WO2017140073A1 - 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 - Google Patents

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 Download PDF

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WO2017140073A1
WO2017140073A1 PCT/CN2016/085303 CN2016085303W WO2017140073A1 WO 2017140073 A1 WO2017140073 A1 WO 2017140073A1 CN 2016085303 W CN2016085303 W CN 2016085303W WO 2017140073 A1 WO2017140073 A1 WO 2017140073A1
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cefathiamidine
crystalline form
cefotaxime
preparing
cephalosporin
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PCT/CN2016/085303
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French (fr)
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陶灵刚
王静康
尹秋响
郝红勋
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海南灵康制药有限公司
天津大学
陶灵刚
王静康
尹秋响
郝红勋
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    • 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
    • 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
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
    • 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
    • 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 technical field of medicine, and particularly relates to a new crystalline form compound and preparation of cefathiamidine using molecular assembly and morphology optimization technology of particle process crystal products.
  • Cefathiamidine also known as cephalosporin 18, has the chemical name (6R,7R)-3[(acetoxy)methyl]-7-[ ⁇ -(N,N'-diisopropylsulfonium sulphide ))-acetamido] 8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid betaine having the formula C 19 H 28 N 4 O 6 S 2 , molecular weight is 472.59, and its chemical structural formula is:
  • Cefotaxime is a ⁇ -lactam antibiotic developed by Shanghai Pharmaceutical Industry Research Institute and Guangzhou Baiyunshan Pharmaceutical Co., Ltd., which has strong antibacterial activity against Gram-positive bacteria, especially for enterococcus. It is widely used clinically.
  • Cephalosporin has a unique molecular structure of zwitterionic inner salt, which is easy to decompose and discolor when exposed to heat, light, and humidity.
  • Cefotaxime uses bromoacetyl bromide in the synthesis process, and if not handled properly, it is easy to leave bromide ions in the product.
  • the solvent system is not well selected, and it is difficult to remove impurities, resulting in a low crude content.
  • the cefotaxime compound in the domestic market has poor purity, poor color grade and poor stability, thus affecting the quality of the preparation.
  • the conventional crystal form of cefathiamidine 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, thereby obtaining a more reliable cephalosporin crystal form.
  • Molecular assembly and morphological optimization techniques for particle process crystal products are designed to perform molecular order assembly and regular alignment for specific functional product shape optimization requirements.
  • the invention mainly aims at the above problems of the cefathiamidine compound, and based on the sufficient consideration of the 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.
  • a first object of the present invention is to provide a novel crystalline form of cefathiamidine which is prepared by molecular assembly and morphology optimization techniques of a particle process crystal product, and has the characteristics of high purity, good color grade and good stability.
  • the cefotaxime new crystalline form compound of the present invention is determined by X-ray powder diffraction, and the X-ray powder diffraction pattern expressed by the 2 ⁇ diffraction angle is 8.82° ⁇ 0.2°, 11.39° ⁇ 0.2°, 16.94° ⁇ 0.2°, 17.72. Characteristic diffraction peaks are shown at ° ⁇ 0.2°, 18.79° ⁇ 0.2°, 21.09° ⁇ 0.2°, 21.64° ⁇ 0.2°, 24.65° ⁇ 0.2°. As shown in Figure 1.
  • the preparation of the cephalosporin new crystalline form compound of the present invention comprises the following steps:
  • N, N'-diisopropyl sulfide is added to dichloromethane, stirred and dissolved, and bromoacetylaminocephalosporanic acid and triethylamine are added thereto, the reaction is kept, and the reaction temperature is lowered to 0 ° C. Crystal, forming a crystallization liquid, suction filtration, acetone washing, vacuum drying to obtain crude cefathiamidine;
  • the weight ratio of the N,N'-diisopropylthio group to the bromoacetylaminocephalosporanic acid is 1:1 to 1:3; more preferably, the weight ratio is 1:2.
  • the heat retention reaction temperature in the step (1) is 30 to 50 °C. More preferably, the reaction temperature is 45 °C.
  • the crystallization temperature in the step (1) is 0 to 10 °C. More preferably, the temperature is 5 °C.
  • the reagent 1 in the step (2) is one of hydrochloric acid, formic acid and glacial acetic acid. More preferably, the reagent 1 is hydrochloric acid.
  • the reagent 1 is adjusted to pH 3 to 5 in the step (2). More preferred Ground, pH is 4 to 4.5.
  • a second object of the present invention is to provide a preparation comprising the cefotaxime compound of the present invention, which has better stability and less side effects than the conventional products.
  • the preparation of the cefathiamidine preparation of the present invention is mainly for aseptically dispensing the cefotaxime new crystalline compound prepared above.
  • Figure 1 X-ray powder diffraction pattern of a new crystalline form of cefathiamidine. 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 cefuroxime sodium.
  • the X-ray powder diffraction pattern of the cefathiamidine of Example 1 showed characteristic diffraction peaks at 8.42 °, 11.39 °, 16.94 °, 17.72 °, 18.79 °, 21.09 °, 21.64 °, 24.65 ° as indicated by the 2 ⁇ diffraction angle. See Figure 1 of the specification for details.
  • the X-ray powder diffraction pattern of the cefathiamidine of Example 2 shows characteristic diffraction peaks at 8.82°, 11.39°, 16.94°, 17.72°, 18.79°, 21.09°, 21.64°, 24.65° in terms of 2 ⁇ diffraction angle.
  • the X-ray powder diffraction pattern of the cefotaxime of Example 3 is represented by a 2 ⁇ diffraction angle at 8.82°, 11.39°, Characteristic diffraction peaks are shown at 16.94°, 17.72°, 18.79°, 21.09°, 21.64°, and 24.65°.
  • a new crystalline form of cefathiamidine was prepared according to the procedure of Example 1, and the raw material was used to prepare cefotaxime for injection, and the specification was 0.5 g.
  • the cefathiamidine compound was prepared according to the method described in CN104530082A.
  • the cefathiamidine compound was prepared in the same manner as in Comparative Example 1, and the raw material was used to prepare cefathiamidine for injection, and the specification was 0.5 g.
  • the present inventors studied the fluidity of cefathiamidine prepared in Example 1 of the present invention and Comparative Example 1.
  • the results of the angle of repose test are shown in the following table:
  • Example Height H Radius r Angle of repose ⁇ Example 1 30mm 59.0mm 27.0° Comparative example 1 30mm 44.6mm 33.9°
  • the fluidity of the cefotaxime new crystal form compound prepared by the invention is significantly higher than that of the prior art cefathiamidine compound, and can meet the needs of the preparation method in the preparation process of the preparation.
  • cefotaxime new crystal form compound and the preparation thereof of the invention have been tested by various indexes and accelerated tests, and the stability is good and the quality is reliable.

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  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种头孢硫脒新晶型化合物及其结晶制备方法，所述头孢硫脒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。本新晶型化合物具有纯度高、杂质含量低、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头孢硫脒制备的制剂—注射用头孢硫脒。

Description

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 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头孢硫脒新晶型化合物及制剂。
背景技术
头孢硫脒(Cefathiamidine)又名头孢菌素18，化学名为(6R，7R)-3[(乙酰氧基)甲基]-7-[α-(N，N'-二异丙基脒硫基)-乙酰氨基]8-氧代-5-硫杂-1-氮杂双环[4，2，0]辛-2-烯-2-甲酸内铵盐，分子式为C19H28N4O6S2，分子量为472.59，其化学结构式为：
Figure PCTCN2016085303-appb-000001
头孢硫脒是由上海医药工业研究院和广州白云山制药股份有限公司共同自主研发的β-内酰胺类抗生素，对革兰阳性菌有较强的抗菌作用,特别是对肠球菌有独特疗效，临床上使用广泛。
头孢硫脒具有两性离子内盐的独特分子结构，遇热、遇光、遇湿不稳定，易分解变色。头孢硫脒在合成过程中使用溴乙酰溴，如果处理不当，易在产品中残留溴离子。此外在缩合反应中，溶剂系统选择不好，不易去除杂质，造成粗品含量低。目前国内市场上的头孢硫脒化合物，其纯度较差，色级不好，稳定性差，从而影响了其制剂质量。
头孢硫脒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，从而得到一种质量更加可靠的头孢硫脒晶型。
粒子过程晶体产品分子组装与形态优化技术，旨在针对特定的功能产品形态优化的要求，进行分子有序组装与规则排列。
本发明主要针对头孢硫脒化合物存在的以上问题，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、稳定性好的头孢硫脒新晶型化合物，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头孢硫脒新晶型化合物，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。
本发明所述的头孢硫脒新晶型化合物用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8.82°±0.2°，11.39°±0.2°，16.94°±0.2°，17.72°±0.2°，18.79°±0.2°，21.09°±0.2°，21.64°±0.2°，24.65°±0.2°处显示特征衍射峰。如附图1所示。
本发明所述的头孢硫脒新晶型化合物制备包括下列步骤：
(1)N,N’-二异丙基硫加入二氯甲烷中,搅拌溶解，向其中加入溴乙酰氨基头孢烷酸和入三乙胺,保温反应，将反应温度降至至0℃保温析晶，形成结晶液，抽滤，丙酮洗涤，真空干燥得头孢硫脒粗品；
(2)将头孢硫脒粗品溶于注射用水中，药用炭脱色，将脱色液采用除菌过滤器进行过滤，用试剂1调节滤液pH值，向滤液中加入异丙醇，析出结晶，用丙酮洗涤，以乙醇为溶剂，重结晶得精制头孢硫脒。
优选地，上述制备方法中，所述N,N’-二异丙基硫与溴乙酰氨基头孢烷酸的重量比为1:1～1:3；更优选地，重量比为1:2。
优选地，上述制备方法中，所述步骤(1)中的保温反应温度为30～50℃。更优选地，反应温度为45℃。
优选地，上述制备方法中，所述步骤(1)中析晶温度为0～10℃。更优选地，温度为5℃。
优选地，上述制备方法中，所述步骤(2)中的试剂1为盐酸、甲酸、冰醋酸中的一种。更优选地，试剂1为盐酸。
优选地，上述制备方法中，所述步骤(2)中用试剂1调pH为3～5。更优选 地，pH为4～4.5。
本发明的第二目的在于提供一种包含本发明所述头孢硫脒化合物的制剂，该制剂较以往产品具有更好的稳定性且副作用小。
本发明所述的头孢硫脒制剂的制备主要是对上述所制备的头孢硫脒新晶型化合物进行无菌分装。
附图说明
图1：头孢硫脒新晶型化合物的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：头孢硫脒新晶型化合物的制备
(1)N,N’-二异丙基硫5.0g加入120mL二氯甲烷中,搅拌溶解，向其中加入溴乙酰氨基头孢烷酸10.1g和入三乙胺3g，45℃℃保温反应1.5h，将反应温度降至至5℃保温析晶1h，形成结晶液。抽滤，丙酮洗涤2次，每次20ml，40℃真空干燥得头孢硫脒粗品9.4g。
(2)向反应器中加入注射用水50ml和头孢硫脒5.0g，搅拌溶解，加入0.1g药用炭，搅拌脱色30min，将脱色液采用除菌过滤器进行过滤，用盐酸调节滤液pH值为4.1，向滤液中加入异丙醇200ml，降温至0～5℃，搅拌1小时，析出结晶，用丙酮洗涤2次，每次50ml，以乙醇为溶剂，重结晶得头孢硫脒4.4g。
采用X-射线粉末衍射法(XRPD)来研究和表征头孢呋辛钠的新的结晶形式。
仪器设备：EMPYREAN(锐影)X射线衍射仪(荷兰Panalytical公司)。
测定结果：实施例1头孢硫脒的X射线粉末衍射图谱以2θ衍射角表示在8.82°，11.39°，16.94°，17.72°，18.79°，21.09°，21.64°，24.65°处显示特征衍射峰。具体参见说明书附图1。
所述XRPD衍射的具体数据见下表：
表1头孢硫脒晶型
编号 d值 2θ(°) I/I0％
1 10.03 8.82 23.11
2 7.77 11.39 82.63
3 5.24 16.94 56.65
4 5.01 17.72 19.74
5 4.72 18.79 63.72
6 4.21 21.09 58.04
7 4.11 21.64 100.00
8 3.61 24.65 16.46
实施例2：头孢硫脒新晶型化合物的制备
(1)N,N’-二异丙基硫10.2g加入120mL二氯甲烷中,搅拌溶解，向其中加入溴乙酰氨基头孢烷酸10.1g和入三乙胺3.1g，50℃℃保温反应1.5h，将反应温度降至至0℃保温析晶1h，形成结晶液。抽滤，丙酮洗涤2次，每次20ml，40℃真空干燥得头孢硫脒粗品10.5g。
(2)向反应器中加入注射用水50ml和头孢硫脒5.5g，搅拌溶解，加入0.1g药用炭，搅拌脱色30min，将脱色液采用除菌过滤器进行过滤，用盐酸调节滤液pH值为3.5，向滤液中加入异丙醇200ml，降温至0～5℃，搅拌1小时，析出结晶，用丙酮洗涤2次，每次50ml，以乙醇为溶剂，重结晶得头孢硫脒4.8g。
实施例2头孢硫脒的X射线粉末衍射图谱以2θ衍射角表示在8.82°，11.39°，16.94°，17.72°，18.79°，21.09°，21.64°，24.65°处显示特征衍射峰。
实施例3：头孢硫脒新晶型化合物的制备
(1)N,N’-二异丙基硫5.4g加入120mL二氯甲烷中,搅拌溶解，向其中加入溴乙酰氨基头孢烷酸15.3g和入三乙胺4.0g，50℃℃保温反应1.5h，将反应温度降至至0℃保温析晶1h，形成结晶液。抽滤，丙酮洗涤2次，每次20ml，40℃真空干燥得头孢硫脒粗品5.4g。
(2)向反应器中加入注射用水50ml和头孢硫脒5.1g，搅拌溶解，加入0.1g药用炭，搅拌脱色30min，将脱色液采用除菌过滤器进行过滤，用盐酸调节滤液pH值为5.5，向滤液中加入异丙醇200ml，降温至0～5℃，搅拌1小时，析出结晶，用丙酮洗涤2次，每次50ml，以乙醇为溶剂，重结晶得头孢硫脒4.6g。
实施例3头孢硫脒的X射线粉末衍射图谱以2θ衍射角表示在8.82°，11.39°， 16.94°，17.72°，18.79°，21.09°，21.64°，24.65°处显示特征衍射峰。
实施例4：注射用头孢硫脒的制备
按照实施例1的步骤制备头孢硫脒新晶型化合物，采用此原料制备注射用头孢硫脒，规格0.5g。
处方：
Figure PCTCN2016085303-appb-000002
制备过程：
(1)备料：根据原料药含量及水分折算后，按处方量称取头孢硫脒；
(2)分装：在充氮的保护下将其分装于洗净并干燥灭菌的西林瓶中，压塞；
(3)轧盖；
对比例1：头孢硫脒化合物的制备
按照CN104530082A中所述的方法制备头孢硫脒化合物。
制备过程：
将三乙醇胺100g加入到140g丙酮中搅拌溶解，接着加入去离子水30g，搅拌溶解，保持溶液温度26℃，再逐步加入头孢硫脒粗品250g(纯度92.3％)进行反应，搅拌溶解后，继续搅拌20min，将混合液滴到30g丙酮中，析出白色沉淀，过滤，用650ml丙酮洗涤二次，过滤，减压干燥，减压干燥温度为32℃，减压干燥时间为4h，得到头孢硫脒三乙醇胺盐284g。
将头孢硫脒三乙醇胺盐284g，加入到100g水和700g异丙醇的混合溶剂中，在搅拌下用浓度4％的盐酸调节pH至4.6，加活性炭16.8g在26℃温度脱色35min，过滤，将滤液加入436.7g异丙醇中进行析晶，以0.8℃/分钟进行一次降温，同时以35rpm的搅拌速度进行搅拌。降温至4℃后，以0.3℃/min进行二次降温至-3℃，同时以65rpm的搅拌速度进行搅拌，完成二次降温后保持温度搅拌析晶1.5h，过滤，用700ml丙酮洗涤三次，抽干，减压干燥，减压干燥温度为26℃，减压干燥时间为5h，得到高纯度的头孢硫脒化合物195g。
对比例2：注射用头孢硫脒的制备
取对比例1制备头孢硫脒化合物，采用此原料制备注射用头孢硫脒，规格0.5g。
处方：
Figure PCTCN2016085303-appb-000003
制备过程：
(1)备料：根据原料药含量及水分折算后，按处方量称取头孢硫脒；
(2)分装：在充氮的保护下将其分装于洗净并干燥灭菌的西林瓶中，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所制备头孢硫脒化合物进行了纯度检测。纯度检测结果见下表：
表2纯度检测结果
Figure PCTCN2016085303-appb-000004
结果：本发明制备的头孢硫脒新晶型化合物纯度明显高于现有技术制备的头孢硫脒化合物。
试验例2：
本发明人对本发明实施例1和对比例1所制备头孢硫脒的流动性进行了研究。休止角检测方法为将颗粒置于固定的漏斗中，使其自由落至水平面上，形成一底部半径为r的圆盘形堆积体，测定堆积体的高度为H，根据公式tanθ＝H/r计算。休止角检测结果见下表:
表3休止角检测结果
实施例 高度H 半径r 休止角θ
实施例1 30mm 59.0mm 27.0°
对比例1 30mm 44.6mm 33.9°
结果：本发明制备的头孢硫脒新晶型化合物的流动性明显高于现有技术的头孢硫脒化合物，在制剂的制备过程中，可以满足制备方式的需要。
试验例3：
本发明人对本发明实施例4和对比例2所制备注射用头孢硫脒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、可见异物、酸度、含量及有关物质。加速试验考察结果见下表：
表4加速试验考察结果
Figure PCTCN2016085303-appb-000005
结果：实施例与对比例产品在上述试验条件下放置6个月，含量和有关物质及其他各项指标均符合规定，质量较稳定。实施例含量和有关物质较对比例变化小。
本发明的头孢硫脒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。

Claims (8)

  1. 一种头孢硫脒新晶型化合物，其特征在于，以2θ衍射角表示的X射线粉末衍射图谱在8.82°±0.2°，11.39°±0.2°，16.94°±0.2°，17.72°±0.2°，18.79°±0.2°，21.09°±0.2°，21.64°±0.2°，24.65°±0.2°处显示特征衍射峰。
  2. 如权利要求1所述的一种头孢硫脒新晶型化合物，其特征在于，制备方法具体步骤为：
    (1)N,N’-二异丙基硫加入二氯甲烷中,搅拌溶解，向其中加入溴乙酰氨基头孢烷酸和入三乙胺,保温反应，将反应温度降至至0℃保温析晶，形成结晶液,抽滤，丙酮洗涤，真空干燥得头孢硫脒粗品；
    (2)将头孢硫脒粗品溶于注射用水中，药用炭脱色，将脱色液采用除菌过滤器进行过滤，用试剂1调节滤液pH值，向滤液中加入异丙醇，析出结晶，用丙酮洗涤，以乙醇为溶剂，重结晶得精制头孢硫脒。
  3. 如权利要求2所述的一种制备头孢硫脒新晶型化合物的方法，其特征在于步骤(1)中的N,N’-二异丙基硫与溴乙酰氨基头孢烷酸的重量比为1:1～1:3。
  4. 如权利要求2所述的一种制备头孢硫脒新晶型化合物的方法，其特征在于步骤(1)中的保温反应温度为30～50℃。
  5. 如权利要求2所述的一种制备头孢硫脒新晶型化合物的方法，其特征在于步骤(1)中的析晶温度为0～10℃。
  6. 如权利要求2所述的一种制备头孢硫脒新晶型化合物的方法，其特征在于步骤(2)中的试剂1为盐酸、甲酸、冰醋酸中的一种。
  7. 如权利要求2所述的一种制备头孢硫脒新晶型化合物的方法，其特征在于步骤(2)中的用试剂1调pH为3～5。
  8. 一种注射用头孢硫脒，其特征在于，其含有权利要求1所述的头孢硫脒新晶型化合物或权利要求2～7任意一项所述的制备方法制得的头孢硫脒新晶型化合物。
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