CN113577317A - Preparation method of sterile amoxicillin - Google Patents

Preparation method of sterile amoxicillin Download PDF

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Publication number
CN113577317A
CN113577317A CN202110872791.7A CN202110872791A CN113577317A CN 113577317 A CN113577317 A CN 113577317A CN 202110872791 A CN202110872791 A CN 202110872791A CN 113577317 A CN113577317 A CN 113577317A
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Prior art keywords
amoxicillin
sterile
sterilization
preparation
filtration
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CN202110872791.7A
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Chinese (zh)
Inventor
黄国明
张民
严正人
郝小良
周宏宇
马玉哲
赵艳青
任玥蓉
周玉敏
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North China Pharmaceutical Group Xiantai Pharmaceutical Co ltd
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North China Pharmaceutical Group Xiantai Pharmaceutical Co ltd
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Priority to CN202110872791.7A priority Critical patent/CN113577317A/en
Publication of CN113577317A publication Critical patent/CN113577317A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0017—Filtration
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20—Targets to be treated
    • A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention provides a preparation method of sterile amoxicillin. The preparation method of the sterile amoxicillin provided by the invention comprises the following steps: firstly, amoxicillin is put into water to prepare amoxicillin suspension; then, acidifying and dissolving the amoxicillin suspension at the pH value of 0.5-1.5 by using hydrochloric acid to obtain an amoxicillin acidified solution; then, performing sterilization filtration on the amoxicillin acidizing fluid by using a sterilization filtration filter element, and performing sterilization filtration on the alkali liquor by using the sterilization filtration filter element; and adding the alkali liquor subjected to sterilization and filtration into the amoxicillin acidizing solution subjected to sterilization and filtration, and adjusting the pH value of the amoxicillin acidizing solution to an isoelectric point for crystallization, wherein the pH value at the end of crystallization is controlled to be 4.5-6.0. The sterile amoxicillin prepared by the method has less impurities and whiter appearance color.

Description

Preparation method of sterile amoxicillin
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of sterile amoxicillin.
Background
Amoxicillin, also known as amoxicillin, is one of the most commonly used broad-spectrum beta-lactam antibiotics of the semi-synthetic penicillins. Is stable under acidic condition, and the gastrointestinal absorption rate is up to 90%. The amoxicillin has strong bactericidal effect and strong capability of penetrating cell membranes, and is one of the oral semi-synthetic penicillins which are widely applied at present. The preparation can be capsule, tablet, granule, dispersible tablet, etc.
Aiming at the amoxicillin injection administration route, two products are provided, namely amoxicillin sodium and sterile amoxicillin. The amoxicillin sodium is a mainstream product in the market, and amoxicillin is converted into a sodium salt, but the stability of amoxicillin is poor under an alkaline condition. The production of the amoxicillin sodium uses an organic solvent, which is not beneficial to environmental protection. The aseptic amoxicillin is the amoxicillin for injection which keeps the original state of the amoxicillin by an aseptic production process without sodium salt conversion.
The sterile amoxicillin which is on the market at present is generally prepared by adopting an ethylene oxide chemical sterilization process or an irradiation sterilization process.
The ethylene oxide sterilization process has the advantage of good sterilization effect on medical instruments, but the sterilization reliability of solid medicine powder is questioned, and the recent aseptic production guidelines of the European Union do not support the sterilization of solid powder by using ethylene oxide. Furthermore, ethylene oxide is a carcinogen and the residue needs to be strictly controlled.
The mechanism of gamma ray radiation sterilization is that the irradiated matter is oxidized or generates free radicals, which act on the powder to break the hydrogen bond, oxidize the double bond, destroy the ring structure or polymerize some powder, etc. to destroy and change the structure of the biological macro molecule, so as to inhibit or kill microbes. This process inevitably entails the simultaneous destruction and degradation of amoxicillin.
Therefore, a safe, environment-friendly and reliable aseptic amoxicillin production process is needed in the market.
Disclosure of Invention
The invention aims to provide a preparation method of sterile amoxicillin, which adopts a sterile filtration production process route to obtain the sterile amoxicillin and is a safe, environment-friendly and reliable sterile amoxicillin production process.
Aiming at the aseptic amoxicillin in the market, the invention provides a new aseptic production route of amoxicillin, which comprises the following steps: and (3) producing the sterile amoxicillin by adopting a sterilization and filtration mode. The aseptic amoxicillin produced by the sterilization process needs to filter materials with strong acid and strong alkali properties, and a proper filter material needs to be selected in the filtering process, so that the filter material is prevented from being damaged by the strong corrosive materials. Parameters such as process concentration, pH, temperature and the like need to be optimized, so that the corrosivity of materials is weakened, the degradation of the product is reduced, the problems that the product is harmful to aseptic realization and the health of users due to the degradation of the product are solved, and the balance between quality and cost is achieved.
The technical scheme adopted by the invention is as follows: a preparation method of sterile amoxicillin comprises the following steps:
a. placing amoxicillin in water to prepare an amoxicillin suspension;
b. acidifying the amoxicillin suspension by using hydrochloric acid to obtain an amoxicillin acidified solution with the pH value of 0.5-1.5;
c. adopting a sterilization filter element to perform sterilization filtration on the amoxicillin acidizing fluid and the alkali liquor; the amoxicillin acidification liquid is sterilized and filtered later than the alkali liquor, or the two are simultaneously sterilized and filtered, so as to avoid the degradation of the amoxicillin acidification liquid.
d. And adding the alkali liquor subjected to sterilization and filtration into the amoxicillin acidizing solution subjected to sterilization and filtration, adjusting the pH value of the amoxicillin acidizing solution to crystallize, controlling the pH value at the end point of crystallization to be 4.5-6.0, and finally cooling, filtering, drying, grinding, subpackaging and the like the amoxicillin crystallized solution to form a sterile amoxicillin product.
In the step a, the weight ratio of amoxicillin to water is 1: 8-20.
In the steps a-d, the temperature is controlled to be 5-30 ℃.
And in the step b, acidifying the amoxicillin suspension to obtain an amoxicillin acidified solution with the pH of 0.7-1.3.
In the step d, the pH value of the crystallization end point is controlled to be 5.0-5.5.
In the step c, the amoxicillin acidizing fluid is subjected to sterilization filtration by adopting an acid-resistant sterilization filtration filter element made of polytetrafluoroethylene, polycarbonate or polyether sulfone.
And c, before the amoxicillin acidizing fluid is subjected to sterilization filtration, clarifying and filtering the amoxicillin acidizing fluid by adopting a 0.4-1.0 micron filter membrane, and then performing sterilization filtration on the amoxicillin acidizing fluid by adopting a sterilization filtration filter element.
In the step c, the alkali liquor is subjected to sterilization filtration by adopting an alkali-resistant sterilization filtration filter element made of polytetrafluoroethylene, polyvinylidene fluoride, polyether sulfone or nylon.
In the step c, the aperture of the sterilizing filter element is less than or equal to 0.22 micron.
In the step c, the alkali liquor is sodium hydroxide solution or ammonia water.
The aseptic amoxicillin obtained by the sterilization and filtration process has white-like appearance color, meets the requirements of the international mainstream pharmacopoeia, and is far superior to the appearance color of the irradiation sterilization product. Moreover, compared with ethylene oxide sterilization, the production process of the invention has higher sterility guarantee degree, eliminates the degradation and ethylene oxide residue in the ethylene oxide sterilization process and has better quality condition.
Detailed Description
The following are some specific embodiments of the present invention, which are provided for further detailed description of the present invention, but not for limiting the scope of the present invention.
The preparation method of the sterile amoxicillin provided by the invention comprises the following steps:
firstly, amoxicillin and water are prepared into suspension. The weight ratio of amoxicillin to water is 1: 8-20.
And then, acidifying the amoxicillin suspension by using hydrochloric acid to obtain an amoxicillin acidified solution with the pH value of 0.5-1.5. The preferable pH value is 0.7-1.3.
And then, performing sterilization filtration on the amoxicillin acidized fluid and the alkali liquor by using a sterilization filtration filter element. The amoxicillin acidizing fluid is sterilized and filtered by an acid-resistant sterilization filter element with a filter membrane made of polytetrafluoroethylene, polycarbonate, polyethersulfone or the like. The alkaline liquid sterilization filtration can use an alkaline-resisting sterilization filter element with a filter membrane made of polytetrafluoroethylene or polyvinylidene fluoride or polyethersulfone or nylon.
And adding the amoxicillin hydrochloride solution subjected to sterilization and filtration into the alkali liquor subjected to sterilization and filtration to adjust the pH value for crystallization. The alkali solution can be sodium hydroxide solution or ammonia water. The pH at the end of crystallization is controlled to be 4.5 to 6.0, and the pH at the end of crystallization is preferably 5.0 to 5.5.
In the processes of preparing suspension, acidifying and crystallizing amoxicillin, the temperature is controlled to be 5-30 ℃.
And finally, filtering, drying, grinding, subpackaging and the like the amoxicillin crystal liquid to form a sterile amoxicillin product.
The embodiment of the invention comprises different process parameter ranges, different filter element materials and different alkali liquors. Different combinations of the above should be considered as one process enabling combination of the present invention, which combinations are disclosed herein.
The implementation of the aseptic amoxicillin related to the invention is carried out strictly according to the requirements of GMP (good manufacturing practice) in the pharmaceutical production, and the equipment used in the implementation is aseptic so as to ensure the aseptic implementation of the product.
The quality tests carried out in the present invention use the methods and standards specified in the EP pharmacopoeia of the european union.
The quality of the prepared aseptic amoxicillin accords with various quality indexes of the amoxicillin in European Union EP pharmacopoeia, the aseptic indexes accord with the regulations, and the bacterial endotoxin index is less than 0.15 EU/mg.
Example 1
The preparation method of the sterile amoxicillin in the embodiment comprises the following steps:
1) 20g of amoxicillin and 160mL of water were mixed to a suspension, the temperature was controlled at 30 ℃.
2) And (3) adding hydrochloric acid with the concentration of 7% into the amoxicillin suspension to adjust the pH value to 0.5, and dissolving to obtain an acidizing solution. The temperature was controlled at 30 ℃.
3) Clarifying and filtering the acidified solution through a 1.0-micron filter membrane, and performing aseptic filtration through a 0.22-micron hydrophilic sterilization filter membrane made of polyether sulfone.
4) Ammonia water with the concentration of 25 percent is sterilized and filtered by a 0.22 micron hydrophilic sterilization filter membrane made of polyether sulfone before the amoxicillin is acidified. The emphasis in this step is on sterile filtration of the aqueous ammonia prior to acidification of amoxicillin, to avoid degradation of the acidified liquor in step 3). Therefore, the sterilization filtration of the alkali liquor is not later than that of the amoxicillin acidizing fluid, and is earlier than or synchronous with that of the amoxicillin acidizing fluid. The same applies below.
5) And adding the ammonia water subjected to sterilization and filtration into the amoxicillin acidizing fluid subjected to sterilization and filtration to adjust the pH of the acidizing fluid to 5.0 for crystallization. The crystallization process was continued at 30 ℃.
6) And cooling the crystallization liquid to 5 ℃ after the adjustment is finished, and then filtering, drying, grinding and subpackaging.
The yield, content and total impurities are shown in table 1.
Example 2
The amoxicillin aseptic production process in the embodiment comprises the following steps:
1) 20g of amoxicillin and 400mL of water were mixed to a suspension, the temperature was controlled at 5 ℃.
2) And (3) adding hydrochloric acid with the concentration of 7% into the amoxicillin suspension to adjust the pH value to 1.0, and dissolving to obtain an acidizing solution. The temperature was controlled at 5 ℃.
3) Clarifying and filtering the acidified solution through a 1.0-micron filter membrane, and performing aseptic filtration through a 0.22-micron hydrophilic sterilization filter membrane made of polyether sulfone.
4) Ammonia water with the concentration of 25 percent is sterilized and filtered by a 0.22 micron hydrophilic sterilization filter membrane made of polyether sulfone before the amoxicillin is acidified.
5) And adding the ammonia water subjected to sterilization and filtration into the amoxicillin acidizing fluid subjected to sterilization and filtration to adjust the pH of the acidizing fluid to 6.0 for crystallization. The crystallization process is continued with a temperature control of 5 ℃.
6) And cooling the crystallization liquid to 5 ℃ after the adjustment is finished, and then filtering, drying, grinding and subpackaging.
The yield, content and total impurities are shown in table 1.
Example 3
The amoxicillin aseptic production process in the embodiment comprises the following steps:
1) before the process operation, the degerming filter membrane made of the polytetrafluoroethylene material is thoroughly soaked by alcohol, and then the filter membrane is washed by water, so that the hydrophobic polytetrafluoroethylene filter membrane can filter water.
2) 20g of amoxicillin and 300mL of water were mixed to a suspension, and the temperature was controlled at 20 ℃.
3) And (3) adding hydrochloric acid with the concentration of 7% into the amoxicillin suspension to adjust the pH to 1.5, and dissolving to obtain an acidizing solution. The temperature was controlled at 20 ℃.
4) Clarifying and filtering the acidified solution with 1.0 micron filter membrane, and sterilizing and filtering with 0.2 micron hydrophobic sterilizing filter membrane made of polytetrafluoroethylene and soaked in alcohol.
5) Before amoxicillin acidification, a 16% sodium hydroxide aqueous solution is sterilized and filtered by a 0.2 micron hydrophobic sterilization filter membrane which is made of polytetrafluoroethylene and is soaked in alcohol.
6) And adding the ammonia water subjected to sterilization and filtration into the amoxicillin acidizing fluid subjected to sterilization and filtration to adjust the pH of the acidizing fluid to 4.5 for crystallization. The crystallization process was continued at a temperature of 20 ℃.
7) And cooling the crystallization liquid to 5 ℃ after the adjustment is finished, and then filtering, drying, grinding and subpackaging.
The yield, content and total impurities are shown in table 1.
Comparative example
The amoxicillin aseptic production process in the embodiment comprises the following steps:
200g of amoxicillin is packaged in separate packages, and then is sterilized by gamma ray irradiation with a Co60 radiation source, and the irradiation dose is more than 25 kGy.
The yield, content and total impurities are shown in table 1.
The above examples and comparative examples have the following yields, contents, maximum individual impurities and total impurities:
table 1:
examples Yield (%) Content (%) Total impurities (%)
Example 1 92.1 100.2 0.41
Example 2 93.8 100.1 0.66
Example 3 94.2 100.4 0.49
Comparative example 99.5 96.0 2.30
The foregoing has described in detail preferred embodiments of the present invention, but the present invention is not limited thereto. The invention adopts an aseptic production process different from the market mainstream. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including various technical features and different combinations. Such simple modifications and combinations are to be considered as within the scope of the present disclosure.

Claims (10)

1. A preparation method of sterile amoxicillin is characterized by comprising the following steps:
a. placing amoxicillin in water to prepare an amoxicillin suspension;
b. acidifying the amoxicillin suspension by using hydrochloric acid to obtain an amoxicillin acidified solution with the pH value of 0.5-1.5;
c. adopting a sterilization filter element to perform sterilization filtration on the amoxicillin acidizing fluid and the alkali liquor;
d. and adding the alkali liquor subjected to sterilization and filtration into the amoxicillin acidizing solution subjected to sterilization and filtration, adjusting the pH value of the amoxicillin acidizing solution to crystallize, controlling the pH value at the end of crystallization to be 4.5-6.0, and carrying out post-treatment on the crystallized solution to obtain the sterile amoxicillin.
2. A process for the preparation of sterile amoxicillin according to claim 1, characterized in that in step a, the weight ratio of amoxicillin to water is between 1:8 and 20.
3. A process for the preparation of sterile amoxicillin according to claim 1, characterized in that in steps a-d, the temperature is controlled between 5 and 30 ℃.
4. A process for the preparation of sterile amoxycillin as claimed in claim 1, wherein in step b, the amoxycillin suspension is acidified to obtain an acidified solution of amoxycillin with pH of 0.7-1.3.
5. A process for the preparation of sterile amoxicillin, as claimed in claim 1, wherein in step d, the end-point pH of crystallization is controlled to 5.0 to 5.5.
6. The process for the preparation of sterile amoxicillin according to claim 1, characterized in that in step c, the acidification of amoxicillin solution is performed with aseptic filtration using acid-resistant sterile filtration cartridges of polytetrafluoroethylene, polycarbonate or polyethersulfone.
7. The preparation method of sterile amoxicillin according to claim 6, further comprising the step of clarifying and filtering the amoxicillin acidified liquid with a 0.4-1.0 micron filter membrane before the step c of sterilizing and filtering the amoxicillin acidified liquid, and then sterilizing and filtering the amoxicillin acidified liquid with a sterilizing and filtering filter element.
8. The method for preparing sterile amoxicillin according to claim 1, characterized in that in step c, the alkaline solution is sterilized by an alkaline-resistant sterilizing filter element of polytetrafluoroethylene, polyvinylidene fluoride, polyethersulfone or nylon.
9. A process for the preparation of sterile amoxicillin according to claim 1, wherein in step c, the pore size of the sterilizing filter cartridge is no greater than 0.22 micron.
10. A process for the preparation of sterile amoxicillin according to any of the claims 1 to 9, characterized in that in step c, the lye is sodium hydroxide solution or ammonia.
CN202110872791.7A 2021-07-30 2021-07-30 Preparation method of sterile amoxicillin Pending CN113577317A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4607029A (en) * 1978-10-03 1986-08-19 Gist-Brocades N.V. Novel sodium amoxicillin preparations
US4863915A (en) * 1986-04-12 1989-09-05 Beecham Group P.L.C. β-lactam antibiotics
CN102268016A (en) * 2011-03-28 2011-12-07 哈药集团制药总厂 Method for preparing amoxicillin sodium
CN105362235A (en) * 2015-11-12 2016-03-02 重庆福安药业(集团)股份有限公司 Compound pharmaceutical composition of amoxicillin sodium and potassium clavulanate and preparation method of compound pharmaceutical composition
CN109867687A (en) * 2017-12-05 2019-06-11 上海朝瑞化工有限公司 A kind of highly-water-soluble Amoxicillin and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4607029A (en) * 1978-10-03 1986-08-19 Gist-Brocades N.V. Novel sodium amoxicillin preparations
US4863915A (en) * 1986-04-12 1989-09-05 Beecham Group P.L.C. β-lactam antibiotics
CN102268016A (en) * 2011-03-28 2011-12-07 哈药集团制药总厂 Method for preparing amoxicillin sodium
CN105362235A (en) * 2015-11-12 2016-03-02 重庆福安药业(集团)股份有限公司 Compound pharmaceutical composition of amoxicillin sodium and potassium clavulanate and preparation method of compound pharmaceutical composition
CN109867687A (en) * 2017-12-05 2019-06-11 上海朝瑞化工有限公司 A kind of highly-water-soluble Amoxicillin and preparation method thereof

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Title
夏焕章等: "《发酵工艺学（第4版）》", 31 December 2019, 北京：中国医药科技出版社 *
曹学君等: "膜分离技术在医药工业中的应用", 《国外医药.抗生素分册》 *

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