WO2017140074A1 - 盐酸头孢甲肟新晶型及制剂 - Google Patents

盐酸头孢甲肟新晶型及制剂 Download PDF

Info

Publication number
WO2017140074A1
WO2017140074A1 PCT/CN2016/085307 CN2016085307W WO2017140074A1 WO 2017140074 A1 WO2017140074 A1 WO 2017140074A1 CN 2016085307 W CN2016085307 W CN 2016085307W WO 2017140074 A1 WO2017140074 A1 WO 2017140074A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefmenoxime hydrochloride
crystalline form
cefmenoxime
hydrochloride
hydrochloric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/085307
Other languages
English (en)
French (fr)
Inventor
陶灵刚
王静康
尹秋响
郝红勋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin University
Hainan Lingkang Pharmaceutical Co Ltd
Original Assignee
Tianjin University
Hainan Lingkang Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin University, Hainan Lingkang Pharmaceutical Co Ltd filed Critical Tianjin University
Publication of WO2017140074A1 publication Critical patent/WO2017140074A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • 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
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medical technology, and particularly relates to a novel crystalline form compound and preparation of cefmenoxime hydrochloride using molecular assembly and morphology optimization technology of particle process crystal products.
  • Cefmenoxime hydrochloride its chemical name is: (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-[[ 1-methyl-1H-tetrazol-5-yl)-sulfo]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-A Acid hydrochloride (2:1), molecular formula: C 16 H 17 N 9 O 5 S 3 ⁇ 1/2HC1, molecular weight: 529.79, structural formula:
  • Cefmenoxime Hydrochloride is a third-generation cephalosporin developed by Takeda, Japan. It was first introduced in Japan in 1983 and is a broad-spectrum antibiotic that achieves bactericidal action by inhibiting the biosynthesis of bacterial cell walls.
  • cefmenoxime hydrochloride prepared by the above method on the market has poor purity, poor color grade and poor stability, thereby affecting the quality of the preparation.
  • the conventional crystal form of cefmenoxime hydrochloride has poor stability and is unstable to heat, acid environment and alkaline environment. It is characterized by easy discoloration, reduced content and degradation products. To solve this problem, it is necessary to develop a new crystallization production technology to optimize process parameters such as solvent, temperature, reaction time, additives, etc., so that crystallization can be carried out under suitable conditions to ensure product quality.
  • the invention mainly aims at the above problems of cefmenoxime hydrochloride, and on the basis of sufficient investigation of factors such as solvent, temperature, external force and additives in the crystal formation process, the molecular assembly and morphology optimization technology of the particle process crystal product obtains a high purity. , good color grade, good fluidity, good stability, cefmenoxime hydrochloride
  • the new crystal form compound, the synthesis step is more focused on the control of the reagents and parameters in the synthesis process than the previous preparation process, the steps are simple, the raw materials used are all cheap, non-toxic or low-toxic products, and are suitable for industrial scale production.
  • Formulations made using the compounds described in the present invention have better stability than previous formulations.
  • a first object of the present invention is to provide a novel crystalline form of cefmenoxime hydrochloride, which is prepared by molecular assembly and morphology optimization technology of a particle process crystal product, and has the characteristics of high purity, good color grade and good stability.
  • the new crystalline form of cefmenoxime hydrochloride according to the present invention is determined by X-ray powder diffraction, and the X-ray powder diffraction pattern represented by the 2 ⁇ diffraction angle is 6.25° ⁇ 0.2°, 13.04° ⁇ 0.2°, 14.31° ⁇ 0.2°, 17.21° ⁇ 0.2°, 18.18° ⁇ 0.2°, 19.95° ⁇ 0.2°, 22.77° ⁇ 0.2°, 23.76° ⁇ 0.2°, 25.88° ⁇ 0.2°, 29.19° ⁇ 0.2°, showing characteristic diffraction peaks, as shown in the attached drawing 1 is shown.
  • the preparation of the new crystalline form of cefmenoxime hydrochloride according to the present invention comprises the following steps:
  • the weight ratio of the 7-ATCA ⁇ HCl to the AE active ester is 1:1 to 1:3. More preferably, the weight ratio is 1:2.
  • the hydrochloric acid concentration in the step (1) is 5-8 mol/L. More preferably, the hydrochloric acid concentration is 6 mol/L.
  • the hydrochloric acid adjusted pH in the step (1) is 1-3. More preferably, the pH is 2.5.
  • the alkali liquid described in the step (2) is an aqueous solution of 8 to 12% sodium hydrogencarbonate. More preferably, the lye is a 10% aqueous solution of sodium hydrogencarbonate.
  • the lye adjusted pH in the step (2) is 6-8. More preferably, the pH is 7.0.
  • the crystal growth time in the step (2) is 2 to 4 hours. More preferably, the crystal growth time is from 3 to 3.5 hours.
  • a second object of the present invention is to provide a cefmenoxime hydrochloride pharmaceutical composition comprising the novel crystalline form of cefmenoxime hydrochloride of the present invention, which is simple in operation and has better stability than the prior products. The side effects are small.
  • the cefmenoxime hydrochloride pharmaceutical composition of the present invention comprises, by weight fractions, the following components by weight: 40-80 parts of cefmenoxime hydrochloride (calcium cefprozil) and 20-60 parts of sodium hydrogencarbonate.
  • Fig. 1 X-ray powder diffraction pattern of a new crystalline form of cefmenoxime hydrochloride, and the 2 ⁇ values corresponding to the diffraction peak numbers in the figure are shown in Table 1.
  • X-ray powder diffraction was used to study and characterize the new crystalline form of cefmenoxime hydrochloride.
  • the X-ray powder diffraction pattern of the product of Example 1 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19. See Figure 1 of the specification for details.
  • the aqueous phase was combined, decolorized by activated carbon at room temperature, filtered, and the carbon layer was washed with ethanol, and the washings were combined.
  • the pH was adjusted to 2.0 with 8 mol/L hydrochloric acid, and the crystal was maintained for 3 hours.
  • the filtrate was washed with water and dried under vacuum at 40 ° C to obtain crude cefmenoxime hydrochloride.
  • the X-ray powder diffraction pattern of the product of Example 2 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19.
  • the X-ray powder diffraction pattern of the product of Example 3 showed characteristic diffraction peaks at 6.25, 13.04, 14.31, 17.21, 18.18, 19.95, 22.77, 23.76, 25.88, 29.19.
  • cefmenoxime hydrochloride compound was prepared according to the procedure of Example 1, and the raw material was used to prepare cefmenoxime hydrochloride for injection, and the specification was 0.25 g.
  • cefmenoxime hydrochloride compound was prepared according to the method described in CN 102675344 A.
  • the aqueous phase was combined and the aqueous phase was stripped with dichloromethane.
  • the aqueous phase was adjusted to pH 6-7 with acid, 0.5 g of activated carbon was added for 20 min, filtered, and the filter cake was washed with 70 ml of water.
  • 20 ml of acetone and 90 ml of 35% concentrated hydrochloric acid were added to the other reaction flask, and the filtrate was added dropwise to the mixture, and the temperature was controlled at 35 ° C to precipitate a white solid.
  • the crystals were crystallized at 25 ° C for 2 h, suction filtered, washed with 100 ml of water, washed with 120 ml of acetone, and dried by suction filtration to give 50 g.
  • the cefmenoxime hydrochloride compound was prepared in the same manner as in Comparative Example 1.
  • the raw material was used to prepare cefmenoxime hydrochloride for injection, and the specification was 0.25 g.
  • the inventors conducted a purity test on the cefmenoxime hydrochloride compound prepared in Example 1 of the present invention and Comparative Example 1.
  • the conditions of investigation were temperature 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%. After 6 months of storage, samples were taken at the end of 0, 1, 2, 3, and 6 months, respectively.
  • the indicators were traits, clarity, solution color, pH, content and related substances. See Table 3.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

本发明公开了一种盐酸头孢甲肟新晶型化合物及其结晶制备方法，所述盐酸头孢甲肟新晶型化合物采用粒子过程晶体产品分子组装与形态优化技术制备而成。本化合物具有纯度高、流动性好、稳定性好的特点。同时，本发明还公开了一种采用上述盐酸头孢甲肟化合物制备的制剂—注射用盐酸头孢甲肟。

Description

[根据细则37.2由ISA制定的发明名称]　盐酸头孢甲肟新晶型及制剂 技术领域
本发明属于医药技术领域，具体涉及一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂。
背景技术
盐酸头孢甲肟，其化学名称为：(6R，7R)-7-[(Z)-2-(2-氨基-4-噻唑基)-2-甲氧亚氨基乙酰氨基]-3-[[1-甲基-1H-四唑-5-基)-硫]甲基]-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-甲酸盐酸盐(2:1)，分子式：C16H17N9O5S3·1/2HC1，分子量：529.79，结构式为：
Figure PCTCN2016085307-appb-000001
盐酸头孢甲肟为日本武田公司研制开发的第三代头孢菌素，1983年在日本首次上市，是一种广谱抗生素，通过抑制细菌细胞壁的生物合成而达到杀菌作用。
关于盐酸头孢甲肟的合成方法，根据文献报道，主要以7-ACA为原料，(1)先3位缩合，再7位缩合；(2)先7位缩合，再3位缩合。目前市场上采用上述方法制备的盐酸头孢甲肟，其纯度较差，色级不好，稳定性差，从而影响了其制剂质量。
盐酸头孢甲肟常规晶型的稳定性较差，对热、偏酸环境、偏碱环境均不稳定，表现在外观易变色、含量降低、出现降解产物等问题。解决这个问题必须研发新型结晶生产技术，以优化溶剂、温度、反应时间、添加剂等过程工艺参数，使结晶在适合的条件下进行，从而保证产品的质量。
本发明主要针对盐酸头孢甲肟存在的以上问题，对晶体形成过程中溶剂、温度、外力、添加剂等因素充分考察的基础上，采用粒子过程晶体产品分子组装与形态优化技术得到了一种纯度高、色级好、流动性好、稳定性好的盐酸头孢甲肟 新晶型化合物，该合成步骤较以往的制备过程更注重合成过程中的试剂及参数的控制，步骤简单，使用的原料等均为价格便宜、无毒或低毒产品，适于工业化规模生产。利用本发明中所述的化合物制成的制剂，较以往制剂具有更好的稳定性。
发明内容
本发明的第一目的在于提供一种盐酸头孢甲肟新晶型化合物，该化合物采用粒子过程晶体产品分子组装与形态优化技术制备而来，具有纯度高、色级好、稳定性好的特点。
本发明所述的盐酸头孢甲肟新晶型化合物用X射线粉末衍射测定，以2θ衍射角表示的X射线粉末衍射图谱在6.25°±0.2°，13.04°±0.2°，14.31°±0.2°，17.21°±0.2°，18.18°±0.2°，19.95°±0.2°，22.77°±0.2°，23.76°±0.2°，25.88°±0.2°，29.19°±0.2°处显示特征衍射峰，如附图1所示。
本发明所述的盐酸头孢甲肟新晶型化合物制备包括下列步骤：
(1)将二氯甲烷、乙醇、(6R,7R)-7-氨基-3-[[(1-甲基-1-H-四氮唑-5-基)硫代]甲基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-烯-2-羧酸盐酸盐(7-ATCA·HCl)和三乙胺混合反应，加入2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(AE活性酯)，水萃取，合并水相，活性炭脱色，收集滤液，用盐酸调节pH值，过滤，洗涤，真空干燥，得盐酸头孢甲肟粗品。
(2)将盐酸头孢甲肟粗品溶于水中，缓慢加入碱液，搅拌反应，调节pH，活性炭脱色，过滤，收集滤液。将滤液滴加入丙酮、纯化水和浓盐酸的混合溶液中，反应结束，活性炭脱色，过滤，滤液中加NaHCO3溶液和注射用水，搅拌养晶，过滤，洗涤，干燥，得精制的盐酸头孢甲肟。
优选地，上述制备方法中，所述的7-ATCA·HCl与AE活性酯的重量比为1:1～1:3。更优选地，重量比为1:2。
优选地，上述制备方法中，所述的步骤(1)中所述的盐酸浓度为5～8mol/L。更优选地，盐酸浓度为6mol/L。
优选地，上述制备方法中，所述的步骤(1)中所述的盐酸调节的pH为1～3。更优选地，pH为2.5。
优选地，上述制备方法中，所述的步骤(2)中所述的碱液为8～12％的碳酸氢钠水溶液。更优选地，碱液为10％的碳酸氢钠水溶液。
优选地，上述制备方法中，所述的步骤(2)中所述的碱液调节的pH为6～8。更优选地，pH为7.0。
优选地，上述制备方法中，所述的步骤(2)中所述的养晶时间为2～4h。更优选地，养晶时间为3～3.5h。
本发明第二目的在于提供一种包含本发明所述盐酸头孢甲肟新晶型化合物的盐酸头孢甲肟药物组合物，该药物组合物制备过程操作简单，较以往产品具有更好的稳定性且副作用小。
本发明所述的盐酸头孢甲肟药物组合物按重量份数计包括以下重量份的组分：盐酸头孢甲肟(以头孢甲肟计)40～80份和碳酸氢钠20～60份。
附图说明
图1：盐酸头孢甲肟新晶型化合物的X-射线粉末衍射图，图中衍射峰编号对应的2θ值参见表1。
具体实施方式
下面将通过具体实施方式对本发明做进一步说明，但并不因此将本发明限制在所述的实施例范围中，本领域的技术人员应理解，对本发明内容所做的等同替换，或相应的改进，仍属于本发明的保护范围之内。
实施例1：盐酸头孢甲肟新晶型化合物的制备
(1)向反应瓶内依次加入二氯甲烷250ml，乙醇25ml、(6R,7R)-7-氨基-3-[[(1-甲基-1-H-四氮唑-5-基)硫代]甲基]-8-氧代-5-硫杂·1-氮杂双环[4,2,0]辛-2-烯-2-羧酸盐酸盐(7-ATCA·HCl)25g，三乙胺20ml，室温反应30min后，加入2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(AE活性酯)50.0g，控制合适的温度反应8h，加水萃取2次，每次150ml，合并水相，经活性炭室温脱色，过滤，用乙醇洗涤炭层，洗液合并，用6mol/L盐酸调pH值至1.5，养晶3h，过滤，水洗过滤物，于40℃真空干燥，得盐酸头孢甲肟粗品。
(2)向反应瓶中加入盐酸头孢甲肟粗品25.9g和水230ml，搅拌30min，缓慢加入10％的碳酸氢钠溶液，调节溶液的pH值为6.5～7.0，室温搅拌反应30min，经0.5g活性炭脱色10min、过滤、冰水洗涤，滤液合并，将滤液滴加入丙酮50ml、纯化水100ml和浓盐酸25ml的混合溶液中，反应结束，加入活性炭0.5g脱色10min，过滤，滤液中加10％的碳酸氢钠溶液，搅拌养晶3.5h，过滤，乙醇洗涤 2次，每次50ml，40℃真空干燥，得精制的盐酸头孢甲肟。
采用X-射线粉末衍射法(XRPD)来研究和表征盐酸头孢甲肟的新的结晶形式。
仪器设备：EMPYREAN(锐影)X射线衍射仪(荷兰Panalytical公司)。
实施例1产品的X射线粉末衍射图谱在6.25°，13.04°，14.31°，17.21°，18.18°，19.95°，22.77°，23.76°，25.88°，29.19°处显示特征衍射峰。具体参见说明书附图1。
所述XRPD衍射的具体数据如下表所示：
表1盐酸头孢甲肟晶型
编号 d值 2θ(°) I/I0％
1 14.13 6.25 54.15
2 6.79 13.04 26.06
3 6.19 14.31 65.95
4 5.15 17.21 21.99
5 4.88 18.18 96.81
6 4.45 19.95 22.17
7 3.91 22.77 100.00
8 3.74 23.76 31.26
9 3.44 25.88 13.91
10 3.06 29.19 16.74
实施例2：盐酸头孢甲肟新晶型化合物的制备
(1)向反应瓶内依次加入二氯甲烷250ml，乙醇25ml、(6R,7R)-7-氨基-3-[[(1-甲基-1-H-四氮唑-5-基)硫代]甲基]-8-氧代-5-硫杂·1-氮杂双环[4,2,0]辛-2-烯-2-羧酸盐酸盐(7-ATCA·HCl)25g，三乙胺20ml，室温反应30min后，加入2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(AE活性酯)25.0g，控制合适的温度反应8h，加水萃取2次，每次150ml，合并水相，经活性炭室温脱色，过滤，用乙醇洗涤炭层，洗液合并，用8mol/L盐酸调pH值至2.0，养晶3h，过滤，水洗过滤物，于40℃真空干燥，得盐酸头孢甲肟粗品。
(2)向反应瓶中加入盐酸头孢甲肟粗品25.1g和水230ml，搅拌30min，缓慢加入10％的碳酸氢钠溶液，调节溶液的pH值为6.7～6.9，室温搅拌反应30min， 经0.5g活性炭脱色10min、过滤、冰水洗涤，滤液合并，将滤液滴加入丙酮50ml、纯化水100ml和浓盐酸25ml的混合溶液中，反应结束，加入活性炭0.5g脱色10min，过滤，滤液中加10％的碳酸氢钠溶液，搅拌养晶2.5h，过滤，乙醇洗涤2次，每次50ml，40℃真空干燥，得精制的盐酸头孢甲肟。
实施例2产品的X射线粉末衍射图谱在6.25°，13.04°，14.31°，17.21°，18.18°，19.95°，22.77°，23.76°，25.88°，29.19°处显示特征衍射峰。
实施例3：盐酸头孢甲肟新晶型化合物的制备
(1)向反应瓶内依次加入二氯甲烷250ml，乙醇25ml、(6R,7R)-7-氨基-3-[[(1-甲基-1-H-四氮唑-5-基)硫代]甲基]-8-氧代-5-硫杂·1-氮杂双环[4,2,0]辛-2-烯-2-羧酸盐酸盐(7-ATCA·HCl)25g，三乙胺20ml，室温反应30min后，加入2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(AE活性酯)75.0g，控制合适的温度反应8h，加水萃取2次，每次150ml，合并水相，经活性炭室温脱色，过滤，用乙醇洗涤炭层，洗液合并，用5mol/L盐酸调pH值至2.0，养晶3h，过滤，水洗过滤物，于40℃真空干燥，得盐酸头孢甲肟粗品。
(2)向反应瓶中加入盐酸头孢甲肟粗品23.7g和水230ml，搅拌30min，缓慢加入10％的碳酸氢钠溶液，调节溶液的pH值为6.0～6.5，室温搅拌反应30min，经0.5g活性炭脱色10min、过滤、冰水洗涤，滤液合并，将滤液滴加入丙酮50ml、纯化水100ml和浓盐酸25ml的混合溶液中，反应结束，加入活性炭0.5g脱色10min，过滤，滤液中加10％的碳酸氢钠溶液，搅拌养晶3.0h，过滤，乙醇洗涤2次，每次50ml，40℃真空干燥，得精制的盐酸头孢甲肟。
实施例3产品的X射线粉末衍射图谱在6.25°，13.04°，14.31°，17.21°，18.18°，19.95°，22.77°，23.76°，25.88°，29.19°处显示特征衍射峰。
实施例4：盐酸头孢甲肟药物组合物的制备
按照实施例1的步骤制备盐酸头孢甲肟化合物，采用此原料制备注射用盐酸头孢甲肟，规格0.25g。
处方：
Figure PCTCN2016085307-appb-000002
制备工艺：
(1)配料：在万级洁净条件下，称取盐酸头孢甲肟无菌粉和无水碳酸钠无菌粉放入混合机中，混合60分钟；
(2)分装：在百级洁净条件下，将混合均匀的无菌粉末置于分装机中，调整装量，分装，压塞；
(3)轧盖；
对比例1：盐酸头孢甲肟化合物的制备
按照CN 102675344 A中所述的方法制备盐酸头孢甲肟化合物。
制备过程：
向反应瓶中加入二氯甲烷260ml、乙醇50ml和异丙醇35ml，降温到-8℃，依次加入7-ACT40g盐酸盐和AE活性酯40g，滴加三乙胺20ml，20min滴毕。滴毕计时保温-4℃进行缩合反应5h。用高效液相色谱检测终点。反应毕，加入无盐水20ml，分层，有机相再用90ml无盐水再萃取一次，合并水相，用二氯甲烷反萃水相。水相用酸调节pH值至6～7，加入活性炭0.5g脱色20min，过滤，滤饼用70ml水洗涤。向另一个反应瓶中加入丙酮20ml和35％的浓盐酸90ml，将滤液向该混合液中滴加，控温35℃，析出白色固体。于25℃养晶2h，抽滤，用100ml水洗涤后用丙酮120ml洗涤，抽滤干燥，得产物50g。
对比例2：
取对比例1制备盐酸头孢甲肟化合物，采用此原料制备注射用盐酸头孢甲肟，规格0.25g。
处方：
Figure PCTCN2016085307-appb-000003
制备工艺：
(1)配料：在万级洁净条件下，称取盐酸头孢甲肟无菌粉和无水碳酸钠无菌粉放入混合机中，混合60分钟；
(2)分装：在百级洁净条件下，将混合均匀的无菌粉末置于分装机中，调整装量，分装，压塞；
(3)轧盖；
试验例1：
本发明人对本发明实施例1和对比例1所制备盐酸头孢甲肟化合物进行了纯度检测。
表2纯度检测结果
Figure PCTCN2016085307-appb-000004
结果：本发明制备的盐酸头孢甲肟新晶型化合物纯度明显高于现有技术制备的头孢甲肟化合物。
试验例2：
本发明人对本发明实施例4和对比例2所制备注射用盐酸头孢甲肟进行了加速稳定性考察试验。考察条件为温度40℃±2℃、相对湿度75％±5％。放置6个月，分别于0、1、2、3、6月末取样。考察指标为性状、澄清度、溶液颜色、酸碱度、含量及有关物质。见表3。
结果：实施例与对比例产品在上述试验条件下放置6个月，pH值、含量和有关物质均未出现明显变化，质量稳定。相比较，实施例的颜色较对比例好，且含量较对比例高。
本发明的盐酸头孢甲肟新晶型化合物及其制剂经各项指标检验和加速试验考察表明稳定性好，质量可靠。
Figure PCTCN2016085307-appb-000005

Claims (10)

  1. 一种盐酸头孢甲肟新晶型化合物，其特征在于，以2θ衍射角表示的X射线粉末衍射图谱在6.25°±0.2°，13.04°±0.2°，14.31°±0.2°，17.21°±0.2°，18.18°±0.2°，19.95°±0.2°，22.77°±0.2°，23.76°±0.2°，25.88°±0.2°，29.19°±0.2°处显示特征衍射峰。
  2. 如权利要求1所述的一种盐酸头孢甲肟新晶型化合物，其特征在于，制备方法具体步骤为：
    (1)将二氯甲烷、乙醇、(6R,7R)-7-氨基-3-[[(1-甲基-1-H-四氮唑-5-基)硫代]甲基]-8-氧代-5-硫杂-1-氮杂双环[4,2,0]辛-2-烯-2-羧酸盐酸盐(7-ATCA·HCl)和三乙胺混合反应，加入2-(2-氨基-4-噻唑基)-2-(甲氧亚氨基)乙酸硫代苯并噻唑酯(AE活性酯)，水萃取，合并水相，活性炭脱色，收集滤液，用盐酸调节pH值，过滤，洗涤，真空干燥，得到盐酸头孢甲肟粗品；
    (2)将盐酸头孢甲肟粗品溶于水中，缓慢加入碱液，搅拌反应，调节pH，活性炭脱色，过滤，收集滤液；将滤液滴加入丙酮、纯化水和浓盐酸的混合溶液中，反应结束，活性炭脱色，过滤，滤液中加NaHCO3溶液和注射用水，搅拌养晶，过滤，洗涤，干燥，得到精制的盐酸头孢甲肟。
  3. 如权利要求2所述的一种制备盐酸头孢甲肟新晶型化合物的方法，其特征在于所述的7-ATCA·HCl与AE活性酯的重量比为1:1～1:3。
  4. 如权利要求2所述的一种制备盐酸头孢甲肟新晶型化合物的方法，其特征在于步骤(1)中所述的盐酸浓度为5～8mol/L。
  5. 如权利要求2所述的一种制备盐酸头孢甲肟新晶型化合物的方法，其特征在于步骤(1)中所述的盐酸调节的pH为1～3。
  6. 如权利要求2所述的一种制备盐酸头孢甲肟新晶型化合物的方法，其特征在于步骤(2)中所述的碱液为8～12％的碳酸氢钠水溶液。
  7. 如权利要求2所述的一种制备盐酸头孢甲肟新晶型化合物的方法，其特征在于步骤(2)中所述的碱液调节的pH为6～8。
  8. 如权利要求2所述的一种制备盐酸头孢甲肟新晶型化合物的方法，其特征在于步骤(2)中所述的养晶时间为2～4h。
  9. 一种盐酸头孢甲肟药物组合物，其特征在于其含有权利要求1所述的盐酸头孢甲肟新晶型化合物或权利要求2～8任意一项所述的制备方法制得的盐酸 头孢甲肟新晶型化合物。
  10. 如权利要求9所述的药物组合物，其特征在于按重量份数计包括以下重量份的组分：盐酸头孢甲肟(以头孢甲肟计)40～80份和碳酸氢钠20～60份。
PCT/CN2016/085307 2016-02-18 2016-06-08 盐酸头孢甲肟新晶型及制剂 Ceased WO2017140074A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610089927.6A CN105566352A (zh) 2016-02-18 2016-02-18 一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂
CN201610089927.6 2016-02-18

Publications (1)

Publication Number Publication Date
WO2017140074A1 true WO2017140074A1 (zh) 2017-08-24

Family

ID=55877041

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/085307 Ceased WO2017140074A1 (zh) 2016-02-18 2016-06-08 盐酸头孢甲肟新晶型及制剂

Country Status (2)

Country Link
CN (1) CN105566352A (zh)
WO (1) WO2017140074A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114540454A (zh) * 2022-03-09 2022-05-27 浙江东邦药业有限公司 一种酶法合成盐酸头孢卡品匹酯的方法及其合成中间体
CN117736068A (zh) * 2023-12-07 2024-03-22 湖北纪源医药科技有限公司 一种ae-活性酯生产中甲醚母液的绿色处理方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566352A (zh) * 2016-02-18 2016-05-11 海南灵康制药有限公司 一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂
CN109134504A (zh) * 2017-06-16 2019-01-04 陈立平 一种1/2水盐酸头孢甲肟化合物及其药物组合物制剂
CN112661776A (zh) * 2020-12-29 2021-04-16 苏州盛达药业有限公司 一种盐酸头孢甲肟的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101735249A (zh) * 2009-12-12 2010-06-16 桂林澳林制药有限责任公司 速溶型盐酸头孢甲肟的制备工艺
CN102603772A (zh) * 2012-03-08 2012-07-25 哈药集团制药总厂 一种制备无菌盐酸头孢甲肟化合物的方法
CN103159786A (zh) * 2011-12-13 2013-06-19 辽宁海思科制药有限公司 一种高纯度无菌盐酸头孢甲肟的制备方法以及包含该盐酸头孢甲肟的药物组合物
CN103554136A (zh) * 2013-10-31 2014-02-05 哈药集团制药总厂 一种盐酸头孢甲肟干粉的制备方法
CN105001239A (zh) * 2015-05-28 2015-10-28 浙江长典医药有限公司 一种小儿用盐酸头孢甲肟化合物实体及其制剂
CN105566352A (zh) * 2016-02-18 2016-05-11 海南灵康制药有限公司 一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040131628A1 (en) * 2000-03-08 2004-07-08 Bratzler Robert L. Nucleic acids for the treatment of disorders associated with microorganisms
CN101007811A (zh) * 2007-01-16 2007-08-01 陈文展 头孢类化合物的有机胺盐及其制备方法
CN102408439B (zh) * 2011-10-20 2012-08-29 桂林澳林制药有限责任公司 一种注射用盐酸头孢甲肟化合物
CN102731531B (zh) * 2012-06-12 2013-09-04 浙江尖峰药业有限公司 盐酸头孢甲肟化合物及其合成方法
CN103145735B (zh) * 2013-03-21 2014-02-26 四川省惠达药业有限公司 一种注射用盐酸头孢甲肟化合物及其药物组合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101735249A (zh) * 2009-12-12 2010-06-16 桂林澳林制药有限责任公司 速溶型盐酸头孢甲肟的制备工艺
CN103159786A (zh) * 2011-12-13 2013-06-19 辽宁海思科制药有限公司 一种高纯度无菌盐酸头孢甲肟的制备方法以及包含该盐酸头孢甲肟的药物组合物
CN102603772A (zh) * 2012-03-08 2012-07-25 哈药集团制药总厂 一种制备无菌盐酸头孢甲肟化合物的方法
CN103554136A (zh) * 2013-10-31 2014-02-05 哈药集团制药总厂 一种盐酸头孢甲肟干粉的制备方法
CN105001239A (zh) * 2015-05-28 2015-10-28 浙江长典医药有限公司 一种小儿用盐酸头孢甲肟化合物实体及其制剂
CN105566352A (zh) * 2016-02-18 2016-05-11 海南灵康制药有限公司 一种采用粒子过程晶体产品分子组装与形态优化技术的盐酸头孢甲肟新晶型化合物及制剂

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114540454A (zh) * 2022-03-09 2022-05-27 浙江东邦药业有限公司 一种酶法合成盐酸头孢卡品匹酯的方法及其合成中间体
CN114540454B (zh) * 2022-03-09 2023-10-17 浙江东邦药业有限公司 一种酶法合成盐酸头孢卡品匹酯的方法及其合成中间体
CN117736068A (zh) * 2023-12-07 2024-03-22 湖北纪源医药科技有限公司 一种ae-活性酯生产中甲醚母液的绿色处理方法

Also Published As

Publication number Publication date
CN105566352A (zh) 2016-05-11

Similar Documents

Publication Publication Date Title
RU2727509C2 (ru) Полиморфные и псевдополиморфные формы фармацевтического соединения
WO2017140074A1 (zh) 盐酸头孢甲肟新晶型及制剂
CN102010426B (zh) 一种制备头孢唑肟钠的方法
CN102372729B (zh) 一种合成头孢哌酮钠化合物的新方法
CN103539803B (zh) 一种制备头孢曲松钠的方法
EP0581552A2 (en) Triazolylthiomethylthio cephalosporin hyrochloride, its crystalline hydrate and the production of the same
CN104725425B (zh) 一种头孢洛林酯的制备方法
CN114249729B (zh) 一种通过反应结晶制备晶型b阿维巴坦钠的方法
WO2017140072A1 (zh) 一种采用粒子过程晶体产品分子组装与形态优化技术的头孢呋辛钠新晶型化合物及制剂
CN101229129A (zh) 一种头孢替唑钠粉针及其合成方法
CN105017286A (zh) 一种头孢类抗感染药物的制备方法
JPH045038B2 (zh)
CN106317080A (zh) 一种采用耦合结晶技术制备的头孢他啶化合物及其制剂
HUT77700A (hu) Eljárás cefotaxim előállítására
US8178521B2 (en) Cefazolin sodium pentahydrate crystal and its molecular assembly preparation method
WO2016128580A1 (en) Cephalosporin intermediate and process for its preparation
CN110143973B (zh) 一种氟氧头孢钠的制备工艺
CN109912625B (zh) 一种降低头孢他啶杂质h的工艺方法
JPH0324086A (ja) 結晶質セフェム酸付加塩およびそれらの製法
CN108033971B (zh) 一种盐酸头孢卡品酯的合成方法
CN107286183B (zh) 一种头孢克肟的精制方法
WO2017140073A1 (zh) 一种采用粒子过程晶体产品分子组装与形态优化技术的头孢硫脒新晶型化合物及制剂
CN102746323A (zh) 一种头孢呋辛酸的新晶型及其结晶制备方法
KR100509737B1 (ko) 7-아미노세팔로스포란산의 결정화 방법
NO158219B (no) Fremgangsmaate for fremstilling av et krystallinsk hemi-syresalt av et cefalosporinderivat.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16890306

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16890306

Country of ref document: EP

Kind code of ref document: A1