no. 8, may 2002 excipients & actives for pharma · terization of kollicoat® ir page 2-3...

CalendarPhysicochemical charac-terization of Kollicoat® IR

page 2-3

Kollicoat® IR – innovationin instant release film coating

page 4-5

Kollicoat® SR 30 D – coat-ings on different drugs

page 6-7

Optimization of an EntericCoating Formulation basedon Kollicoat® MAE 30 DP

page 8-11

Contract ManufacturingServices page 12

News page 13

Preview page 14

New Media page 14

Contact page 14

ImprintPublisher:BASF Aktiengesellschaft

Editorial staff:Dr. Volker Bühler, Valérie Filiatreau,Dr. Hubertus Folttmann, Dr. Bernhard Fussnegger,Dr. Karl Kolter, Silke Werth

Realisation:printec GmbH, Kaiserslautern

20th to 25thJuly, 2002

29th International Symposium

on Controlled Release of

Bioactive Materials

Seoul*, South Korea

31st to 2ndAugust, 2002

FCE Pharma

International Pharmaceutical Industry

Exhibition

Sao Paulo*, Brazil

9th to 11thSeptember, 2002

11th International Pharmaceutical

Technology Symposium

Istanbul, Turkey

1st to 3rdOctober, 2002

CPhI Worldwide

Paris*, France

21th to 23thOctober, 2002

7th European Congress of Pharmaceutical

Sciences

Stockholm, Sweden

8th to 14thNovember, 2002

AAPS (American Association of

Pharmaceutical Scientists) Annual Meeting

Toronto*, Canada

*: BASF will be represented.

Dear reader,

As announced in the 7th edition, we are currently in the process of launching our new polymer,Kollicoat IR.

At BASF continuous development of new excipi-ents with improved functionality is our top priority.

Our initial range of coating polymers with theKollicoat MAE grades for gastro-resistant coating,Kollicoat EMM 30 D and Kollicoat SR 30 D forsustained release formulations is now strength-ened by Kollicoat IR for instant release formula-tions. We are now in a position to provide you afull range of functional polymers for all major fieldsof coating applications.

Kollicoat IR, a film-former with an entirely new chemical formula is superior to existing polymersfor instant release formulations in many aspectswith regard to product properties and handling. Itwill rapidly become a synonym for fast and econo-mic instant release coating.

You will find detailed information concerningKollicoat IR including physicochemical propertiesand application on pages 4 to 5.

Excipients & Actives for Pharma

No. 8, May 2002

Yours sincerely,

BASF AktiengesellschaftStrategic MarketingPharma Solutions

Gabriel Tanbourgi

BASF ExAct

K. Kolter, M. Gotsche and T. Schneider,BASF Aktiengesellschaft, Development Pharma Ingredients, 67056 Ludwigshafen, Germany

page 2 – No. 8, May 2002

Physicochemical Characterization of Kol

Purpose

Kollicoat IR, a polyvinyl alcohol – polyethylene gly-col graft copolymer is a new pharmaceutical exci-pient that was specially developed as a coatingpolymer for instant release tablets. Since coating is a rather complex process, thephysicochemical properties of the polymer play animportant role. They determine the process para-meters, handling properties as well as the charac-teristics of the finished dosage forms (1).Furthermore, in order to determine the dissolutionspeed of a film, a new method based on thepaddle model was developed.The objective of this study was to evaluate thephysicochemical properties of Kollicoat IR that arerelevant to the coating of pharmaceutical dosageforms.

Methods

• Materials:Kollicoat IR (BASF)

• Preparation of films:Cast on an Erichsen 509/3 using a 20 % polymersolution to give a thickness of about 100 µm.

• Elongation at break and tensile strength:According to DIN 53504 using a TA-XT2.HiRTexture analyzer (Stable Micro Systems); the testwas performed at different humidities.

• Dissolution speed:A film of about 100 µm was clamped in a photo-graphic slide frame with an opening of 35 x 23mm and positioned radially in a vessel of a paddleapparatus 3 cm below the surface; stirrer speed:50 rpm; the times for rupture and complete disso-lution were recorded.

• Tack:Films were cast on glass plates and stored for 12hours under given conditions; testing was thenperformed by the Hoessel method (2).

CH2 O CH2 CH2 O CH2 CH2 OCHO CH CH2 O CH2 O CH2

CH2

CH-OH

CH2

CH-OH

CH2

CH-OH

CH2

CH-OH

Table 1: Physicochemical properties of Kollicoat IR

Physical form free-flowing powder

Molecular weight about 45,000 daltons

Solubility water > 50 %0.08 N HCI > 50 %phosphate buffer pH 6.8 > 50 %

pH (20 % solution) 6.7

Viscosity (20 % solution) 115 mPas

Melting temperature 209 °C

Film formation clear, transparent films

(figure 1) (figure 2)

Molecular structure of Kollicoat IR

0

Concentration [%]

5 15 20 25 3010

Surface tension of Kollicoat IR solution

Sur

face

ten

sion

[mN

/m]

35

40

50

60

65

45

55

61.6

53.7

47.5

41.541.4

42.644.3

Differential Scanning Calorimetry of Kollicoat IR

Hea

t Fl

ow [W

/g]

0

Temperature [°C]

50 150 200 250100–1

–0.5

0

0.5

No. 8, May 2002 BASF ExAct

Results

Kollicoat IR is a polyvinyl alcohol-polyethylene gly-col graft copolymer with a molecular weight ofabout 45,000 daltons as determined by GPC. Themolecule is hydrophilic and thus readily soluble inwater. As its structure is nonionic, its solubilitydoes not change when the pH is decreased orincreased. As a result of its extremely low thickening effect,highly concentrated solutions can be sprayedonto tablet cores.

Both parts of the Kollicoat IR molecule contributeto the mechanical properties of films. The polyvinylalcohol moiety provides good film-forming pro-perties and the polyethylene glycol part acts as aninternal plasticizer leading to excellent flexibility(elongation at break: 105 %). In contrast to otherfilm formulations, the plasticizer cannot migratebecause it is covalently bound in the molecule. Incontrast to pure polyvinyl alcohol films, the flexibili-

ty is maintained in storage because rearrange-ment of the molecules to a high level of order(“crystallization”) is prohibited.Relative humidity in the range of 30–75 % haspractically no influence on the mechanical pro-perties of the Kollicoat IR films.Instant release coatings should dissolve quickly inorder to avoid any influence on the dissolutionrate of the tablet as a whole. A new method wasdeveloped to determine the dissolution speedusing the well known paddle apparatus. The film was clamped in a slide frame, this devicewas positioned in the paddle apparatus and thetime was determined for the first rupture of thefilm and subsequently for the complete dissolutionof the film. There was no difference in the dissolu-tion speed in 0.08 N HCl and phosphate bufferpH 6.8.Polymers for coating tablets must have low tack.Low tack values of 0.75–1.25 were measuredeven at high relative humidities using the Hoesselmethod.

licoat® IR

(figure 3)

Elongation at break of various instant release coatings

Elo

ngat

ion

at b

reak

[%]

112.9105

69.6

4.8 4.2 4.411.8

17.111

Kollicoat IR Pharmacoat 603 Pharmacoat 606

20

40

60

80

0

100

120 33 % r. h.54 % r. h.75 % r. h.

(figure 4) (figure 6)

(figure 5)

Tackiness of Kollicoat IR films

23 °C / 54 % r. h. 30 °C / 75 % r. h. 20 °C / 80 % r. h.

2

4

5

0

1

3

0.751.25

1

0.08 N HCl disintegration timeph 6.8 phosphate buffer disintegration time0.08 N HCl dissolution timeph 6.8 phosphate buffer dissolution time

Dissolution speed of instant release polymers(film thickness: 100 µm)

Tim

e [m

in:s

]


03:08

06:21

03:02

06:31

05:02

04:06

01:31 01:33

00:42 00:44

01:27 01:26

2

3

4

5

0

6

7

1

Conclusions

• Kollicoat IR has demonstrated very promising characteristics for instant release coatings:– high water solubility– high dissolution speed– low viscosity– low tack– enormous flexibility

• The newly developed method for determiningthe film dissolution time gives reliable andreproducible results.

References[1] A. O. Okhamafe and P. York, J. Pharm.

Pharmacol. 38, 414-419 (1986).[2] P. Hoessel, Cosmetics and toiletries

111 (8), 73 ff (1996).

Determination ofdissolution speed

Paddle dissolution tester

Slide frame(orifice 35 x 23 mm)

Film

BASF ExAct

K. Kolter,BASF Aktiengesellschaft, Development Pharma Ingredients, 67056 Ludwigshafen, Germany

page 4 – No. 8, May 2002

Kollicoat® IR – Innovation in Instant Rele

Purpose

Only a few polymers, such as hydroxypropylmethyl-cellulose, hydroxypropylcellulose andEudragit E can be used for instant release coatingson pharmaceuticals. The drawbacks of these polmers are mainly high viscosity in solution, whichlimits the polymer concentration in spray solutionsto a maximum of 10 %, and a limited flexibility ofthe films [1,2]. To overcome these drawbacks, a new polymerwas developed: polyvinyl alcohol – polyethyleneglycol graft copolymer (Kollicoat IR). This study investigates the technical properties ofKollicoat IR in comparison with HPMC, and deter-mines the optimum parameters for a coating pro-cess in a horizontal pan coater.

Methods

• Materials:Kollicoat IR (BASF), Pharmacoat 603, -606 (Shinetsu), tablet cores (caffeine 50 mg; Ludipress229 mg, Avicel PH 102 40 mg; Kollidon CL 10mg; magnesium stearate 1 mg).

• Preparation of films:Cast on an Erichsen M 509/3 using a 20 % poly-mer solution to give a thickness of about 100 µm.

• Elongation at break:According to DIN 53504 using a TA-XT2 HiR tex-ture analyzer (Stable Micro Systems) at 23 °C / 53% r. h.

• Viscosity:Brookfield RVT (Brookfield)

• Tablet coating:Accela Cota (Manesty)3.0 mg/cm• coating level

Table 1: Composition of the spray suspension

Kollicoat IR 20.8 %

Talc 7.7 %

Titanium dioxide 4.0 %

Water 67.5 %

All ingredients were stirred into water and this sus-pension was homogenized using a corundum mill.

Table 2: Coating parameters

Inlet air temperature 60 °C

Outlet air temperature 39 °C

Atomizing pressure 3 bar

Spraying rate 30 g/min.

Coating suspension 520 g for 5.0 kgcores

Spraying time 18 min.

Drying 4 min.

(figure 1)Viscosity of a Kollicoat IR solution as a functionof polymer concentration and temperature

Vis

cosi

ty [m

Pas

]

0

100

200

400

600

700

300

500

Polymer concentration [%]

5 15 20 25 30100

23 °C70 °C

Table3: Properties of film-coated tablets

Core Film-coated tablet

Appearance White White

Hardness 116 N 119 N

Friability 0 % 0 %

Disintegration time 0:58 [min:s] 0:51 [min:s]

Drug release 10 min.: 93 % 10 min.: 92 %20 min.: 98 % 20 min.: 98 %


Results

The sprayability of a coating solution is stronglyinfluenced by the viscosity, because viscous for-mulations cannot be atomized properly. The limitcan be set at about 250 mPas.When the polymer concentration is increased upto 30 % solids, the viscosity at 23 °C of aKollicoat IR solution increases slowly. Beyond this,the increase is more rapid. The viscosity can bereduced by warming the solution, e.g. to 70 °C(Figure 1).The viscosities of solutions of the instant releasepolymers Kollicoat IR, Pharmacoat 603 andPharmacoat 606 were compared at a polymerconcentration of 20 %. Kollicoat IR gave a muchlower viscosity than the cellulose derivatives, thusallowing it to be sprayed in solutions of higherconcentration (Figure 2).It is a well known phenomenon that coatings witha low flexibility often develop cracks, particularlywhen the dosage form is stored at elevated humi-dity, because the coating cannot accommodatethe swelling of the core. The elongation at breakof Kollicoat IR films (105 %) far exceeds that ofthe cellulose derivatives (4 and 17 %) and shouldtherefore prevent any cracking. There is no needto add any plasticizer to Kollicoat IR films (Figure3, 4).Tablet coating experiments were performed in ahorizontal pan coater, to test the conclusions fromthe physicochemical data. Whereas a Kollicoat IRformulation containing 20.8 % polymer and 11.7% pigments (total solids: 32.5 %) with a viscosityof 193 mPas could be applied easily, this was notpossible when Pharmacoat 606 was used.

ease Film Coatings

Conclusions• Kollicoat IR gives solutions of much lower vis-

cosity and films of greater flexibility than cellulose derivatives.

• It can be applied easily on tablet cores at highsolids concentrations.

• A plasticizer is not needed.• Coating times can be shortened.• Coatings with Kollicoat IR are stable in storage

even at high humidity.

References[1] M. E. Aulton et al, Proc. 4th Int. Conf. Pharm.

Techn., APGI, Paris 133-40 (1986).[2] T. Nagai et al, Aqueous Polymeric Coatings for

Pharmaceutical Dosage Forms 2nd Edition,Marcel Dekker Inc., 1997, 177-225.

(figure 2)Viscosity of different instant release polymersat 20 % concentration and 23 °C

1000

2000

3000

4000

0

5000

6000

115

800

5150

Vis

cosi

ty [m

Pas

]


(figure 3)

20

40

0

60

80

100

120


105

4

17

Elongation at break of different instant release polymersat 23 °C / 53 % r. h.

Elo

ngat

ion

at b

reak

[%]

Determination ofelongation atbreak (figure 4)

BASF ExAct

K. Kolter and T. C. Rock,BASF Aktiengesellschaft, Product Development Pharma/Food, 67056 Ludwigshafen, Germany

page 6 – No. 8, May 2002

Kollicoat® SR 30 D – Coatings on Differe

Introduction

There exists only a limited number of excipients forcoated sustained release dosage forms. Thisvariety is extended by Kollicoat® SR 30 D, a newlydeveloped sustained release coating based onpolyvinyl acetate [1]. Due to the absence of ioniza-ble groups it offers the opportunity to formulate solid dosage forms with a pH-independent drugrelease. By adding a small amount of plasticizer(10 % propylene glycol or 5 % triacetin) film forma-tion and film flexibility are increased tremendouslyand a curing of the finished dosage form is oftennot necessary. Up to now only results with caffeineand theophylline as model drugs had been pub-lished. This work shows the development of sus-tained release dosage forms of drugs (propranolol-HCl, carbamazepine, acetaminophen) with differentsolubility.

Experimental Methods

• Materials:Kollidon® SR 30 D (polyvinyl acetate dispersion 30 %, BASF AG), propranolol-HCl (Knoll AG), acetaminophen gran.(Knoll AG), carbamazepine (Farchemia FIS).• Methods:The pellets were produced by extrusion in anAlexanderwerk apparatus with a 1.5 mm sieve andsubsequent rounding in a spheronizer. The fraction0.71–1.4 mm was used for coating.Acetaminophen granules were used without pre-vious pelletisation.

The coating (1 for propranolol-HCl and carbama-zepine pellets, 2 for acetaminophen granules) wasapplied on 0.5 kg pellets in a fluidized bed coater(Aeromatic) under the following conditions:

Inlet air temperature 60 °COutlet air temperature 35 °CAtomizing pressure 1.0 barSpraying rate 11.5 g/minDrying 40 °C/3 minCoating level 1; 2; 3; 4 mg/cm2

Drug dissolution was determined using aPharmatest paddle apparatus.

Table 2: Coating composition

1 2

Kollicoat® SR 30 D 60.5 91

Propylene glycol 1.8 –

Triacetin – 2.7

Water 37.6 6.3

Table 3: Drug dissolution

medium stirrer[rpm]

Propranolol-HCl 0.08 N-HCl (0-2 h); 100 phosphate buffer

pH 6.8 (2-24 h)

Acetaminophen Water 50

Carbamazepine 1 % Sodium 75lauryl sulfate

Table 4: Drug solubility

Propranolol- Acetamino- Carbama- HCl phen zepine

[mg/ml] [mg/ml] [mg/ml]

Water – 16 ~ 0

0.08 N HCl 94 – –

Phosphate 114 – ~ 0buffer pH 6.8

1 % Sodium – – 2lauryl sulfate

Table 1: Pellet composition

Parts by weight [%]

Propranolol-HCl 30 – –

Carbamazepine – 50 –

Acetaminophen granules – – 100

Avicel® PH 101 46.66 47.5 –

Lactose 20.84 – –

Kollidon® VA 64 2.5 2.5 –


Results and Discussion

The coated pellets of propranolol-HCl showed astrong correlation between coating level and drugrelease. With a coating level of 1 mg/cm2 the pel-lets were not completely coated. Therefore, morethan 90 % of propranolol was released within 2hours. Using 2 to 4 mg/cm2 the release rate of > 80 % can be adjusted in a time period from 4 to24 hours.Although acetaminophen has a lower solubility inthe dissolution medium (table 4) the release ratesof the coated granules were for all coating levelscomparatively fast. Even with a coating level of 3 mg/cm2 the drug release reached 100 % after 8h. This fact is caused by the sharp edges of theirregular shaped granules which are very difficultto coat. Furthermore, due to the non-sphericalstructure the real surface area is larger than thecalculated one. However, this example shows thatthe surface properties and the structure of thepellets are as important as the coating level toachieve a certain release rate.As expected from the low water solubility carba-mazepine pellets exhibited a slow dissolution pro-file already with a coating level of 1mg/cm2.

ent Drugs

Conclusions• The release rate is strongly influenced by the

surface properties and the structure of thecores.

• A higher water solubility of the drug requires ahigher coating level.

• For a low batch to batch variation of drug dis-solution it is essential to reproduce exactly thecores.

References[1] K. Kolter and F. Ruchatz, Proceedings of the

26th CRS symposium, Boston 1999, paper 6311.

(figure 1)

Drug release of propranolol pellets as afunction of coating level

Dru

g re

leas

e [%

]

Time [h]

0 1284 16 2420

120

40

20

0

100

60

80

medium: 0.08 N HCl (0–2 h)phosphate buffer pH 6.8 (2–24 h)

1 mg/cm2

4 mg/cm23 mg/cm22 mg/cm2

(figure 2)

Drug release of acetaminophen granules coatedwith different coating levels

Dru

g re

leas

e [%

]

120

40

20

0

100

60

80

medium: water

Time [h]

0 842 10 12

1 mg/cm2

3 mg/cm22 mg/cm2

(figure 3)

Drug release of carbamazepine pellets

Dru

g re

leas

e [%

]

Time [h]

0 1284 16 2420

120

40

20

0

100

60

80

medium: 1 % sodium lauryl sulfate in water 1 mg/cm2

uncoated

BASF ExAct

K. Kolter, H-B. Reich, BASF Aktiengesellschaft, Product Development Pharma, 67056 Ludwigshafen, GermanyC. Dangel, G. Schepky, Fachhochschule, Dept. Pharma Technology, 72488 Sigmaringen, Germany

page 8 – No. 8, May 2002

Optimization of an Enteric Coating Form

Introduction

Aqueous enteric coatings based on methacrylicacid – ethyl acrylate copolymer (Kollicoat® MAE 30DP) are known to provide excellent gastric resist-ance and short production times [1]. Because thepolymer dispersion is usually not applied solely, thegastric resistance is influenced by additives.Furthermore, it is known, that polymer dispersionscan coagulate by improper handling, high shearforces, high concentrations of finely dispersed par-ticles, some salts or other incompatible materials.Therefore, it is particularly important to use safeand reproducable spray formulations and proces-ses in the production of pharmaceutical dosageforms.

Objective

The objective of this study was to optimize a pig-mented enteric coating formulation based onKollicoat® MAE 30 DP with regard to gastric resist-ance, color distribution and coagulation behavior.

Materials and Methods

• MaterialsMethacrylic acid-ethyl acrylate copolymer(Kollicoat® MAE 30 DP, BASF AG).

• ApparatusAccela Cota 24” (Manesty Machines Ltd.), disin-tegration tester (DES-4 AS, Krämer Elektronik),dissolution apparatus (PTW-S, PharmatestApparatebau).

• Composition and preparation of caffeinecoresAnhydrous caffeine 50 mg (Knoll AG), Ludipress229 mg (BASF AG), Avicel PH 101 40 mg (FMC),Kollidon CL 10 mg (BASF AG), Magnesium stea-rate 1 mg (Bärlocher).The ingredients of the formulation were mixed ina Diosna mixer and compressed with a force of10 kN into cores with the following parameters:9 mm diameter, 12 mm radius of curvature, 330mg weight.

• Composition and preparation of the spraydispersions

Pigment dispersionTo prepare the pigment dispersion Kollidon® 30was dissolved in water. Then Sicovit® red 30, tita-nium dioxide and talc were intensively stirred inand homogenized using a corundum disc mill.

Polymer dispersionSeperately propylene glycol was mixed with waterand then Kollicoat® MAE 30 DP was added understirring.

Spray suspensionThe pigment dispersion was mixed under stirringinto the polymer dispersion.

Table 1: Spray formulations

Polymer dispersion A B

Kollicoat® MAE 30 DP 50.0 50.0

Plasticizer 1.5 – 4.5 1.5 – 4.5

(related to polymer) (10 – 25 %)

Water ad 84.5 ad 84.5

Pigment dispersion A B

Kollidon® 30 0.5 –

Sicovit® red 30 0.5 0.5

Titanium dioxide 0.5 0.5

Talc 4.0 4.0

Water 10.0 10.5

100.0 100.0


ulation based on Kollicoat® MAE 30 DP

• Coating process

• Determination of the uptake of gastric fluidinto enteric coated tablets during the resi-stance testSix film-coated tablets were agitated in 0.1 n-HCl in a disintegration tester for 1 and 2 hours.The increase of the tablet weight is given as per-centage of the initial weight.

• Determination of dissolutionAccording to USP 23, apparatus 2, method Busing 0.1 n-HCl and phosphate buffer 6.8.Caffeine was determined spectrophotometricallyat 273 nm.

• CoagulationCoagulation was determined visually by inspec-tion directly after the preparation of the spraysupensions and after 24 h.

Table 2: Coating parameter

Tablet mass 5 kg

Atomizing nozzle 1.0 mm

Atomizing pressure 2.0 bar

Inlet air temperature 52 °C

Outlet air temperature 37 °C

Drying 5 min / 52 °C

Table 3: Coagulation of spray formulations

Plasticizer Concentration Formulation A Formulation Brelated to polymer (without

[%] Kollidon® 30)

Propylene glycol 10 stable stable

20 stable stable

30 stable stable

Triethylcitrate 10 tend to coagulate stable

20 coagulate stable

30 coagulate stable

PEG 400 10 coagulate stable

20 coagulate stable

30 coagulate stable

PEG 1500 10 coagulate stable

20 coagulate stable

30 coagulate stable

PEG 6000 10 stable stable

20 stable stable

30 stable stable

Cremophor® RH 40 10 tend to coagulate stable

20 coagulate stable

30 coagulate stable

BASF ExAct page 10 – No. 8, May 2002

Results

• CoagulationCoagulation of the spray formulation A wasobserved, when Triethylcitrate, PEG 400, 1500or Cremophor® RH 40 were used as plasticizer.This is due to a triple interaction between theseplasticizers, pigments and Kollidon® 30, sincewithout either pigments or Kollidon® 30 no coa-gulation could be detected. The competition pro-duct to Kollicoat® MAE 30 DP, Eudragit® L 30 Dshowed the same coagulation behavior. Withrespect to coagulation, propylene glycol andPEG 6000 are preferred (table 3). The eliminationof Kollidon® 30 led to an uneven color distribu-tion of the red pigment in the film, which can becompensated by a longer stirring time of the pig-ment dispersion (12 h).

• Gastric resistanceThe determination of the uptake of gastric fluidinto the film-coated tablets is a very sensitivemethod for gastric resistance, particularly if acore with a strong absorption of water is used.In this test, propylene glycol and triethylcitrateexhibited lower weight increases as PEG 400. Asexpected, the plasticizer PEG 400 needed amuch higher coat weight compared to other pla-sticizers to achieve the same level of resistance(figure 1).

In the case of triethylcitrate, it was expected, thatgastric resistance would not be influenced byincreasing amounts of plasticizer. Surprisingly, thiswas also seen with the hydrophilic propylene gly-col. Either these plasticizer are not leached out, orif they are leached out, no pores are created (figu-re 2).Talc is known to modify the gastric resistance. Anamount of 27 % related to polymer can be recom-mended, since 13 % were less effective in redu-cing acid uptake and 40 % showed no furtherimprovement.Gastric resistance was also tested using a dissolu-tion tester. At a coat level of 3 mg/cm , the amountof propylene glycol did not influence the dissolu-tion. After 2 h in gastric fluid, no dissolution wasobserved and in phosphate buffer 6.8, the drugwas released (> 90 % after 10 min) very quickly(figure 3).

(figure 1)Uptake of gastric fluid into enteric coated caffeinetablets after 2 h in the disintegration testerPlasticizer concentration: 15 % related to polymer

Wei

ght

incr

ease

[%]

Propylene glycol Triethylcitrate PEG 400

(figure 2)Uptake of gastric fluid into enteric coated caffeinetablets after 2 h in the disintegration testerCoating level: 4 mg/cm2

Wei

ght

incr

ease

[%]

Propylene glycol Triethylcitrate PEG 400

(figure 3)Dissolution of enteric coated caffeine tabletsCoating level: 3 mg/m2

Dis

solu

tion

[%]

Time [min]

0.1 n-HCI phosphate buffer pH 6.8


Conclusions• To avoid coagulation, propylene glycol should

be used as plasticizer in spray formulations withpigments.

• A triple interaction can occur in spray formula-tions with pigments between1) triethylcitrate, low molecular weight PEG or

Cremophor® RH 402) fine dispersed pigments and3) Kollidon® 30

• The plasticizers propylene glycol and triethyl-citrate produced film coats showing the bestgastric resistance.

• The gastric resistance was independent fromthe amount of plasticizer (10 – 25 %).

• Propylene glycol should be the plasticizer ofchoice for methacrylic acid-ethyl acrylate copo-lymer and should be used in 15 % concentra-tion.

References[1] S. Scheiffele, K. Kolter, G. Schepky, Drug Dev.

Ind. Pharm. 24 (9), 807-818 (1998)

Kollicoat® grades and Applications

Grade Availability Major application Pharmacopoeial monographs

Kollicoat® IR (new) Powder Rapidly disintegrating coatings

Kollicoat® MAE 30 DP Aqueous Enteric coatings Ph. Eur., JPE, NFDispersion

Kollicoat® MAE 100 P Powder Enteric coatings

Kollicoat® SR 30 D Aqueous Sustained Dispersion release

formulations

Kollicoat® EMM 30 D Aqueous Sustained Ph. Eur., JPEDispersion release

formulations

BASF ExAct page 12 – No. 8, May 2002

This new unit is based at BASF headquarter inLudwigshafen, Germany and acts as a flexible,globally operating business unit while takingadvantages from BASF global organization andinfrastructure. Our pharmaceutical know-howcombined with BASF’s chemical research will sup-port our life science partners.It disposes of a specialized and flexible team tofulfill the customers’ needs and offer them the bestindividual support at any time throughout the lifecycle of their products and projects.

A Dedicated Business Unit

Dr. Antonio GermaniHead of Contract ManufacturingPhone: +49-621-60-95876Fax: +49-621-60-95770E-mail: [email protected]

Christa MüllerOfficePhone: +49-621-60-95506Fax: +49-621-60-95770E-mail: [email protected]

Wolfgang FalkenbergAccount ManagerPhone: +49-621-60-95606Fax: +49-621-60-95549E-mail: [email protected]

Dr. Martin-Jochen KlattAccount ManagerPhone: +49-621-60-48894Fax: +49-621-60-95549E-mail: [email protected]

Dr. Daniele PiergentiliAccount ManagerPhone: +49-621-60-59266Fax: +49-621-60-95770E-mail: [email protected]

Pia NoackProduct StewardshipPhone: +49-621-60-41975Fax: +49-621-60-95539E-mail: [email protected]

Valérie FiliatreauProduct StewardshipPhone: +49-621-60-95716Fax: +49-621-60-95539E-mail: [email protected]

Contract Manufacturing by BASF - A dedicated Business Unit

Picture from left to right:Christa Müller, Dr. Martin-Jochen Klatt, Valérie Filiatreau, Dr. Antonio Germani, Wolfgang Falkenberg, Pia Noack (Dr. Piergentili not on the picture)


NewsSolutol HS 15 now

monographed in

DAB 2001

After being marketed for more than fifteen years,the solubilizing agent Solutol HS 15 was finallymonographed in the „Deutsches Arzneibuch 2001(DAB 2001)“ as „Macrogol-15-hydroxystearat“.This became possible after the product becamepart of registered formulations. An identical version of this monograph is presentlyunder discussion as a draft in the correspondingcommission for European Pharmacopoeia. It isexpected that it will be published in one of thenext supplements of the European Pharmacopoeia2002, 4th edition.

50th Anniversary of

Theophylline Production

50 years of Theophylline production at our Mindensite in Germany - over all the years the site atwhich Knoll, and today BASF, has manufacturedthis pharmaceutical active compound.The production process which has been devel-oped by Knoll staff in the 1940’s, is still state-of-the-art today and is operated successfully atMinden. Continuous optimisation has led to amanufacturing capacity and product quality thatmeet market needs.Initially, the main fields of application forTheophylline were cardiac insufficiency, circulatorydisorders and as a diuretic - today, it is usedalmost exclusively for the treatment of asthma.It is an interesting fact that, up to the beginning ofthe seventies, the opinion prevailed thatTheophylline was unsuitable as such for the treat-ment of asthma, because the doses that wererequired very quickly led to undesirable side effectswithout having achieved the asthma-relievingaction. It was also the opinion at that time that the organ-ism could only take up a small proportion of theTheophylline dose.

The breakthrough for Theophylline in the treatmentof asthma came with the development of retardforms. (companies involved were Byk Gulden,Dooner Labs (later RPR), Klinge and Schering). Itemerged that Theophylline was indeed virtually100% bioavailable and that it was now possible tocontrol the release of the active compound in sucha way that the exact therapeutic dose was effec-tive for a period of six to eight hours without theundesirable side effects occurring.With the technical advances of today and newmedical knowledge, the market with its needs haschanged and led to other therapeutic solutions. Inparticular, the advent of asthma sprays for localtreatment caused the demand for Theophylline tostagnate.For years, BASF has been the world’s biggest pro-ducer of purines. We are committed to thesustainable production of Theophylline in thecoming years and intend to remain the leadingsupplier of Theophylline.

The increasing number of water insoluble activesrepresents a challenge forpharmaceutical scientists.

BASF ExActpage 14 – No. 8, May 2002

ContactPlease 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 – J 550Mr. Peter HoffmannD-67056 LudwigshafenGermanyFax: **49 /62160-22627

NAFTABASF CorporationPharma SolutionsMr. Patrick Glaser3000 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

Preview

With the ExAct edition in hand we presentedto you the physicochemical characterisationand instant release film coating properties ofKollicoat IR, an innovative excipient based onan entirely new chemical formula.

Kollicoat IR gives solutions of much lower viscosity and films of greater flexibility than cel-lulose derivatives. Coating times can be shor-tened leading to reduced manufacturing cost.Besides other topics ExAct No. 9 will informabout the scale-up of an instant release coat-

ing process with Kollicoat IR and other appli-cation data.

Should you require information in advance,please contact your local BASF company orone of our regional marketing offices.

New MediaKollidon – Polyvinylpyrrolidone for thepharmaceutical industry(New: 6th edition, October 2001)

ME

FM 0

1021

e

Kollicoat IR - A new instant release coating polymer

Meanwhile the book „Kollidon- Polyvinylpyrrolidonefor the pharmaceutical industry“ by Volker Bühler is a classic and well known tomany professionals in the pharmaceutical and rela-ted industries.

This book is intended for all persons in pharma-ceutical technology and quality control who areinvolved in the processing of povidone, crospovi-done and copovidone. A comprehensive alphabet-ical index leads the reader straight to the productproperties, applications, and formulations with alarge number of drugs, processing technologiesfor a wide range of dosage forms, and the analyti-cal methods.

In this revised edition a chapter on Kollidon SR, anew sustained release matrix polymer, was added.Also some specifications were updated.

This book can be ordered with the attached replycard.

no. 8, may 2002 excipients & actives for pharma · terization of kollicoat® ir page 2-3...

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