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

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1 Excipients & Actives for Pharma No. 8, May 22 Calendar 2 th to 25 th July, th International Symposium on Controlled Release of Bioactive Materials Seoul*, South Korea 31 st to 2 nd August, 22 FCE Pharma International Pharmaceutical Industry Exhibition São Paulo*, Brazil 9 th to 11 th September, th International Pharmaceutical Technology Symposium Istanbul, Turkey 1 st to 3 rd October, 22 CPhI Worldwide Paris*, France 21 th to 23 th October, 22 7 th European Congress of Pharmaceutical Sciences Stockholm, Sweden 8 th to 14 th November, 22 AAPS (American Association of Pharmaceutical Scientists) Annual Meeting Toronto*, Canada *: BASF will be represented. Imprint Publisher: BASF Aktiengesellschaft Editorial staff: Dr. Volker Bühler, Valérie Filiatreau, Dr. Hubertus Folttmann, Dr. Bernhard Fussnegger, Dr. Karl Kolter, Silke Werth Realisation: printec GmbH, Kaiserslautern Dear reader, As announced in the 7 th edition, we are currently in the process of launching our new polymer, Kollicoat IR. At BASF continuous development of new excipients with improved functionality is our top priority. Our initial range of coating polymers with the Kollicoat MAE grades for gastro-resistant coating, Kollicoat EMM 3 D and Kollicoat SR 3 D for sustained release formulations is now strengthened by Kollicoat IR for instant release formulations. We are now in a position to provide you a full range of functional polymers for all major fields of coating applications. Kollicoat IR, a film-former with an entirely new chemical formula is superior to existing polymers for instant release formulations in many aspects with regard to product properties and handling. It will rapidly become a synonym for fast and economic instant release coating. You will find detailed information concerning Kollicoat IR including physicochemical properties and application on pages 4 to 5. Yours sincerely, BASF Aktiengesellschaft Strategic Marketing Pharma Solutions Gabriel Tanbourgi Physicochemical characterization of Kollicoat IR page 2-3 Kollicoat IR innovation in instant release film coating page 4-5 Kollicoat SR 3 D coatings on different drugs page 6-7 Optimization of an Enteric Coating Formulation based on Kollicoat MAE 3 DP page 8-11 Contract Manufacturing Services page 12 News page 13 Preview page 14 New Media page 14 Contact page 14

2 BASF ExAct page 2 No. 8, May 22 Physicochemical Characterization of Kol K. Kolter, M. Gotsche and T. Schneider, BASF Aktiengesellschaft, Development Pharma Ingredients, 6756 Ludwigshafen, Germany Purpose Kollicoat IR, a polyvinyl alcohol polyethylene glycol graft copolymer is a new pharmaceutical excipient that was specially developed as a coating polymer for instant release tablets. Since coating is a rather complex process, the physicochemical properties of the polymer play an important role. They determine the process parameters, handling properties as well as the characteristics of the finished dosage forms (1). Furthermore, in order to determine the dissolution speed of a film, a new method based on the paddle model was developed. The objective of this study was to evaluate the physicochemical properties of Kollicoat IR that are relevant to the coating of pharmaceutical dosage forms. Methods Materials: Kollicoat IR (BASF) Preparation of films: Cast on an Erichsen 59/3 using a 2 % polymer solution to give a thickness of about 1 µm. Elongation at break and tensile strength: According to DIN 5354 using a TA-XT2.HiR Texture analyzer (Stable Micro Systems); the test was performed at different humidities. Dissolution speed: A film of about 1 µm was clamped in a photographic slide frame with an opening of 35 x 23 mm and positioned radially in a vessel of a paddle apparatus 3 cm below the surface; stirrer speed: 5 rpm; the times for rupture and complete dissolution were recorded. Tack: Films were cast on glass plates and stored for 12 hours under given conditions; testing was then performed by the Hoessel method (2). Table 1: Physicochemical properties of Kollicoat IR Molecular structure of Kollicoat IR Physical form free-flowing powder Molecular weight Solubility water > 5 %.8 N HCI > 5 % phosphate buffer ph 6.8 > 5 % ph (2 % solution) 6.7 Viscosity (2 % solution) about 45, daltons 115 mpas Melting temperature 29 C CH 2 O CH 2 CH 2 O CH 2 CH 2 O O CH CH 2 O CH 2 CH O CH 2 CH 2 CH-OH CH 2 CH-OH CH 2 CH-OH CH 2 CH-OH Film formation clear, transparent films.5 Differential Scanning Calorimetry of Kollicoat IR Surface tension of Kollicoat IR solution (figure 1) 65 (figure 2) Heat Flow [W/g].5 Surface tension [mn/m] Temperature [ C] Concentration [%]

3 page 3 No. 8, May 22 BASF ExAct licoat IR Elongation at break [%] Elongation at break of various instant release coatings % r. h. 54 % r. h % r. h (figure 3) Time [min:s] Dissolution speed of instant release polymers (film thickness: 1 µm).8 N HCl disintegration time ph 6.8 phosphate buffer disintegration time.8 N HCl dissolution time ph 6.8 phosphate buffer dissolution time 1:27 1:26 :42 :44 1:31 1:33 5:2 4:6 3:2 3:8 6:21 6:31 (figure 5) Kollicoat IR Pharmacoat 63 Pharmacoat 66 Kollicoat IR Pharmacoat 63 Pharmacoat 66 Determination of dissolution speed Paddle dissolution tester Tackiness of Kollicoat IR films (figure 4) (figure 6) 5 Slide frame (orifice 35 x 23 mm) 4 Film C / 54 % r. h. 3 C / 75 % r. h. 2 C / 8 % r. h. Results Kollicoat IR is a polyvinyl alcohol-polyethylene glycol graft copolymer with a molecular weight of about 45, daltons as determined by GPC. The molecule is hydrophilic and thus readily soluble in water. As its structure is nonionic, its solubility does not change when the ph is decreased or increased. As a result of its extremely low thickening effect, highly concentrated solutions can be sprayed onto tablet cores. Both parts of the Kollicoat IR molecule contribute to the mechanical properties of films. The polyvinyl alcohol moiety provides good film-forming properties and the polyethylene glycol part acts as an internal plasticizer leading to excellent flexibility (elongation at break: 15 %). In contrast to other film formulations, the plasticizer cannot migrate because it is covalently bound in the molecule. In contrast to pure polyvinyl alcohol films, the flexibility is maintained in storage because rearrangement of the molecules to a high level of order ( crystallization ) is prohibited. Relative humidity in the range of 3 75 % has practically no influence on the mechanical properties of the Kollicoat IR films. Instant release coatings should dissolve quickly in order to avoid any influence on the dissolution rate of the tablet as a whole. A new method was developed to determine the dissolution speed using the well known paddle apparatus. The film was clamped in a slide frame, this device was positioned in the paddle apparatus and the time was determined for the first rupture of the film and subsequently for the complete dissolution of the film. There was no difference in the dissolution speed in.8 N HCl and phosphate buffer ph 6.8. Polymers for coating tablets must have low tack. Low tack values of were measured even at high relative humidities using the Hoessel method. 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 determining the film dissolution time gives reliable and reproducible results. References [1] A. O. Okhamafe and P. York, J. Pharm. Pharmacol. 38, (1986). [2] P. Hoessel, Cosmetics and toiletries 111 (8), 73 ff (1996).

4 BASF ExAct page 4 No. 8, May 22 Kollicoat IR Innovation in Instant Rele K. Kolter, BASF Aktiengesellschaft, Development Pharma Ingredients, 6756 Ludwigshafen, Germany Purpose Only a few polymers, such as hydroxypropyl methyl-cellulose, hydroxypropylcellulose and Eudragit E can be used for instant release coatings on pharmaceuticals. The drawbacks of these polmers are mainly high viscosity in solution, which limits the polymer concentration in spray solutions to a maximum of 1 %, and a limited flexibility of the films [1,2]. To overcome these drawbacks, a new polymer was developed: polyvinyl alcohol polyethylene glycol graft copolymer (Kollicoat IR). This study investigates the technical properties of Kollicoat IR in comparison with HPMC, and determines the optimum parameters for a coating process in a horizontal pan coater. Methods Materials: Kollicoat IR (BASF), Pharmacoat 63, -66 (Shinetsu), tablet cores (caffeine 5 mg; Ludipress 229 mg, Avicel PH 12 4 mg; Kollidon CL 1 mg; magnesium stearate 1 mg). Table 1: Composition of the spray suspension Kollicoat IR 2.8 % Talc 7.7 % Titanium dioxide 4. % Water 67.5 % All ingredients were stirred into water and this suspension was homogenized using a corundum mill. Table3: Properties of film-coated tablets Core Table 2: Coating parameters Inlet air temperature 6 C Outlet air temperature 39 C Atomizing pressure Spraying rate Coating suspension Spraying time Drying Film-coated tablet 3 bar 3 g/min. 52 g for 5. kg cores 18 min. 4 min. Preparation of films: Cast on an Erichsen M 59/3 using a 2 % polymer solution to give a thickness of about 1 µm. Elongation at break: According to DIN 5354 using a TA-XT2 HiR texture analyzer (Stable Micro Systems) at 23 C / 53 % r. h. Appearance White White Hardness 116 N 119 N Friability % % Disintegration time :58 [min:s] :51 [min:s] Drug release 1 min.: 93 % 1 min.: 92 % 2 min.: 98 % 2 min.: 98 % Viscosity: Brookfield RVT (Brookfield) Tablet coating: Accela Cota (Manesty) 3. mg/cm coating level 7 6 Viscosity of a Kollicoat IR solution as a function of polymer concentration and temperature 23 C 7 C (figure 1) Viscosity [mpas] Polymer concentration [%]

5 page 5 No. 8, May 22 BASF ExAct ase Film Coatings Results Viscosity [mpas] Elongation at break [%] Viscosity of different instant release polymers at 2 % concentration and 23 C Kollicoat IR Pharmacoat 63 Pharmacoat 66 Elongation at break of different instant release polymers at 23 C / 53 % r. h. 15 Kollicoat IR Pharmacoat 63 Pharmacoat Determination of elongation at break (figure 4) (figure 2) (figure 3) The sprayability of a coating solution is strongly influenced by the viscosity, because viscous formulations cannot be atomized properly. The limit can be set at about 25 mpas. When the polymer concentration is increased up to 3 % solids, the viscosity at 23 C of a Kollicoat IR solution increases slowly. Beyond this, the increase is more rapid. The viscosity can be reduced by warming the solution, e.g. to 7 C (Figure 1). The viscosities of solutions of the instant release polymers Kollicoat IR, Pharmacoat 63 and Pharmacoat 66 were compared at a polymer concentration of 2 %. Kollicoat IR gave a much lower viscosity than the cellulose derivatives, thus allowing it to be sprayed in solutions of higher concentration (Figure 2). It is a well known phenomenon that coatings with a low flexibility often develop cracks, particularly when the dosage form is stored at elevated humidity, because the coating cannot accommodate the swelling of the core. The elongation at break of Kollicoat IR films (15 %) far exceeds that of the cellulose derivatives (4 and 17 %) and should therefore prevent any cracking. There is no need to add any plasticizer to Kollicoat IR films (Figure 3, 4). Tablet coating experiments were performed in a horizontal pan coater, to test the conclusions from the physicochemical data. Whereas a Kollicoat IR formulation containing 2.8 % polymer and 11.7 % pigments (total solids: 32.5 %) with a viscosity of 193 mpas could be applied easily, this was not possible when Pharmacoat 66 was used. Conclusions Kollicoat IR gives solutions of much lower viscosity and films of greater flexibility than cellulose derivatives. It can be applied easily on tablet cores at high solids 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 (1986). [2] T. Nagai et al, Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms 2nd Edition, Marcel Dekker Inc., 1997,

6 BASF ExAct page 6 No. 8, May 22 Kollicoat SR 3 D Coatings on Differe K. Kolter and T. C. Rock, BASF Aktiengesellschaft, Product Development Pharma/Food, 6756 Ludwigshafen, Germany Introduction Experimental Methods There exists only a limited number of excipients for coated sustained release dosage forms. This variety is extended by Kollicoat SR 3 D, a newly developed sustained release coating based on polyvinyl acetate [1]. Due to the absence of ionizable groups it offers the opportunity to formulate solid dosage forms with a ph-independent drug release. By adding a small amount of plasticizer (1 % propylene glycol or 5 % triacetin) film formation and film flexibility are increased tremendously and a curing of the finished dosage form is often not necessary. Up to now only results with caffeine and theophylline as model drugs had been published. This work shows the development of sustained release dosage forms of drugs (propranolol- HCl, carbamazepine, acetaminophen) with different solubility. Table 1: Pellet composition Materials: Kollidon SR 3 D (polyvinyl acetate dispersion 3 %, BASF AG), propranolol-hcl (Knoll AG), acetaminophen gran. (Knoll AG), carbamazepine (Farchemia FIS). Methods: The pellets were produced by extrusion in an Alexanderwerk apparatus with a 1.5 mm sieve and subsequent rounding in a spheronizer. The fraction mm was used for coating. Acetaminophen granules were used without previous pelletisation. Table 3: Drug dissolution The coating (1 for propranolol-hcl and carbamazepine pellets, 2 for acetaminophen granules) was applied on.5 kg pellets in a fluidized bed coater (Aeromatic) under the following conditions: Inlet air temperature 6 C Outlet air temperature 35 C Atomizing pressure 1. bar Spraying rate 11.5 g/min Drying 4 C/3 min Coating level 1; 2; 3; 4 mg/cm 2 Drug dissolution was determined using a Pharmatest paddle apparatus. Parts by weight [%] medium stirrer [rpm] Propranolol-HCl 3 Carbamazepine 5 Acetaminophen granules 1 Avicel PH Lactose 2.84 Kollidon VA Propranolol-HCl.8 N-HCl (-2 h); 1 phosphate buffer ph 6.8 (2-24 h) Acetaminophen Water 5 Carbamazepine 1 % Sodium 75 lauryl sulfate Table 4: Drug solubility Table 2: Coating composition 1 2 Propranolol- Acetamino- Carbama- HCl phen zepine [mg/ml] [mg/ml] [mg/ml] Water 16 ~ Kollicoat SR 3 D Propylene glycol 1.8 Triacetin 2.7 Water N HCl 94 Phosphate 114 ~ buffer ph % Sodium 2 lauryl sulfate

7 page 7 No. 8, May 22 BASF ExAct nt Drugs Results and Discussion The coated pellets of propranolol-hcl showed a strong correlation between coating level and drug release. With a coating level of 1 mg/cm 2 the pellets were not completely coated. Therefore, more than 9 % of propranolol was released within 2 hours. Using 2 to 4 mg/cm 2 the release rate of > 8 % can be adjusted in a time period from 4 to 24 hours. Although acetaminophen has a lower solubility in the dissolution medium (table 4) the release rates of the coated granules were for all coating levels comparatively fast. Even with a coating level of 3 mg/cm 2 the drug release reached 1 % after 8 h. This fact is caused by the sharp edges of the irregular shaped granules which are very difficult to coat. Furthermore, due to the non-spherical structure the real surface area is larger than the calculated one. However, this example shows that the surface properties and the structure of the pellets are as important as the coating level to achieve a certain release rate. As expected from the low water solubility carbamazepine pellets exhibited a slow dissolution profile already with a coating level of 1mg/cm 2. Drug release [%] Drug release [%] Drug release of propranolol pellets as a function of coating level medium:.8 N HCl ( 2 h) phosphate buffer ph 6.8 (2 24 h) 1 mg/cm 2 2 mg/cm 2 3 mg/cm 2 4 mg/cm Time [h] Drug release of acetaminophen granules coated with different coating levels (figure 1) (figure 2) 2 1 mg/cm 2 2 mg/cm 2 medium: water 3 mg/cm Time [h] Conclusions The release rate is strongly influenced by the surface properties and the structure of the cores. A higher water solubility of the drug requires a higher coating level. For a low batch to batch variation of drug dissolution it is essential to reproduce exactly the cores. Drug release [%] Drug release of carbamazepine pellets (figure 3) References [1] K. Kolter and F. Ruchatz, Proceedings of the 26th CRS symposium, Boston 1999, paper medium: 1 % sodium lauryl sulfate in water uncoated 1 mg/cm Time [h]

8 BASF ExAct page 8 No. 8, May 22 Optimization of an Enteric Coating Form K. Kolter, H-B. Reich, BASF Aktiengesellschaft, Product Development Pharma, 6756 Ludwigshafen, Germany C. Dangel, G. Schepky, Fachhochschule, Dept. Pharma Technology, Sigmaringen, Germany Introduction Aqueous enteric coatings based on methacrylic acid ethyl acrylate copolymer (Kollicoat MAE 3 DP) are known to provide excellent gastric resistance and short production times [1]. Because the polymer dispersion is usually not applied solely, the gastric resistance is influenced by additives. Furthermore, it is known, that polymer dispersions can coagulate by improper handling, high shear forces, high concentrations of finely dispersed particles, some salts or other incompatible materials. Therefore, it is particularly important to use safe and reproducable spray formulations and processes in the production of pharmaceutical dosage forms. Objective The objective of this study was to optimize a pigmented enteric coating formulation based on Kollicoat MAE 3 DP with regard to gastric resistance, color distribution and coagulation behavior. Materials and Methods Materials Methacrylic acid-ethyl acrylate copolymer (Kollicoat MAE 3 DP, BASF AG). Apparatus Accela Cota 24 (Manesty Machines Ltd.), disintegration tester (DES-4 AS, Krämer Elektronik), dissolution apparatus (PTW-S, Pharmatest Apparatebau). Composition and preparation of caffeine cores Anhydrous caffeine 5 mg (Knoll AG), Ludipress 229 mg (BASF AG), Avicel PH 11 4 mg (FMC), Kollidon CL 1 mg (BASF AG), Magnesium stearate 1 mg (Bärlocher). The ingredients of the formulation were mixed in a Diosna mixer and compressed with a force of 1 kn into cores with the following parameters: 9 mm diameter, 12 mm radius of curvature, 33 mg weight. Composition and preparation of the spray dispersions Table 1: Spray formulations Polymer dispersion A B Kollicoat MAE 3 DP Plasticizer (related to polymer) (1 25 %) Water ad 84.5 ad 84.5 Pigment dispersion A B Kollidon 3.5 Sicovit red Titanium dioxide.5.5 Talc Water Pigment dispersion To prepare the pigment dispersion Kollidon 3 was dissolved in water. Then Sicovit red 3, titanium dioxide and talc were intensively stirred in and homogenized using a corundum disc mill. Polymer dispersion Seperately propylene glycol was mixed with water and then Kollicoat MAE 3 DP was added under stirring. Spray suspension The pigment dispersion was mixed under stirring into the polymer dispersion

9 page 9 No. 8, May 22 BASF ExAct ulation based on Kollicoat MAE 3 DP Coating process Table 3: Coagulation of spray formulations Table 2: Coating parameter Tablet mass 5 kg Atomizing nozzle 1. mm Atomizing pressure 2. bar Inlet air temperature 52 C Outlet air temperature 37 C Drying 5 min / 52 C Determination of the uptake of gastric fluid into enteric coated tablets during the resistance test Six film-coated tablets were agitated in.1 n- HCl in a disintegration tester for 1 and 2 hours. The increase of the tablet weight is given as percentage of the initial weight. Determination of dissolution According to USP 23, apparatus 2, method B using.1 n-hcl and phosphate buffer 6.8. Caffeine was determined spectrophotometrically at 273 nm. Coagulation Coagulation was determined visually by inspection directly after the preparation of the spray supensions and after 24 h. Plasticizer Concentration Formulation A Formulation B related to polymer (without [%] Kollidon 3) Propylene glycol 1 stable stable 2 stable stable 3 stable stable Triethylcitrate 1 tend to coagulate stable 2 coagulate stable 3 coagulate stable PEG 4 1 coagulate stable 2 coagulate stable 3 coagulate stable PEG 15 1 coagulate stable 2 coagulate stable 3 coagulate stable PEG 6 1 stable stable 2 stable stable 3 stable stable Cremophor RH 4 1 tend to coagulate stable 2 coagulate stable 3 coagulate stable

10 BASF ExAct page 1 No. 8, May 22 Results Coagulation Coagulation of the spray formulation A was observed, when Triethylcitrate, PEG 4, 15 or Cremophor RH 4 were used as plasticizer. This is due to a triple interaction between these plasticizers, pigments and Kollidon 3, since without either pigments or Kollidon 3 no coagulation could be detected. The competition product to Kollicoat MAE 3 DP, Eudragit L 3 D showed the same coagulation behavior. With respect to coagulation, propylene glycol and PEG 6 are preferred (table 3). The elimination of Kollidon 3 led to an uneven color distribution of the red pigment in the film, which can be compensated by a longer stirring time of the pigment dispersion (12 h). Weight increase [%] Uptake of gastric fluid into enteric coated caffeine tablets after 2 h in the disintegration tester Plasticizer concentration: 15 % related to polymer Propylene glycol Triethylcitrate PEG 4 (figure 1) Gastric resistance The determination of the uptake of gastric fluid into the film-coated tablets is a very sensitive method for gastric resistance, particularly if a core with a strong absorption of water is used. In this test, propylene glycol and triethylcitrate exhibited lower weight increases as PEG 4. As expected, the plasticizer PEG 4 needed a much higher coat weight compared to other plasticizers to achieve the same level of resistance (figure 1). In the case of triethylcitrate, it was expected, that gastric resistance would not be influenced by increasing amounts of plasticizer. Surprisingly, this was also seen with the hydrophilic propylene glycol. Either these plasticizer are not leached out, or if they are leached out, no pores are created (figure 2). Talc is known to modify the gastric resistance. An amount of 27 % related to polymer can be recommended, since 13 % were less effective in reducing acid uptake and 4 % showed no further improvement. Gastric resistance was also tested using a dissolution tester. At a coat level of 3 mg/cm, the amount of propylene glycol did not influence the dissolution. After 2 h in gastric fluid, no dissolution was observed and in phosphate buffer 6.8, the drug was released (> 9 % after 1 min) very quickly (figure 3). Weight increase [%] Dissolution [%] Uptake of gastric fluid into enteric coated caffeine tablets after 2 h in the disintegration tester Coating level: 4 mg/cm 2 Propylene glycol Triethylcitrate PEG 4 Dissolution of enteric coated caffeine tablets Coating level: 3 mg/m 2.1 n-hci phosphate buffer ph 6.8 (figure 2) (figure 3) Time [min]

11 page 11 No. 8, May 22 BASF ExAct Conclusions To avoid coagulation, propylene glycol should be used as plasticizer in spray formulations with pigments. A triple interaction can occur in spray formulations with pigments between 1) triethylcitrate, low molecular weight PEG or Cremophor RH 4 2) fine dispersed pigments and 3) Kollidon 3 The plasticizers propylene glycol and triethylcitrate produced film coats showing the best gastric resistance. The gastric resistance was independent from the amount of plasticizer (1 25 %). Propylene glycol should be the plasticizer of choice for methacrylic acid-ethyl acrylate copolymer and should be used in 15 % concentration. References [1] S. Scheiffele, K. Kolter, G. Schepky, Drug Dev. Ind. Pharm. 24 (9), (1998) Kollicoat grades and Applications Grade Availability Major application Pharmacopoeial monographs Kollicoat IR (new) Powder Rapidly disintegrating coatings Kollicoat MAE 3 DP Aqueous Enteric coatings Ph. Eur., JPE, NF Dispersion Kollicoat MAE 1 P Powder Enteric coatings Kollicoat SR 3 D Aqueous Sustained Dispersion release formulations Kollicoat EMM 3 D Aqueous Sustained Ph. Eur., JPE Dispersion release formulations

12 BASF ExAct page 12 No. 8, May 22 Contract Manufacturing by BASF - A dedicated Business Unit This new unit is based at BASF headquarter in Ludwigshafen, Germany and acts as a flexible, globally operating business unit while taking advantages from BASF global organization and infrastructure. Our pharmaceutical know-how combined with BASF s chemical research will support our life science partners. It disposes of a specialized and flexible team to fulfill the customers needs and offer them the best individual support at any time throughout the life cycle of their products and projects. A Dedicated Business Unit Dr. Antonio Germani Head of Contract Manufacturing Phone: Fax: antonio.germani@basf-ag.de Christa Müller Office Phone: Fax: christa.mueller@basf-ag.de 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) Wolfgang Falkenberg Account Manager Phone: Fax: wolfgang.falkenberg@basf-ag.de Dr. Martin-Jochen Klatt Account Manager Phone: Fax: martin.klatt@basf-ag.de Dr. Daniele Piergentili Account Manager Phone: Fax: daniele.piergentili@basf-ag.de Pia Noack Product Stewardship Phone: Fax: pia.noack@basf-ag.de Valérie Filiatreau Product Stewardship Phone: Fax: valerie.filiatreau@basf-ag.de

13 page 13 No. 8, May 22 BASF ExAct News Solutol HS 15 now monographed in DAB 21 5 th Anniversary of Theophylline Production After being marketed for more than fifteen years, the solubilizing agent Solutol HS 15 was finally monographed in the Deutsches Arzneibuch 21 (DAB 21) as Macrogol-15-hydroxystearat. This became possible after the product became part of registered formulations. An identical version of this monograph is presently under discussion as a draft in the corresponding commission for European Pharmacopoeia. It is expected that it will be published in one of the next supplements of the European Pharmacopoeia 22, 4 th edition. 5 years of Theophylline production at our Minden site in Germany - over all the years the site at which Knoll, and today BASF, has manufactured this pharmaceutical active compound. The production process which has been developed by Knoll staff in the 194 s, is still state-ofthe-art today and is operated successfully at Minden. Continuous optimisation has led to a manufacturing capacity and product quality that meet market needs. Initially, the main fields of application for Theophylline were cardiac insufficiency, circulatory disorders and as a diuretic - today, it is used almost exclusively for the treatment of asthma. It is an interesting fact that, up to the beginning of the seventies, the opinion prevailed that Theophylline was unsuitable as such for the treatment of asthma, because the doses that were required very quickly led to undesirable side effects without having achieved the asthma-relieving action. It was also the opinion at that time that the organism could only take up a small proportion of the Theophylline dose. The breakthrough for Theophylline in the treatment of asthma came with the development of retard forms. (companies involved were Byk Gulden, Dooner Labs (later RPR), Klinge and Schering). It emerged that Theophylline was indeed virtually 1% bioavailable and that it was now possible to control the release of the active compound in such a way that the exact therapeutic dose was effective for a period of six to eight hours without the undesirable side effects occurring. With the technical advances of today and new medical knowledge, the market with its needs has changed and led to other therapeutic solutions. In particular, the advent of asthma sprays for local treatment caused the demand for Theophylline to stagnate. For years, BASF has been the world s biggest producer of purines. We are committed to the sustainable production of Theophylline in the coming years and intend to remain the leading supplier of Theophylline. The increasing number of water insoluble actives represents a challenge for pharmaceutical scientists.

14 page 14 No. 8, May 22 BASF ExAct Preview Kollicoat IR - A new instant release coating polymer With the ExAct edition in hand we presented to you the physicochemical characterisation and instant release film coating properties of Kollicoat IR, an innovative excipient based on an entirely new chemical formula. New Media Kollidon Polyvinylpyrrolidone for the pharmaceutical industry (New: 6 th edition, October 21) Meanwhile the book Kollidon- Polyvinylpyrrolidone for the pharmaceutical industry by Volker Bühler is a classic and well known to many professionals in the pharmaceutical and related industries. This book is intended for all persons in pharmaceutical technology and quality control who are involved in the processing of povidone, crospovidone and copovidone. A comprehensive alphabetical index leads the reader straight to the product properties, applications, and formulations with a large number of drugs, processing technologies for a wide range of dosage forms, and the analytical methods. In this revised edition a chapter on Kollidon SR, a new sustained release matrix polymer, was added. Also some specifications were updated. This book can be ordered with the attached reply card. Kollicoat IR gives solutions of much lower viscosity and films of greater flexibility than cellulose derivatives. Coating times can be shortened leading to reduced manufacturing cost. Besides other topics ExAct No. 9 will inform about the scale-up of an instant release coating process with Kollicoat IR and other application data. Should you require information in advance, please contact your local BASF company or one of our regional marketing offices. Contact Please contact your local BASF company or one of the following regional centres: Asia BASF Asia Pacific Regional HQ Pharma Solutions Dr. Danilo Mercado BASF South East Asia Pte Ltd 9/F., Suntec Tower Three 7 Temasek Boulevard Singapore Fax: **65 / Europe BASF Aktiengesellschaft LNF/FP J 55 Mr. Peter Hoffmann D-6756 Ludwigshafen Germany Fax: **49 / NAFTA BASF Corporation Pharma Solutions Mr. Patrick Glaser 3 Continental Drive-North Mount Olive, NJ USA Fax: **1 / South America BASF S.A. Human Fine Chemicals Mr. Claudio Lehmann Estrada Samuel Aizemberg, São Bernardo do Campo - SP Brazil Fax: **55 / Phone: **55 / Eastern Europe /Africa / West Asia BASF Aktiengesellschaft LRM/M D 25 Mr. Rolf Hanssen D-6756 Ludwigshafen Germany Fax: **49 / Or visit our website: MEFM 121e