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[求助]
硼替佐米原料药草案已有2人参与
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| 硼替佐米原料药草案里面现在的储存条件是密闭避光室温保存，但是现在按照这个草案做稳定性达不到要求（很多专利也明确说原料药不稳定），有没有哪位大神做过这个，确认一下，到底是草案还是工艺的问题！！！谢谢 |
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gwmgyp
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19楼2017-12-01 12:31:06
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BRIEFING Bortezomib. Because there is no existing USP monograph for this drug substance, a new monograph based on validated methods of analysis is proposed. The liquid chromatographic procedure used in the Assay and Organic Impurities test is based on analyses performed using the Waters Symmetry C18 brand of column with L1 packing. The typical retention time for bortezomib is about 10–14 min. (CHM3: F. Mao.) Correspondence Number—C159416 Comment deadline: January 31, 2017 Add the following: Bortezomib C19H25BN4O4 384.24 (boronic acid form) Boronic acid, [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]-; {(R)-3-Methyl-1-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid; N-[(1S)-1-Benzyl-2-[[(1R)-1-(dihydroxyboranyl)-3-methylbutyl]amino]-2-oxoethyl]pyrazinecarboxamide [179324-69- 7].C57H69B3N12O9 1098.67 (trimeric boroxine form) DEFINITION Bortezomib contains NLT 97.0% and NMT 103.0% of bortezomib (C19H25BN4O4), calculated on the anhydrous basis. IDENTIFICATION • A. Infrared Absorption 〈197〉: [Note—Methods described in 〈197K〉 or 〈197A〉 may be used.] • B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. ASSAY • Procedure Protect the solutions containing bortezomib from light and store at 2°–8° for NMT 7 days. Solution A: Acetonitrile, formic acid, and water (30: 0.1: 70) Solution B: Acetonitrile, formic acid, and water (80: 0.1: 20) Mobile phase: See Table 1. Return to original conditions, and equilibrate the system for 10 min. Table 1 Time (min) Solution A (%) Solution B (%) 0 100 0 15 100 0 30 0 100 45 0 100 Standard solution: 1.0 mg/mL of USP Bortezomib RS prepared as follows. Transfer USP Bortezomib RS into a suitable volumetric flask, add Solution B equivalent to 10% of the final volume, sonicate to dissolve, and dilute with Solution A to volume. Sample solution: 1.0 mg/mL of Bortezomib prepared as follows. Transfer Bortezomib into a suitable volumetric flask, add Solution B equivalent to 10% of the final volume, sonicate to dissolve, and dilute with Solution A to volume. Chromatographic system (See Chromatography 〈621〉, System Suitability.) Mode: LC Detector: UV 270 nm Column: 4.6-mm × 25-cm; 5-μm packing L1 Autosampler temperature: 5° Flow rate: 1.0 mL/min Injection volume: 20 μL System suitability Sample: Standard solution Suitability requirements Tailing factor: NMT 2.0 Relative standard deviation: NMT 1.1% Analysis Samples: Standard solution and Sample solution Calculate the percentage of bortezomib (C19H25BN4O4) in the portion of Bortezomib taken: Result = (rU/rS) × (CS/CU) ×100 rU = peak response from the Sample solution rS = peak response from the Standard solution CS = concentration of USP Bortezomib RS (trimeric boroxine form) in the Standard solution (mg/mL) CU = concentration of Bortezomib (trimeric boroxine form) in the Sample solution (mg/mL) Acceptance criteria: 97.0%–103.0% on the anhydrous basis IMPURITIES • Organic Impurities Protect the solutions containing bortezomib and bortezomib related compound A from light and store at 2°–8° for NMT 7 days. Solution A, Solution B, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay. Standard stock solution: Use the Standard solution from the Assay. Standard solution: 0.01 mg/mL of USP Bortezomib RS in Solution A, from Standard stock solution System suitability stock solution: 0.25 mg/mL of USP Bortezomib Related Compound A RS in Solution B System suitability solution: 0.01 mg/mL of USP Bortezomib Related Compound A RS and 1.0 mg/mL of USP Bortezomib RS prepared as follows. Transfer 1.0 mL of System suitability stock solution into a 25-mL volumetric flask and dilute with Standard solution to volume. Peak identification solution: Transfer 25 mg of USP Bortezomib RS into a 25-mL volumetric flask and add 3.0 mL of Solution B to dissolve. Add 15 mL of Solution A and 0.4 mL of hydrogen peroxide. Incubate this solution for 2 h at 70°. Cool to room temperature and dilute with Solution A to volume. Sensitivity solution: 0.5 μg/mL of USP Bortezomib RS in Solution B, from Standard solution System suitability Samples: System suitability solution and Sensitivity solution [Note—The relative retention times for bortezomib and bortezomib related compound A are 1.0 and 1.29, respectively.] Suitability requirements Resolution: NLT 2.0 between the bortezomib and bortezomib related compound A peaks, System suitability solution Signal-to-noise ratio: NLT 10, Sensitivity solution Analysis Samples: Sample solution, Standard solution, and Peak identification solution Inject Peak identification solution to identify peaks for bortezomib amide analog, (S,R)-bortezomib hydroxyisopentyl amide analog, (S,S)-bortezomib hydroxyisopentyl amide analog, and bortezomib R-hydroperoxide. Calculate the percentage of each impurity in the portion of Bortezomib taken: Result = (rU/rS) × (CS/CU) × (1/F) × 100 rU = peak response of each individual impurity from the Sample solution rS = peak response of bortezomib from the Standard solution CS = concentration of USP Bortezomib RS (trimeric boroxine form) in the Standard solution (mg/mL) CU = concentration of bortezomib (trimeric boroxine form) in the Sample solution (mg/mL) F = relative response factor for each impurity (see Table 2) Acceptance criteria: See Table 2. Disregard any peak less than 0.05%. Table 2 Name Relative Retention Time Relative Response Factor Acceptance Criteria, NMT (%) Bortezomib desphenylalanyl analoga 0.38 1.7 0.20 Bortezomib amide analogb 0.43 1.5 0.20 Hydroxybortezomibc 0.66 1.0 0.20 Bortezomib acid analogd 0.77 1.4 0.1 Bortezomib N-formyl analoge and bortezomib hydroxyketone analogf 0.89 1.0 0.20 Bortezomib 1.00 — — Bortezomib diastereomer (S,S)g and bortezomib diastereomer (R,R)h 1.29 0.92 0.50 (S,R)-Bortezomib hydroxyisopentyl amide analogi and (S,S)-bortezomib hydroxyisopentyl amide analogj 1.50, 1.82 1.1 0.45k Bortezomib R-hydroperoxidel and bortezomib S-hydroperoxidem 1.87, 2.02 1.0 0.65n Bortezomib l-phenylalanyl analogo 2.01 0.67 0.1 Bortezomib d-phenylalanyl analogp 2.07 0.66 0.1 Any individual unspecified impurity — 1.0 0.1 Total impurities — — 1.8 a (R)-[3-Methyl-1-(pyrazine-2-carboxamido)butyl]boronic acid. b N-(1-Amino-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide. c {(R)-3-Hydroxy-3-methyl-1-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. d (S)-3-Phenyl-2-(pyrazine-2-carboxamido)propanoic acid. e (S)-N-(1-Formamido-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide. f (S)-N-[1-(3-Hydroxy-3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. g {(S)-3-Methyl-1-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. h {(R)-3-Methyl-1-[(R)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. It is bortezomib related compound A. i N-[(S)-1-{[(R)-1-Hydroxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. j N-[(S)-1-{[(S)-1-Hydroxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. k It is the sum of (S,R)-bortezomib hydroxyisopentyl amide analog and (S,S)-bortezomib hydroxyisopentyl amide analog. l N-[(S)-1-{[(R)-1-Hydroperoxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. m N-[(S)-1-{[(S)-1-Hydroperoxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. n It is the sum of the bortezomib R-hydroperoxide and bortezomib S-hydroperoxide. o [(R)-3-Methyl-1-{(S)-3-phenyl-2-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]propanamido}butyl]boronic acid. p [(R)-3-Methyl-1-{(S)-3-phenyl-2-[(R)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]propanamido}butyl]boronic acid. SPECIFIC TESTS • Water Determination 〈921〉, Method I, Method Ic: NMT 1.5% • Optical Rotation 〈781S〉, Procedures, Specific Rotation Sample solution: 5 mg/mL in methanol Acceptance criteria: −49.5° to −54.0° • Bacterial Endotoxins Test 〈85〉: It contains NMT 16 USP Endotoxin Units/mg ADDITIONAL REQUIREMENTS • Packaging and Storage: Preserve in well-closed containers. Store at room temperature and protect from light. • USP Reference Standards 〈11〉 USP Bortezomib RS [Note—It exists in trimeric boroxine form.] USP Bortezomib Related Compound A RS {(R)-3-Methyl-1-[(R)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. C57H69B3N12O9 1098.67 [Note—It exists in trimeric boroxine form.] Auxiliary Information - Please check for your question in the FAQs before contacting USP. USP41 |
7楼2017-11-30 13:20:23
浆果0906
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2楼2017-11-24 11:51:08
3楼2017-11-30 13:10:32
浆果0906
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- 专业: 有机合成
4楼2017-11-30 13:12:03
gwmgyp
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- DRDEPI: 8
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5楼2017-11-30 13:14:39
gwmgyp
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- DRDEPI: 8
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- 专业: 药物分析
- 管辖: 新药研发
6楼2017-11-30 13:19:55
|
不行行你看看把！！ BRIEFING Bortezomib. Because there is no existing USP monograph for this drug substance, a new monograph based on validated methods of analysis is proposed. The liquid chromatographic procedure used in the Assay and Organic Impurities test is based on analyses performed using the Waters Symmetry C18 brand of column with L1 packing. The typical retention time for bortezomib is about 10–14 min. (CHM3: F. Mao.) Correspondence Number—C159416 Comment deadline: January 31, 2017 Add the following: Bortezomib C19H25BN4O4 384.24 (boronic acid form) Boronic acid, [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]-; {(R)-3-Methyl-1-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid; N-[(1S)-1-Benzyl-2-[[(1R)-1-(dihydroxyboranyl)-3-methylbutyl]amino]-2-oxoethyl]pyrazinecarboxamide [179324-69- 7].C57H69B3N12O9 1098.67 (trimeric boroxine form) DEFINITION Bortezomib contains NLT 97.0% and NMT 103.0% of bortezomib (C19H25BN4O4), calculated on the anhydrous basis. IDENTIFICATION • A. Infrared Absorption 〈197〉: [Note—Methods described in 〈197K〉 or 〈197A〉 may be used.] • B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. ASSAY • Procedure Protect the solutions containing bortezomib from light and store at 2°–8° for NMT 7 days. Solution A: Acetonitrile, formic acid, and water (30: 0.1: 70) Solution B: Acetonitrile, formic acid, and water (80: 0.1: 20) Mobile phase: See Table 1. Return to original conditions, and equilibrate the system for 10 min. Table 1 Time (min) Solution A (%) Solution B (%) 0 100 0 15 100 0 30 0 100 45 0 100 Standard solution: 1.0 mg/mL of USP Bortezomib RS prepared as follows. Transfer USP Bortezomib RS into a suitable volumetric flask, add Solution B equivalent to 10% of the final volume, sonicate to dissolve, and dilute with Solution A to volume. Sample solution: 1.0 mg/mL of Bortezomib prepared as follows. Transfer Bortezomib into a suitable volumetric flask, add Solution B equivalent to 10% of the final volume, sonicate to dissolve, and dilute with Solution A to volume. Chromatographic system (See Chromatography 〈621〉, System Suitability.) Mode: LC Detector: UV 270 nm Column: 4.6-mm × 25-cm; 5-μm packing L1 Autosampler temperature: 5° Flow rate: 1.0 mL/min Injection volume: 20 μL System suitability Sample: Standard solution Suitability requirements Tailing factor: NMT 2.0 Relative standard deviation: NMT 1.1% Analysis Samples: Standard solution and Sample solution Calculate the percentage of bortezomib (C19H25BN4O4) in the portion of Bortezomib taken: Result = (rU/rS) × (CS/CU) ×100 rU = peak response from the Sample solution rS = peak response from the Standard solution CS = concentration of USP Bortezomib RS (trimeric boroxine form) in the Standard solution (mg/mL) CU = concentration of Bortezomib (trimeric boroxine form) in the Sample solution (mg/mL) Acceptance criteria: 97.0%–103.0% on the anhydrous basis IMPURITIES • Organic Impurities Protect the solutions containing bortezomib and bortezomib related compound A from light and store at 2°–8° for NMT 7 days. Solution A, Solution B, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay. Standard stock solution: Use the Standard solution from the Assay. Standard solution: 0.01 mg/mL of USP Bortezomib RS in Solution A, from Standard stock solution System suitability stock solution: 0.25 mg/mL of USP Bortezomib Related Compound A RS in Solution B System suitability solution: 0.01 mg/mL of USP Bortezomib Related Compound A RS and 1.0 mg/mL of USP Bortezomib RS prepared as follows. Transfer 1.0 mL of System suitability stock solution into a 25-mL volumetric flask and dilute with Standard solution to volume. Peak identification solution: Transfer 25 mg of USP Bortezomib RS into a 25-mL volumetric flask and add 3.0 mL of Solution B to dissolve. Add 15 mL of Solution A and 0.4 mL of hydrogen peroxide. Incubate this solution for 2 h at 70°. Cool to room temperature and dilute with Solution A to volume. Sensitivity solution: 0.5 μg/mL of USP Bortezomib RS in Solution B, from Standard solution System suitability Samples: System suitability solution and Sensitivity solution [Note—The relative retention times for bortezomib and bortezomib related compound A are 1.0 and 1.29, respectively.] Suitability requirements Resolution: NLT 2.0 between the bortezomib and bortezomib related compound A peaks, System suitability solution Signal-to-noise ratio: NLT 10, Sensitivity solution Analysis Samples: Sample solution, Standard solution, and Peak identification solution Inject Peak identification solution to identify peaks for bortezomib amide analog, (S,R)-bortezomib hydroxyisopentyl amide analog, (S,S)-bortezomib hydroxyisopentyl amide analog, and bortezomib R-hydroperoxide. Calculate the percentage of each impurity in the portion of Bortezomib taken: Result = (rU/rS) × (CS/CU) × (1/F) × 100 rU = peak response of each individual impurity from the Sample solution rS = peak response of bortezomib from the Standard solution CS = concentration of USP Bortezomib RS (trimeric boroxine form) in the Standard solution (mg/mL) CU = concentration of bortezomib (trimeric boroxine form) in the Sample solution (mg/mL) F = relative response factor for each impurity (see Table 2) Acceptance criteria: See Table 2. Disregard any peak less than 0.05%. Table 2 Name Relative Retention Time Relative Response Factor Acceptance Criteria, NMT (%) Bortezomib desphenylalanyl analoga 0.38 1.7 0.20 Bortezomib amide analogb 0.43 1.5 0.20 Hydroxybortezomibc 0.66 1.0 0.20 Bortezomib acid analogd 0.77 1.4 0.1 Bortezomib N-formyl analoge and bortezomib hydroxyketone analogf 0.89 1.0 0.20 Bortezomib 1.00 — — Bortezomib diastereomer (S,S)g and bortezomib diastereomer (R,R)h 1.29 0.92 0.50 (S,R)-Bortezomib hydroxyisopentyl amide analogi and (S,S)-bortezomib hydroxyisopentyl amide analogj 1.50, 1.82 1.1 0.45k Bortezomib R-hydroperoxidel and bortezomib S-hydroperoxidem 1.87, 2.02 1.0 0.65n Bortezomib l-phenylalanyl analogo 2.01 0.67 0.1 Bortezomib d-phenylalanyl analogp 2.07 0.66 0.1 Any individual unspecified impurity — 1.0 0.1 Total impurities — — 1.8 a (R)-[3-Methyl-1-(pyrazine-2-carboxamido)butyl]boronic acid. b N-(1-Amino-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide. c {(R)-3-Hydroxy-3-methyl-1-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. d (S)-3-Phenyl-2-(pyrazine-2-carboxamido)propanoic acid. e (S)-N-(1-Formamido-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide. f (S)-N-[1-(3-Hydroxy-3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. g {(S)-3-Methyl-1-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. h {(R)-3-Methyl-1-[(R)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. It is bortezomib related compound A. i N-[(S)-1-{[(R)-1-Hydroxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. j N-[(S)-1-{[(S)-1-Hydroxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. k It is the sum of (S,R)-bortezomib hydroxyisopentyl amide analog and (S,S)-bortezomib hydroxyisopentyl amide analog. l N-[(S)-1-{[(R)-1-Hydroperoxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. m N-[(S)-1-{[(S)-1-Hydroperoxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide. n It is the sum of the bortezomib R-hydroperoxide and bortezomib S-hydroperoxide. o [(R)-3-Methyl-1-{(S)-3-phenyl-2-[(S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]propanamido}butyl]boronic acid. p [(R)-3-Methyl-1-{(S)-3-phenyl-2-[(R)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]propanamido}butyl]boronic acid. SPECIFIC TESTS • Water Determination 〈921〉, Method I, Method Ic: NMT 1.5% • Optical Rotation 〈781S〉, Procedures, Specific Rotation Sample solution: 5 mg/mL in methanol Acceptance criteria: −49.5° to −54.0° • Bacterial Endotoxins Test 〈85〉: It contains NMT 16 USP Endotoxin Units/mg ADDITIONAL REQUIREMENTS • Packaging and Storage: Preserve in well-closed containers. Store at room temperature and protect from light. • USP Reference Standards 〈11〉 USP Bortezomib RS [Note—It exists in trimeric boroxine form.] USP Bortezomib Related Compound A RS {(R)-3-Methyl-1-[(R)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido]butyl}boronic acid. C57H69B3N12O9 1098.67 [Note—It exists in trimeric boroxine form.] Auxiliary Information - Please check for your question in the FAQs before contacting USP. USP41 |
8楼2017-11-30 13:21:11
gwmgyp
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9楼2017-11-30 14:38:58
gwmgyp
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- DRDEPI: 8
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10楼2017-11-30 14:40:48
5