CN115364048A - Preparation method of brivaracetam injection - Google Patents
Preparation method of brivaracetam injection Download PDFInfo
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- CN115364048A CN115364048A CN202211083399.5A CN202211083399A CN115364048A CN 115364048 A CN115364048 A CN 115364048A CN 202211083399 A CN202211083399 A CN 202211083399A CN 115364048 A CN115364048 A CN 115364048A
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- brivaracetam
- injection
- solution
- preparation
- nitrogen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 229940054133 brivaracetam injection Drugs 0.000 title claims abstract description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 45
- 229960002161 brivaracetam Drugs 0.000 claims abstract description 40
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 claims abstract description 40
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 30
- 239000000243 solution Substances 0.000 claims abstract description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000008215 water for injection Substances 0.000 claims abstract description 20
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims abstract description 19
- 235000019799 monosodium phosphate Nutrition 0.000 claims abstract description 19
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 18
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 16
- 239000011780 sodium chloride Substances 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 239000002033 PVDF binder Substances 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 239000012528 membrane Substances 0.000 claims abstract description 9
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims abstract description 9
- 230000001954 sterilising effect Effects 0.000 claims abstract description 9
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 9
- 238000010926 purge Methods 0.000 claims abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 4
- 229940090044 injection Drugs 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000000337 buffer salt Substances 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000003860 storage Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000001502 supplementing effect Effects 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 231100001124 band 1 compound Toxicity 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of brivaracetam injection, which comprises the following steps: a. adding water for injection into a preparation container, cooling to below 30 ℃, and continuously introducing nitrogen into the solution; b. adding the sodium dihydrogen phosphate and the sodium chloride with the prescription amount into the solution a, and stirring for dissolving; c. adding brivaracetam in a prescription amount into the solution b, and stirring to dissolve; d. adjusting pH to 5.0-6.0 with phosphoric acid or sodium hydroxide; e. supplementing water for injection; f. filtering with 0.2 μm PVDF filter membrane, filling, purging with nitrogen curtain, and plugging; g.121 ℃ moist heat sterilization to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml. The invention continuously introduces nitrogen, which is beneficial to the subsequent stability of the product; and the buffer salt is most stable by adopting a sodium dihydrogen phosphate and phosphoric acid system, so that the impurity level of the brivaracetam injection can be kept low during storage.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of brivaracetam injection.
Background
Brivaracetam (also known as brivaracetam) is a white or off-white crystalline powder, and is a BCS class I drug. The European Medicine Administration (EMA) and the U.S. Food and Drug Administration (FDA) have respective trade names of Brivaracetam (BRV), a third-generation antiepileptic drug developed by UCB of Belgium, 2016 and 18 months, 2016, and
can be used for treating partial seizure type epilepsy patients of 16 years old or older, with or without secondary systemic seizure as adjuvant therapy. The brivaracetam has high bioavailability and short peak reaching time, can reach stable blood concentration within one week after repeated administration, and the absorption of the brivaracetam is not influenced by food. The good pharmacological activity, clinical curative effect and safety of the brivaracetam are expected to become a second-pound antiepileptic drug after levetiracetam. The existing commercially available preparations are brivaracetam tablets, brivaracetam oral liquid and brivaracetam injection.
CN102046153 discloses a pharmaceutical composition containing brivaracetam, mainly relates to a prolonged drug release preparation, and teaches a solid preparation for achieving sustained release of the drug by adding various auxiliary materials. CN101945647 discloses a pharmaceutical solution, a preparation method and a therapeutic application, mainly teaching the stability difference of brivaracetam and cetroratam in solutions with different pH, but the patent does not further screen the composition of auxiliary materials and the types of buffer salts in the solutions, nor elaborates the preparation process, and only describes the prescription and the preparation process in a simple manner by way of one example. According to relevant documents, the brivaracetam has non-corresponding isomers SS-BRV and RR-BRV and corresponding isomers RS-BRV, the isomers of brivaracetam have no pharmacological activity, and the brivaracetam is converted into other isomers to different degrees under different pH, oxygen-containing conditions and different temperature conditions. Therefore, different preparation processes and buffer salts have great influence on the stability of the brivaracetam injection. Therefore, there is still a need to provide a complete formulation and preparation process to ensure that the impurity level of the brivaracetam injection is kept low during storage.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the defects of the prior art, the invention provides a preparation method of a brivaracetam injection.
The technical scheme is as follows: a preparation method of brivaracetam injection comprises the following components by weight per 1000ml of injection: 10g of brivaracetam, 1.64g of sodium dihydrogen phosphate, 9g of sodium chloride and a proper amount of phosphoric acid or sodium hydroxide to adjust the pH value to 5.0-6.0, wherein the preparation method comprises the following steps:
a. adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, and continuously introducing nitrogen into the solution;
b. adding the sodium dihydrogen phosphate and the sodium chloride with the prescription amount into the solution a, and stirring for dissolving;
c. adding brivaracetam in a prescription amount into the solution b, and stirring to dissolve;
d. adjusting pH to 5.0-6.0 with phosphoric acid or sodium hydroxide;
e. adding the water for injection to 1000ml;
f. filtering with 0.2 μm PVDF filter membrane, filling, purging with nitrogen curtain, and plugging;
g.121 ℃ moist heat sterilization to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
As optimization, nitrogen is continuously introduced into the solution in the preparation process, and the dissolved oxygen of the solution is controlled to be lower than 5 percent.
As optimization, the buffer system adopted in the preparation process is sodium dihydrogen phosphate and phosphoric acid buffer solution.
As optimization, the brivaracetam injection is purged by a nitrogen curtain before and after filling and then plugged, so that the lower headspace residual oxygen level is ensured.
Has the advantages that: the invention continuously introduces nitrogen when preparing and filling the brivaracetam injection, which is beneficial to the subsequent stability of the product; and the buffer salt is most stable by adopting a sodium dihydrogen phosphate and phosphoric acid system, so that the impurity level of the brivaracetam injection can be kept low during storage.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below so that those skilled in the art can better understand the advantages and features of the present invention, and thus the scope of the present invention will be more clearly defined. The embodiments described herein are only a few embodiments of the present invention, rather than all embodiments, and all other embodiments that can be derived by one of ordinary skill in the art based on the embodiments described herein are intended to be within the scope of the present invention.
Examples
The inventor finds that the change of the type of the buffer salt in the formula has great influence on the subsequent stability of the finished brivaracetam product, and by comparison, the impurity change levels of the finished brivaracetam injection in the stable storage process are different by using sodium acetate, citric acid, sodium dihydrogen phosphate and no buffer salt, wherein the total impurity content detected after the finished brivaracetam injection with the sodium dihydrogen phosphate is influenced for 10 days (high temperature 60 ℃ and illumination) is the lowest.
The inventors have found, by study, that brivaracetam is unstable under oxidizing conditions, 30% H 2 O 2 Under the condition, the total impurities are greatly increased, so that the brivaracetam injection with lower impurity content can be obtained by introducing nitrogen into the solution to control the residual oxygen amount in the solution in the preparation process.
Therefore, the invention provides a more stable preparation method of brivaracetam injection, and each 1000ml of injection contains the following components by weight: 10g of brivaracetam, 1.64g of sodium dihydrogen phosphate, 9g of sodium chloride and a proper amount of phosphoric acid or sodium hydroxide are used for adjusting the pH value to 5.0-6.0.
The preparation method comprises the following steps:
a. adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, continuously introducing nitrogen into the solution, and controlling the dissolved oxygen to be lower than 5%;
b. adding the sodium dihydrogen phosphate and the sodium chloride with the prescription amount into the solution a, and stirring for dissolving;
c. adding brivaracetam in a prescription amount into the solution b, and stirring to dissolve;
d. adjusting pH to 5.0-6.0 with phosphoric acid or sodium hydroxide;
e. adding water for injection to 1000ml;
f. filtering with 0.2 μm PVDF filter membrane, filling, purging with nitrogen curtain, and plugging;
g.121 ℃ moist heat sterilization to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
Comparative example 1
Table 1 ingredient usage table of comparative example 1
| Composition (I) | Dosage (g) |
| Brivaracetam | 10.0 |
| Sodium dihydrogen phosphate | 1.64 |
| Phosphoric acid | Proper amount of |
| Sodium chloride | 9 |
| Sodium hydroxide | Proper amount of |
| Water for injection | Proper amount of |
| Total amount of | 1000.0 |
The preparation method comprises the following steps: adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, adding sodium dihydrogen phosphate and sodium chloride according to the prescription amount, and stirring for dissolving; adding brivaracetam in a prescription amount into the solution, and stirring to dissolve; adjusting pH to 5.0-6.0 with phosphoric acid or sodium hydroxide, and adding water for injection to 1000ml; filtering with 0.2 μm PVDF filter membrane, filling and plugging, and performing moist heat sterilization at 121 ℃ to obtain brivaracetam injection containing 10mg brivaracetam per 1 ml.
Comparative example 2
Table 2 ingredient amount table of comparative example 2
The preparation method comprises the following steps: adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, continuously introducing nitrogen into the solution, and controlling the dissolved oxygen to be lower than 5%; adding the sodium acetate and the sodium chloride with the prescription amount, and stirring for dissolving; adding brivaracetam in a prescription amount into the solution, and stirring to dissolve; adjusting pH to 5.0-6.0 with glacial acetic acid or sodium hydroxide, and adding injectable water to 1000ml; filtering with 0.2 μm PVDF filter membrane, filling, purging with nitrogen curtain, and plugging; performing moist heat sterilization at 121 ℃ to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
Comparative example 3
Table 3 ingredient usage table for comparative example 3
| Composition (I) | Dosage (g) |
| Brivaracetam | 10.0 |
| Citric acid | 1.64 |
| Sodium chloride | 9 |
| Sodium hydroxide | Proper amount of |
| Water for injection | Proper amount of |
| Total amount of | 1000.0 |
The preparation method comprises the following steps: adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, continuously introducing nitrogen into the solution, and controlling the dissolved oxygen to be lower than 5%; adding citric acid and sodium chloride according to the prescription amount, and stirring for dissolving; adding brivaracetam in a prescription amount into the solution, and stirring to dissolve; adjusting pH to 5.0-6.0 with sodium hydroxide, and adding water for injection to 1000ml; filtering with 0.2 μm PVDF filter membrane, filling after filtering, purging with nitrogen curtain before and after filling, and plugging; performing moist heat sterilization at 121 ℃ to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
Comparative example 4
Table 4 ingredient dosage table for comparative example 4
The preparation method comprises the following steps: adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, continuously introducing nitrogen into the solution, and controlling the dissolved oxygen to be lower than 5%; adding the sodium chloride with the prescription amount, and stirring for dissolving; adding brivaracetam in a prescription amount into the solution, and stirring to dissolve; adjusting pH to 5.0-6.0 with hydrochloric acid and sodium hydroxide, and adding water for injection to 1000ml; filtering with 0.2 μm PVDF filter membrane, filling, purging with nitrogen curtain, and plugging; performing moist heat sterilization at 121 ℃ to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
Example 1
TABLE 5 ingredient usage table of example 1
| Composition (A) | Dosage (g) |
| Brivaracetam | 10.0 |
| Sodium dihydrogen phosphate | 1.64 |
| Phosphoric acid | Proper amount of |
| Sodium chloride | 9 |
| Sodium hydroxide | Proper amount of |
| Water for injection | Proper amount of |
| Total amount of | 1000.0 |
The preparation method comprises the following steps: adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, continuously introducing nitrogen into the solution, and controlling the dissolved oxygen to be lower than 5%; adding the sodium dihydrogen phosphate and the sodium chloride with the prescription amount, and stirring for dissolving; adding brivaracetam in a prescription amount into the solution, and stirring to dissolve; adjusting pH to 5.0-6.0 with phosphoric acid or sodium hydroxide, and adding water for injection to 1000ml; filtering with 0.2 μm PVDF filter membrane, filling after filtering, purging with nitrogen curtain before and after filling, and plugging; performing moist heat sterilization at 121 ℃ to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
The samples of comparative example 1, comparative example 2, comparative example 3, comparative example 4 and example 1 were subjected to the influence factor test, and the test results are shown in tables 6 and 7, respectively, by high performance liquid chromatography under high temperature of 60 ℃ and light.
TABLE 6 examination results of related substances at 60 deg.C
TABLE 7 examination results of the relevant substances under light conditions
The test results of the present invention were analyzed as follows:
1. under the condition of high temperature of 60 ℃, compared with a 10-day sample and a 0-day sample, the impurity increase amplitude of the combination without nitrogen filling and the combination without buffer salt is obviously higher than that of other groups; secondly, the related substances of the citric acid composition and the sodium acetate composition which are impurities are all larger than those of the sodium dihydrogen phosphate composition.
2. Compared with the sample of 0 day, the sample of 10 days under the illumination condition has slightly increased related substances of the system without nitrogen filling and buffer salt, and the rest groups have no obvious change.
From the above results analysis, the following conclusions can be drawn: in the combination related to the test, the sample is inspected for related substances under the conditions of high temperature and illumination, and the result shows that the subsequent stability of the product is facilitated by nitrogen filling in the preparation and filling processes; the buffer salt is most stable with sodium dihydrogen phosphate and phosphoric acid systems.
Claims (4)
1. A preparation method of brivaracetam injection comprises the following components by weight per 1000ml of injection: 10g of brivaracetam, 1.64g of sodium dihydrogen phosphate, 9g of sodium chloride and a proper amount of phosphoric acid or sodium hydroxide are used for adjusting the pH value to 5.0-6.0, and the method is characterized in that: the preparation method comprises the following steps:
a. adding 800ml of water for injection into a preparation container, cooling to below 30 ℃, and continuously introducing nitrogen into the solution;
b. adding the sodium dihydrogen phosphate and the sodium chloride with the prescription amount into the solution a, and stirring for dissolving;
c. adding brivaracetam in a prescription amount into the solution b, and stirring to dissolve;
d. adjusting pH to 5.0-6.0 with phosphoric acid or sodium hydroxide;
e. adding water for injection to 1000ml;
f. filtering with 0.2 μm PVDF filter membrane, filling, purging with nitrogen curtain, and plugging;
g.121 ℃ moist heat sterilization to obtain the brivaracetam injection containing 10mg brivaracetam per 1 ml.
2. The method for preparing a brivaracetam injection according to claim 1, wherein: in the preparation process, nitrogen is continuously introduced into the solution, and the dissolved oxygen of the solution is controlled to be lower than 5 percent.
3. The method for preparing a brivaracetam injection according to claim 1, wherein: the buffer system adopted in the preparation process is sodium dihydrogen phosphate and phosphoric acid buffer solution.
4. The method for preparing brivaracetam injection according to claim 1, wherein the method comprises the following steps: the brivaracetam injection is purged by a nitrogen curtain before and after filling, and then is plugged, so that the lower headspace residual oxygen level is ensured.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211083399.5A CN115364048A (en) | 2022-09-06 | 2022-09-06 | Preparation method of brivaracetam injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211083399.5A CN115364048A (en) | 2022-09-06 | 2022-09-06 | Preparation method of brivaracetam injection |
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| CN115364048A true CN115364048A (en) | 2022-11-22 |
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| CN202211083399.5A Withdrawn CN115364048A (en) | 2022-09-06 | 2022-09-06 | Preparation method of brivaracetam injection |
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| Country | Link |
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- 2022-09-06 CN CN202211083399.5A patent/CN115364048A/en not_active Withdrawn
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Application publication date: 20221122 |
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| WW01 | Invention patent application withdrawn after publication |