprofen can beproduced using the direct tabletting process without aprevious granulation step. In addition extremely highconcentrations of the active ingredient are achieved inthis process.

Which advantages does Ibuprofen DTP offer forthe manufacture of rapidly soluble combinationpreparations?

■ No need for an expensive and time-consuming granulation

■ A mixing process with a few inactive components is the only manufacturing step required before tabletting

■ A high tabletting speed can be attained, as only a low compression force is required

■ Rapid release of the active ingredient in vitro■ A high content of the active ingredient in the tablet

corresponding to a smaller amount of excipients results in a larger number of tablets per batch

■ Major cost reductions compared to the conventional processes

■ Applicable for all dosage strengths

Which advantages does Ibuprofen DTP offerfor the manufacture of sustained-releasepreparations?

■ No need for an expensive and time-consuming granulation

■ A mixing process with a few inactive retarding components is the only intermediate step required before tabletting

■ Extremely high concentrations of the active ingredient are also possible in this case

2. Ibuprofen DC 80DC grades are ready-to-use mixtures which canbe compressed into tablets without any furtherprocessing. DC grades are used for many activeingredients. For example, there are many DCgrades available for the active ingredientparacetamol (acetaminophen). Now, such DCgrades can also be made available for ibuprofen.DC 80 means that the tabletting mixture contains80% of the pure active ingredient. A 200 mgibuprofen tablet produced from Ibuprofen DC 80is described in Table 3.

■ Table 3, Ibuprofen 200 mg tabletfrom Ibuprofen DC 80– Content of

DC 80 250 mgContent of Ibuprofen = 200 mg

Weight of tablets 250 mg

Quantity of active ingredient 80 %

Compression force: Hardness:A = 4.6 kN A = 91.8 NB = 6.9 kN B = 93.9 NC = 11.7 kN C = 126.5 N

Friability A = 1.5 %B = 1 %C = 0.6 %

In vitro dissolution of drug(according to USP XXIII)Sample B after:5 min 61,6 %10 min 100.1 %

The ibuprofen DC 80 granulate can be compresseddirectly into tablets on a rotary press without anyprevious processing steps. In spite of the lowcompression force, the high degree of tablet hard-ness that is attained, allow the tabletting process torun at high speed (see Table 3).The active ingredient is released in vitro within10 minutes. Similarly, other doses of the activeingredient can also be produced from ibuprofenDC 80, as shown in the case of a 600 mg tablet inTable 4:

page 11 – No. 3, November 1999 BASF ExAct

Which advantages does Ibuprofen DC 80 offerto monopreparations?

■ No need for customers to develop their own formulations

■ All intermediate steps in manufacturing priorto tabletting are rendered superfluous

■ A high tabletting speed can be attained,as only a low compression force is required

■ Manufacture of all doses from ibuprofen DC 80 is possible

■ Very rapid release of the active ingredient■ A high content of the active ingredient in the

tablet corresponding to a smaller amount of excipients results in a larger number of tabletsper batch

Product LaunchLycoVit 10% – A new lycopene powder grade for dietary supplements

BASF has for several years marketed BetaVit 10%and BetaVit 20% especially suitable in tablet prepa-rations. Today our BetaVit grades are widely usedin multivitamin tablets.

A natural extension is the inclusion of the carotenoidlycopene into our product range. Lycopene is thecarotenoid giving the tomato its beautiful red color.Lycopene is an emerging antioxidant in diseaseprevention and health enhancement as many studiessuggest that the intake of tomato products can beassociated with lower incidences of prostate cancer,digestive tract cancers and cardiovascular diseases.The inclusion of lycopene along side beta-carotene

and vitamins in dietary supplements is thus a naturalevolution. For this purpose BASF has developedLycoVit 10% which is a powder for dietary supplements.

LycoVit 10% contains 10% lycopene and shows thesame excellent stability and powder properties as thewell known BetaVit grades.The potency of LycoVit 10% is higher than otherproducts found in the market place thus taking up lessspace in the dietary supplements products.The nature-identical lycopene from BASF is producedbased on several years BASF experience in terms ofmanufacturing of carotenoids. This in combination withour competence regarding micro-encapsulation of

active ingredients has enabled us to bringLycoVit 10% into the market place.

A scientific booklet on lycopene can beordered with the attached reply card.

Ibuprofen 600 mgtablets fromIbuprofen DC 80.(Table 4)

■ High patient compliance because of the small size of the tablets

■ Major cost reductions compared to the conventional method of producing tablets

3. Ibuprofen DC 92The development of DC grade ibuprofen hasreached its culmination in the DC 92 grade.A patented production process makes it possible tomanufacture ibuprofen tablets in all sizes from 200to 800 mg with the following characteristics:

■ Highest active ingredient content with 92% ibuprofen

■ Shortest disintegration time only 30 seconds in water

■ Extremely rapid release of 100% of the active ingredient within 3 to 5 minutes

■ Very high tabletting speed■ Very favourable compression/hardness ratio■ High degree of bioavailability

– Content of DC 80 750 mg Ibuprofen DC 80 Content of Ibuprofen = 600 mg

Weight of tablets 750 mg

Quantity of active ingredient 80%

Compression force: 6.6 kN Hardness of the tablet: 97.8 N

Friability 0.9%

In vitro dissolution of drug(according to USP XXIII) after5 min 100.5%

10 min 101.5%

Please contact your local BASF company

or one of the following regional centres:

Asia

BASF East Asia Regional

Headquarters Ltd.

Dr. Lutz End, Dr. Danilo Mercado

7/F., Tower I, South Seas Centre East

Tsim Sha Tsui

P.O. Box 98427

Kowloon, Hong-Kong

Fax: **852/23122261

Europe

BASF Health & Nutrition A/S

Mr. Clemens Karg

Malmparken 5

DK-2750 Ballerup

Denmark

Fax: **45/44730102

NAFTA

BASF Corporation

Pharma Specialties, Mr. Richard Becker

3000 Continental Drive-North

Mount Olive, NJ 07828-1234

USA

Fax: **1/9734265369

South America

BASF S.A.

Fine Chemicals, Mr. Torsten Meid

Caixa Postal 136

09701-970 São Bernardo do Campo

Brazil

Fax: **55/117512199

Or visit our website:

http://www.basf.de/pharma

ContactPreview

page 12 – No. 3, November 1999 BASF ExAct

ME

R 9

942

Kollidon¤ SR – A new excipient for sustainedrelease matrices.With the ExAct edition in hand we presented to youKollicoat SR 30 D, a real break-through in sustainedrelease coating. Besides other topics ExAct No. 4will deal with Kollidon SR, a brand-new excipientfor the manufacture of sustained release matrixtablets by direct compression.

Most of the matrix-forming polymers used at presenthave certain disadvantages, which complicate thedevelopment and production of matrix tablets:the lack of polymer flowability hampering the direct

compression process, the influence of the pHvalue (alginates, xanthan gum) and the ionicstrength (HPMC) on the release profile, and thepoor compressibility of the hydrogel formers.

Kollidon SR retains the useful properties of ahydrophilic matrix-forming agent, avoiding thedrawbacks of the commercially available products.Should you require information on Kollidon SRin advance, please fill in the attached reply cardor contact your local BASF company or one of ourregional centers (addresses on the back of thisnewsletter).

New MediaKollidon¤ Book and Generic Drug Formulationsnow available on CD-ROM.

Now BASF offers interested industry and univer-sity readers of ExAct a new service: Informationon Kollidon and an extensive collection ofpharmaceutical formulations on CD-ROM.

The Kollidon Book – which can also be ordered inbook form – contains information on soluble andinsoluble Kollidon grades. It also covers general

subjects like registration in pharmaceuticals/foodas well as toxicological data.

In Generic Drug Formulations, the user will find aselection of about 500 formulations of human andveterinary drugs which have all been developed byBASF’s Application Laboratories. The formulationsincluded are in solid, liquid, and semi-solid form.However, emphasis is placed on tablets. These datacan still be ordered in binder form.