generic drug formulations with kollicoat and kollidon
TRANSCRIPT
Generic Drug Formulations
with
Kollicoat® SR 30 D
and
Kollidon® SR
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page2/51 MEF/EP076 Contents
Contents
I. Kollicoat® SR 30 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)
3.2.1 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
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page3/51 MEF/EP076 Contents
Granulation
9. Propranolol HCl sustained-release tablet
10. Theophylline sustained-release tablet
11. Carbamazepine sustained-release tablet
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page4/51 MEF/EP076 Contents
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
20. Tramadol HCl sustained-release tablet
21. Diltiazem HCl sustained-release tablet
22. Naphtidrofuryl oxalate sustained-releasetablet
23. Theophylline sustained-release tablet
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page5/51 Caffeine sustained-release pellets
®
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page6/51 Caffeine sustained-release pellets
1.1 Theophylline sustained-release pellets
a) Formulation
The formulation is designed for 500g of pure theophylline pellets (Spherofillin [1];diameter 0.8-1.3mm)
Polymer suspension Kollicoat® SR 30 D [1] 223.67gPropylene glycol [1] 6.71gWater 149.86g
Pigment suspension Kollidon® 30 [1] 2.24gTitanium dioxide [2] 2.24gSicovit® Red 30 [1] 2.24gTalc [3] 15.66gWater 44.73g
b) Preparation of the spray suspension
Polymer suspension Add propylene glycol followed by Kollicoat® SR30 D to the given quantity of water with stirring.
Pigment suspension Dissolve Kollidon® 30 in the given quantity ofwater. Add Sicovit® Red 30, titanium dioxide andtalc with vigorous stirring and homogenize themixture in a corundum disk mill.
Spray suspension Incorporate the pigment suspension into thepolymer suspension with stirring. The suspensionmust be stirred during the spraying process toprevent settling.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page7/51 Caffeine sustained-release pellets
c) Coating
The pellets were coated in an Aeromatic Strea-1 (Aeromatic AG). The suspensionwas sprayed continuously onto the fluidized, pre-heated pellets from the top.
Process parameters Inlet air temperature 60°COutlet air temperature 37°CProduct temperature 38°CAir flow 80m³/hNozzle diameter 0.8mmSpraying rate approx. 11.5g/minSpraying time 39 minAtomizing pressure 1.0barDrying 45°C/ 5minCoating weight 2mg film former/cm²
The coating weight of 2mg film former / cm² given here was determined from thesurface area of the pellets. Since the particle size distribution and surface structureinfluence the polymer quantity required, calculating the surface area is recommendedas a means of estimating the required coating weight in each specific case.
0
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0 4 8 12 16 20 24
time [h]
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ase
[%]
0.5 mg Kollicoat SR 30 D/cm² 1.0 mg Kollicoat SR 30 D/cm² 2.0 mg Kollicoat SR 30 D/cm²
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page8/51 Caffeine sustained-release pellets
1.2 Theophylline sustained-release pellets(drug-layering process)
a) Formulation
The formulation is designed for 800g of pellets manufactured by drug layering ofnonpareilles.
Polymer suspension Kollicoat® SR 30 D [1] 533.0gTriethyl citrate (TEC) [4] 16.0gWater 433.0g
Pigment suspension Talc [3] 56.0gWater 100.0g
b) Preparation of the spray suspension
Polymer suspension Add TEC followed by Kollicoat® SR 30 D to thegiven quantity of water with stirring.
Pigment suspension Add talc to the given quantity of water withvigorous stirring.
Spray suspension Incorporate the pigment suspension into thepolymer suspension with stirring. The suspensionmust be stirred during the spraying process toprevent settling.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page9/51 Caffeine sustained-release pellets
c) Coating
The pellets were coated in an GPCG1 (Glatt). The suspension was sprayedcontinuously onto the fluidized, pre-heated pellets by the Wurster method.
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50-55°COutlet air temperature 29-32°CProduct temperature 35-40°CAir flow 90m³/hNozzle diameter 1.2mmSpraying time 260 minSpraying rate approx. 4.5 g/minAtomizing pressure 1.2barDrying 40°C/ 15minCoating weight 20%
0
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
method: paddle 100 rpm; 37°C0-20h: pH 7.4
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page10/51 Caffeine sustained-release pellets
2. Caffeine sustained-release pellets
a) Formulation
The formulation is designed for 500g of pellets (composition of pellets: 10% caffeine[1], 43.75% Avicel® PH 101 [5], 43.75% lactose [6], 2.5% Kollidon® VA 64 [1];diameter 0.7-1.4mm; made by wet extrusion).
Polymer suspension Kollicoat® SR 30 D [1] 269.44gPropylene glycol [1] 8.09gWater 188.61g
Pigment suspension Kollidon® 30 [1] 2.7gTitanium dioxide [2] 2.7gSicovit® Red 30 [1] 2.7gTalc [3] 18.87gWater 53.89g
b) Preparation of the spray suspension
Polymer suspension Add propylene glycol followed by Kollicoat® SR 30 Dto the given quantity of water with stirring.
Pigment suspension Dissolve Kollidon® 30 in the given quantity of water.Add Sicovit® Red 30, titanium dioxide and talc withvigorous stirring and homogenize the mixture in acorundum disk mill.
Spray suspension Incorporate the pigment suspension into the polymersuspension with stirring. The suspension must bestirred during the spraying process to prevent settling.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page11/51 Caffeine sustained-release pellets
c) Coating
The pellets were coated in an Aeromatic Strea-1 (Aeromatic AG). The suspensionwas sprayed continuously onto the fluidized, pre-heated pellets from the top.
Process parameters Inlet air temperature 60°COutlet air temperature 36°CProduct temperature 37°CAir flow 80m³/hNozzle diameter 0.8mmSpraying rate approx. 12g/minSpraying time 45 minAtomizing pressure 1.0barDrying 45°C/ 5minCoating weight 3mg film former/cm²
The coating weight of 3mg film former / cm² given here was established for thepellets by surface area determination. Since the particle size distribution and surfacestructure influence the required polymer quantity, calculating the surface area isrecommended as a means of estimating the required coating weight in each specificcase.
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0 4 8 12 16 20 24
time [h]
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ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page12/51 Acetminophen – taste masked
3.1 Propranolol HCl sustained-release pellets(extrusion process)
a) Formulation
The formulation is designed for 500g of pellets (composition of pellets: 20%propranolol HCl [1], 51.66% Avicel® PH 101 [5], 25.84% lactose [6], 2.5% Kollidon®
VA 64 [1]; diameter 0.4-1.5mm; made by wet extrusion).)
Polymer suspension Kollicoat® SR 30 D [1] 249.41gPropylene glycol [1] 7.49gWater 174.59g
Talc suspension Talc [3] 29.94gWater 44.91g
b) Preparation of the spray suspension
Polymer suspension Add propylene glycol followed by Kollicoat® SR30 D to the given quantity of water with stirring.
Talc suspension Add talc with vigorous stirring and homogenizethe mixture in a corundum disk mill.
Spray suspension Incorporate the talc suspension into the polymersuspension with stirring. The suspension must bestirred during the spraying process to preventsettling.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page13/51 Acetminophen – taste masked
c) Coating
The pellets were coated in an Aeromatic Strea-1 (Aeromatic AG). The suspensionwas sprayed continuously onto the fluidized, pre-heated pellets from the top.
Process parameters Inlet air temperature 60°COutlet air temperature 35°CProduct temperature 36°CAir flow 80m³/hNozzle diameter 0.8mmSpraying rate approx. 13g/minSpraying time 39 minAtomizing pressure 1.0barDrying 45°C/ 5minCoating weight 3mg film former/cm²
The coating weight of 3mg film former / cm² given here was established for thepellets by surface area determination. Since the particle size distribution and surfacestructure influence the required polymer quantity, calculating the surface area isrecommended as a means of estimating the required coating weight in each specificcase.
0
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page14/51 Acetminophen – taste masked
3.2 Propranolol HCl sustained-release pellets(drug-layering process)
a) Formulation
The formulation is designed for 800g of pellets manufactured by drug layering ofnonpareilles.
Polymer suspension Kollicoat® SR 30 D [1] 533.0gTriethyl citrate (TEC) [4] 16.0gWater 433.0g
Pigment suspension Talc [3] 56.0gWater 100.0g
b) Preparation of the spray suspension
Polymer suspension Add TEC followed by Kollicoat® SR 30 D to thegiven quantity of water with stirring.
Pigment suspension Add talc to the given quantity of water withvigorous stirring.
Spray suspension Incorporate the pigment suspension into thepolymer suspension with stirring. The suspensionmust be stirred during the spraying process toprevent settling.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page15/51 Acetminophen – taste masked
c) Coating
The pellets were coated in a Glatt GPCG1 coater. The suspension was sprayedcontinuously onto the fluidized, pre-heated pellets from the bottom by the Wurstermethod. Weight gains of 5, 10, 15 and 20% were tested.
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50-55°COutlet air temperature 29-32°CProduct temperature 35-40°CAir flow 90m³/hNozzle diameter 1.2mmSpraying time 220 minSpraying rate approx. 4.5 g/minAtomizing pressure 1.2barDrying 40°C/ 15minCoating weight 20%
0
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
5% Kollicoat SR 30 D10% Kollicoat SR 30 D15% Kollicoat SR 30 D20% Kollicoat SR 30 D
method: paddle 50 rpm; 37°C0-20h: 0.1M HCl
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page16/51 Acetminophen – taste masked
3.2.1 Propranolol HCl pellet-releasing tablet
a) Formulation
The formulation is designed for 500g of tablets:
Propranolol HCl/ Kollicoat® SR pellets 250.0gMicrocrystalline cellulose (Vivapur® 200) [7] 250.0gMagnesium stearate [8] 2.5g
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 15kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 15kN
c) Tablet properties
Weight 400mgDiameter 10mmForm biplanarHardness 82-112N
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time [h]
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rele
ase
[%]
Tablets 850 - 1000 µmTablets 710 - 850 µmPellets 850 - 1000 µmPellets 710 - 850 µm
method: paddle 100 rpm; 37°Ccoating level: 20%0-20h: 0.1M HCl
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page17/51 Acetminophen – taste masked
4. Acetaminophen - taste masked
a) Formulation
The formulation is designed for 500g of acetaminophen granules [1].
Polymer suspension Kollicoat® SR 30 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 dispersionwas sprayed continuously onto the fluidized, pre-heated crystals from the top.
Process parameters Inlet air temperature 60°COutlet air temperature 40°CProduct temperature 41°CAir flow 80m³/hNozzle diameter 0.8mmSpraying rate approx. 9g/minSpraying time 9 minAtomizing pressure 1.0barDrying 45°C/ 5minCoating weight 4%
Crystalline acetaminophen is coated with 4% Kollicoat® SR 30 D.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page18/51 Acetminophen – taste masked
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0 15 30 45 60
time [min]
drug
rele
ase
[%]
0.1N HClphosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page19/51 Ibuprofen sustained-release pellets
5. Ibuprofen sustained-release pellets(drug-layering process)
The formulation is designed for 800g of pellets manufactured by drug layering ofnonpareilles.
a) Subcoating
The polymer spray solution for a weight gain of 5%:
Spray solution Mowiol® 4-88 (PVA) [9] 48.0gWater 432.0g
b) Preparation of the spray solution (subcoating)
Dissolve Mowiol in hot water and cool with stirring.
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50°COutlet air temperature 35°CProduct temperature 40°CAir flow 80m³/hNozzle diameter 1.2mmSpraying time 56 minSpraying rate approx. 3.1g/minAtomizing pressure 1.2barDrying 40°C/ 15minSubcoating weight 5%
c) Polymer coating
The formulation is designed for 800g of subcoated pellets.
Polymer suspension Kollicoat® SR 30 D [1] 533.0gTriethyl citrate (TEC) [4] 16.0gWater 433.0g
Pigment suspension Talc [3] 56.0gWater 100.0g
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page20/51 Ibuprofen sustained-release pellets
d) Preparation of the spray suspension (polymer coating):
Polymer suspension Add TEC followed by Kollicoat® SR 30 D to thegiven quantity of water with stirring.
Pigment suspension Add talc to the given quantity of water withvigorous stirring.
Spray suspension Incorporate the pigment suspension into thepolymer suspension with stirring. The suspensionmust be stirred during the spraying process toprevent settling.
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50-55°COutlet air temperature 29-32°CProduct temperature 35-40°CAir flow 90m³/hNozzle diameter 1.2mmSpraying time 230 minSpraying rate approx. 4.5 g/minAtomizing pressure 1.2barDrying 40°C/ 15min
Spray the suspension continuously onto fluidized pre-heated pellets by the wursterspray method. Weight gains 5, 10, 15 and 20%.
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
5% Kollicoat SR 30D10% Kollicoat SR 30D15% Kollicoat SR 30D20% Kollicoat SR 30D
method: paddle 100 rpm; 37°C0-20h: pH 7.4
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page21/51 Ambroxol HCl sustained-release pellets
6. Ambroxol HCl sustained-release pellets(drug-layering process)
The formulation is designed for 800g of pellets manufactured by drug layering ofnonpareilles.
a) Formulation
Polymer suspension Kollicoat® SR 30 D [1] 533.0gTriethyl citrate (TEC) [4] 16.0gWater 433.0g
Pigment suspension Talc [3] 56.0gWater 100.0g
b) Preparation of the spray suspension
Polymer suspension Add TEC followed by Kollicoat® SR 30 D to thegiven quantity of water with stirring.
Pigment suspension Add talc to the given quantity of water withvigorous stirring.
Spray suspension Incorporate the pigment suspension into thepolymer suspension with stirring. The suspensionmust be stirred during the spraying process toprevent settling.
c) Coating
The pellets were coated in an GPCG1 (Glatt). The suspension was sprayedcontinuously onto the fluidized, pre-heated pellets by the Wurster method.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page22/51 Ambroxol HCl sustained-release pellets
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50-55°COutlet air temperature 29-32°CProduct temperature 35-40°CAir flow 90m³/hNozzle diameter 1.2mmSpraying time 220 minSpraying rate approx. 4.5 g/minAtomizing pressure 1.2barDrying 40°C/ 15minWeight gain 20%
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
5% Kollicoat SR 30D10% Kollicoat SR 30D15% Kollicoat SR 30D20% Kollicoat SR 30D
method: paddle 100 rpm; 37°C0-20h: pH 7.4
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page23/51 Ambroxol HCl sustained-release pellets
6.1 Ambroxol HCl pellet-releasing tablet
d) Formulation
The formulation is designed for 500g of tablets:
Ambroxol HCl/ Kollicoat® SR pellets 250.0gMicrocrystalline cellulose (Vivapur® 200) [7] 250.0gMagnesium stearate [8] 2.5g
e) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 15kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 15kN
f) Tablet properties
Weight 400mgDiameter 10mmForm biplanarHardness 92-116N
0
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
5% Kollicoat SR 30D10% Kollicoat SR 30D15% Kollicoat SR 30D20% Kollicoat SR 30D
method: paddle 100 rpm; 37°C0-20h: pH 7.4
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page24/51 Tramadol HCl sustained-release pellets
7. Tramadol HCl sustained-release pellets(drug-layering process)
a) Polymer coating
The formulation is designed for 800g of pellets manufactured by drug layering ofnonpareilles.
Polymer suspension Kollicoat® SR 30 D [1] 533.0gTriethyl citrate (TEC) [4] 16.0gWater 433.0g
Pigment suspension Talc [3] 56.0gWater 100.0g
b) Preparation of the spray suspension
Polymer suspension Add TEC followed by Kollicoat® SR 30 D to thegiven quantity of water with stirring.
Pigment suspension Add talc to the given quantity of water withvigorous stirring.
Spray suspension Incorporate the pigment suspension into thepolymer suspension with stirring. The suspensionmust be stirred during the spraying process toprevent settling.
c) Coating
The pellets were coated in an GPCG1 (Glatt). The suspension was sprayedcontinuously onto the fluidized, pre-heated pellets by the Wurster method.
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page25/51 Tramadol HCl sustained-release pellets
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50-55°COutlet air temperature 29-32°CProduct temperature 35-40°CAir flow 90m³/hNozzle diameter 1.2mmSpraying time 225 minSpraying rate approx. 4.5 g/minAtomizing pressure 1.2barDrying 40°C/ 15minWeight gain 20%
0
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0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
tablets, 15% Kollicoat SR 30 Dtablets, 20% Kollicoat SR 30 Dpellets, 15% Kollicoat SR 30 Dpellets, 20% Kollicoat SR 30 D
method: paddle 100 rpm; 37°C0-20h: pH 7.4
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page26/51 Acetylsalicylic acid crystals
8. Acetylsalicylic acid crystals
a) Formulation
The formulation is designed for 800g of acetylicsalicylic acid crystals [12].
Spray suspension Kollicoat® SR 30 D [1] 666.25gTalc [3] 70.00gWater 666.25g
b) Preparation of the spray suspension
Add talk to the given amount of water with vigorous stirring.Then add Kollicoat SR 30 D with slow stirring.
c) Coating
The crystals were coated in a Glatt GPCG1 coater. The suspension was sprayedcontinously onto the fluidized, pre-heated crystals by the Wurster method. Weightgains of 5, 10, 15 and 20% were tested.
Process parameters Machine Glatt GPCG1Method Bottom-spray (Wurster)Inlet air temperature 50-55°COutlet air temperature 29-32°CProduct temperature 35-40°CAir flow 90m³/hNozzle diameter 1.2mmSpraying time 166 minSpraying rate approx. 8.9 g/minAtomizing pressure 1.2barDrying 40°C/ 15minCoating weight 20%
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page27/51 Acetylsalicylic acid crystals
0
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time [h]
drug
rele
ase
[%]
crystals10% Kollicoat SR 30D15% Kollicoat SR 30D20% Kollicoat SR 30D25% Kollicoat SR 30D
method: paddle 100 rpm; 37°C0-20h: pH 7.4no plasticizer
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page28/51 Kollicoat® SR 30 D - Granulation
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page29/51 Propranolol HCl sustained-release tablet
9. Propranolol HCl sustained-release tablet
a) Formulation of the granules
Propranolol HCl Powder 80 [1] 250.0gGranulac® 140 (lactose) [6] 100.0g
Kollicoat® SR 30 D [1] 525.0g
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°COutlet air temperature 22 – 27°CNozzle diameter 1.2mmSpraying rate approx. 10g/minAtomizing pressure 2.0bar
c) Formulation of the tablets
Propranolol HCl powder 80 [1] 160.0mgKollicoat® SR 30 D [1] 96.0mgGranulac® 140 [6] 64.0mgAerosil® 200 [13] 1.6mgMagnesium stearate [8] 1.6mg
d) Tableting
The granules were passed together with magnesium stearate (0.5%) and Aerosil®200 (0.5%) through an 800µm sieve, blended for 10 min in a Turbula mixer andcompressed into tablets with a force of about 18kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 17.7kN
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page30/51 Propranolol HCl sustained-release tablet
e) Tablet properties
Weight 323.0mgDiameter 10mmForm biplanarHardness 260N
0
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80
100
0 4 8 12 16 20
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-20h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page31/51 Theophylline sustained-release tablet
10. Theophylline sustained-release tablet
a) Formulation of the granules
Theophylline powder [1] 250.0gGranulac® 140 [6] 212.5g
Kollicoat® SR 30 D [1] 131.25g
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°COutlet air temperature 22 – 27°CNozzle diameter 1.2mmSpraying rate approx. 10g/minAtomizing pressure 2.0bar
c) Formulation of the tablets
Theophylline pdr [1] 400.0mgKollicoat® SR 30 D [1] 60.0mgGranulac® 140 [6] 340.0mgAerosil® 200 [13] 4.0mgMagnesium stearate [8] 4.0mg
d) Tableting
The granules were passed together with magnesium stearate (0.5%) and Aerosil®200 (0.5%) through an 800µm sieve, blended for 10 min in a Turbula mixer andcompressed into tablets with a force of about 18kN.
Tablet press Korsch PH 106, 30 rpmCompression force 18.7kN
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page32/51 Theophylline sustained-release tablet
e) Tablet properties
Weight 808.0mgDiameter football shape 19.0x8.5mmHardness 276N
0
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100
0 2 4 6 8 10 12 14 16 18 20 22 24
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page33/51 Carbamazepine sustained-release tablet
11. Carbamazepine sustained-release tablet
a) Formulation of the granules
Carbamazepine [14] 250.0gGranulac® 140 [6] 185.3gKollidon® CL-M [1] 25.3g
Kollicoat® SR 30 D [1] 131.25g
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°COutlet air temperature 22 – 27°CNozzle diameter 1.2mmSpraying rate approx. 10g/minAtomizing pressure 2.0bar
c) Formulation of the tablets
Carbamazepine [14] 200.0mgKollicoat® SR 30 D [1] 30.0mgKollidon® CL-M [1] 20.2mgGranulac® 140 [6] 149.8mgAerosil® 200 [13] 2.0mgMagnesium stearate [8] 2.0mg
d) Tableting
The granules were passed together with magnesium stearate (0.5%) and Aerosil®200 (0.5%) through an 800µm sieve, blended for 10 min in a Turbula mixer andcompressed into tablets with a force of about 18kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 18.0kN
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page34/51 Carbamazepine sustained-release tablet
e) Tablet properties
Weight 404.0mgDiameter 11mmForm biconvexHardness 136N
0
20
40
60
80
100
0 4 8 12 16
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-16h: SDS-solution (1%; water)
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page35/51 Kollidon SR
®
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page36/51 Metoprolol tartrate sustained-release tablet
12. Metoprolol tartrate sustained-release tablet
a) Formulation of the granules
Metoprolol tartrate [15] 454.5gKollicoat® SR 30 D [1] 45.5g
b) Manufacture of the granules
The active ingredient was granulated in an Aeromatic Strea-1 (Aeromatic AG). Thepolymer dispersion was sprayed into the fluid bed from the top.
Process parameters Inlet air temperature 50°COutlet air temperature 24 – 28°CNozzle diameter 1.2mmSpraying rate approx. 10g/minAtomizing pressure 2.0bar
c) Formulation of the tablets
Metoprolol tartrate [15] 200.0mgKollicoat® SR 30 D solid polymer 6.0mgKollidon® SR [1] 250.0mgMagnesium stearate [8] 2.5mg
d) Tableting
The granules were passed together with magnesium stearate (0.5%) and Kollidon®
SR (54.5%) through an 800µm sieve, blended for 10 min in a Turbula mixer andcompressed into tablets with a force of about 10kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 9,3kN
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page37/51 Metoprolol tartrate sustained-release tablet
e) Tablet properties
Weight 458.5mgDiameter 12mmForm biplanarHardness 220N
0
20
40
60
80
100
120
0 2 4 6 8 10 12
time [h]
method: paddle 100 rpm; 37°C0-2h: 0.08 M HCl2-12h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page38/51 Propranolol HCl sustained-release tablet
13. Propranolol HCl sustained-release tablet
a) Formulation
Propranolol HCl [1] 160.0mgKollidon® SR [1] 160.0mgAerosil® 200 [13] 3.4mgMagnesium stearate [8] 1.6mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress intotablets with a force of about 10kN.
Tablet press Korsch PH 100/6 30 rpmCompression force 9,9kN
c) Tablet properties
Weight 325.0mgDiameter 10mmForm biplanarHardness 172N
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-16h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page39/51 Caffeine sustained-release tablet
14. Caffeine sustained-release tablet
a) Formulation
Caffeine gran. 0,2/0,5 [1] 160.0mg 160.0mg 160.0mgKollidon® SR [1] 160.0mg 120.0mg 80.0mgAvicel® PH 102 [5] -- 40.0mg 80.0mgMagnesium stearate [8] 1.6mg 1.6mg 1.6mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 10kN.
Tablet press Korsch PH100/6, 30 rpmCompression force 9.6kN 9.8kN 10.1kN
c) Tablet properties
Weight 322.0mg 322.0mg 322.0mgDiameter 10mm 10mm 10mmForm biplanarHardness 213N 201N 193NFriability <0.1% <0.1% <0.1%
0
20
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60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24
time [h]
drug
rele
ase
[%]
caffeine/ Kollidon SR (160mg/ 80mg)
caffeine/ Kollidon SR (160mg/ 120mg)
caffeine/ Kollidon SR (160mg/ 160mg)
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page40/51 Caffeine sustained-release tablet
15. Diclofenac Na sustained-release tablet
a) Formulation
Diclofenac Na [16] 100.0mg 100.0mgKollidon® SR [1] 100.0mg 150.0mgAerosil® 200 [13] 3.4mg 3.4mgMagnesium stearate [8] 3.0mg 3.0mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 8kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 7.9kN 7.0kN
c) Tablet properties
Weight 206.0mg 256.0mgDiameter 8mmForm biplanarHardness 195N 229NFriability <0.1% <0.1%
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14 16
time [h]
drug
rele
ase
[%]
diclofenac Na/ Kollidon SR (100mg/ 100mg)
diclofenac Na/ Kollidon SR (100mg/ 150mg)
method: paddle 50 rpm; 37°C0-16h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page41/51 Carbamazepine sustained-release tablet
16. Ascorbic acid sustained-release tablet
a) Formulation
Ascorbic acid cryst. [1] -- 200.0mg 200.0mgAscorbic acid pdr. [1] 200.0mg -- --Kollidon® SR [1] 200.0mg 200.0mg 280.0mgLudipress® LCE [1] 75.0mg 80.0mg --Aerosil® 200 [13] 5.0mg -- --Magnesium stearate [8] 9.0mg 9.0mg 9.0mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 18kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 17.1kN 20.0kN 18.6kN
c) Tablet properties
Weight 489.0mg 489.0mg 489.0mgDiameter 12mmForm biplanarHardness 164N 140N 151NFriability 0.1% 0.1% 0.2%
0
20
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60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24time [h]
drug
rele
ase
[%]
ascorbic acid plv./ K.SR/ L.LCE (200mg/ 200mg/ 75mg)
ascorbic acid cryst./ K.SR/ L.LCE (200mg/ 200mg/ 80mg)
ascorbic acid cryst./ K.SR/ L.LCE (200mg/ 200mg/ 80mg)
method: paddle 50 rpm; 37°C0-24h: phosphate buffer pH 4.0(1% cysteine HCl-solution)
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page42/51 Carbamazepine sustained-release tablet
17. Indometacin sustained-release tablet
a) Formulation
Indometacin [12] 75.0mg 75.0mgKollidon® SR [1] 125.0mg 125.0mgLudipress® LCE [1] 100.0mg --Aerosil® 200 [13] 1.5mg 4.0mgMagnesium stearate [8] 1.5mg 2.0mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 10kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 8.7kN 13.0kN
c) Tablet properties
Weight 303.0mg 203.0mgDiameter 10mmForm biplanarHardness 163N 133NFriability <0.1% 0.1%
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16
time [h]
drug
rele
ase
[%]
indometacin/ K.SR (75mg/ 125 mg)
indometacin/ K.SR/L.LCE (75mg/ 125mg/100mg)
method: paddle 50 rpm; 37°C0-16h: phosphate buffer pH 7.2
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page43/51 Carbamazepine sustained-release tablet
18. Carbamazepine sustained-release tablet
a) Formulation
Carbamazepine [14] 200.0mg 200.0mgKollidon® SR [1] 100.0mg 100.0mgLudipress® LCE [1] 200.0mg 150.0mgKollidon® CL-M [13] -- 20.0mgMagnesium stearate [8] 2.5mg 2.5mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 25kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 24.7kN 23.1kN
c) Tablet properties
Weight 503.0mg 473.0mgDiameter 12mmForm biplanarHardness 146N 164NFriability 0.1% <0.1%
0
20
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60
80
100
120
0 2 4 6 8 10 12 14 16
time [h]
drug
rele
ase
[%]
carbamazepine/ K. SR/ L. LCE (200mg/ 100mg/ 200mg)
carbamazepine/ K. SR/ L. LCE/ K. CL-M (200mg/ 100mg/ 150mg/ 20mg)
method: paddle 75 rpm; 37°C0-16h: SDS-solution (1%; water)
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page44/51 Nifedipine sustained-release tablet
19. Nifedipine sustained-release tablet
a) Formulation
Nifedipine [17] 20.0mgKollidon® SR [1] 100.0mgLudipress® LCE [1] 100.0mgMagnesium stearate [8] 1.0mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 6kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 5.8kN
c) Tablet properties
Weight 221.0mgDiameter 8mmForm biplanarHardness 193NFriability <0.1%
0
20
40
60
80
100
0 4 8 12 16 20 24
time [h]
drug
rele
ase
[%]
method: paddle 100 rpm; 37°C0-24h: phosphate buffer 6.8/0.5% SDS
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page45/51 Tramadol HCl sustained-release tablet
20. Tramadol HCl sustained-release tablet
a) Formulation
Tramadol HCl [11] 100.0mgKollidon® SR [1] 150.0mgAerosil® 200 [13] 2.5mgMagnesium stearate [8] 1.5mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 10kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 12.6kN
c) Tablet properties
Weight 254.0mgDiameter 10mmForm biplanarHardness 211NFriability <0.1%
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page46/51 Diltiazem HCl sustained-release tablet
21. Diltiazem HCl sustained-release tablet
a) Formulation
Diltiazem HCl [18] 120.0mgKollidon® SR [1] 180.0mgAerosil® 200 [13] 3.0mgMagnesium stearate [8] 1.5mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 10kN.
Tablet press Korsch EK0, 30 tablets/ minCompression force 8.0kN
c) Tablet properties
Weight 305.0mgDiameter 10mmForm biplanarHardness 217NFriability <0.1%
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16
time [h]
drug
rele
ase
[%]
method: paddle 100 rpm; 37°C0-16h: deionized water
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page47/51 Naphtidrofuryl oxalate sustained-release tablet
22. Naphtidrofuryl oxalate sustained-release tablet
a) Formulation
Naphtidrofuryl oxalate [18] 100.0mgKollidon® SR [1] 150.0mgTalc [3] 25.0mgAerosil® 200 [13] 5.4mgMagnesium stearate [8] 2.5mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 18kN.
Tablet press Korsch PH106, 30 rpmCompression force 17.0kN
c) Tablet properties
Weight 283.0mgDiameter 10mmForm biplanarHardness 197NFriability <0.1%
0
20
40
60
80
100
0 4 8 12 16 20 24time [h]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page48/51 Theophylline sustained-release tablet
23. Theophylline sustained-release tablet
a) Formulation
Theophylline pdr. [1] 500.0mgKollidon® SR [1] 200.0mgLudipress® LCE [1] 225.0mgMagnesium stearate [8] 3.0mg
b) Procedure
Mix the ingredients together, pass through a 0.8mm sieve and compress into tabletswith a force of about 10kN.
Tablet press Korsch PH 106, 30 rpmCompression force 10.8kN
c) Tablet properties
Weight 928.0mgDiameter 19.0x8.5mmForm football shapeHardness 172NFriability <0.1%
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24
time [h]
drug
rele
ase
[%]
method: paddle 50 rpm; 37°C0-2h: 0.08 M HCl2-24h: phosphate buffer pH 6.8
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page49/51 Substances
Substances[1] BASF Aktiengesellschaft Excipients
Carl-Bosch Str. 38 Kollicoat® SR 30 D67056 Ludwigshafen, Germany Kollidon® 30
Kollidon® CLKollidon® CL-MKollidon® SRKollidon® VA 64Ludipress® LCEPropylene glycolSicovit® Red 30
ActivesAcetaminophen gran.Ascorbic acid cryst.Ascorbic acid powderCaffeine gran. 0.2/0.5IbuprofenPropranolol HCl powder 80Theophylline powderSpherofillin
[2] Kronos Titan GmbH Titanium dioxidePostfach 10072051307 Leverkusen, Germany
[3] Riedel-de-Haën AG TalcWunstdorferstr. 4030926 Seelze, Germany
[4] Merck-Schuchardt Triethyl citrate85662 Hohenbrunn, Germany
[5] FMC Corp. Food + Pharmaceutical Avicel® PH 101Products Avicel® PH 102735 Market StreetPhiladelphia, PA 19103, USA
[6] Meggle Milchindustrie Granulac® 140Postfach 40 Granulac® 23083512 Wasserburg, Germany
[7] J. Rettenmaier & Söhne Vivapur® 200Holzmühle 173494 Rosenberg, Germany
[8] Bärlocher GmbH Magnesium stearate80992 Munich, Germany
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page50/51 Substances
[9] Clariant GmbH Mowiol® 4-88 PVADivision CP/TQM-QP65926 Frankfurt am Main, Germany
[10] Heumann Pharma GmbH Ambroxol HClPostfach 226090008 Nuremberg, Germany
[11] Chemagis Ltd. Tramadol HClP.O. Box 9091Tel Aviv 61090, Israel
[12] Synopharm GmbH Acetylicsalicylic acid crystalsPostfach 1205 Indometacin22882 Barsbüttel, Germany
[13] Degussa-Hüls AG Aerosil® 200Weissfrauenstr. 960287 Frankfurt, Germany
[14] Fabbrica Italiana Sintetici S.p.A. CarbamazepineViale Milano, 2636041 Alte di Montecclio Maggiore,Italy
[15] Moehs S.A. Metoprolol tartrateApartado 5908191 Rubi, Spain
[16] Irotec Laboratories Diclofenac NaLittle Island, Cork, Ireland
[17] Prosintex Industrie ChimicheItaliano
Nifedipine
Via E. Ferm, 20/2620019 Seltimo Milanese (Mi), Italy
[18] Farmak a.s. Diltiazem HClNa Vlcinci 3 Naphtidrofuryl oxalate77117 Olomouc, Czech Republic
Generic Drug Formulations with Kollicoat® SR 30 D and Kollidon® SR
Page51/51
Note
The data submitted in this publication are based on our current knowledge andexperience. They do not constitute a guarantee in the legal sense of the term and, inview of the mainfold factors that may effect processing and application, do not relieveprocessors from the responsibility of carrying out their own tests and experiments.Any relevant patent rights and existing legislation and regulations must be observed.
BASF AktiengesellschaftUnternehmensbereich Fine Chemicals67056 Ludwigshafen, Germany