Calendar

Excipients & Actives for Pharma

No. 6, May 2001

Dear reader,In the 5th edition of ExAct we reported onthe reorganised pharma active ingredientsbusiness within the BASF. BASF now providesa whole range of active ingredients and excipientsfrom one source.

At the beginning of this year BASF’s andTakeda’s vitamin businesses were combinedunder BASF’s responsibility. This substantiallystrengthens our vitamin product portfolio for thepharmaceutical and nutritional supplementindustries.

Detailed information on this widened vitaminproduct range, product grades and applicationsis given in a separate article within this ExActedition.

11th to 13thJune, 2001

INTERPHEX Asia (Internat. Exhibition forthe Pharmaceutical Industry)Singapur, Singapore

23rd to 27thJune, 2001

28th International Symposium on ControlledRelease of Bioactive MaterialsSan Diego*, USA

10th to 12thJuly, 2001

CPhI, Pharmaceutical Ingredients ChinaShanghai, China

24th to 26thJuly, 2001

FCE Pharma InternationalExhibition For the Pharma IndustrySão Paulo, Brasil

8th to 10thOctober, 2001

CPhI, Pharmaceutical IngredientsWorldwideLondon*, United Kingdom

21st to 25thOctober, 2001

AAPS (American Association ofPharmaceutical Scientists) Annual MeetingDenver*, USA

9th to 12thNovember, 2001

PHARMA INDIA (Internat. Congress andExposition for the Pharmaceutical Industry)Mumbai, India

8th to 11thApril, 2002

4th World meeting onPharmaceutics, BiopharmaceuticsPharmaceutical TechnologyFlorence*, Italy

* BASF will be represented.

Aqueous Enteric Coatingof Aspirin withKollicoat® MAE 30 DP

page 2-4

PropertiesofKollidon® SRas a New Excipientfor Sustained ReleaseDosage Forms page 5-7

(+)-Pseudoephedrine –A Potent and WellTolerated Decongestant

page 8-11

Vitamins page 12-13

Technical MarketingServices page 14

News page 14-16

Preview page 16

Contact page 16Yours sincerely,

BASF AktiengesellschaftGlobal MarketingPharma Solutions

Dr. Jens-Uwe Bliesener

ImprintPublisher:BASF Aktiengesellschaft

Editorial staff:Dr. Volker Bühler, Valérie Filiatreau,Dr. Hubertus Folttmann, Klaus Kalter,Dr. Karl Kolter

Realisation:printec GmbH, Kaiserslautern

BASF ExAct

Kollicoat® MAE 30 DPAqueous Enteric Coating of Aspirin with Kollicoat® MAE 30 DPK.Kolter, H.-B. Reich, C.Dangel, G.Schepky

page 2 – No. 6, May 2001

Composition and preparation of Aspirin coresAll ingredients were blended in a Diosna mixer andcompressed with 10 kN compression force intocores of 9 mm diameter, 12 mm radius ofcurvature and 300 mg weight.

Determination of the uptake of gastric fluid intoenteric coated tablets during the resistance testSix film-coated tablets were agitated in 0.1 N HClin a disintegration tester for 1 and 2 hours. Theincrease in tablet weight is given as a percentageof the initial weight.

IntroductionAqueous enteric coatings are gaining significantimportance and are substituting manufacturingprocesses with organic solvents for ecological andeconomical reasons. Among the aqueous entericcoatings, methacrylic acid copolymers type C(Kollicoat® MAE 30 DP) offers advantages in acidresistance and manufacturing time compared toenteric cellulose derivatives [1]. Acid resistancewas as strong as with coatings applied fromorganic solvents. The expectations are that thelarge amount of water in aqueous dispersionswould interfere with the core and would lead todegradation in the core when humidity sensitivedrugs are used. Aspirin and pancreatine areexamples for such sensitive drugs.

ObjectiveThe objective of this study was to show whetherAspirin dosage forms can be coated using anaqueous dispersion of a methacrylic acid-ethylacrylate copolymer (Kollicoat® MAE 30 DP) withoutdegradation of this humidity sensitive drug. Twodifferent dosage forms should be used, a bolusform (tablet) and a multiple unit form (crystals),which differ in excipients, porosity and watersorption.

Materials and MethodsMaterialsKollicoat® MAE 30 DP (methacrylic acid-ethylacrylate copolymer 1:1), BASF AG; Aspirin crystalline, E.Merck; Aspirin crystals 0.5-0.8 mm, Chemische Fabrik Aubing GmbH.

ApparatusAccela Cota 24”, Manesty Machines Ltd.;Aeromatic Strea 1, Aeromatic AG

Composition and preparation of the spray suspension

Coating processAccording to technical brochure Kollicoat® MAE 30 DP.

Determination of dissolutionAspirin tablets: According to USP 23 (75 rpm)Aspirin crystals: According to USP 23 (150 rpm)

Determination of Aspirin and salicylic acidSpectrophotometrically at 280 and 310 nm [2]

Coating parameters Aspirin tablets Aspirin crystalsAccela Cota 24” Aeromatic Strea 1

Top spray

Core mass 5 kg 0.5 kgPrewarming 30°C 30°CNozzle diameter 1.0 mm 1.0 mmAtomizing pressure 2.0 bar 2.0 barInlet air 52°C 60°COutlet air 32-35°C 35°C

Spray formulation % %

Polymer disperson Pigment dispersionKollicoat® MAE 30 DP 50.00 Sicovit® Red 30 (BASF AG) 0.5Propylene glycol 2.25 Titanium dioxide 0.5Water 32.25 Talc 4.0

Water 10.5

Tablet formulation mg per tablet

Aspirin 100.0Ludipress® (BASF AG) 148.5Avicel PH 102 50.0Magnesium stearate 1.5

Total mass 300.0

BASF ExActpage 3 – No. 6, May 2001

Aspirin film-coated crystalsAt equivalent coating levels a higher amount ofdrug was released into gastric fluid from theAspirin crystals (1.82% at 4mg/cm2 coat weight)than from the tablets. This is due to the angularshape of the crystals with edges, where thecoating is not sufficient to prevent drug releasecompletely. Nevertheless the requirements of theUSP were fulfilled (figure 3).

Dissolution rate in intestinal fluid was quick with adelay of about 5min compared to the uncoatedcrystals. Compared to the tablets, the hydrolysisrate of the crystals was low, too. The higher surface/volume ratio, which shouldresult in a higher rate of hydrolysis, is offset by thelack of porosity and a low water sorption of thecrystals. Film-coated Aspirin crystals with 4mg/cm2 coating level stored at 25°C/55% r. h.for 6 months, exhibited no sign of degradation.With a higher level of coating (6mg/cm2) even40°C/75% r. h. were tolerated. An increasingcoating level resulted in a higher stability duringstorage.

At 6mg/cm2, the coated Aspirin crystals passedthe stress test (40°C/75% r. h./3 months),whereas the 4mg/cm2 coating level failed. From astability point of view a higher coating level shouldbe used (figure 4).

ResultsAspirin film-coated tabletsTo determine exactly the gastric resistance of abolus form, the USP resistance test was completedby detecting the weight increase representing theacid uptake through the film. The Aspirin film-coated tablets with 4 mg/cm2 coating showed nosign of disintegration and comparably low valuesof 3.15 % weight increase after 1 hour and 4.78%after 2 hours in gastric fluid. It must be taken intoconsideration that a part of the acid uptake didn’tpenetrate into the core due to swelling of the coat(figure 1).

The results are confirmed by the dissolution testingwhere less than 0.04% Aspirin was delivered after2 hours in gastric fluid. After changing thedissolution medium to intestinal fluid, a quickrelease of Aspirin occured, which was nearly asfast as from the uncoated tablets (figure 2). Lessthan 1 % salicylic acid was found in the tabletsafter film-coating, as well as after 2 hourstreatment in gastric fluid, indicating that the rate ofhydrolysis was very low. It is important to start thecoating process initially with a low spraying rateand a high bed temperature, resulting in a “dry”process to minimize water uptake from the spraysuspension into the tablet. A low water uptake ofthe core is important, particularly to achieve highstability during storage. The stability can be furtherincreased by selecting a core with a low porosityand a smooth surface.

Weight increase offilm-coated tabletsafterthe entericresistance testaccordingto USP 23(figure 1)

wei

ght

incr

ease

[%]

coat weight [mg/cm2]

after 1 hour

0

6

5

4

3

2

1

3 4 6

after 2 hours

BASF ExAct

Conclusion Aspirin tablets and crystals can be enteric

coated using aqueous Kollicoat® MAE 30 DPwithout degradation of the drug.

Initially a reduced spraying rate should be usedresulting in a “dry” process.

A higher stability of Aspirin during storage isachieved by applying higher coating levels.

The manufacturing process is easy to handle,fast and cost saving.

References[1] S.Scheiffele, K.Kolter und G.Schepky,Drug Dev. Ind. Pharm. 24 (9), 807-18 (1998)[2] E.R.Hackmann, N.R.Vals and M. I.Santaro,Rev. Farm. Bioquim. Univ. São Paulo (1),53-58 (1997) 33

Drug releaseof enteric-coatedand uncoatedAspirin tablets(figure 2)

page 4 – No. 6, May 2001

Drug releaseof enteric-coatedand uncoatedAspirin crystals(figure 3)

Degradationof Aspirinin enteric-coatedcrystals atdifferent coatinglevels andstorage conditions(figure 4)

dru

g r

elea

se [%

]

time [min]

gastric juice

3 mg/cm2 core

4 mg/cm2

intestinal fluid

030 60 90 120 5 10 15 20 25 30 35 40

20

100

80

60

40

dru

g r

elea

se [%

]

time [min]

gastric juice

without coating 4 mg/cm2

3 mg/cm2 6 mg/cm2

intestinal fluid

030 60 90 120 5 10 15 20 25 30 35 40 45 50

20

100

80

60

40

salic

ylic

aci

d [%

]

4 mg/cm2

0

6

7

8

9

10

5

4

3

2

1

start

0.16 0.18 0.21 0.22

1.12 0.5

1.5 0.71

2.88 0.84

1.02

3 months25∞C/

45% r.h.

6 months25∞C/

45% r.h.

3 months30∞C/

70% r.h.

6 months30∞C/

70% r.h.

3 months40∞C/

75% r.h.

6 mg/cm2

>10

BASF ExAct

Kollidon® SRProperties of Kollidon® SR as a New Excipient for Sustained Release Dosage FormsK. Kolter, W. Fraunhofer and F. Ruchatz

page 5 – No. 6, May 2001

IntroductionSustained release of active drugs is highlyattractive and consequently controlled releaseformulations are gaining more and more interest.In particular the manufacture of matrix tablets bydirect compression is a cost saving simple processpreferably suitable for economic production ofcontrolled release formulations. However,prerequisites for an easy processing and a reliablerelease control are a good flowability and sufficientbinding properties accompanied by a strongprolongation of the drug release provided by thematrix former. Some drawbacks of directlycompressed matrices using the well knownhydrogel formers such as HPMC, HPC, xanthangum, alginates amongst others are the poorflowability and the insufficient compressibilityhampering the direct compression process.Tablets with a low hardness and a high friabilitywere achieved in particular when using alginatesand xanthan gum.

ObjectiveAs a new direct compressible excipient forsustained release matrices offering severaladvantages Kollidon® SR was developed. Kollidon® SR is a spray formulated, free flowing,non-hygroscopic powder consisting of 8 parts(w/w) polyvinyl acetate and 2 parts(w/w) polyvinylpyrrolidone.

The intention of the presented study was tocharacterise Kollidon® SR, with respect to thecompression behaviour and to the influence ofdifferent tabletting processes, speeds and tabletdimensions on the properties of Kollidon® SRformulations. Furthermore the impact of differentvariables on the release profile of Kollidon® SRtablets using caffeine as model drug wasinvestigated.

Materials and MethodsBy varying the dimensions (10,11, 12 mmdiameter, convex and flat beveled edge) tabletswere manufactured using a rotary press underconstant conditions. Furthermore tablets wereproduced using different types of machinery(single punch and rotary press) and differenttabletting speeds as shown in table 2.

MaterialsKollidon® SR (BASF Aktiengesellschaft);caffeine (BASF Aktiengesellschaft);Mg-stearate (Bärlocher);Aerosil® 200 (Degussa Aktiengesellschaft).

Powder propertiesThe bulk and tap density were determined usingan Erweka SVM volumeter, the angle of reposeand the flow time were measured with a Pfrenglefunnel. The particle size was investigated bymeans of a Malvern Mastersizer.

Manufacture of the tabletsThe ingredients were weighed (see table1),blended for 10 min in a turbula mixer (T3C) andpassed through a 800 µm sieve. The mixtureswere compressed under the conditions listed intable 2.

Determination of the tablet propertiesDimensions, weight and hardness using a Krämertablet tester (HT-TMB), disintegration time (KrämerDES-5-AS), friability with an Erweka friabilator.

Release studiesThe dissolution experiments were performedusing a PTS-W Pharma test with the buffer solutions

a) 0.08 N HCl USP XXIII [2h]

b) phosphate buffer solution pH 7.4(USP XXIII [14h] ).

Table 2: Production conditions for Kollidon® SR matrix tablets

Single punch press Rotary pressType Korsch® EK0, instrumented Korsch®PH106,instrumentedSpeed [rpm] 10/20/30/40/50/55 20/40/60/80Compression force [kN] 15 15Tooling 10 mm flat 10 mm flat

Table 1: Tablet composition withKollidon® SR and the model drugcaffeine (amount per tablet [mg])

Kollidon® SR 160.0Caffeine 160.0Aerosil® 200 3.4Mg-stearate 1.6

Tablet weight 325.0

BASF ExAct page 6 – No. 6, May 2001

Influence ofdifferent tabletdiameters on therelease profile ofKollidon® SRmatrices(figure 1)

Release rate ofcaffeine fromKollidon® SRmatrices produced viarotary press(figure 3)

Release rate ofcaffeine fromKollidon® SRmatricesproduced viasingle punchpress(figure 2)

rele

ased

dru

g [%

]

time [h]

10 mm 12 mm

11 mm

00 2 4 6 8 10 12 14 16 18

20

100

80

60

40

rele

ased

dru

g [%

]

time [h]

10 U/min

55 U/min

00 2 4 6 8 10 12 14 16 18

20

100

80

60

40

rele

ased

dru

g [%

]

time [h]

20 rpm

80 rpm

00 2 4 6 8 10 12 14 16 18

20

100

80

60

40

Results and DiscussionThe outstanding flow properties of Kollidon® SRare shown in table 3. The angle of repose wasbelow 25° and the flow time of 150 ml powderthrough the funnel was fast and consistent.

The direct compression resulted in tablets with ahigh hardness and low friability (table 4). Thehardness was reduced with increasing tabletdimension caused by the reduction of thecompression pressure when keeping thecompression force constant. According to thechemical composition and the adjusted particlesize distribution, the dry binding capacity incombination with the flow properties can beregarded as additional benefits when usingKollidon® SR as a sustained release excipient.

Different dimensions of the tablets influenced therelease rate only slightly due to the differentsurface areas as shown in figure 5. A sustainedrelease of the water soluble drug caffeine wasobtained over a period of more than 16 hours.

Due to the good flowability of the powder mixtureno influence of the tabletting speed could beobserved when using a single punch press. Thetablet hardness (> 200 N) and friability (0.02%)were excellent. The standard deviation of weightand drug content were below 1% as shown intable 5.

Again a diffusion controlled release of caffeine for aperiod of more than 16 hours was obtained. Thedifferent tabletting speeds did not influence therelease profile of the tablets.The variation of rotation speed did not influencethe release rate (figure 7) or the tablet weight andcontent uniformity when using a rotary press.However with increasing rotation speed the tablethardness was reduced and the friability increased.But again the tablet hardness was considerablyhigh (>180 N).

BASF ExActpage 7 – No. 6, May 2001

Conclusion

Kollidon® SR could be shown as a promisingnew excipient with good sustained releasecapacity, excellent flowability and dry bindingproperties.

Therefore it is in particular suitable for directcompression of sustained release matrices.

Table 4: Tablet properties of Kollidon® SR matrices with varying tablet dimensions

Parameter 10 mm 11 mm 12 mmCompressionforce[kN] 18 18 18Compression pressure [MPa] 229 189 159Dev. tablet mass [%] 1.1 0.9 0.5Hardness [N] 279 172 187Friability [%] 0.03 0.02 0.02

Table 5: Tablet properties using a single punch press

[Tablets/min] Drug amount Mass Srel Hardness [mg] [mg] [%] [N]

10 159.2 323.0 1.0 22120 158.5 321.9 0.9 21830 158.6 322.6 0.8 19940 158.7 322.6 0.7 19850 159.9 324.5 0.6 21555 159.4 324.1 0.5 217

Table 3: Powder propertiesof Kollidon® SR

Bulk density 0.37 g/mlTap density 0.44 g/mlHausner ratio 1.13Angle of repose 21.9°Flow time 9.50 sMedium particle size appr. 100 µm

Table 6: Tablet properties using a rotary press

Speed Drug amount Mass Srel Friability Hardness [rpm] [mg] [mg] [%] [%] [N]

20 160.4 324.2 1.0 0.06 24240 158.0 321.5 0.9 0.06 21060 158.8 322.4 1.1 0.10 20380 158.2 320.9 1.8 0.11 184

IntroductionThe common cold is not only a very unpleasantdisorder for those affected; it is also one of themain causes of loss of working hours. Allergicrhinitis also poses a great problem today.

Therefore, nasal decongestants are beingsuccessfully used for colds with a congested orstuffy nose and for allergic reactions of the nose.They are either applied locally in the formof a solution or are increasingly administered assystemically acting agents.At present, the main decongestants available fororal administration are as follows:Ephedrine, phenylpropanolamine, phenylephrine,and pseudoephedrine.

Recently it has been published that(±)-phenylpropanolamine (PPA) increases theincidence of stroke as a result of bleedings in thebrain. Meanwhile the FDA requested manu-facturers of pharmaceuticals containing PPA totake these products off the market or to replacePPA by another active ingredient.Accordingly (+)-pseudoephedrine got into thefocus of attention as a potent and well tolerateddecongestant.

Chemistry(+)-Pseudoephedrine is one of the alkaloidsoccuring in the cultivated plant Ephedra vulgaris.BASF manufactures (+)-pseudoephedrine free ofisomeric contaminants in a biotechnological process with the biocatalyst yeast and producesan active ingredient identical with that found naturally. BASF is the largest producer of (+)-pseudoephedrine in the world.

PharmacologyThe oral decongestants are sympathomimeticsand have the same structural elements as thechemically similar natural hormones adrenaline ornoradrenaline. The decongestant effect on thenasal mucosa is based on the generalvasoconstrictive properties of adrenergicsubstances. The a-adrenergic receptors of thesmooth vascular muscles in the nose arestimulated, the dilated arterioles of the mucosa areconstricted, the flow of blood in the nasal mucosais reduced and a contraction of the mucosa isinduced. In this way, the nose becomes clearagain (John F. Cormier and Bobby G. Bryant,Cold and Allergy Products, Handbook ofNonprescription Drugs, Am. Pharmac. Assoc.,Washington 1973, page 73).

Sympathomimetics may activate a-, b1-and b2-adrenergic receptors to a more or less considerable degree and thus have different effects and side effects depending on theirchemical structure. For example, in the case of (-)-ephedrine, the decongestant effect on thenasal mucosa is very pronounced. However,(-)-ephedrine also has the pronounced effect ofincreasing blood pressure and has considerableeffects on the central nervous system so that itsuse as a nasal decongestant is limited.

Tolerance of (+)-pseudoephedrineIn spite of the chemical similarity with othersympathomimetic decongestants, no increase inblood pressure was observed in clinically controlleddouble blind trials with (+)-pseudoephedrineinvolving simultaneous administration of a placeboin patients with controlled hypertension. Even incases where toxic doses of up to 4,500mg (+)-pseudoephedrine were ingested, no dramaticincrease in blood pressure was observed.

The side effects of (+)-pseudoephedrine on thecentral nervous system are also considerably lesspronounced than those of (-)-ephedrine or (±)-phenylpropanolamine. Such serious sideeffects as schizophrenia, mania, psychosesor suicide attempts, as reported for(±)-phenylpropanolamine, do not occur withpseudoephedrine. In placebo-controlled doubleblind trials, reports of side effects such asanorexia, anxiety or disorientation have been veryrare and, apart from general difficulties in sleeping,were not statistically significant.

BASF ExAct page 8 – No. 6, May 2001

(+)-Pseudoephedrine A Potent and Well Tolerated DecongestantH.Einig

(+)-PseudoephedrineChemical name:(1S, 2S)-2-methylamino-1-phenylpropan-1-ol

BASF ExActpage 9 – No. 6, May 2001

PharmacokineticsThe absorption of (+)-pseudoephedrine is nearlyquantitative. The maximum plasma peaks can bereached within 0.5 to 2 hours. The substance isdistributed in the extracellular space. The apparentdistribution volume is between 3 and 5 l/kg. Theelimination of (+)-pseudoephedrine is predominantlyrenal. The biological half-life of (+)-pseudoephedrineis approximately 6 hours whereas that ofphenylephrine is approximately 2.5 hours.Therefore, to reach effective phenylephrine plasmalevels a frequent and inconvenient administration isindicated.

DosagesThe American FDA OTC Panel on Cold, Cough,Bronchodilator and Antihistaminic Productsrecommends the following doses as safe andeffective (Category I) for pseudoephedrine:

Therapeutic use(+)-Pseudoephedrine is in most cases usedas the salt in the form of the hydrochloride orsulfate. As a monoproduct, it is used indoses of about 10 to 60 mg as an instantrelease form usually in tablets. Slow releasepreparations with doses of 120 mg and 240 mgonce or twice daily have recently beenreceiving considerable attention.

Most (+)-pseudoephedrine is used for combination products. However, instantrelease formulations used to treat commoncolds and allergic rhinitis predominate here.

Such combinatory active ingredients may be:Paracetamol, acetylsalicylic acid, ibuprofen,codeine, dextromethorphan, guafenesin,diphenhydramine, chlorpheniramine, loratadine,terfenadine, etc.

Physical propertiesCompression behaviourThe compression behaviour of the 5 grades of (+)-pseudoephedrine hydrochloride wasdetermined by producing pure active ingredienttablets containing 200mg of pure substance.The resulting hardness of the specific tablet wasdetermined at compression forces of about12-16kN. The higher the resulting hardness of atablet at a constant compression force, the moresuitable this grade is for direct compression. Theresults of the following table 1 show that, accordingto a cost-effective direct compression process, thegrades “fine powder” and “powder 200” with theaddition of suitable tabletting ingredients such asLudipress® are most suitable for the production of(+)-pseudoephedrine hydrochloride tablets.

(Punch parameters: Ø 9 mm; facetted and flat onboth sides; filling quantity 200mg)

Because of the extremely strong water sorption athigh humidity, the containers always have to be tightly sealed as otherwise there will be considerable caking.

Pharmacopoeias, CoSs and DMFsUSP XXIII, EPDrug Master Files (DMF) and Certificates ofSuitability (CoS) are available:

Sulfates:AUS, B, D, F, GR, GB, FIN, IRL, I, NZ, NL, A, S, E,ZA, TR, DK and USA

Hydrochlorides:AUS, DK, F, GB, IRL, I, NZ, NL, S, E, ZA, TR,CDN, USA and EU

Table 1: Compressibility of different grades of (+)-pseudoephedrine hydrochloride

Fine Powder Coarse Crystals Crystalspowder 200 powder 60/140

Compression force asthe mean from upperand lower punches 14.6 kN 13.9 kN 12.3 kN 16.3 kN 21.7 kN

Tablet hardness 34 N 24 N 14 N 7 N 9 N

every maximum4 hours amount

Adults 60 mg 360 mg

Children6-12 years 30 mg 180 mg

Children2-6 years 15 mg 90 mg

Formulation examples1. Tablet with 60mg (+)-pseudoephedrinehydrochloride (granulation process)

Batch size: 2.4kg

1.2kg (+)-pseudoephedrine HCl, fine powder,0.60kg lactose monohydrate,0.340kg Avicel® PH 101 and 0.10kg Kollidon® 30are vigorously mixed in a Stefan® granulator,subsequently thoroughly moistened withdemineralized water until an earth-moist mass isobtained (snowball effect), stirred vigorously for afurther 2 minutes and forced through a sieve of 3mm mesh. The wet granules are dried in a fluidbed drier (laboratory drier of Glatt®, inlet air 60°C),homogenized through a sieve of 1mm meshand mixed into the granules ready for tablettingwith the additives 0.140kg Kollidon® CL,0.010kg magnesium stearate and0.010kg Aerosil® 200.

Croscarmellose sodium, NF (AcDiSol®) andsodium carboxymethyl starch (Primojel®)were investigated as alternative disintegrants.Kollidon® Cl led to distinctly higher hardnesses asdemonstrated in the following diagram:

BASF ExAct page 10 – No. 6, May 2001

Compressionforce/hardnessdiagram on the basisof lactose/Avicel(figure 1)

hard

ness

[N]

Compression force [kN]

Kollidon® CL

Primojel®

00 5 10 15 20 25 30

20

140

100

120

80

60

40

AcDiSol®

Composition per tablet

(+)-Pseudoephedrinehydrochloride, fine powder 60.0 mg

Lactose monohydrate 30.0 mg

Avicel® PH 101 17.0 mg

Kollidon 30 5.0 mg

Kollidon® CL 7.0 mg

Magnesium stearate 0.5 mg

Aerosil® 200 0.5 mg

Tabletting: Korsch® EK-0 excentric press

Weight 120mg

Tablet punch 7 mm round

Compression force 10kN

Hardness 90N

Disintegrationinto 0.1 N HCl (37°C) 2 minutes

Release in vitro0.1 N HCl (37°C)50 rpm paddle app. 5 minutes: 85%

10 minutes: 98%

BASF ExActpage 11 – No. 6, May 2001

Tabletting: Korsch® EK-0 excentric pressTablet punch: 9 mm round

At request we will provide further formulationexamples for (+)-pseudoephedrine salts especiallyin combination with other active ingredients.

Table 4: Pharmaceutical properties of the Ludipress® formulationat different compression forces

Compression force 3.4 kN 8.9 kN 29.3 kNHardness of the tablet 20.4 N 80.6 N 98.9 NDisintegration in water 6 min. 7 min. 8 min.Release 10 min. 88.7% 85% 89.4%Release 20 min. 98.9% 101.4% 102.2%

SEMphotographs of(+)-pseudoephedrinehydrochloride(fine powder grade)

2. Tablet with 60mg (+)-pseudoephedrinehydrochloride (direct compression process)

Batch size: 3kgAll constituents of the above formulation are mixedin the specific ratio only in a dry form.

Table 3: Compositions ofthe Ludipress® formulations(amount per tablet [mg])

(+)-Pseudoephedrinehydrochloride,powder 200 60 mg

Ludipress® 138 mg

Magnesium stearate 1 mg

Aerosil® 200 1 mg

Total 200 mg

BASF ExAct page 12 – No. 6, May 2001

VitaminsBroader product portfolio through Takeda vitamin acquisitionN. Maruyama

IntroductionAt the beginning of this year BASF’s andTakeda’s vitamin businesses were combinedunder BASF’s responsibility. This merger did notonly substantially strengthen the productportfolio of water-soluble vitamins for food, butalso to a large extent our range of specialityvitamin products for pharma: we can nowsupply vitamin C, B1, B6 in direct compressibleforms and B2 and folic acid in a High Flow form.The agreement with Takeda does not only coverTakeda’s vitamin products, patents & licensesand trademarks, but above all their staff, whichcontributes to our expertise in the pharmaingredients business. In a dedicated laboratoryin Japan they are already working on technicalservices and improvements which will add valueto your business. 2 former employees fromTakeda Vitamin and Food in Japan have alreadystarted working in Germany and are reinforcingour human nutrition team in Ludwigshafen.

ProductsOur water-soluble product line is now nearlycomplete and provides a large variety ofspecialities for individual solutions. And they areespecially suitable for the pharmaceutical area.The vitamin C portfolio alone contains now morethan 10 specialities, tailor made to suit thespecific requirements of the pharma and foodindustry. There are direct compressibleformulations and coated products, eitherascorbic acid, sodium ascorbate or calciumascorbate with 90, 97 or 99 % activity. Not tothe same large extent but still remarkable areour two other direct compressible (DC) productsB1 and B6 as well as our two High Flowproducts B2 and folic acid, which are first choiceproducts if it comes to tabletting.

FutureThe merger was only a starting point for amuch more complex programme of investmentin modern plants to provide our customersefficiently and on a long-term basis with reliableproducts. We will reach this target through ourcommitment to quality, technical support andknow how, our global presence and above allthrough our dedicated staff. One important stepon the way to our target is to achieve world-wide cost leadership through the realisation ofworld scale effects and the sustainedenhancement of our cost, sales and above allour customer service.

Takeda’s DC product portfolioWith the increasing population, and growingeconomy and health awareness, the vitaminsupplement market is expected to continue togrow at a rate of more than 4.0 % a year. Theworld population is expected to grow at a rate of1.1 % a year until 2015 according to the WorldHealth Organisation. The population aged 65and above will increase from 6.9 % in 1998 to7.9 % in 2015. This will result in a higher medicalcare cost, especially in developed countries.Governments will try to cut on expenditure,resulting in a focus on preventive medicine andself medication, which will then lead to increasedinterest in vitamins. Due to these circumstancesplus economic growth, the overall vitamin Cdemand has increased more than 1.3 times asmuch as per-capita GDP (PPP) growth world-wide from 1990 to 1998, and this trend isexpected to continue.

The positive trends of preventive medicine andself medication will contribute to substantialgrowth of the dietary supplement market. Theintroduction of the Dietary Supplement Healthand Education Act (DSHEA) in the USA in 1994led to the classification of Dietary Supplementand to a liberalisation for the approval of newproducts, especially tablets, since a tablet is themost common form for dietary supplement. InEU member states and Japan, a classificationsimilar to Dietary Supplement in USA is beingdiscussed. If a similar classification is introducedin other countries, the demand for vitamin tabletswill increase.

Direct Compressible (DC) products are theperfect solution to produce high-quality tablets.The material for the tabletting must possessthe following properties:

- Free-flowing- Good cohesiveness- Proper bulk density

The conventional method requires a separate granulation process to give the three propertiesto the materials. The DC method, on the otherhand, by utilising new types of activeingredients, binders and fillers that have therequired properties, does not require agranulation step. With DC products, we justneed to mix active ingredients and additives,and then compress to make tablets.

With the DC method, we can expect the followingadvantages:

- Shortening of operating timeThe only steps involved are mixing andcompressing. Granulation and drying stepsare not necessary and therefore the tabletprocessing time is considerably shorter thanwith the conventional method.

- Reduction of labor cost and energy costShort processing time is not the only factorfor economical operation. DC saves cost by notrequiring granulation equipment, man power forgranulation, energy for granulation and drying,and space requirements for the granulation anddrying process. All contribute to an economicaltabletting operation.

- Efficient quality controlThe simple process makes it easier to acquireGMP certification. The lot-to-lot uniformity offinished products is excellent. DC is a completely dry process, therefore, there is nonegative influence by water and heat to vitaminstability from the granulation. As a consequence,the tablets which are made by DC have betterstability in both content and color. In general,less overage is necessary to compensate for losscompared to wet granulation.

Vitamin C

BASF ExActpage 13 – No. 6, May 2001

SA-99 can be used as a sodium ascorbate sourcefor formulations such as chewable C tablets. Thecombination of SA-99 and C-97 result in excellentchewable vitamin C tablets. C·Cal-97 can be usedas a calcium ascorbate source and to manufacturelow-acidity products without excess sodium.

For B vitamins, we have two DC grade vitaminB1s and one DC grade vitamin B6. In addition, wehave other B vitamins that can be used for dietarysupplements along with DC products. They areriboflavin High Flow 95 and Folic Acid High Flow.These are high flow products with good flowability.

BASF can now supply a large variety of specialitiesto meet the various needs of pharmaceutical anddietary supplement industries. We can play aleadership role in the dietary supplement industryby offering solutions to ever growing healthawareness and self-medication trends.

- Simplification of equipmentThe process does not use organic solvents,whereas the wet-granulation method sometimesneeds organic solvents when making granules.DC is also environmentally friendly.

However, there are limitations to DC methods: - The number of additives and active ingredients

for DC are limited.

- DC grade active ingredients and additives aregranules and, therefore, low dosages of activeingredients must be considered carefully. Theactive is not “locked” into granules. DC mixturesare subject to separation in subsequentprocessing steps.

- Some of the DC grade additives are not available in certain countries.

BASF now has the following DC product rangesupplied by Takeda to meet various needs ofpharmaceutical and dietary supplement industries(see tables on the right).

There are a total of five DC products in the vitamin Cgroup: three with ascorbic acid as the activeingredient, one with sodium ascorbate and onewith calcium ascorbate. C-97 has excellent colourstability, and is recommended for straight vitaminC tablets. C-97 SF has good compressibility andcan be used for “sugar and starch free” formulationsbecause it does not contain starch or sugar.

Vitamin C

C-97 97% ascorbic acid and3% corn starch

C-97 SF 97% ascorbic acid and3% hydroxypropylmethylcellulose

TC-90 90% ascorbic acid and10% corn starch

SA-99 99% sodium ascorbate and1% corn starch

C·Cal-97 97% calcium ascorbate,3% hydroxypropylmethylcellulose, and0.1% tartaric acid

Vitamin B1

TH-97 97% thiamine hydrochlorideand 3% hydroxypropylmethylcellulose

TM-97 97% thiamine mononitrateand 3% hydroxypropylmethylcellulose

Vitamin B6

B6-97 97% pyridoxinehydrochlorideand 3% hydroxypropylmethylcellulose

BASF ExAct page 14 – No. 6, May 2001

Technical Marketing Services

In May 2000 the above mentioned study waspublished in the Journal of the American MedicalAssociation. Here are the important conclusions:

ParticipantsData was analysed from 30 years of follow up of8004 Japanese-American men (age 45-68 years)enrolled in the prospective longitudinal HonoluluHeart Program between 1965 and 1968.

ContextThe projected expansion of the elderly populationat highest risk for Parkinson disease (PD) in thenext several decades makes identification offactors that promote or prevent the disease animportant goal.

ObjectiveTo explore the association of coffee and dietarycaffeine intake with risk of PD.

See also the latest publishing “Study points topotential role for Caffeine in reducing the risk ofParkinson’s Disease” made by the MassachusettsGeneral Hospital, USA underwww.massgeneral.org/DEPTS/pubaffairs/releases/050401parkinsons.htm

Conclusion

Our findings indicate that higher coffeeand caffeine intake is associated with asignificantly lower incidence of PD. This effectappears to be independent of smoking. Thedata suggest that the mechanism is relatedto caffeine intake and not to othernutrients contained in coffee.

NewsCaffeine“Association of coffee and caffeine intake with the risk of Parkinson disease”

From the right side: Mr Vincent Bettevy, Mrs Maureen Mistry, and Dr. Michael Black

In the European Region

In the European Region the Technical MarketingServices have been re-organised to provide BASFcustomers with a direct contact person who willcoordinate all customer support and all technicalactivities. The Technical Marketing Service will beprepared to discuss specific applications andprojects using BASF Pharma Ingredients relating tocustomer needs.

The contact persons are:Mrs Maureen Mistry, based in Ballerup, Denmark.She is responsible for Scandinavia, UK, Ireland,Poland and the Netherlands.(tel: 0045 44 73 0166; fax: 0045 44 73 0102)

Mr Vincent Bettevy, located in France. He is responsible for France, Belgium, Spain and Portugal.(tel: 0033 1 49 64 5687; fax: 0033 1 49 64 5622)

Dr. Michael Black, situated at BASF AGin Ludwigshafen. He is responsible for Germany,Switzerland, Austria, Hungary, Italy and Greece.(tel: 0049 621 60 94830; fax: 0049 621 60 94789).

ObjectiveDebates about the suspected association betweenrenal disease and use of analgesics led to thequestion whether caffeine could stimulate anundesirable overuse of phenacetin-free combinedanalgesics. A committee was asked to criticallyreview the pertinent literature in order to guideclinical practice and contribute to considerations ofregulatory authorities.

EvidencePublished literature relevant to the subject wassent to all invited experts, who added further research.

We have the complete studies in our files and areprepared to mail them to you.

BASF ExActpage 15 – No. 6, May 2001

Another interesting conclusion was found duringan expert review in January 2000. We believe thatthis information is of interest for those pharmacustomers which are using caffeine in analgesiccombinations or intend to develop a newformulation.

ParticipantsInternational scientists were jointly selected by theregulatory authorities of Germany, Switzerland andAustria and the pharmaceutical industry to meet inNew York.

NewsCaffeine“Do caffeine-containing analgesics promote dependence?”

Conclusion

Although more experimental and longtermdata on mechanisms of dependence wouldbe desirable, the committee concluded that the available evidence does not support the claim that analgesics coformulatedwith caffeine, in absence of phenacetin,stimulate or sustain overuse.

Equipment of the caffeine productionin Minden, Germany.

Caffeine

BASF ExActpage 16 – No. 6, May 2001

Contact

Kollicoat® SR 30 DIn previous editions we reported aboutKollicoat® SR 30 D, a new aqueous polyvinylacetate dispersion for sustained release filmcoating. In 2000 a USA-DMF has been submitted.The DMF no. is 15055.

CD-ROM “ExAct”In November 1998 we published the first editionof ExAct. The number of readersis continously growing. We often receive requestsconcerning previous ExAct editions. For thisreason we are now offering the editions 1-6 on aCD-ROM that can be ordered with the attachedreply card.

News

New Media

Please contact your local BASF companyor one of the following regional centres:

AsiaBASF Asia Pacific Regional HQPharma SolutionsDr. Danilo MercadoBASF South East Asia Pte Ltd9/F., Suntec Tower Three7 Temasek BoulevardSingaporeFax: **65 /4309812

EuropeBASF AktiengesellschaftLNF/FP – J550Mr. Peter HoffmannD-67056 LudwigshafenGermanyFax: **49 /62160-22627

NAFTABASF CorporationPharma SolutionsMr. Charles Dods3000 Continental Drive-NorthMount Olive, NJ 07828-1234USAFax: **1 /9734265355

South AmericaBASF S.A.Human Fine ChemicalsMr. Claudio LehmannEstrada Samuel Aizemberg, 170709851-550 São Bernardo do Campo-SPBrazilFax: **55 /1143432255Phone: **55 /1143432284

Eastern Europe /Africa /West AsiaBASF AktiengesellschaftLRM/M – D 205Mr. Rolf HanssenD-67056 LudwigshafenGermanyFax: **49 /62160-44689

Or visit our website:http://www.basf.de/pharma

PreviewMasking of unpleasantly tasting activeingredients

Launched as a film-forming polymer based onpolyvinyl acetate for sustained-release coating,the properties of Kollicoat® SR 30 D are notcompletely highlighted. The combination withwater-soluble excipients or at least acomponent that swells after being contactedwith water make Kollicoat® SR 30 D a versatileexcipient for taste-masking purposes: Integercoating combined with the fast release of theactive ingredient.

ExAct No.7 will inform you about the suitabilityof Kollicoat® SR 30 D in different formulationsto cope with unpleasantly tasting actives orexcipients.

For any information in advance please contactyour local BASF office or our regional centres.

1st-6th Edition