Generic Drug Formulations. with. and. Kollidon SR

Transcription

1 Generic Drug Formulations with Kollicoat SR 3 D and Kollidon SR

2 Contents I. Kollicoat SR 3 D Coating 1.1 Theophylline sustained-release pellets 1.2 Theophylline sustained-release pellets (drug-layering process) 2. Caffeine sustained-release pellets (extrusion process) 3.1 Propranolol HCl sustained-release pellets (extrusion process) 3.2 Propranolol HCl sustained-release pellets (drug-layering process) Propranolol HCl pellet-releasing tablet 4. Acetaminophen taste masked 5. Ibuprofen sustained-release pellets (drug-layering process) 6. Ambroxol HCl sustained-release pellets (drug-layering process) 6.1 Ambroxol HCl pellet-releasing tablet 7. Tramadol HCl sustained-release pellets (drug-layering process) 8. Acetylsalicylic acid crystals Page2/51 MEF/EP76 Contents

3 Granulation 9. Propranolol HCl sustained-release tablet 1. Theophylline sustained-release tablet 11. Carbamazepine sustained-release tablet Page3/51 MEF/EP76 Contents

4 II. Kollidon SR 12. Metoprolol tartrate sustained-release tablet 13. Propranolol HCl sustained-release tablet 14. Caffeine sustained-release tablet 15. Diclofenac Na sustained-release tablet 16. Ascorbic acid sustained-release tablet 17. Indometacin sustained-release tablet 18. Carbamazepine sustained-release tablet 19. Nifedipine sustained-release tablet. Tramadol HCl sustained-release tablet 21. Diltiazem HCl sustained-release tablet 22. Naphtidrofuryl oxalate sustained-release tablet 23. Theophylline sustained-release tablet Page4/51 MEF/EP76 Contents

5 Page5/51 Caffeine sustained-release pellets

6 1.1 Theophylline sustained-release pellets a) Formulation The formulation is designed for 5g of pure theophylline pellets (Spherofillin [1]; diameter.8-1.3mm) Polymer suspension Kollicoat SR 3 D [1] g Propylene glycol [1] 6.71g Water g Pigment suspension Kollidon 3 [1] 2.24g Titanium dioxide [2] 2.24g Sicovit Red 3 [1] 2.24g Talc [3] 15.66g Water 44.73g b) Preparation of the spray suspension Polymer suspension Add propylene glycol followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Dissolve Kollidon 3 in the given quantity of water. Add Sicovit Red 3, titanium dioxide and talc with vigorous stirring and homogenize the mixture in a corundum disk mill. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. Page6/51 Caffeine sustained-release pellets

7 c) Coating The pellets were coated in an Aeromatic Strea-1 (Aeromatic AG). The suspension was sprayed continuously onto the fluidized, pre-heated pellets from the top. Process parameters Inlet air temperature 6 C Outlet air temperature 37 C Product temperature 38 C Air flow 8m³/h Nozzle diameter.8mm Spraying rate approx. 11.5g/min Spraying time 39 min Atomizing pressure 1.bar Drying 45 C/ 5min Coating weight 2mg film former/cm² The coating weight of 2mg film former / cm² given here was determined from the surface area of the pellets. Since the particle size distribution and surface structure influence the polymer quantity required, calculating the surface area is recommended as a means of estimating the required coating weight in each specific case. 1 1 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph drug release [%] mg Kollicoat SR 3 D/cm² 1. mg Kollicoat SR 3 D/cm² 2. mg Kollicoat SR 3 D/cm² Page7/51 Caffeine sustained-release pellets

8 1.2 Theophylline sustained-release pellets (drug-layering process) a) Formulation The formulation is designed for 8g of pellets manufactured by drug layering of nonpareilles. Polymer suspension Kollicoat SR 3 D [1] 533.g Triethyl citrate (TEC) [4] 16.g Water 433.g Pigment suspension Talc [3] 56.g Water 1.g b) Preparation of the spray suspension Polymer suspension Add TEC followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Add talc to the given quantity of water with vigorous stirring. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. Page8/51 Caffeine sustained-release pellets

9 c) Coating The pellets were coated in an GPCG1 (Glatt). The suspension was sprayed continuously onto the fluidized, pre-heated pellets by the Wurster method. Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5-55 C Outlet air temperature C Product temperature 35-4 C Air flow 9m³/h Nozzle diameter 1.2mm Spraying time 26 min Spraying rate approx. 4.5 g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Coating weight % 1 8 method: paddle 1 rpm; 37 C -h: ph 7.4 drug release [%] Page9/51 Caffeine sustained-release pellets

10 2. Caffeine sustained-release pellets a) Formulation The formulation is designed for 5g of pellets (composition of pellets: 1% caffeine [1], 43.75% Avicel PH 11 [5], 43.75% lactose [6], 2.5% Kollidon VA 64 [1]; diameter.7-1.4mm; made by wet extrusion). Polymer suspension Kollicoat SR 3 D [1] g Propylene glycol [1] 8.9g Water g Pigment suspension Kollidon 3 [1] 2.7g Titanium dioxide [2] 2.7g Sicovit Red 3 [1] 2.7g Talc [3] 18.87g Water 53.89g b) Preparation of the spray suspension Polymer suspension Add propylene glycol followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Dissolve Kollidon 3 in the given quantity of water. Add Sicovit Red 3, titanium dioxide and talc with vigorous stirring and homogenize the mixture in a corundum disk mill. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. Page1/51 Caffeine sustained-release pellets

11 c) Coating The pellets were coated in an Aeromatic Strea-1 (Aeromatic AG). The suspension was sprayed continuously onto the fluidized, pre-heated pellets from the top. Process parameters Inlet air temperature 6 C Outlet air temperature 36 C Product temperature 37 C Air flow 8m³/h Nozzle diameter.8mm Spraying rate approx. 12g/min Spraying time 45 min Atomizing pressure 1.bar Drying 45 C/ 5min Coating weight 3mg film former/cm² The coating weight of 3mg film former / cm² given here was established for the pellets by surface area determination. Since the particle size distribution and surface structure influence the required polymer quantity, calculating the surface area is recommended as a means of estimating the required coating weight in each specific case. 1 8 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph 6.8 drug release [%] Page11/51 Caffeine sustained-release pellets

12 3.1 Propranolol HCl sustained-release pellets (extrusion process) a) Formulation The formulation is designed for 5g of pellets (composition of pellets: % propranolol HCl [1], 51.66% Avicel PH 11 [5], 25.84% lactose [6], 2.5% Kollidon VA 64 [1]; diameter.4-1.5mm; made by wet extrusion).) Polymer suspension Kollicoat SR 3 D [1] g Propylene glycol [1] 7.49g Water g Talc suspension Talc [3] 29.94g Water 44.91g b) Preparation of the spray suspension Polymer suspension Add propylene glycol followed by Kollicoat SR 3 D to the given quantity of water with stirring. Talc suspension Add talc with vigorous stirring and homogenize the mixture in a corundum disk mill. Spray suspension Incorporate the talc suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. Page12/51 Acetminophen taste masked

13 c) Coating The pellets were coated in an Aeromatic Strea-1 (Aeromatic AG). The suspension was sprayed continuously onto the fluidized, pre-heated pellets from the top. Process parameters Inlet air temperature 6 C Outlet air temperature 35 C Product temperature 36 C Air flow 8m³/h Nozzle diameter.8mm Spraying rate approx. 13g/min Spraying time 39 min Atomizing pressure 1.bar Drying 45 C/ 5min Coating weight 3mg film former/cm² The coating weight of 3mg film former / cm² given here was established for the pellets by surface area determination. Since the particle size distribution and surface structure influence the required polymer quantity, calculating the surface area is recommended as a means of estimating the required coating weight in each specific case. 1 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph drug release [%] Page13/51 Acetminophen taste masked

14 3.2 Propranolol HCl sustained-release pellets (drug-layering process) a) Formulation The formulation is designed for 8g of pellets manufactured by drug layering of nonpareilles. Polymer suspension Kollicoat SR 3 D [1] 533.g Triethyl citrate (TEC) [4] 16.g Water 433.g Pigment suspension Talc [3] 56.g Water 1.g b) Preparation of the spray suspension Polymer suspension Add TEC followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Add talc to the given quantity of water with vigorous stirring. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. Page14/51 Acetminophen taste masked

15 c) Coating The pellets were coated in a Glatt GPCG1 coater. The suspension was sprayed continuously onto the fluidized, pre-heated pellets from the bottom by the Wurster method. Weight gains of 5, 1, 15 and % were tested. Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5-55 C Outlet air temperature C Product temperature 35-4 C Air flow 9m³/h Nozzle diameter 1.2mm Spraying time 2 min Spraying rate approx. 4.5 g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Coating weight % 1 method: paddle 5 rpm; 37 C -h:.1m HCl 8 drug release [%] % Kollicoat SR 3 D 1% Kollicoat SR 3 D 15% Kollicoat SR 3 D % Kollicoat SR 3 D Page15/51 Acetminophen taste masked

16 3.2.1 Propranolol HCl pellet-releasing tablet a) Formulation The formulation is designed for 5g of tablets: Propranolol HCl/ Kollicoat SR pellets 25.g Microcrystalline cellulose (Vivapur ) [7] 25.g Magnesium stearate [8] 2.5g b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 15kN. Tablet press Compression force Korsch EK, 3 tablets/ min 15kN c) Tablet properties Weight 4mg Diameter 1mm Form biplanar Hardness N 1 8 method: paddle 1 rpm; 37 C coating level: % -h:.1m HCl drug release [%] Tablets 85-1 µm Tablets µm Pellets 85-1 µm Pellets µm Page16/51 Acetminophen taste masked

17 4. Acetaminophen - taste masked a) Formulation The formulation is designed for 5g of acetaminophen granules [1]. Polymer suspension Kollicoat SR 3 D [1] 73.33g b) Preparation of the spray suspension The dispersion is used directly without any additives. c) Coating The crystals were coated in an Aeromatic Strea-1 (Aeromatic AG). The dispersion was sprayed continuously onto the fluidized, pre-heated crystals from the top. Process parameters Inlet air temperature 6 C Outlet air temperature 4 C Product temperature 41 C Air flow 8m³/h Nozzle diameter.8mm Spraying rate approx. 9g/min Spraying time 9 min Atomizing pressure 1.bar Drying 45 C/ 5min Coating weight 4% Crystalline acetaminophen is coated with 4% Kollicoat SR 3 D. Page17/51 Acetminophen taste masked

18 1 8 drug release [%] time [min].1n HCl phosphate buffer ph 6.8 Page18/51 Acetminophen taste masked

19 5. Ibuprofen sustained-release pellets (drug-layering process) The formulation is designed for 8g of pellets manufactured by drug layering of nonpareilles. a) Subcoating The polymer spray solution for a weight gain of 5%: Spray solution Mowiol 4-88 (PVA) [9] 48.g Water 432.g b) Preparation of the spray solution (subcoating) Dissolve Mowiol in hot water and cool with stirring. Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5 C Outlet air temperature 35 C Product temperature 4 C Air flow 8m³/h Nozzle diameter 1.2mm Spraying time 56 min Spraying rate approx. 3.1g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Subcoating weight 5% c) Polymer coating The formulation is designed for 8g of subcoated pellets. Polymer suspension Kollicoat SR 3 D [1] 533.g Triethyl citrate (TEC) [4] 16.g Water 433.g Pigment suspension Talc [3] 56.g Water 1.g Page19/51 Ibuprofen sustained-release pellets

20 d) Preparation of the spray suspension (polymer coating): Polymer suspension Add TEC followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Add talc to the given quantity of water with vigorous stirring. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5-55 C Outlet air temperature C Product temperature 35-4 C Air flow 9m³/h Nozzle diameter 1.2mm Spraying time 23 min Spraying rate approx. 4.5 g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Spray the suspension continuously onto fluidized pre-heated pellets by the wurster spray method. Weight gains 5, 1, 15 and %. 1 8 method: paddle 1 rpm; 37 C -h: ph 7.4 drug release [%] % Kollicoat SR 3D 1% Kollicoat SR 3D 15% Kollicoat SR 3D % Kollicoat SR 3D Page/51 Ibuprofen sustained-release pellets

21 6. Ambroxol HCl sustained-release pellets (drug-layering process) The formulation is designed for 8g of pellets manufactured by drug layering of nonpareilles. a) Formulation Polymer suspension Kollicoat SR 3 D [1] 533.g Triethyl citrate (TEC) [4] 16.g Water 433.g Pigment suspension Talc [3] 56.g Water 1.g b) Preparation of the spray suspension Polymer suspension Add TEC followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Add talc to the given quantity of water with vigorous stirring. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. c) Coating The pellets were coated in an GPCG1 (Glatt). The suspension was sprayed continuously onto the fluidized, pre-heated pellets by the Wurster method. Page21/51 Ambroxol HCl sustained-release pellets

22 Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5-55 C Outlet air temperature C Product temperature 35-4 C Air flow 9m³/h Nozzle diameter 1.2mm Spraying time 2 min Spraying rate approx. 4.5 g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Weight gain % 1 8 method: paddle 1 rpm; 37 C -h: ph 7.4 drug release [%] % Kollicoat SR 3D 1% Kollicoat SR 3D 15% Kollicoat SR 3D % Kollicoat SR 3D Page22/51 Ambroxol HCl sustained-release pellets

23 6.1 Ambroxol HCl pellet-releasing tablet d) Formulation The formulation is designed for 5g of tablets: Ambroxol HCl/ Kollicoat SR pellets 25.g Microcrystalline cellulose (Vivapur ) [7] 25.g Magnesium stearate [8] 2.5g e) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 15kN. Tablet press Compression force Korsch EK, 3 tablets/ min 15kN f) Tablet properties Weight 4mg Diameter 1mm Form biplanar Hardness N 1 method: paddle 1 rpm; 37 C -h: ph drug release [%] % Kollicoat SR 3D 1% Kollicoat SR 3D 15% Kollicoat SR 3D % Kollicoat SR 3D Page23/51 Ambroxol HCl sustained-release pellets

24 7. Tramadol HCl sustained-release pellets (drug-layering process) a) Polymer coating The formulation is designed for 8g of pellets manufactured by drug layering of nonpareilles. Polymer suspension Kollicoat SR 3 D [1] 533.g Triethyl citrate (TEC) [4] 16.g Water 433.g Pigment suspension Talc [3] 56.g Water 1.g b) Preparation of the spray suspension Polymer suspension Add TEC followed by Kollicoat SR 3 D to the given quantity of water with stirring. Pigment suspension Add talc to the given quantity of water with vigorous stirring. Spray suspension Incorporate the pigment suspension into the polymer suspension with stirring. The suspension must be stirred during the spraying process to prevent settling. c) Coating The pellets were coated in an GPCG1 (Glatt). The suspension was sprayed continuously onto the fluidized, pre-heated pellets by the Wurster method. Page24/51 Tramadol HCl sustained-release pellets

25 Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5-55 C Outlet air temperature C Product temperature 35-4 C Air flow 9m³/h Nozzle diameter 1.2mm Spraying time 225 min Spraying rate approx. 4.5 g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Weight gain % 1 8 method: paddle 1 rpm; 37 C -h: ph 7.4 drug release [%] tablets, 15% Kollicoat SR 3 D tablets, % Kollicoat SR 3 D pellets, 15% Kollicoat SR 3 D pellets, % Kollicoat SR 3 D Page25/51 Tramadol HCl sustained-release pellets

26 8. Acetylsalicylic acid crystals a) Formulation The formulation is designed for 8g of acetylicsalicylic acid crystals [12]. Spray suspension Kollicoat SR 3 D [1] g Talc [3] 7.g Water g b) Preparation of the spray suspension Add talk to the given amount of water with vigorous stirring. Then add Kollicoat SR 3 D with slow stirring. c) Coating The crystals were coated in a Glatt GPCG1 coater. The suspension was sprayed continously onto the fluidized, pre-heated crystals by the Wurster method. Weight gains of 5, 1, 15 and % were tested. Process parameters Machine Glatt GPCG1 Method Bottom-spray (Wurster) Inlet air temperature 5-55 C Outlet air temperature C Product temperature 35-4 C Air flow 9m³/h Nozzle diameter 1.2mm Spraying time 166 min Spraying rate approx. 8.9 g/min Atomizing pressure 1.2bar Drying 4 C/ 15min Coating weight % Page26/51 Acetylsalicylic acid crystals

27 1 1 8 method: paddle 1 rpm; 37 C -h: ph 7.4 no plasticizer drug release [%] 6 4 crystals 1% Kollicoat SR 3D 15% Kollicoat SR 3D % Kollicoat SR 3D 25% Kollicoat SR 3D Page27/51 Acetylsalicylic acid crystals

28 Page28/51 Kollicoat SR 3 D - Granulation

29 9. Propranolol HCl sustained-release tablet a) Formulation of the granules Propranolol HCl Powder 8 [1] 25.g Granulac 14 (lactose) [6] 1.g Kollicoat SR 3 D [1] 525.g b) Manufacture of the granules The active ingredient and excipient were granulated in an Aeromatic Strea-1 (Aeromatic AG). The polymer dispersion was sprayed into the fluid bed from the top. Process parameters Inlet air temperature 55 C Outlet air temperature C Nozzle diameter 1.2mm Spraying rate approx. 1g/min Atomizing pressure 2.bar c) Formulation of the tablets Propranolol HCl powder 8 [1] Kollicoat SR 3 D [1] Granulac 14 [6] Aerosil [13] Magnesium stearate [8] 16.mg 96.mg 64.mg 1.6mg 1.6mg d) Tableting The granules were passed together with magnesium stearate (.5%) and Aerosil (.5%) through an 8µm sieve, blended for 1 min in a Turbula mixer and compressed into tablets with a force of about 18kN. Tablet press Compression force Korsch EK, 3 tablets/ min 17.7kN Page29/51 Propranolol HCl sustained-release tablet

30 e) Tablet properties Weight Diameter Form Hardness 323.mg 1mm biplanar 26N 1 8 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-h: phosphate buffer ph 6.8 drug release [%] Page3/51 Propranolol HCl sustained-release tablet

31 1. Theophylline sustained-release tablet a) Formulation of the granules Theophylline powder [1] 25.g Granulac 14 [6] 212.5g Kollicoat SR 3 D [1] g b) Manufacture of the granules The active ingredient and excipient was granulated in an Aeromatic Strea-1 (Aeromatic AG). The polymer dispersion was sprayed into the fluid bed from the top. Process parameters Inlet air temperature 55 C Outlet air temperature C Nozzle diameter 1.2mm Spraying rate approx. 1g/min Atomizing pressure 2.bar c) Formulation of the tablets Theophylline pdr [1] Kollicoat SR 3 D [1] Granulac 14 [6] Aerosil [13] Magnesium stearate [8] 4.mg 6.mg 34.mg 4.mg 4.mg d) Tableting The granules were passed together with magnesium stearate (.5%) and Aerosil (.5%) through an 8µm sieve, blended for 1 min in a Turbula mixer and compressed into tablets with a force of about 18kN. Tablet press Compression force Korsch PH 16, 3 rpm 18.7kN Page31/51 Theophylline sustained-release tablet

32 e) Tablet properties Weight Diameter Hardness 88.mg football shape 19.x8.5mm 276N 1 8 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph 6.8 drug release [%] Page32/51 Theophylline sustained-release tablet

33 11. Carbamazepine sustained-release tablet a) Formulation of the granules Carbamazepine [14] 25.g Granulac 14 [6] 185.3g Kollidon CL-M [1] 25.3g Kollicoat SR 3 D [1] g b) Manufacture of the granules The active ingredient and excipients were granulated in an Aeromatic Strea-1 (Aeromatic AG). The polymer dispersion was sprayed into the fluid bed from the top. Process parameters Inlet air temperature 55 C Outlet air temperature C Nozzle diameter 1.2mm Spraying rate approx. 1g/min Atomizing pressure 2.bar c) Formulation of the tablets Carbamazepine [14] Kollicoat SR 3 D [1] Kollidon CL-M [1] Granulac 14 [6] Aerosil [13] Magnesium stearate [8].mg 3.mg.2mg 149.8mg 2.mg 2.mg d) Tableting The granules were passed together with magnesium stearate (.5%) and Aerosil (.5%) through an 8µm sieve, blended for 1 min in a Turbula mixer and compressed into tablets with a force of about 18kN. Tablet press Compression force Korsch EK, 3 tablets/ min 18.kN Page33/51 Carbamazepine sustained-release tablet

34 e) Tablet properties Weight Diameter Form Hardness 44.mg 11mm biconvex 136N 1 method: paddle 5 rpm; 37 C -16h: SDS-solution (1%; water) 8 drug release [%] Page34/51 Carbamazepine sustained-release tablet

35 Page35/51 Kollidon SR

36 12. Metoprolol tartrate sustained-release tablet a) Formulation of the granules Metoprolol tartrate [15] 454.5g Kollicoat SR 3 D [1] 45.5g b) Manufacture of the granules The active ingredient was granulated in an Aeromatic Strea-1 (Aeromatic AG). The polymer dispersion was sprayed into the fluid bed from the top. Process parameters Inlet air temperature 5 C Outlet air temperature C Nozzle diameter 1.2mm Spraying rate approx. 1g/min Atomizing pressure 2.bar c) Formulation of the tablets Metoprolol tartrate [15] Kollicoat SR 3 D solid polymer Kollidon SR [1] Magnesium stearate [8].mg 6.mg 25.mg 2.5mg d) Tableting The granules were passed together with magnesium stearate (.5%) and Kollidon SR (54.5%) through an 8µm sieve, blended for 1 min in a Turbula mixer and compressed into tablets with a force of about 1kN. Tablet press Compression force Korsch EK, 3 tablets/ min 9,3kN Page36/51 Metoprolol tartrate sustained-release tablet

37 e) Tablet properties Weight Diameter Form Hardness 458.5mg 12mm biplanar 2N method: paddle 1 rpm; 37 C -2h:.8 M HCl 2-12h: phosphate buffer ph Page37/51 Metoprolol tartrate sustained-release tablet

38 13. Propranolol HCl sustained-release tablet a) Formulation Propranolol HCl [1] Kollidon SR [1] Aerosil [13] Magnesium stearate [8] 16.mg 16.mg 3.4mg 1.6mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 1kN. Tablet press Compression force Korsch PH 1/6 3 rpm 9,9kN c) Tablet properties Weight Diameter Form Hardness 325.mg 1mm biplanar 172N 1 8 drug release [%] 6 4 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-16h: phosphate buffer ph Page38/51 Propranolol HCl sustained-release tablet

39 14. Caffeine sustained-release tablet a) Formulation Caffeine gran.,2/,5 [1] 16.mg 16.mg 16.mg Kollidon SR [1] 16.mg 1.mg 8.mg Avicel PH 12 [5] -- 4.mg 8.mg Magnesium stearate [8] 1.6mg 1.6mg 1.6mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 1kN. Tablet press Korsch PH1/6, 3 rpm Compression force 9.6kN 9.8kN 1.1kN c) Tablet properties Weight 322.mg 322.mg 322.mg Diameter 1mm 1mm 1mm Form biplanar Hardness 213N 1N 193N Friability <.1% <.1% <.1% 1 8 drug release [%] 6 4 caffeine/ Kollidon SR (16mg/ 8mg) caffeine/ Kollidon SR (16mg/ 1mg) caffeine/ Kollidon SR (16mg/ 16mg) method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph Page39/51 Caffeine sustained-release tablet

40 15. Diclofenac Na sustained-release tablet a) Formulation Diclofenac Na [16] 1.mg 1.mg Kollidon SR [1] 1.mg 15.mg Aerosil [13] 3.4mg 3.4mg Magnesium stearate [8] 3.mg 3.mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 8kN. Tablet press Korsch EK, 3 tablets/ min Compression force 7.9kN 7.kN c) Tablet properties Weight 6.mg 256.mg Diameter 8mm Form biplanar Hardness 195N 229N Friability <.1% <.1% 1 method: paddle 5 rpm; 37 C -16h: phosphate buffer ph drug release [%] 6 4 diclofenac Na/ Kollidon SR (1mg/ 1mg) diclofenac Na/ Kollidon SR (1mg/ 15mg) Page4/51 Caffeine sustained-release tablet

41 16. Ascorbic acid sustained-release tablet a) Formulation Ascorbic acid cryst. [1] --.mg.mg Ascorbic acid pdr. [1].mg Kollidon SR [1].mg.mg 28.mg Ludipress LCE [1] 75.mg 8.mg -- Aerosil [13] 5.mg Magnesium stearate [8] 9.mg 9.mg 9.mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 18kN. Tablet press Korsch EK, 3 tablets/ min Compression force 17.1kN.kN 18.6kN c) Tablet properties Weight 489.mg 489.mg 489.mg Diameter 12mm Form biplanar Hardness 164N 14N 151N Friability.1%.1%.2% 1 8 drug release [%] 6 4 method: paddle 5 rpm; 37 C -24h: phosphate buffer ph 4. (1% cysteine HCl-solution) ascorbic acid plv./ K.SR/ L.LCE (mg/ mg/ 75mg) ascorbic acid cryst./ K.SR/ L.LCE (mg/ mg/ 8mg) ascorbic acid cryst./ K.SR/ L.LCE (mg/ mg/ 8mg) Page41/51 Carbamazepine sustained-release tablet

42 17. Indometacin sustained-release tablet a) Formulation Indometacin [12] 75.mg 75.mg Kollidon SR [1] 125.mg 125.mg Ludipress LCE [1] 1.mg -- Aerosil [13] 1.5mg 4.mg Magnesium stearate [8] 1.5mg 2.mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 1kN. Tablet press Korsch EK, 3 tablets/ min Compression force 8.7kN 13.kN c) Tablet properties Weight 33.mg 3.mg Diameter 1mm Form biplanar Hardness 163N 133N Friability <.1%.1% 1 8 method: paddle 5 rpm; 37 C -16h: phosphate buffer ph 7.2 drug release [%] 6 4 indometacin/ K.SR (75mg/ 125 mg) indometacin/ K.SR/L.LCE (75mg/ 125mg/1mg) Page42/51 Carbamazepine sustained-release tablet

43 18. Carbamazepine sustained-release tablet a) Formulation Carbamazepine [14].mg.mg Kollidon SR [1] 1.mg 1.mg Ludipress LCE [1].mg 15.mg Kollidon CL-M [13] --.mg Magnesium stearate [8] 2.5mg 2.5mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 25kN. Tablet press Korsch EK, 3 tablets/ min Compression force 24.7kN 23.1kN c) Tablet properties Weight 53.mg 473.mg Diameter 12mm Form biplanar Hardness 146N 164N Friability.1% <.1% 1 1 method: paddle 75 rpm; 37 C -16h: SDS-solution (1%; water) 8 drug release [%] 6 4 carbamazepine/ K. SR/ L. LCE (mg/ 1mg/ mg) carbamazepine/ K. SR/ L. LCE/ K. CL-M (mg/ 1mg/ 15mg/ mg) Page43/51 Carbamazepine sustained-release tablet

44 19. Nifedipine sustained-release tablet a) Formulation Nifedipine [17] Kollidon SR [1] Ludipress LCE [1] Magnesium stearate [8].mg 1.mg 1.mg 1.mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 6kN. Tablet press Compression force Korsch EK, 3 tablets/ min 5.8kN c) Tablet properties Weight 221.mg Diameter 8mm Form biplanar Hardness 193N Friability <.1% 1 method: paddle 1 rpm; 37 C -24h: phosphate buffer 6.8/.5% SDS 8 drug release [%] Page44/51 Nifedipine sustained-release tablet

45 . Tramadol HCl sustained-release tablet a) Formulation Tramadol HCl [11] Kollidon SR [1] Aerosil [13] Magnesium stearate [8] 1.mg 15.mg 2.5mg 1.5mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 1kN. Tablet press Compression force Korsch EK, 3 tablets/ min 12.6kN c) Tablet properties Weight 254.mg Diameter 1mm Form biplanar Hardness 211N Friability <.1% 1 8 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph 6.8 drug release [%] Page45/51 Tramadol HCl sustained-release tablet

46 21. Diltiazem HCl sustained-release tablet a) Formulation Diltiazem HCl [18] Kollidon SR [1] Aerosil [13] Magnesium stearate [8] 1.mg 18.mg 3.mg 1.5mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 1kN. Tablet press Compression force Korsch EK, 3 tablets/ min 8.kN c) Tablet properties Weight 35.mg Diameter 1mm Form biplanar Hardness 217N Friability <.1% 1 method: paddle 1 rpm; 37 C -16h: deionized water 8 drug release [%] Page46/51 Diltiazem HCl sustained-release tablet

47 22. Naphtidrofuryl oxalate sustained-release tablet a) Formulation Naphtidrofuryl oxalate [18] Kollidon SR [1] Talc [3] Aerosil [13] Magnesium stearate [8] 1.mg 15.mg 25.mg 5.4mg 2.5mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 18kN. Tablet press Compression force Korsch PH16, 3 rpm 17.kN c) Tablet properties Weight 283.mg Diameter 1mm Form biplanar Hardness 197N Friability <.1% 1 8 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph Page47/51 Naphtidrofuryl oxalate sustained-release tablet

48 23. Theophylline sustained-release tablet a) Formulation Theophylline pdr. [1] Kollidon SR [1] Ludipress LCE [1] Magnesium stearate [8] 5.mg.mg 225.mg 3.mg b) Procedure Mix the ingredients together, pass through a.8mm sieve and compress into tablets with a force of about 1kN. Tablet press Compression force Korsch PH 16, 3 rpm 1.8kN c) Tablet properties Weight 928.mg Diameter 19.x8.5mm Form football shape Hardness 172N Friability <.1% 1 8 method: paddle 5 rpm; 37 C -2h:.8 M HCl 2-24h: phosphate buffer ph 6.8 drug release [%] Page48/51 Theophylline sustained-release tablet

49 Substances [1] BASF Aktiengesellschaft Excipients Carl-Bosch Str. 38 Kollicoat SR 3 D 6756 Ludwigshafen, Germany Kollidon 3 Kollidon CL Kollidon CL-M Kollidon SR Kollidon VA 64 Ludipress LCE Propylene glycol Sicovit Red 3 Actives Acetaminophen gran. Ascorbic acid cryst. Ascorbic acid powder Caffeine gran..2/.5 Ibuprofen Propranolol HCl powder 8 Theophylline powder Spherofillin [2] Kronos Titan GmbH Titanium dioxide Postfach Leverkusen, Germany [3] Riedel-de-Haën AG Talc Wunstdorferstr Seelze, Germany [4] Merck-Schuchardt Triethyl citrate Hohenbrunn, Germany [5] FMC Corp. Food + Pharmaceutical Avicel PH 11 Products Avicel PH Market Street Philadelphia, PA 1913, USA [6] Meggle Milchindustrie Granulac 14 Postfach 4 Granulac Wasserburg, Germany [7] J. Rettenmaier & Söhne Vivapur Holzmühle Rosenberg, Germany [8] Bärlocher GmbH Magnesium stearate 8992 Munich, Germany Page49/51 Substances

50 [9] Clariant GmbH Mowiol 4-88 PVA Division CP/TQM-QP Frankfurt am Main, Germany [1] Heumann Pharma GmbH Ambroxol HCl Postfach Nuremberg, Germany [11] Chemagis Ltd. Tramadol HCl P.O. Box 991 Tel Aviv 619, Israel [12] Synopharm GmbH Acetylicsalicylic acid crystals Postfach 15 Indometacin Barsbüttel, Germany [13] Degussa-Hüls AG Aerosil Weissfrauenstr Frankfurt, Germany [14] Fabbrica Italiana Sintetici S.p.A. Carbamazepine Viale Milano, Alte di Montecclio Maggiore, Italy [15] Moehs S.A. Metoprolol tartrate Apartado Rubi, Spain [16] Irotec Laboratories Diclofenac Na Little Island, Cork, Ireland [17] Prosintex Industrie Chimiche Italiano Via E. Ferm, /26 19 Seltimo Milanese (Mi), Italy Nifedipine [18] Farmak a.s. Diltiazem HCl Na Vlcinci 3 Naphtidrofuryl oxalate Olomouc, Czech Republic Page5/51 Substances

51 Note The data submitted in this publication are based on our current knowledge and experience. They do not constitute a guarantee in the legal sense of the term and, in view of the mainfold factors that may effect processing and application, do not relieve processors from the responsibility of carrying out their own tests and experiments. Any relevant patent rights and existing legislation and regulations must be observed. BASF Aktiengesellschaft Unternehmensbereich Fine Chemicals 6756 Ludwigshafen, Germany Page51/51