BASF Aktiengellschaft
Development and Stability of Enteric Omeprazole Formulations bad on Kollicoat ® MAE Polymers
K. Mäder, Martin-Luther-University, 06099 Halle, Germany
K. Bräunig, K. Meyer and K. Kolter (karl.kolter@basf-ag.de), BASF Aktiengellschaft, Development Pharma Ingredients, 67056 Ludwigshafen, Germany
Abstract Summary
Enteric omeprazole tablet and pellet formulations bad on Kollicoat ® MAE polymers were developed. A coating level of 6 mg/cm² was required to achieve a good gastric resistance. Degradation of omeprazole upon storage can be decelerated by addition of Na 2HPO 4 to the core and an impermeable packaging material.
Introduction
Omeprazole is known to be very nsitive towards acids and therefore requires for oral applications an effective enteric coating 1). In this study the influence of formulation parameters of enteric-coated tablets and pellets on stability was investigated.
Experimental Methods
• Materials
Sugar pellets 710-850 µm (suglets ® NP Pharm), omeprazole (Knoll AG), povidone (Kollidon ® 30, BASF Aktiengellschaft), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat ® IR, BASF Aktiengellschaft), methacrylic acid-ethyl acrylate copolymers (Kollicoat ® MAE 30 DP and 100 P , BASF Aktiengellschaft), triethyl citrate (Merck KGaA), talc (Riedel-de Haen), titanium dioxide (E171, Kronos), red iron oxide (Sicovit ® Red 30, E172, BASF Aktiengellschaft).• Preparations Tablets
All tablet ingredients were blended in the Diosna mixer V 50 for 3 min and compresd on a Kilian RL 15 rotary press at 10 kN compression force.
USP Resistance test (Dissolution)
The tablets were tested in a USP-dissolution tester apparatus 2 at 100 rpm using 0.08 N HCl and phosphate buffer pH 6.8. The liberated omeprazole was determined by means of UV-VIS (306 nm). The concentration of omeprazole was calculated according to a previously determined decomposition curve.Stability test
The formulations were stored in open containers at 25 °C/60 % r. h.
30 °C/70 % r. h.
The omeprazole content of the formulations was determined by HPLC.
Coating
A standard coating formulation 2) (Table 3) was prepared for gastric resistant coating (Kollicoat ® MAE 30 DP , 100 P and pigments).
The tablet coating was performed in an Accela Cota 24" in 5 kg batches (Table 4).
The pellets were coated in a Strea 1 (Aeromatic) in 500 g batches (Table 4).
Pellets
A mixture of omeprazole and Kollidon ® 30 in water neutralized to pH 8 (Table 2) was applied on sugar pellets in the Aeromatic Strea 1 by top spraying process. Drug layered pellets with an average omeprazole content of 9.4 % were obtained.
Tablet formulations
Omeprazole Na 2HPO 4 x 2H 2O Ludipress
Magnesium stearate Total Diameter Batch size
Omeprazole tablets Omeprazole tablets with Na 2HPO 4高中英语教材
mg mg mg mg mg
mm kg
20.0 31.3 197.45 1.25 250.0 9 18.5mg mg mg mg mm kg
20.0 - 228.75 1.25 250.0 9 18.5
Table 1
Spray formulation for drug layering on pellets
Omeprazole Kollidon 30
Sodium hydroxide 1M Water Batch size
g g pH 8gmerry什么意思
kg
freshfresh280140 q.s. ad 1400 1.5Table 2
Results and Discussion
No or < 10% omeprazole was liberated within 2 h in 0.08 N HCl from tablets and pellets coated with at least 6 mg/cm² enteric polymer (Figure 1).After buffering the solution to pH 6.8, dissolution started after approximately 10 min. and the formulations liberated > 85% within 60 min.
No significant difference in enteric properties could be found when increasing the coating level or changing from Kollicoat ® MAE 30 DP to 100 P , which is partly neutralized.
Regarding stability, omeprazole showed a high nsitivity to moisture
and temperature. At 30 °C/70 % r. h. all formulations were less stable than at 25 °C/60 % r. h.
Whereas the different coating levels (6 mg/cm² and 10 mg/cm²) and Kollicoat ® MAE type had no effect on the degradation of omeprazole upon storage, an alkaline buffering agent like Na 2HPO 4 significantly improved the stability of omeprazole at 30 °C/70 % r. h.. Generally, the pellets were less stable probably due to the larger surface area, more hygroscopic ingredients and a higher moisture uptake.
References
1) B. Wallmark, Mechanism of action of omeprazole, Scand. J. Gastroenterol. Suppl., 118, 11-17 (1986).2) C. Dangel, K. Kolter, H.-B. Reich and G. Schepky, Pharm. Techn. 24 (3), 64-70 (2000).
MEM/PD 145
Stability of omeprazole tablets coated with Kollicoat ® MAE 30 DP
Influence of Na 2HPO 4 addition and coating level
Figure 2D r u g c o n t e n t [%]
75
85
95100
90
80
Time [months]
6
3
counterattack
without Na 2HPO 4; 6 mg/cm²; 25 °C/60 % r.h.without Na 2HPO 4; 6 mg/cm²; 30 °C/70 % r.h.without Na 2HPO 4; 10 mg/cm²; 25 °C/60 % r.h.without Na 2HPO 4; 10 mg/cm²; 30 °C/70 % r.h.with Na 2HPO 4; 6 mg/cm²; 25 °C/60 % r.h.with Na 2HPO 4; 6 mg/cm²; 30 °C/70 % r.h.with Na 2HPO 4; 10 mg/cm²; 25 °C/60 % r.h.with Na 2HPO 4; 10 mg/cm²; 30 °C/70 % r.h.
Figure 3
Dissolution of omeprazole pellets
after storage (6 months, 25 °C/60 % r.h.)
L i b e r a t e d o m e p r a z o l e [%]Resistance Test
HCl 0.08 N pH = 1
Dissolution Test
Phosphate buffer pH = 6.8
Time [min]
10
9090
60
20
30
40
romantic spring
50
70
80
10011010
60
20
30
40
50
电子科技大学专科
70
80
120–20
206010040800Conclusion
• The application of Kollicoat ® MAE polymers on omeprazole tablets and pellets at ≥ 6 mg/cm² resulted in excellent enteric properties.
• Addition of an alkaline substance like Na 2HPO 4 improves the stability of omeprazole.
• The enteric dosage form should have a low moisture content and should be stored in an impermeable packaging material.
Figure 1
computergraphicsDissolution of omeprazole tablets coated with Kollicoat ® MAE 30 DP
after storage (6 months, 25 °C/60 % r.h.)
L i b e r a t e d o m e p r a z o l e [%]
Resistance Test
HCl 0.08 N pH = 1
Dissolution Test
Phosphate buffer pH = 6.8
bodTime [min]
10
9090
60
20
30
40
50
70
80
10011010
60
20
30
40
50
70
80
120–20
206010040800without Na 2HPO 4; 6 mg/cm²without Na 2HPO 4; 10 mg/cm²with Na 2HPO 4; 6 mg/cm²with Na 2HPO 4; 10 mg/cm²
Kollicoat MAE 30 DP , 6 mg/cm²Kollicoat MAE 30 DP , 10 mg/cm²Kollicoat MAE 100 P , 6 mg/cm²Kollicoat MAE 100 P 10 mg/cm²
Stability of omeprazole pellets
Influence of MAE – type and coating level
D r u g c o n t e n t [%]
Time [months]
6
3
haiku
40
6090100705080MAE 30 DP; 6 mg/cm²; 25 °C/60 % r.h.MAE 30 DP; 6 mg/cm²; 30 °C/70 % r.h.MAE 30 DP; 10 mg/cm²; 25 °C/60 % r.h.MAE 30 DP; 10 mg/cm²; 30 °C/70 % r.h.MAE 100 P; 6 mg/cm²; 25 °C/60 % r.h.MAE 100 P; 6 mg/cm²; 30 °C/70 % r.h.MAE 100 P; 10 mg/cm²; 25 °C/60 % r.h.MAE 100 P; 10 mg/cm²; 30 °C/70 % r.h.admit是什么意思
Figure 4
Table 4
Process parameters
50 °C 30 °C 360 m³/h 1.0 mm 2.0 bar 20 g/min 3; 6; 10 mg polymer/cm²
Accela Cota Strea 1 60 °C 35 °C 360 m³/h 1.0 mm 2.0 bar 10 g/min
Inlet air temperature Outlet air temperature Air volume
Nozzle diameter
Atomizing air pressure Spraying rate Coating level
Coating formulation
Table 3
Formulation I Proportion [%]
50.00– 2.25 32.25 0.50 0.50 4.00 10.50100.00
Formulation II Proportion [%]
– 15.00 2.25 67.25 0.50 0.50 4.00 10.50100.00
Polymer suspension Kollicoat MAE 30 DP Kollicoat MAE 100 P Triethyl citrate Water
Pigment suspension Sicovit Red 30Titanium dioxide Talc Water Total
CRS 2005 / 32nd International Symposium on Controlled Relea of Bioactive Materials / 18.-22.06.2005 / Miami, Florida, U.S.A.
