WO2016107331A1 - 一种头孢硫脒化合物新晶型及其制备方法 - Google Patents

一种头孢硫脒化合物新晶型及其制备方法 Download PDF

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WO2016107331A1
WO2016107331A1 PCT/CN2015/095233 CN2015095233W WO2016107331A1 WO 2016107331 A1 WO2016107331 A1 WO 2016107331A1 CN 2015095233 W CN2015095233 W CN 2015095233W WO 2016107331 A1 WO2016107331 A1 WO 2016107331A1
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compound
solution
cefathiamidine
preparation
cefotaxime
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PCT/CN2015/095233
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English (en)
French (fr)
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郝红勋
陶灵刚
孙志红
侯宝红
吕军
尹秋响
王永莉
龚俊波
谢闯
鲍颖
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天津大学
海南灵康制药有限公司
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Priority to US15/304,824 priority Critical patent/US9637502B2/en
Publication of WO2016107331A1 publication Critical patent/WO2016107331A1/zh

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    • 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
    • C07D501/60—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 3 and 4
    • 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
    • C07D501/26—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
    • 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 chemical engineering crystallization, and particularly relates to a novel crystal form of a cefathiamidine compound and a crystallization preparation method thereof.
  • 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 , the molecular weight is 472.59, and its chemical structural formula is as follows.
  • Cefmenoxime is a ⁇ -lactam antibiotic, belonging to the first generation cephalosporin. Its antibacterial spectrum is similar to that of cefotaxime. It has antibacterial activity against Gram-positive bacteria and some negative bacteria, and is mainly used for Staphylococcus aureus, pneumococcal and chain. Infections caused by cocci, respiratory infections, biliary infections, urinary tract infections, gynecological infections, sepsis, pneumonia, meningitis, etc.
  • Cephalosporin has a polymorphic phenomenon, and various crystal forms and preparation methods thereof have been reported in the literature.
  • CN1462751A discloses a crystalline cefotaxime and a preparation method and use thereof
  • FIG. 1 shows an X-ray powder diffraction pattern of cefathiamidine obtained by the method. The method controls the pH of the cefathiamidine solution to 3.5-6.5, controls the saturation process and the crystal growth rate by adding an appropriate lysing agent, crystallizes, filters, and dries to obtain crystalline cefathiamidine.
  • cefathiamidine has a molecular structure of a zwitterionic inner salt, which is unstable in heat and easily forms an amorphous powder, resulting in low purity of the drug and unstable storage.
  • Patent CN1495187A discloses a crystalline cefotaxime and a preparation method thereof, and FIG. 2 shows an X-ray powder diffraction pattern of cefathiamidine obtained by the method. The method comprises the steps of: adding a suitable eluent to a cefotaxime solution to crystallize the solution, separating and drying to obtain a cefathiamidine crystal.
  • the crystal form has better stability than amorphous and has a decomposition temperature of 154 ⁇ 1 ° C or more, but the crystallinity is not high as judged from the xrd data.
  • "Preparation and Stability of Different Crystal Forms of Cephalosporin” [Liu Shuzhen, Sun Yuexi, Preparation and Stability of Different Crystal Forms of Cefotaxime[J], Chinese Journal of Antibiotics, 2010, 35 (10): 760-762]
  • the crystallization of cefathiamidine in different solvents was studied, and a new crystalline form of cefathiamidine was obtained in acetonitrile solvent.
  • Figure 3 shows the cephalosporin crystal form X. Ray powder diffraction pattern.
  • the thermal decomposition temperature of the crystal form is 145.4 ° C
  • the thermal decomposition temperature of the crystal form II obtained by recrystallization from isopropanol is (153.2 ° C)
  • the stability of the crystal form is lower than that of the crystal form prepared by the patent CN1495187A.
  • CN103012434A discloses a cefathiamidine compound crystal, a preparation method thereof and a pharmaceutical composition thereof
  • Fig. 4 shows a cephalosporin X-ray powder diffraction pattern obtained by the method.
  • the method has high operating temperature, high energy consumption and long process flow, and the pharmaceutical composition contains sodium benzoate, which is harmful to the human liver when the dose is increased.
  • the present invention has a novel crystal form of a cefathiamidine compound having a higher melting point and a higher thermal cracking temperature, and a melting point thereof (169.6). Both ⁇ 1 ° C) and thermal cracking temperature (172.2 ⁇ 1 ° C) are higher than the reported crystal forms.
  • the crystalline product has been found to have excellent thermal stability by drug storage tests. At the same time, the purity of the crystal form product can reach above 99.0%, and the yield of the crystallization process is above 85%.
  • the new crystalline form of the cefathiamidine compound provided by the present invention is determined by X-ray powder diffraction, and the X-ray powder diffraction pattern represented by the 2 ⁇ diffraction angle is 7.26° ⁇ 0.2°, 8.08° ⁇ 0.2°, 10.38° ⁇ 0.2°, 12.64°. ⁇ 0.2°, 13.96° ⁇ 0.2°, 14.52° ⁇ 0.2°, 16.60° ⁇ 0.2°, 19.22° ⁇ 0.2°, 20.04° ⁇ 0.2°, 21.14° ⁇ 0.2°, 21.84° ⁇ 0.2°, 22.74° ⁇ 0.2
  • the characteristic diffraction peak is shown at ° as shown in FIG.
  • the new crystalline crystal of the cefotaxime new compound provided by the invention has a DSC melting endothermic peak at 169.6 ⁇ 1°C, and the liberation heat temperature is 172.2 ⁇ 1°C, as shown in the drawing. 6 is shown.
  • Test conditions temperature range 25 to 200 ° C, heating rate 10 ° C / min, nitrogen protection: 80 ml / min.
  • the crystallization method for preparing a new crystalline form of a cefathiamidine compound provided by the present invention is as follows:
  • the cefathiamidine compound having a purity of 98% or more is dissolved in a solvent to form a solution at a temperature of 30 to 45 ° C, and the solution concentration is controlled at 0.05 to 0.2 g/mL, and then the solution is added dropwise to the solution.
  • the volume of the precipitation agent is 3 to 5 times the amount of the solvent; after the addition of the dissolution agent, the solution is cooled to 0 to 10 ° C at a temperature decreasing rate of 0.2 to 1 ° C / min; stirring is continued for 1 to 3 hours, and the obtained solid-liquid suspension is obtained. Separation and drying to obtain a new crystalline product of cefathiamidine compound.
  • the solvent is selected from one or a mixture of methanol, ethanol or water.
  • the leaching agent is selected from the group consisting of n-propanol, isopropanol, n-butanol, cyclohexane or n-hexane or A mixture of several.
  • the elution agent is added dropwise for 3 to 6 hours.
  • the drying conditions are a temperature of 25 to 35 ° C, a degree of vacuum of 0.08 to 0.1 MPa, and a drying time of 4 to 8 hours.
  • the preparation method of the new crystalline form of the cefathiamidine compound of the invention has the advantages that the operating conditions are simple and easy to control, the product crystal slurry is easy to be filtered, washed and dried, and the X-ray powder diffraction result shows that the product has high crystallinity, complete crystal form, and crystallization process.
  • the single pass molar yield is above 85%, and the product purity is above 99%.
  • the melting temperature of the new crystal product reached 169.6 ⁇ 1°C
  • the thermal cracking temperature reached 172.2 ⁇ 1°C, which was higher than the melting and thermal cracking temperature of the crystal form already reported by the patent.
  • Figure 1 X-ray powder diffraction pattern of crystalline cefotaxime disclosed by CN1462751A;
  • Figure 2 X-ray powder diffraction pattern of crystalline cefotaxime disclosed in CN1495187A;
  • Figure 3 X-ray powder diffraction pattern of crystalline cefotaxime obtained in acetonitrile solvent reported in the literature;
  • Figure 4 X-ray powder diffraction pattern of crystalline cefotaxime disclosed in CN103012434A;
  • Figure 5 X-ray powder diffraction pattern of a new crystalline form of the cefathiamidine compound of the present invention
  • the PXRD pattern of the crystalline product is as shown in Figure 5, at 2 ⁇ diffraction angles of 7.26°, 8.08°, 10.38°, 12.64°, 13.96°, 14.52°, 16.60°, 19.22°, 20.04°, There are characteristic peaks at 21.14°, 21.84°, 22.74°; the DSC data of the crystal product is as shown in Fig. 6, which has a melting endothermic peak at 169.6 ° C and a liberation heat peak at 172.1 ° C; the product HPLC purity is 99.2. %, the molar yield of the crystallization process was 85.5%.
  • the melting and thermal decomposition temperatures of the new crystalline form of the cefotaxime compound of the present invention are 169.6 ° C and 172.1 ° C, respectively, which are higher than the crystal forms already reported by the patent, and therefore have better thermal stability, confirmed by thermal stability test. It was left at 30 ° C for 4 months and the crystal form did not change.
  • the PXRD pattern of the crystalline product has a 2 ⁇ diffraction angle of 7.24°, 8.08°, 10.36°, 12.74°, 13.86°, 14.42°, 16.70°, 19.22°, 20.04°, 21.26°, 21.84°, 22.92°.
  • the characteristic peak its DSC spectrum has a melting endothermic peak at 169.8 ° C, and a liberation heat peak at 172.3 ° C; the product HPLC purity is 99.4%, and the molar yield of the crystallization process is 90.3%.
  • the melting and thermal decomposition temperatures of the new crystalline form of the cefathiamidine compound of the present invention are 169.8 ° C and 172.3 ° C, respectively, both higher than the crystal forms already reported by the patent, and thus have better thermal stability, confirmed by thermal stability test, It was left at 30 ° C for 4 months and the crystal form did not change.
  • the obtained filter cake was dried at 35 ° C and a vacuum of 0.09 MPa for 5 hours to obtain a new crystalline form of the final cephalosporin compound having a PXRD pattern at a 2 ⁇ diffraction angle of 7.46°, 8.28°, 10.37°, 12.75°. , 13.86 °, 14.48 °, 16.60 °, 19.22 °, 20.24 °, 21.34 °, 21.84 °, 22.74 ° characteristic peak; its DSC spectrum has a melting endothermic peak at 169.7 ° C, 172.0 ° C has a liberation heat peak;
  • the HPLC purity was 99.4% and the molar yield of the crystallization process was 90.5%.
  • the melting and thermal decomposition temperatures of the new crystalline form of the cefotaxime compound of the present invention are 169.7 ° C and 172.0 ° C, respectively, which are higher than the crystal forms already reported by the patent, and thus have better thermal stability, confirmed by thermal stability test. It was left at 30 ° C for 4 months and the crystal form did not change.
  • the PXRD pattern of the crystalline product has a 2 ⁇ diffraction angle of 7.06°, 7.99°, 10.36°, 12.63°, 13.88°, 14.42°, 16.62°, 19.22°, 20.04°, 21.14°, 21.86°, 22.76°.
  • the PXRD pattern of the crystalline product was at a diffraction angle of 2.14, 8.06, 10.18, 12.44, 13.76, 14.32, 16.64. °, 19.10 °, 20.16 °, 21.02 °, 21.64 °, 22.78 ° has a characteristic peak; its DSC spectrum has a melting endothermic peak at 169.3 ° C, 171.8 ° C has a liberation heat peak; product HPLC purity is 99.3%, crystallization process The molar yield was 91.1%.
  • the melting and thermal decomposition temperatures of the new crystalline form of the cefotaxime compound of the present invention are 169.3 ° C and 171.8 ° C, respectively, both higher than the crystal form already reported by the patent, and thus have better thermal stability.
  • Sexuality confirmed by thermal stability test, it did not change when stored at 30 ° C for 4 months.
  • Toxicity studies showed that the LD50 of intravenous injection in mice was (1.10 ⁇ 0.02) g/kg, and the LD50 of intraperitoneal injection was (1.30 ⁇ 0.20) g/kg, which was superior to the prior art; reproductive toxicity test showed that the preparation of the present invention The reproductive toxicity of cefathiamidine compounds is superior to the prior art and is more suitable for clinical research.
  • the in vitro antibacterial activity test showed that the MIC90 of S. pneumoniae was 0.24 ⁇ g/ml, the MIC90 of S. pyogenes was 0.48 ⁇ g/ml, and the MIC90 of the other three bacteria was less than 7.8 ⁇ g/ml, and the MIC90 against Haemophilus influenzae was MIC90. 1.8 ⁇ g/ml, the MIC90 of Enterococcus is 1.9 ⁇ g/ml, and the antibacterial activity is better than the prior art, which is more suitable for clinical application.

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Abstract

一种头孢硫脒化合物的新晶型及其如下制备方法：将纯度大于等于98％的头孢硫脒化合物溶解在选自甲醇等的溶剂中形成浓度为0.05～0.2g/mL的溶液，再向溶液中滴加选自正丙醇等的溶析剂；随后以0.2～1℃/min降温速率将溶液降温至0～10℃；继续搅拌1～3h，将所得的固液悬浮液分离，干燥，得到该晶型产品。

Description

一种头孢硫脒化合物新晶型及其制剂和制备方法 技术领域
本发明属于化学工程结晶技术领域，特别涉及一种头孢硫脒化合物的新晶型及其结晶制备方法。
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，其化学结构式如下所示。
Figure PCTCN2015095233-appb-000001
头孢硫脒为β-内酰胺类抗生素，属于第一代头孢菌素，抗菌谱与头孢噻吩相似，对革兰阳性菌及部分阴性菌有抗菌活性，主要用于金葡菌、肺炎球菌及链球菌所致呼吸道感染、胆道感染、尿路感染、妇科感染、败血症、肺炎、脑膜炎等感染。
头孢硫脒具有多晶型现象，文献中报道了多种晶型及其制备方法。CN1462751A公开了一种结晶头孢硫脒及其制备方法和用途，附图1所示为该方法所得头孢硫脒X射线粉末衍射图。该方法将头孢硫脒溶液的pH控制在3.5-6.5，通过加入适当溶析剂控制饱和过程和晶体生长速度，结晶，过滤，干燥得到结晶头孢硫脒。但头孢硫脒具有两性离子內盐的分子结构，遇热不稳定，容易形成无定形粉末，造成药品纯度低，储存不稳定。专利CN1495187A公开了一种结晶头孢硫脒及其制备方法，附图2所示为该方法所得头孢硫脒X射线粉末衍射图。该方法通过向头孢硫脒溶液中加入合适溶析剂至溶液结晶，分离，干燥，得到头孢硫脒晶体。该晶型比无定形稳定性好，具有154±1℃以上的分解温度，但从xrd数据判断，其结晶度不高。“不同晶型头孢硫脒的制备及稳定性研究”【刘书妤，孙悦蛟，不同晶型头孢硫脒的制备及稳定性研究[J]，中国抗生素杂志，2010,35 (10)：760-762】研究了头孢硫脒在不同溶剂中的结晶情况，并在乙腈溶剂中得到了一种头孢硫脒新晶型，附图3所示为该头孢硫脒晶型X射线粉末衍射图。但该晶型的热裂解温度为145.4℃，小于异丙醇中重结晶得到的晶型II的热裂解温度为(153.2℃)，该晶型的稳定性低于专利CN1495187A制备的晶型。CN103012434A公开了一种头孢硫脒化合物晶体及其制备方法及其药物组合物，附图4所示为该方法所得头孢硫脒X射线粉末衍射图。该方法操作温度高，能耗大，工艺流程长，其药物组合物含有苯甲酸钠，当药量增大时对人体肝脏存在危害。
为了进一步提高头孢硫脒化合物的热稳定性和产品纯度，本专利发明了一种头孢硫脒化合物的新晶型，该晶型具有更高的熔点和更高的热裂解温度，其熔点(169.6±1℃)和热裂解温度(172.2±1℃)均高于已报道的晶型。通过药品储存试验发现，该晶型产品具有优良的热稳定性。同时,该晶型产品纯度可以达到99.0％以上,结晶过程收率在85％以上。
发明内容
本发明的目的是提供一种头孢硫脒化合物的新晶型及其结晶制备方法。
本发明提供的头孢硫脒化合物新晶型用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7.26°±0.2°,8.08°±0.2°,10.38°±0.2°,12.64°±0.2°,13.96°±0.2°,14.52°±0.2°,16.60°±0.2°,19.22°±0.2°,20.04°±0.2°,21.14°±0.2°，21.84°±0.2°，22.74°±0.2°处显示特征衍射峰，如附图5所示。
本发明提供的头孢硫脒新化合物新晶型晶体，用差式扫描量热仪测定，在169.6±1℃有一个DSC熔化吸热峰，其分解放热温度为172.2±1℃，如附图6所示。测试条件：温度范围25～200℃，升温速率为10℃/min，保护氮气：80ml/min。
本发明提供的头孢硫脒化合物新晶型的结晶制备方法如下：
在温度30～45℃的条件下，将纯度大于等于98％的头孢硫脒化合物溶解在溶剂中形成溶液，溶液浓度控制在0.05～0.2g/mL，再向溶液中滴加溶析剂，溶析剂体积用量为溶剂用量的3～5倍；加完溶析剂后以0.2～1℃/min降温速率将溶液降温至0～10℃；继续搅拌1～3h，将所得的固液悬浮液分离，干燥，得到头孢硫脒化合物新晶型产品。
上述方法中,所述的溶剂选自甲醇、乙醇或水中的一种或者几种的混合物。
上述方法中,所述的溶析剂选自正丙醇、异丙醇、正丁醇、环己烷或正己烷的一种或 者几种的混合物。
上述方法中,所述的溶析剂滴加时间为3～6h。
上述方法中,所述的干燥条件是温度为25～35℃，真空度为0.08～0.1MPa，干燥时间为4～8小时。
本发明的头孢硫脒化合物新晶型的制备方法的优点是操作条件简单易控，产品晶浆易过滤、洗涤和干燥，X射线粉末衍射结果显示产品结晶度高，晶型完整，结晶过程的单程摩尔收率在85％以上，产品纯度在99％以上。同时，新晶型产品熔化温度达到169.6±1℃,热裂解温度达到172.2±1℃，比专利已经报道的晶型的熔化和热裂解温度更高，同时通过稳定性研究发现，该晶型产品具有更优良的热稳定性。
本发明获得的头孢硫脒新晶型化合物的毒性研究和体外抗菌活性试验表明，其优于现有技术，更加适合于临床研究和应用。
附图说明
图1：CN1462751A公开的结晶头孢硫脒X射线粉末衍射图谱；
图2：CN1495187A公开的结晶头孢硫脒X射线粉末衍射图谱；
图3：文献报道的在乙腈溶剂中得到的结晶头孢硫脒X射线粉末衍射图谱；
图4：CN103012434A公开的结晶头孢硫脒X射线粉末衍射图谱；
图5：本专利发明的头孢硫脒化合物新晶型的X射线粉末衍射图谱；
图6：本专利发明的头孢硫脒化合物新晶型的DSC图谱；
具体实施方式
下面通过附图和实施例对本发明进一步详细说明。通过这些说明，本发明的特点和优点将变得更为清楚明确。
实施例1
在温度为45℃条件下，将5g纯度为98％的头孢硫脒固体加入100mL乙醇中，使其完全溶解，向溶液中滴加300mL异丙醇,滴加3h；加完溶析剂后以0.2℃/min降温速率将溶液降温至0℃；继续搅拌3h，将所得的固液悬浮液分离，在25℃、真空度为0.08Mpa下干燥所得滤饼4小时，得到最终头孢硫脒化合物新晶型，该晶型产品的PXRD图谱如附图5所示，在2θ衍射角7.26°,8.08°,10.38°,12.64°,13.96°,14.52°,16.60°,19.22°,20.04°, 21.14°，21.84°，22.74°处有特征峰；该晶型产品的DSC数据如附图6所示，其在169.6℃有熔化吸热峰,172.1℃有分解放热峰；产品HPLC纯度为99.2％，结晶过程的摩尔收率为85.5％。本发明的头孢硫脒化合物新晶型的熔化和热分解温度分别为169.6℃和172.1℃,均高于专利已经报道的晶型,因此具有更好的热稳定性,经热稳定性试验证实,其置于30℃存放4个月晶型未发生变化。
实施例2
在温度为42℃条件下，将15g纯度为98.3％的头孢硫脒固体加入100mL甲醇中，使其完全溶解，向溶液中滴加400mL正己烷,滴加6h；加完溶析剂后以0.5℃/min降温速率将溶液降温至10℃；继续搅拌3h，将所得的固液悬浮液分离，在25℃、真空度为0.1Mpa下干燥所得滤饼8小时，得到最终头孢硫脒化合物新晶型，该晶型产品的PXRD图谱在2θ衍射角7.24°,8.08°,10.36°,12.74°,13.86°,14.42°,16.70°,19.22°,20.04°,21.26°，21.84°，22.92°处有特征峰；其DSC谱图在169.8℃有熔化吸热峰,172.3℃有分解放热峰；产品HPLC纯度为99.4％，结晶过程的摩尔收率为90.3％。本发明的头孢硫脒化合物新晶型的熔化和热分解温度分别为169.8℃和172.3℃,均高于专利已经报道的晶型,因此具有更好的热稳定性,经热稳定性试验证实,其置于30℃存放4个月晶型未发生变化。
实施例3
在温度为30℃条件下，将18g纯度为98.7％的头孢硫脒固体加入100mL水中，使其完全溶解，向溶液中滴加500mL正丁醇,滴加6h；加完溶析剂后以1℃/min降温速率将溶液降温至5℃；继续搅拌2h，将所得的固液悬浮液分离，在30℃、真空度为0.09Mpa下干燥所得滤饼6小时，得到最终头孢硫脒化合物新晶型，该晶型产品的PXRD图谱在2θ衍射角7.24°,8.18°,10.40°,12.66°,13.86°,14.54°,16.62°,19.14°,19.96°,21.14°，21.66°，22.76°处有特征峰；其DSC图谱在169.4℃有熔化吸热峰,172.3℃有分解放热峰；产品HPLC纯度为99.0％，结晶过程的摩尔收率为89.3％。本发明的头孢硫脒化合物新晶型的熔化和热分解温度分别为169.4℃和172.3℃,均高于专利已经报道的晶型,因此具有更好的热稳定性,经热稳定性试验证实,其置于30℃存放4个月晶型未发生变化。
实施例4
在温度为35℃条件下，将10g纯度为98.5％的头孢硫脒固体加入100mL甲醇中，使 其完全溶解，向溶液中滴加400mL正丙醇,滴加5h；加完溶析剂后以0.6℃/min降温速率将溶液降温至0℃；继续搅拌1h，将所得的固液悬浮液分离，在35℃、真空度为0.09Mpa下干燥所得滤饼5小时，得到最终头孢硫脒化合物新晶型，该晶型产品的PXRD图谱在2θ衍射角7.46°,8.28°,10.37°,12.75°,13.86°,14.48°,16.60°,19.22°,20.24°,21.34°，21.84°，22.74°处有特征峰；其DSC图谱在169.7℃有熔化吸热峰,172.0℃有分解放热峰；产品HPLC纯度为99.4％，结晶过程的摩尔收率为90.5％。本发明的头孢硫脒化合物新晶型的熔化和热分解温度分别为169.7℃和172.0℃,均高于专利已经报道的晶型,因此具有更好的热稳定性,经热稳定性试验证实,其置于30℃存放4个月晶型未发生变化。
实施例5
在温度为32℃条件下，将20g纯度为98.7％的头孢硫脒固体加入100mL水中，使其完全溶解，向溶液中滴加350mL环己烷,滴加3h；加完溶析剂后以0.2℃/min降温速率将溶液降温至8℃；继续搅拌2h，将所得的固液悬浮液分离，在25℃、真空度为0.08Mpa下干燥所得滤饼8小时，得到最终头孢硫脒化合物新晶型，该晶型产品的PXRD图谱在2θ衍射角7.06°,7.99°,10.36°,12.63°,13.88°,14.42°,16.62°,19.22°,20.04°,21.14°，21.86°，22.76°处有特征峰；其DSC图谱在169.2℃有熔化吸热峰,172.1℃有分解放热峰；产品HPLC纯度为99.3％，结晶过程的摩尔收率为89.6％。本发明的头孢硫脒化合物新晶型的熔化和热分解温度分别为169.2℃和172.1℃,均高于专利已经报道的晶型,因此具有更好的热稳定性,经热稳定性试验证实,其置于30℃存放4个月晶型未发生变化。
实施例6
在温度为38℃条件下，将12g纯度为98.5％的头孢硫脒固体加入100mL水/乙醇混合溶剂中，其中水和乙醇的体积比为1:1，头孢硫脒完全溶解后向溶液中滴加500mL正丙醇,滴加6h；加完溶析剂后以0.5℃/min降温速率将溶液降温至2℃；继续搅拌1h，将所得的固液悬浮液分离，在28℃、真空度为0.1Mpa下干燥所得滤饼5小时，得到最终头孢硫脒化合物新晶型，该晶型产品的PXRD图谱在2θ衍射角7.14°,8.06°,10.18°,12.44°,13.76°,14.32°,16.64°,19.10°,20.16°,21.02°，21.64°，22.78°处有特征峰；其DSC图谱在169.3℃有熔化吸热峰,171.8℃有分解放热峰；产品HPLC纯度为99.3％，结晶过程的摩尔收率为91.1％。本发明的头孢硫脒化合物新晶型的熔化和热分解温度分别为169.3℃和171.8℃,均高于专利已经报道的晶型,因此具有更好的热稳定 性,经热稳定性试验证实,其置于30℃存放4个月晶型未发生变化。
毒性实验和体外抗菌活性实验：
对本发明获得的头孢硫脒新晶型化合物进行毒性实验和体外抗菌活性实验(以实施例1获得的头孢硫脒化合物晶型为例)。
毒性研究显示，小鼠静脉注射的LD50为(1.10±0.02)g/kg，腹腔注射的LD50为(1.30±0.20)g/kg，优于现有技术；生殖毒性试验显示，本发明制得的头孢硫脒化合物的生殖毒性优于现有技术，更加适用于临床研究。
体外抗菌活性试验显示，对肺炎链球菌MIC90为0.24μg/ml，对化脓性链球菌MIC90为0.48μg/ml，对其他3种细菌的MIC90均小于7.8μg/ml，对流感嗜血杆菌MIC90为1.8μg/ml，对肠球菌MIC90为1.9μg/ml，抗菌活性优于现有技术，更加适合临床应用。
本发明公开和提出的头孢硫脒化合物新晶型及其制备方法，本领域技术人员可通过借鉴本文内容，适当改变原料、工艺参数等环节实现。本发明的方法与产品已通过较佳实施例子进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和产品进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，他们都被视为包括在本发明精神、范围和内容中。

Claims (7)

  1. 一种头孢硫脒化合物新晶型，其特征是：以2θ衍射角表示的X射线粉末衍射图谱在7.26°±0.2°,8.08°±0.2°,10.38°±0.2°,12.64°±0.2°,13.96°±0.2°,14.52°±0.2°,16.60°±0.2°,19.22°±0.2°,20.04°±0.2°,21.14°±0.2°，21.84°±0.2°，22.74°±0.2°处显示特征衍射峰。
  2. 如权利要求1所述的头孢硫脒化合物新晶型，其特征是差示扫描量热曲线在169.6±1℃处有一个熔化吸热峰，在172.2±1℃处有一个分解放热峰。
  3. 一种制备头孢硫脒化合物新晶型的方法，其特征是：在温度30～45℃的条件下，将纯度大于等于98％的头孢硫脒化合物溶解在溶剂中形成溶液，溶液浓度控制在0.05～0.2g/mL，再向溶液中滴加溶析剂，溶析剂体积用量为溶剂用量的3～5倍；加完溶析剂后以0.2～1℃/min降温速率将溶液降温至0～10℃；继续搅拌1～3h，将所得的固液悬浮液分离，干燥，得到头孢硫脒化合物新晶型产品。
  4. 如权利要求3所述的制备方法，其特征是所述的溶剂为甲醇、乙醇或水中的一种或者几种的混合物。
  5. 如权利要求3所述的制备方法，其特征是所述溶析剂选自正丙醇、异丙醇、正丁醇、环己烷或正己烷的一种或几种的混合物。
  6. 如权利要求3所述的制备方法，其特征是所述的溶析剂滴加时间为3～6h。
  7. 如权利要求3所述的制备方法，其特征是所述的干燥条件是温度为25～35℃，真空度为0.08～0.1MPa，干燥时间为4～8小时。
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