WO2023070822A1 - 一种注射用头孢唑林钠的制备工艺 - Google Patents

一种注射用头孢唑林钠的制备工艺 Download PDF

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WO2023070822A1
WO2023070822A1 PCT/CN2021/134861 CN2021134861W WO2023070822A1 WO 2023070822 A1 WO2023070822 A1 WO 2023070822A1 CN 2021134861 W CN2021134861 W CN 2021134861W WO 2023070822 A1 WO2023070822 A1 WO 2023070822A1
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cefazolin sodium
sodium
injection
cefazolin
add
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PCT/CN2021/134861
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English (en)
French (fr)
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陆一峰
路国荣
陈兴禹
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海南海灵化学制药有限公司
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    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms

Definitions

  • the application relates to the field of anti-infective drugs, in particular to a preparation process of cefazolin sodium for injection.
  • Cefazolin sodium is the first-generation cephalosporin antibiotic; it has a broad antibacterial spectrum. Except Enterococcus and methicillin-resistant Staphylococcus, this product has good antibacterial activity against other Gram-positive cocci. Streptococcus pneumoniae and hemolytic Streptococcus is highly sensitive to this product, and the domestic market capacity is more than 1.7 billion yuan. The preparation process of cefazolin sodium for injection is easy to introduce new impurities, and the hygroscopicity is high, which is not conducive to product quality control.
  • the application proposes a preparation process of cefazolin sodium for injection to solve the above technical problems.
  • a preparation process of cefazolin sodium for injection comprising the following steps:
  • step (1) the mass-volume kg/L ratio of the crude cefazolin sodium to dichloromethane is 1:4-6.
  • step (1) the quality of the chitosan is 1-2% of the crude product quality of cefazolin sodium.
  • step (1) the total mass of the sodium ethoxide and 5-ethyl-2-picoline is 4-6% of the mass of the crude product of cefazolin sodium.
  • step (2) the total mass of the added disodium edetate and ethanol is 4.5-5.5 times of the mass of the crude product of cefazolin sodium.
  • step (2) the total mass of glycerin, L-cysteine and xylan is 12-14% of the raw material mass of cefazolin sodium.
  • step (2) the vacuum freeze-drying temperature is -50 to -45°C.
  • step (3) the sterilization temperature of the rubber stopper is 121° C., and the sterilization time is 30 minutes.
  • step (3) the sterilization temperature of the aluminum cap is 121°C, and the sterilization time is 1800s.
  • the preparation method of the present application can effectively remove impurities while avoiding the introduction of new impurities, reduce the content of related substances, and reduce the hygroscopicity of medicines.
  • the application uses chitosan, more fully removes impurity, helps to reduce hygroscopicity simultaneously; Impurities are generated, and cefazolin sodium is effectively coated to significantly reduce hygroscopicity; this application optimizes the ratio of sodium ethoxide and 5-ethyl-2-picoline to promote the full dissolution of cefazolin sodium and further remove impurities.
  • the application helps to reduce hygroscopicity; the application optimizes the proportioning ratio of disodium edetate and ethanol, further improves the effect of cooling and crystallization, better reduces the total impurity content of the product, and reduces hygroscopicity; the application optimizes glycerin, L - The ratio of cysteine and xylan further strengthens the protective effect, better reduces product impurities and reduces hygroscopicity.
  • a preparation process of cefazolin sodium for injection comprising the following steps:
  • a preparation process of cefazolin sodium for injection comprising the following steps:
  • a preparation process of cefazolin sodium for injection comprising the following steps:
  • adjust step (1) process chitosan replaces gac.
  • step (2) process L-cysteine and xylan are not added.
  • step (1) adjust the process of step (1): wherein, the mass ratio of sodium ethoxide to 5-ethyl-2-picoline is 1:1.
  • step (2) adjust the process of step (2): wherein, the mass ratio of disodium edetate to ethanol is 1:14.
  • step (2) adjust the process of step (2): wherein, the mass ratio of glycerin, L-cysteine and xylan is 1:1:1.
  • the hygroscopicity determination method is as follows:
  • Humidification weight gain is not less than 15%, that is, very hygroscopic
  • Wetting weight gain is less than 2% and not less than 0.2%, that is, slightly hygroscopic.
  • Example 1 comparing Example 1 with Comparative Example 1, the present application uses chitosan to more fully remove impurities while helping to reduce moisture absorption.
  • Embodiment 1 is compared with comparative example 2, and the present application adds L-cysteine and xylan, better protects cefazolin sodium in vacuum freeze-drying process, reduces impurity generation, and effectively coats cefazolin sodium, significantly Reduce humidity.
  • Comparing Example 1 with Comparative Example 4 this application optimizes the ratio of disodium edetate and ethanol to further improve the effect of cooling and crystallization, better reduce the total impurity content of the product, and reduce the moisture absorption.
  • Example 1 Compared with Example 1 and Comparative Example 5, the present application optimizes the ratio of glycerin, L-cysteine and xylan to further enhance the protective effect, better reduce product impurities and reduce moisture absorption.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

提供一种注射用头孢唑林钠的制备工艺，包括以下步骤：(1)将头孢唑林钠粗品加入二氯甲烷，加入壳聚糖，再加入乙醇钠和5-乙基-2-甲基吡啶，在温度8-10℃下搅拌1.5-2.5h，过滤，得到溶液A；(2)向溶液A中加入乙二胺四乙酸二钠和乙醇，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，加入甘油、L-半胱氨酸和木聚糖，真空冻干，得到注射用头孢唑林钠；(3)将西林瓶、胶塞、铝盖分别清洗、灭菌，将注射用头孢唑林钠分装至西林瓶，压塞，轧盖，得到目标产品。采用该制备方法，有效去除杂质同时避免引入新杂质，降低有关物质含量，同时降低药品的引湿性。

Description

一种注射用头孢唑林钠的制备工艺 技术领域
本申请涉及抗感染药物领域，特别涉及一种注射用头孢唑林钠的制备工艺。
背景技术
头孢唑林钠为第一代头孢类抗生素；抗菌谱广，除肠球菌属、耐甲氧西林葡萄球菌属外，本品对其他革兰阳性球菌均有良好抗菌活性，肺炎链球菌和溶血性链球菌对本品高度敏感，国内市场容量达17多亿元以上。注射用头孢唑林钠制备过程容易引入新杂质，而且引湿性高，不利于产品质量控制。
发明内容
鉴于此，本申请提出一种注射用头孢唑林钠的制备工艺，解决上述技术问题。
本申请的技术方案是这样实现的：
一种注射用头孢唑林钠的制备工艺，包括以下步骤：
(1)将头孢唑林钠粗品加入二氯甲烷，加入壳聚糖，再加入质量比为1：3-5的乙醇钠和5-乙基-2-甲基吡啶，在温度8-10℃下搅拌1.5-2.5h，过滤，得到溶液A；
(2)向溶液A中加入质量比为1：8-10的乙二胺四乙酸二钠和乙醇，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，加入质量比为1：0.2-0.3：0.7-0.8的甘油、L-半胱氨酸和木聚糖，真空冻干，得到注射用头孢唑林钠；
(3)将西林瓶、胶塞、铝盖分别清洗、灭菌，将注射用头孢唑林钠分装至西林瓶，压塞，轧盖，得到目标产品。
进一步的，步骤(1)中，所述头孢唑林钠粗品和二氯甲烷的质量体积kg/L比为1：4～6。
进一步的，步骤(1)中，所述壳聚糖的质量为头孢唑林钠粗品质量的1-2％。
进一步的，步骤(1)中，所述乙醇钠和5-乙基-2-甲基吡啶的总质量为头孢唑林钠粗品质量的4-6％。
进一步的，步骤(2)中，所述加入乙二胺四乙酸二钠和乙醇的总质量为头孢唑林钠粗品质量的4.5-5.5倍。
进一步的，步骤(2)中，所述甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的12-14％。
进一步的，步骤(2)中，所述真空冻干温度为-50～-45℃。
进一步的，步骤(3)中，所述胶塞的灭菌温度为121℃，灭菌时间为30min。
进一步的，步骤(3)中，所述铝盖的灭菌温度为121℃，灭菌时间为1800s。
与现有技术相比，本申请的有益效果是：
采用本申请的制备方法，有效去除杂质同时避免引入新杂质，降低有关物质含量，同时降低药品的引湿性。其中，本申请使用壳聚糖，更加充分去除杂质，同时有助于降低吸湿性；本申请加入L-半胱氨酸和木聚糖，更好在真空冻干过程保护头孢唑林钠，减少杂质生成，而且有效包覆头孢唑林钠，显著降低吸湿性；本申请优化乙醇钠和5-乙基-2-甲基吡啶的配比，促进头孢唑林钠充分溶解，同时进一步去除杂质，同时有助于降低吸湿性；本申请优化乙二胺四乙酸二钠和乙醇的配比，进一步提高降温析晶的效果，更好减少产品总杂含量、降低吸湿性；本申请优化甘油、L-半胱氨酸和木聚糖的配比，进一步加强保护作用，更好减少产品杂质、降低吸湿性。
具体实施方式
为了更好理解本申请技术内容，下面提供具体实施例，对本申请做进一步的说明。
本申请实施例所用的实验方法如无特殊说明，均为常规方法。
本申请实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
一种注射用头孢唑林钠的制备工艺，包括以下步骤：
(1)将头孢唑林钠粗品100kg加入二氯甲烷500L，加入壳聚糖1.3kg，再 加入乙醇钠1kg和5-乙基-2-甲基吡啶4.2kg，在温度8-10℃下搅拌2.0h，经0.45μm过滤膜过滤，得到溶液A；
(2)向溶液A中加入乙二胺四乙酸二钠50kg和乙醇450kg，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入质量比为1：0.25：0.75的甘油、L-半胱氨酸和木聚糖，加入甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的13％，并在-50～-45℃温度条件下真空冻干，得到注射用头孢唑林钠；
(3)将西林瓶、胶塞、铝盖分别清洗、灭菌，其中胶塞的灭菌温度为121℃，灭菌时间为30min，铝盖的灭菌温度为121℃，灭菌时间为1800s；将注射用头孢唑林钠分装至西林瓶，压塞，轧盖，得到目标产品。
实施例2
一种注射用头孢唑林钠的制备工艺，包括以下步骤：
(1)将头孢唑林钠粗品100kg加入二氯甲烷400L，加入壳聚糖1kg，再加入乙醇钠1kg和5-乙基-2-甲基吡啶3kg，在温度8-10℃下搅拌2.5h，经0.45μm过滤膜过滤，得到溶液A；
(2)向溶液A中加入乙二胺四乙酸二钠50kg和乙醇400kg，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入质量比为1：0.2：0.8的甘油、L-半胱氨酸和木聚糖，加入甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的12％，并在-50～-45℃温度条件下真空冻干，得到注射用头孢唑林钠；
(3)将西林瓶、胶塞、铝盖分别清洗、灭菌，其中胶塞的灭菌温度为121℃，灭菌时间为30min，铝盖的灭菌温度为121℃，灭菌时间为1800s；将注射用头孢唑林钠分装至西林瓶，压塞，轧盖，得到目标产品。
实施例3
一种注射用头孢唑林钠的制备工艺，包括以下步骤：
(1)将头孢唑林钠粗品100kg加入二氯甲烷600L，加入壳聚糖2kg，再加入乙醇钠1kg和5-乙基-2-甲基吡啶5kg，在温度8-10℃下搅拌1.5h，经0.45μm过滤膜过滤，得到溶液A；
(2)向溶液A中加入乙二胺四乙酸二钠50kg和乙醇500kg，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入质量比为1：0.3：0.7的甘油、L-半胱氨酸和木聚糖，加入甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的14％，并在-50～-45℃温度条件下真空冻干，得到注射用头孢唑林钠；
(3)将西林瓶、胶塞、铝盖分别清洗、灭菌，其中胶塞的灭菌温度为121℃，灭菌时间为30min，铝盖的灭菌温度为121℃，灭菌时间为1800s；将注射用头孢唑林钠分装至西林瓶，压塞，轧盖，得到目标产品。
对比例1
参照实施例1，调整步骤(1)工艺：壳聚糖替换活性炭。
具体为：将头孢唑林钠粗品100kg加入二氯甲烷500L，加入活性炭1.3kg，再加入乙醇钠1kg和5-乙基-2-甲基吡啶4.2kg，在温度8-10℃下搅拌2.0h，得到溶液A。其他步骤与实施例1一致。
对比例2
参照实施例1，调整步骤(2)工艺：没有加入L-半胱氨酸和木聚糖。
具体为：向溶液A中加入乙二胺四乙酸二钠50kg和乙醇450kg，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入甘油，加入甘油的质量为头孢唑林钠原料质量的13％，并在-50～-45℃温度条件下真空冻干，得到注射用头孢唑林钠。其他步骤与实施例1一致。
对比例3
参照实施例1，调整步骤(1)工艺：其中，乙醇钠和5-乙基-2-甲基吡啶的质量比为1：1。
具体为：将头孢唑林钠粗品100kg加入二氯甲烷500L，加入壳聚糖1.3kg，再加入乙醇钠2.6kg和5-乙基-2-甲基吡啶2.6kg，在温度8-10℃下搅拌2.0h，得到溶液A。其他步骤与实施例1一致。
对比例4
参照实施例1，调整步骤(2)工艺：其中，乙二胺四乙酸二钠和乙醇的质量比为1：14。
具体为：向溶液A中加入乙二胺四乙酸二钠38kg和乙醇532kg，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入质量比为1：0.25：0.75的甘油、L-半胱氨酸和木聚糖，加入甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的13％，并在-50～-45℃温度条件下真空冻干，得到注射用头孢唑林钠。其他步骤与实施例1一致。
对比例5
参照实施例1，调整步骤(2)工艺：其中，甘油、L-半胱氨酸和木聚糖的质量比为1：1：1。
具体为：向溶液A中加入乙二胺四乙酸二钠50kg和乙醇450kg，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入质量比为1：1：1的甘油、L-半胱氨酸和木聚糖，加入甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的13％，并在-50～-45℃温度条件下真空冻干，得到注射用头孢唑林钠。其他步骤与实施例1一致。
将上述实施例1-3以及对比例1-5制得注射用头孢唑林钠，参照中国药典2020版检测有关物质以及引湿性。
其中引湿性测定方法如下：
(1)取一定量供试品置一已精密称重(m 1)的具塞玻璃称量瓶(外径为50mm，高为15mm)中，精密称定(m 2)；
(2)把称量瓶口置于人工气候箱(设定温度为25℃±1℃)，相对湿度为 (80％±2％)内。
(3)放置24h；
(4)盖好称量瓶盖子，精密称重(m 3)。
(5)计算增重百分率＝(m 3-m 2)/(m 2-m 1)×100％
引湿增重不小于15％，即极具引湿性；
引湿增重小于15％且不小于2％，即有引湿性；
引湿增重小于2％且不小于0.2％，即略有引湿性。
结果如下：
  总杂(％) 引湿性(％)
粗品 0.68 10.54
实施例1 0.02 2.21
实施例2 0.05 3.14
实施例3 0.03 2.82
对比例1 0.27 3.05
对比例2 0.49 5.57
对比例3 0.18 3.65
对比例4 0.11 4.37
对比例5 0.13 4.58
上述结果表明，采用本申请的制备方法，有效去除杂质同时避免引入新杂质，降低有关物质含量，同时降低药品的引湿性。
其中，实施例1与对比例1对比，本申请使用壳聚糖，更加充分去除杂质，同时有助于降低引湿性。
实施例1与对比例2对比，本申请加入L-半胱氨酸和木聚糖，更好在真空冻干过程保护头孢唑林钠，减少杂质生成，而且有效包覆头孢唑林钠，显著降低引湿性。
实施例1与对比例3对比，本申请优化乙醇钠和5-乙基-2-甲基吡啶的配比，促进头孢唑林钠充分溶解，同时进一步去除杂质，同时有助于降低引湿性。
实施例1与对比例4对比，本申请优化乙二胺四乙酸二钠和乙醇的配比，进一步提高降温析晶的效果，更好减少产品总杂含量、降低引湿性。
实施例1与对比例5对比，本申请优化甘油、L-半胱氨酸和木聚糖的配比，进一步加强保护作用，更好减少产品杂质、降低引湿性。
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (9)

  1. 一种注射用头孢唑林钠的制备工艺，其特征在于，包括以下步骤：
    (1)将头孢唑林钠粗品加入二氯甲烷，加入壳聚糖，再加入质量比为1：3-5的乙醇钠和5-乙基-2-甲基吡啶，在温度8-10℃下搅拌1.5-2.5h，过滤，得到溶液A；
    (2)向溶液A中加入质量比为1：8-10的乙二胺四乙酸二钠和乙醇，降温析晶，干燥后，再溶解于水中，过滤，灭菌，得到头孢唑林钠原料，再加入质量比为1：0.2-0.3：0.7-0.8的甘油、L-半胱氨酸和木聚糖，真空冻干，得到注射用头孢唑林钠；
    (3)将西林瓶、胶塞、铝盖分别清洗、灭菌，将注射用头孢唑林钠分装至西林瓶，压塞，轧盖，得到目标产品。
  2. 根据权利要求1所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(1)中，所述头孢唑林钠粗品和二氯甲烷的质量体积kg/L比为1：4～6。
  3. 根据权利要求2所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(1)中，所述壳聚糖的质量为头孢唑林钠粗品质量的1-2％。
  4. 根据权利要求3所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(1)中，所述乙醇钠和5-乙基-2-甲基吡啶的总质量为头孢唑林钠粗品质量的4-6％。
  5. 根据权利要求4所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(2)中，所述加入乙二胺四乙酸二钠和乙醇的总质量为头孢唑林钠粗品质量的4.5-5.5倍。
  6. 根据权利要求5所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(2)中，所述甘油、L-半胱氨酸和木聚糖的总质量为头孢唑林钠原料质量的12-14％。
  7. 根据权利要求6所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(2)中，所述真空冻干温度为-50～-45℃。
  8. 根据权利要求7所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(3)中，所述胶塞的灭菌温度为121℃，灭菌时间为30min。
  9. 根据权利要求8所述的注射用头孢唑林钠的制备工艺，其特征在于，步骤(3)中，所述铝盖的灭菌温度为121℃，灭菌时间为1800s。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030469A2 (en) * 2000-10-12 2002-04-18 Orchid Chemicals And Pharmaceuticals Limited Beta-lactam antibiotic-polysaccharide complex
CN104610282A (zh) * 2015-02-14 2015-05-13 石药集团中诺药业（石家庄）有限公司 一种头孢唑啉酸的提纯方法
CN106432276A (zh) * 2016-09-21 2017-02-22 陕西顿斯制药有限公司 一种采用新型智能化结晶技术制备的头孢唑林钠化合物及其制剂
CN110894197A (zh) * 2019-09-25 2020-03-20 上海欣峰制药有限公司 一种注射用头孢唑林钠的制备方法
CN111548357A (zh) * 2020-04-16 2020-08-18 华北制药河北华民药业有限责任公司 一种高纯度头孢唑林钠及其药物制剂的制备方法
CN113398072A (zh) * 2020-09-10 2021-09-17 广东金城金素制药有限公司 注射用头孢唑林钠及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103550247A (zh) * 2013-10-15 2014-02-05 海南卫康制药(潜山)有限公司 注射用头孢匹胺钠组合物冻干粉针

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030469A2 (en) * 2000-10-12 2002-04-18 Orchid Chemicals And Pharmaceuticals Limited Beta-lactam antibiotic-polysaccharide complex
CN104610282A (zh) * 2015-02-14 2015-05-13 石药集团中诺药业（石家庄）有限公司 一种头孢唑啉酸的提纯方法
CN106432276A (zh) * 2016-09-21 2017-02-22 陕西顿斯制药有限公司 一种采用新型智能化结晶技术制备的头孢唑林钠化合物及其制剂
CN110894197A (zh) * 2019-09-25 2020-03-20 上海欣峰制药有限公司 一种注射用头孢唑林钠的制备方法
CN111548357A (zh) * 2020-04-16 2020-08-18 华北制药河北华民药业有限责任公司 一种高纯度头孢唑林钠及其药物制剂的制备方法
CN113398072A (zh) * 2020-09-10 2021-09-17 广东金城金素制药有限公司 注射用头孢唑林钠及其制备方法

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