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Ibuprofen DC 85

® = Registered trademark of BASF group

Technical Information

April 2010 Supersedes issue dated January 2010

03_060201e-07/ of 16

03_060201e-07 April 2010 of 16 Ibuprofen DC 85

General Information It is a current trend in the pharmaceutical industry to simplify the manufacturing process of pharmaceutical formulations and thus to reduce the costs of manu-facturing.

So-called direct compression grades (DC grades) can be used to produce tablets without any previous granulation or compaction process. In some cases, small amounts of additional excipients should be added and blended with the DC grade. It is also possible to compress the DC grades without any additional substances.

Many Ibuprofen DC grades are in the market, mostly from Asian producers.

The BASF product Ibuprofen DC 85 distinguishes itself from its competitors allowing the use of high-speed compression processes and by eliminating sticking on the tablet tools.

Ibuprofen DC 85 means: the composition contains 85% pure Ibuprofen and 15% of inactive ingredients.

If necessary, Ibuprofen DC 85 can be diluted by additional inactive ingredients and combined with other active ingredients.

The medical indication, given in the next chapter, is generally applicable for the administration of Ibuprofen.

1. Medical indication Ibuprofen is a chiral propionic acid derivative belonging to the class of non-steroidal anti-inflammatory drugs (NSAIDs). Due to its analgesic, antipyretic and anti-inflammatory actions it is used in the treatment of inflammatory conditions such as rheumatoid arthritis, osteoarthritis, ankylosing spondyolitis, mild and moderate pain, dysmenorrhoea, vascular headache and fever. The application of Ibuprofen as a pain reliever or an antipyretic needs only low dosages (200 – 400 mg). The dose level as an anti-rheumatic for adults is about 1.2 to 3.2 g orally per day in 3 or 4 divided doses. The common dosage ranges are tablets with 200 mg, 400 mg, 600 mg and 800 mg and slow release tablets with 800 mg. The OTC dosage forms are mainly the 200 mg and 400 mg forms (except for the United States and other countries, here the 200 mg form is the only OTC form). Ibuprofen is often combined with oral decongestants and cough and cold drugs. Other forms are syrups, suspensions and topical dosage forms like creams.

Pharmacology The mode of action is believed to involve the reversible inhibition of the enzyme cyclooxygenase (COX) which is responsible for the biosynthesis of prostaglandins (PGs) from arachidonic acid in the cellular membrane. Prostaglandins are distributed in the various tissues, and have among other properties a powerful effect on the smooth muscles. In case of an inflammatory stimulus or blood flow disturbances, PGs are synthesized in increased amounts and sensitise the tissues to the action of other agents such as histamine and kinins. Therefore the symptoms like pain and inflammation appear.The incidence of fever is raised by the influence of the PGs on the heat regulation centre in the hypothalamus. There they scale up the normal set point of 37 °C.

The inhibitory action of NSAIDs on PG synthesis is also the most probable cause of the gastrointestinal side effects.

PGs play an important role for physiological functions, like the synthesis of protective, alkaline secretion in gastric mucosa cells. The inhibition of the PG synthesis means an absence of protection of the gastric mucosa and this may lead to sickness, abdominal pain and ulcers.

But among the NSAIDs Ibuprofen has the best benefit to risk profile and the lowest incidence of serious gastrointestinal adverse effects.

Pharmacokinetics Ibuprofen is readily absorbed by the gastrointestinal tract. The peak plasma levels are reached within 1 – 2 h. After an oral dose of 200 – 400 mg, 15 – 25 mg/ml appear in the blood serum. Ibuprofen has an extensive protein binding capacity (99%).

Ibuprofen is excreted via the kidneys. The biological half-life is about 2 hours. After 24 h 100% of the active substance is excreted in the urine.


2. Chemical information

Name The name of the main component is Ibuprofen. The quantity of the active drug substance is exactly 85 ± 3% Chemical name of the active drug substance (2RS)-2[4-(2-Methylpropyl)phenyl]propanoic acid

CAS-No. 15687-27-1

EINECS-No. 239-784-6

Synonymous names (±)-2-[4-(2-methylprpyl)phenyl]propanoic acid(±)-Benzeneacetic acid, a-methyl-4-(2-methylpropyl) (±)-p-Isobutylhydratropic acid (±)-2-p-Isobutylphenyl)propionic acid

Ibuprofen is the racemate of (+)-Ibuprofen and (-)-Ibuprofen (optical rotation[a]D = 0 ° ).The pharmacologically active form is (+)-Ibuprofen. According to the literature (“Ibuprofen: a critical bibliographic review”, K. D. Rainsford, Taylor & Francis Ltd., London 1999, page 104) approximately 30 to 70% of the (-)-Ibuprofen is converted to the active form (+)-Ibuprofen in the body. This process proceeds solely from the (-)- form to the (+)- form.

Structural formula

Empirical formula C13H18O2

Molecular weight 206.28 g/mol

3. Grades PRD-No.

30255646 Ibuprofen DC 85

50 kg

2 kg (sample)

Retest period See separate documentation: "Q&R PI (not for regulatory purposes)“ available at BASF‘s WorldAccount: https://worldaccount.basf.com (registered access).

4. Physical and chemical properties

Appearance: granules with a broad particle size distributionColor: white to almost white

Odor: characteristicMelting range: DC grade contains several chemical substances, therefore

melting point or range doesn’t make any senseSolubility in water: insoluble until sparingly soluble


5. Regulatory status Ibuprofen DC 85 is a formulation of Ibuprofen with excipients. A regulatory technical package is available that includes

- Exact composition - Manufacturing process - Analytical method for the DC grade including methods for stability tests - Stability report - Specifications of the used active drug substance and the inactive excipients - General statement, that the used active substance and the inactive excipients

comply with the corresponding specifications

A US-DMF is available upon request. The active drug substance for Ibuprofen DC 85 is Ibuprofen. The Ibuprofen used meets specifications of the current editions of Ph. Eur., USP and JP. A CEP is available and DMFs are active in Europe and the US.

6. Specification See separate document: “Standard Specification (not for regulatory purposes)“ available via BASF’s WorldAccount: https://worldaccount.basf.com (registered access).

7. Product characterization (not part of specification)

Identification IR-Spectrum Must complyContent of Ibuprofen [%] 85.0Bulk density [g/ml] 0.55Tapped density [g/ml] 0.64Loss on drying [%] 0.89Flowability [°] 33.0 free flowing Particle size

>1400 µm

1400 – 1180 µm

1180 – 1000 µm

1000 – 850 µm

850 – 300 µm

300 – 180 µm

<180 µm

[%]

0.1

4.5

26.2

16.0

48.3

3.4

0.6


Particle distribution

The roughly D 50 value of particle size distribution is 700 – 800 µm.

SEM photograph of particles Ibuprofen DC 85 does not contain a lubricant like magnesium stearate, stearic acid, sodium stearyl fumarate or others. Mixtures with such kind of lubricants lead to a physical changing of Ibuprofen until becoming a liquid. Therefore, to avoid a lumping of Ibuprofen DC 85 over a long storage time, the DC grade doesn’t contain any lubricant.


8. Application examples General impression of reducing manufacturing steps by using Ibuprofen DC 85 Steps by wet granulation (main process for Ibuprofen tablets)

1. Weighing in of all ingredients 2. Preparing of granulation solution 3. Granulation process 4. Wet sieving process 5. Drying of the granules 6. Sieving of the dried granules 7. Adding of the outer phase 8. Final blending to granules ready for compression 9. Compression into tablets

Steps by dry compaction (often used in the latest times)

1. Weighing in of all ingredients 2. Blending of ingredients 3. First compaction run 4. Milling and sieving of the compacted materials 5. Second compaction run of the fines 6. Milling of the secondly compacted material 7. Adding of the outer phase 8. Final blending to granules ready for compression 9. Compression into tablets

Steps by using Ibuprofen DC 85

1. Weighing in of the DC grade (optionally weighing of a lubricant) 2. Optional blending with lubricant 3. Compression into tablets

8.1 Use of lubricants As generally known, Ibuprofen is not compatible with the most used lubricants like magnesium stearate, stearic acid or sodium stearyl fumarate, which is demon strated by lowering the melting point of Ibuprofen until becoming a liquid in some cases. But that is not the case during compression into tablets with a quantity of 0.5% magnesium stearate.

The pure Ibuprofen DC 85 can be compressed into tabletts without any lubricant or by adding 0.5% Magnesium stearate. If the DC grade is diluted with other inactive excipients or other drug substances, certain quantities of lubricants could be used.

The following design was tested for lubrication:

Blend Ibuprofen DC 85 [%]

Mg-stearate

[%]

Lutrol F127 micro [%]

Lutrol F68 micro [%]

PRUV [%] sodium stearyl

fumarate

0 100 - - - -

1 99.5 0.5 - - -

2 98.0 2.0 - - -

3 96.0 4.0 - - -

4 99.5 - 0.5 - -

5 98.0 - 2.0 - -

6 96.0 - 4.0 - -

7 99.5 - - 0.5 -

8 98.0 - - 2.0 -

9 96.0 - - 4.0 -

10 99.5 - - - 0.5

11 98.0 - - - 2.0

12 96.0 - - - 4.0


Compression trials

Turbula Blender T2C 22 Upm

Compression

Rotary press Korsch PH 100/6 30 rpmCompression force 15 kN

Tablet tools 9 mm round, light curvation without engravings

Characteristic of tablets

Ejection force [N] tablet press Korsch PH 100/6Hardness [N] hardness tester Erweka

Results The previous results demonstrate, that the higher the content of lubricants is, the lower the ejection forces for the tablets. But with higher quantities the tendency of sticking increases.

No. of trial

Lubricant Quantity of lubricant

[%]

Ejection force [N]

Time of compressing

[min]

Sticking [yes/no]

0 - - 265 30 no

1

Mg-stearate

0.5 230 30 no

2 2.0 160 30 no

3 4.0 130 10 yes

4Lutrol® F127 micro

0.5 240 30 no

5 2.0 220 15 yes

6 4.0 170 5 yes

7Lutrol F68 micro

0.5 240 30 no

8 2.0 210 15 yes

9 4.0 170 5 yes

10Sodium stearyl fumarate

0.5 220 30 no

11 2.0 180 30 no

12 4.0 160 30 no

8.1.1 Long time compression test Previous trial was independently performed on a rotary press Korsch PH100/6 with 30 rpm and compression force of 15 kN for 5 hours.

Results Absolute no sticking could be observed. Despite of good results by compressing tablets over more than 5 hours, BASF recommends to use magnesium stearate in low quantities of 0.25 to 0.5%.

8.2 Other excipients to dilute Ibuprofen DC 85

Ibuprofen DC 85 was diluted with additional excipients like microcrystalline cellu-lose, corn starch, lactose and others. The examples are discribed under items 8.2.1 to 8.2.4.


8.2.1 Formulation with microcrystalline cellulose

Ibuprofen DC 85 formulation 1, single punch press

[%] 200 mg 400 mg

Ibuprofen DC 85 88.24 235.3 470.6Microcrystalline cellulose 7.76 20.7 41.4Crosslinked sodium carboxymethylcellulose 3.00 8.0 16.0Silica 0.50 1.3 2.6Magnesium stearate 0.50 1.3 2.6Sum 100.00 266.6 533.2

Tablet press: Excenter Korsch EK0

Compression tools: 1

Compression speed: 30 Upm (1,800 tablets/h)

Compression force: 15 kN

Characteristics of tablets 200 mg 400 mg

Hardness [N] 121 156

Friability [%] 0.05 0.15

Disintegration [min] 3:49 3:21

Dissolution [%] 5 min 75.5 78.9

10 min 98.9 98.5

15 min 101.2 100.8

30 min 102.0 101.8


8.2.2 Formulation with corn (maize) starch


[%] 200 mg 400 mg

Ibuprofen DC 85 88.24 235.3 470.6

Corn starch 7.76 20.7 41.4

Crosslinked sodium carboxymethylcellulose 3.00 8.0 16.0

Silica 0.50 1.3 2.6

Magnesium stearate 0.50 1.3 2.6

Sum 100.00 266.6 533.2






Hardness [N] 92 111




10 min 97.7 97.8

15 min 100.3 98.4

30 min 99.0 99.1


8.2.3 Formulation with lactose Ibuprofen DC 85 formulation 3, single punch press

[%] 200 mg 400 mg

Ibuprofen DC 85 88.24 235.3 470.6

Lactose 7.76 20.7 41.4

Crosslinked sodium carboxymethylcellulose 3.00 8.0 16.0

Silica 0.50 1.3 2.6


Sum 100.00 266.6 533.2






Hardness [N] 86 99




10 min 98.7 96.3

15 min 100.5 99.0

30 min 101.9 99.3


8.2.4 Formulation with microcryst. cellulose and Kollidon® CL instead of AcDiSol


[%] 200 mg 400 mg

Ibuprofen DC 85 88.24 235.3 470.6

Microcrystalline cellulose 7.76 20.7 41.4

Crosslinked Kollidon 3.00 8.0 16.0

Silica 0.50 1.3 2.6


Sum 100.00 266.6 533.2






Hardness [N] 117 178




10 min 96.8 97.9

15 min 100.0 99.6

30 min 101.3 100.0


9. Production tests on high- performance rotary com pressing machines

9.1 Compression on a Korsch PH 106 (lab machine)9.2 Compression on a Fette 1200i at an European toll manufacturer9.3 Compression on a Fette 3090 high speed rotary press in BASF plant

Shreveport

9.1 Compression on a Korsch PH 100/6 (lab machine)

9.1.1 Formulation with microcrystalline cellulose

Ibuprofen DC 85 formulation 5, standard rotary press

[%] 200 mg

Ibuprofen DC 85 88.24 235.3

Microcrystalline cellulose 7.76 20.7

Crosslinked sodium carboxymethylcellulose 3,00 8.0

Silica 0.50 1.3

Magnesium stearate 0.50 1.3

Sum 100.00 266.6

Tablet press: Korsch PH 106




Characteristics of tablets 200 mg

Hardness [N] 85

Friability [%] <0.1

Disintegration [min] 2:24

Dissolution [%]

5 min 87.6

10 min 98.9

15 min 99.0

30 min 100.6


9.1.2 Ibuprofen DC 85 blended with 0.5% magnesium stearate

Ibuprofen DC 85 formulation 6, rotary press

[%]

Ibuprofen DC 85 99.50

Magnesium stearate 0.50

Sum 100.00






Hardness [N] 54

Friability [%] < 0.1


Dissolution [%] 5 min 86.5

10 min 98.8

15 min 99.8

30 min 100.2

9.1.3 Ibuprofen DC 85 without any lubricant

Ibuprofen DC 85 formulation 7, rotary press

[%]

Ibuprofen DC 85 100.00

Sum 100.00






Hardness [N] 47

Friability [%] 0.71


Dissolution [%] 5 min 91.810 min 100.815 min 102.230 min 102.5

All trials were performed over 6 hours without any sticking and interruption.

Trial 9.1.3 demonstrates that Ibuprofen DC 85 can be compressed into tablets without any lubricant.


9.2.1 Ibuprofen DC 85 diluted to 75% active substance, manufactured at a European toll manufacturer

Ibuprofen DC 85 formulation 8, batch size 200 kg

[%] 200 mg


Microcrystalline cellulose 7.76 20.7

Crosslinked sodium carboxymethylcellulose 3. 00 8.0

Silica 0.50 1.3


Total 100.00 266.6

Tablet press: Fette 1200i


Compression speed: 60 – 80 rpm (90,000 – 120,000 tablets/h)


Characteristics of tablets

Dosage [mg] 200

Hardness [N] 65

Friability [%] 0.46



No sticking and no interruption occured over the entire batch size

9.2.2 Ibuprofen DC 85 + 0.5% magnesium stearate, same machinery as in 9.2.1

Ibuprofen DC 85 formulation 9, batch size 200 kg

[%] 200 mg



Total 100.00 236.5

Tablet press: Fette 1200i


Compression speed: 60 – 80 rpm (90,000 – 120,000 tablets/h)


Characteristics of tablets

Dosage [mg] 200

Hardness [N] 65

Friability [%] 0.46




No sticking and no interruption over the entire batch size

9.3. Compressing on a high speed rotary press at a BASF plant

Batch size: 500 kg each

Study design:

Study No.:

Ibu DC + excipients

dosage Batch size

Percen-tage of Drug/tablet

Compression speed

Comment

1 Pure DC grade + 0.5% Mg stearate

200 mg 500 kg ~85% 700,000 tablets/hour

Continuous compression of tablets. No interruption, no sticking

2 Pure DC grade + 0.5% Mg stearate

400 mg 500 kg ~85% 720,000 tablets/hour


3 Ibu DC grade + additional ingredients*

200 mg 500 kg 75% 750,000 tablets/hour


4 Ibu DC grade + additional ingredients*

400 mg 500 kg 75% 750,000 tablets/hour


* Additional ingredients: 0.5% Magnesium stearate, 7.8% Avicel PH 102, 3% Ac-Di-Sol, 0.5% Aerosil 200

Compression conditions: Rotary press: Fette 3090 with 61 compression tools and 2 compression stations Compression speed: upper limit with 750,000 tablets per hour

Tools: 200 mg dosage Ø 9 mm, concave without engravings 400 mg dosage, oval shaped, 14 mm x 8.5 mm

Parameters Comment

Flowability free-flowing (angle of repose: 33°)

Drug release very fast (85% within 5 minutes)

Compression speed(200 mg tablets)

very high < 700,000 tabs/hstable process

Compression speed(400 mg tablets)

very high: 700 – 750,000 tabs/hstable process

Compression force 11 – 15 kN (which is relatively low for Ibuprofen compression)

In vitro dissolution profile of tablets produced on Fette 3090

BASF SE - Care Chemicals Division - Pharma Ingredients & Services - 67117 Limburgerhof - www.pharma-ingredients.basf.com


Summary • IbuprofenDC85isadirectcompressiongradewith85%Ibuprofen • IbuprofenDC85isaproductwithmodifiedsurface • IbuprofenDC85doesnotshowanystickingtendencyduringcompression • IbuprofenDC85isabletobecompressedintotabletswithoutanylubricant • Differentlubricantsinlowconcentrationscanbeused • IbuprofenDC85canbedilutedwithotherexcipientstotherequestedcontent

of the active ingredient • IbuprofenDC85canbecompressedwithhighcompressionspeed • Documentationforregistrationcanbeprovidedtocustomers

Note This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. NO WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, ARE MADE REGARDING PRODUCTS DESCRIBED OR DESIGNS, DATA OR INFORMATION SET FORTH, OR THAT THE PRODUCTS, DESIGNS, DATA OR INFORMATION MAY BE USED WITHOUT INFRINGING THE INTELLECTUAL PROPERTY RIGHTS OF OTHERS. IN NO CASE SHALL THE DESCRIPTIONS, INFORMATION, DATA OR DESIGNS PROVIDED BE CONSIDERED A PART OF OUR TERMS AND CONDITIONS OF SALE. April 2010

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