Kiểm nghiệm tạp chất esomeprazole tổng hợp - Chương trình đào tạo Dược sĩ Đại học Năm 5 - ĐH Y Dược TPHCM
PHARMACEUTICAL IMPURITIES TESTING ESOMEPRAZOLE GROU P1 » Brand name: Nexium® -AstraZeneca and Nexium® OTC- Pfizer » Ranking 18th (Nexium®) in top 50 pharmaceutical products by global sales (2014) GENER IC content BACKGROUND IMPURITIES OF ESOMEPRAZOLE IMPURITY ORIGIN TOXICITY QUALIFICATION & IMPURITY TEST Let’s go with the second set of slides “ the important thing is to never stop questioning” -Albert Einstein- IMPURITIE S Esomeprazole impurities include A, B, C, D, E, F and S-binol ESOMEPRAZOLE IMPURITIES Impurity A 5-Methoxy-1Hbenzimidazole-2thiol Impurity B 2-[(RS)-[(3,5-Dimethylpyridin-2yl)methyl] sulphinyl]-5-methoxy-1H-benzimidazole Impurity C 5-Methoxy-2-[[(4-methoxy3,5-dimethyl pyridin-2-yl)methyl]sulphanyl] -1H-benzimidazole ESOMEPRAZOLE IMPURITIES Impurity D 5-Methoxy-2-{[(4-methoxy-3,5dimethyl-2pyridinyl)methyl]sulfonyl}-1Hbenzimidazole Impurity E 4-Methoxy-2-[[(RS)-(5-methoxy-1Hbenzimidazol -2-yl)sulfinyl]methyl]-3,5dimethylpyridine-1-oxide Impurity F 6-methoxy-2-[(4-(R)-methoxy-3,5dimethylpyridin -2-yl)methylsulfinyl]-1H-benzimidazole ESOMEPRAZOLE IMPURITIES Impurity S-binol 1-(2-Hydroxynaphthalen-1yl)naphthalene-2-ol IMPURITY ORIGIN Imp-E is degradent Imp-D and Imp-C are process impurities as well as degradents Imp-A, Imp-B and S-binol are process impurities UALIFICATION IMPURITY TEST British Pharmacopoeia 2016, European Pharmacopoeia 8.0, United States Pharmacopoeia 40, Vietnamese Pharmacopoeia IV qualification MONOGRAPHS MATERIAL Esomeprazole Magnesium Dihydrate, Trihydrate and Anhydrous Esomeprazole Strontium Tetrahydrate and Anhydrous PRODUCT Esomeprazole Magnesium Delayed-release Capsule MATERIAL Esomeprazole Magnesium Dihydrate Esomeprazole Magnesium Trihydrate MONOGRAPHS MATERIAL Esomeprazole Magnesium Trihydrate MATERIAL IMPURITY CRITERION MATERIAL Esomeprazole Magnesium Dihydrate IMPURITY USP 40 BP 2016 EP 8.0 unspecified impurity Impurity D Impurity E 0.1% 0.2% 0.1% 0.1% 0.15% 0.15% - Total NMT Total maximum 0.3% - Impurity F 0.2% 0.6% - unspecified impurity Impurity D Impurity E 0.1% 0.2% 0.1% 0.1% 0.15% 0.15% 0.1% 0.2% 0.1% Total NMT Total maximum Total maximum 0.2% 0.2% 0.2% 0.5% Esomeprazole Magnesium Trihydrate 0.5% Impurity F 0.3% 0.5% MATERIAL IMPURITY CRITERION MATERIAL Esomeprazole Magnesium Anhydrous Esomeprazole Strotium Tetrahydrate and Anhydrous IMPURITY USP 40 BP 2016 EP 8.0 unspecified impurity Impurity D Impurity E 0.1% 0.2% 0.1% - - 0.5% - - Impurity F 0.2% - - unspecified impurity Impurity D Impurity S-binol 0.1% 0.1% 0.05% - - 0.3% - - 0.1% - - Total NMT Total NMT Impurity F IMPURITIES CRITERION IN PRODUCTS PRODUCT Esomeprazole Magnesium Delayed-release Capsule IMPURITY USP 40 BP 2016 EP 8.0 Impurity D 0.5% - - Any other individual impurity 0.2% - - - - Total NMT 2% RELATED IMPURITY TESTING METHOD Pharmacop oeia Monograph s USP 40 Esomeprazol e Strontium BP 2016 Esomeprazol e Magnesium Esomeprazole Magnesium Delayed- Release Capsules Esomeprazole Magnesium Method LC LC LC LC Stationary phase Packing L7 (Octyl silane) μm Packing L7 (Octyl silane) μm Packing L1 (Octadecyl silane) μm Octylsilyl silica gel for chromatography R μm Mobile phase Acetonitrile + phosphate buffer pH7.6 Acetonitrile + phosphate buffer pH 7.6 Acetonitrile + phosphate buffer pH7.6 UV at 280 nm UV at 280 nm UV at 302 nm Detection Run time/distan ce 4.5 times the retention time of Acetonitrile R+phosphate buffer pH 7.6 UV at 280 nm times the retention time of esomeprazole RELATED IMPURITY TESTING METHOD Pharmacop oeia USP 40 BP 2016 Esomeprazol e Magnesium Esomeprazole Magnesium Delayed- Release Capsules Column 4.6-mm ì 15cm; 5-àm 4.0-mm ì 12.5-cm or 4.6mm ì 15-cm; 5-àm 4.6-mm ì 10-cm; 3-àm Flow rate mL/min 0.8-1 mL/min mL/min 50µL 20 μl Monograph s Injection Column temperatur e Esomeprazol e Strontium 5µL 300 Esomeprazole Magnesium 4.6-mm × 12.5-cm mL/min 40 μl ENANTIOMER IMPURITY TESTING METHOD Pharmacop oeia Monograph s USP 40 Esomeprazole Strontium BP 2016 Esomeprazole Magnesium Esomeprazole Magnesium Method LC LC LC Stationary phase Packing L41 (Immobilized α1acid glycoprotein on spherical silica particles) μm Packing L7 L41 (Immobilized α1-acid glycoprotein on spherical silica particles) α1-acid-glycoprotein silica gel for chiral separation R μm Mobile phase Acetonitrile and phosphate buffer pH 6.5 Acetonitrile and phosphate buffer Acetonitrile R and phosphate buffer pH 6.0 Detection UV at 280 nm UV at 302 nm UV at 302 nm Run time/distan ce times the retention time of esomeprazole RELATED IMPURITY TESTING METHOD Pharmacop oeia USP 40 BP 2016 Monograph s Esomeprazol e Strontium Esomeprazole Magnesium Column 4.0-mm ì 15cm; 5-àm 4.0-mm ì 12.5cm or 4.6-mm × 15-cm; 5-µm 4.0-mm × 10-cm ; 5-µm Flow rate 0.8 mL/min 0.6 mL/min 0.6 mL/min 20µL 20 μl Injection Column temperatur e 5µL 300 Esomeprazole Magnesium SUMMARY The Universe in a Nutshell ESOMEPRAZOLE IMPURTIES A, B, C D, E F Sbinol DƯỢC ĐIỂN VIỆT NAM IV ? 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