这个原料药是不稳定的，至少应该是冷冻保存

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2楼: Originally posted by 浆果0906 at 2017-11-24 11:51:08
这个原料药是不稳定的，至少应该是冷冻保存

但是现在FDA草案里面就是室温密闭避光保存，我们自己按照草案那样保存，稳定性一个月都达不到，同时测水分，但是测水分的时候硼酸要是指示剂反应，不知道为什么草案这样弄。草案会不会有错误？

不明白你说的FDA草案是什么？这个原料本身性质就是不稳定的

楼主所见草案太奇怪了吧？FDA与EMA上都明确说了冷冻保存的！

楼主所说刚好是原研制剂的贮存条件！呵呵！

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5楼: Originally posted by gwmgyp at 2017-11-30 13:14:39
楼主所见草案太奇怪了吧？FDA与EMA上都明确说了冷冻保存的！

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

引用回帖:

5楼: Originally posted by gwmgyp at 2017-11-30 13:14:39
楼主所见草案太奇怪了吧？FDA与EMA上都明确说了冷冻保存的！

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
，