WO2016095660A1 - 头孢孟多酯钠化合物新晶型及其制剂和制备方法 - Google Patents

头孢孟多酯钠化合物新晶型及其制剂和制备方法 Download PDF

Info

Publication number
WO2016095660A1
WO2016095660A1 PCT/CN2015/095229 CN2015095229W WO2016095660A1 WO 2016095660 A1 WO2016095660 A1 WO 2016095660A1 CN 2015095229 W CN2015095229 W CN 2015095229W WO 2016095660 A1 WO2016095660 A1 WO 2016095660A1
Authority
WO
WIPO (PCT)
Prior art keywords
sodium
suspension
crystal
preparation
product
Prior art date
Application number
PCT/CN2015/095229
Other languages
English (en)
French (fr)
Inventor
郝红勋
陶灵刚
何芳
侯宝红
王静康
吕军
尹秋响
王永莉
龚俊波
谢闯
鲍颖
Original Assignee
天津大学
海南灵康制药有限公司
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 天津大学, 海南灵康制药有限公司 filed Critical 天津大学
Priority to US15/305,661 priority Critical patent/US20170050982A1/en
Publication of WO2016095660A1 publication Critical patent/WO2016095660A1/zh
Priority to US15/687,359 priority patent/US9834567B1/en

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
    • 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
    • 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 separation, and particularly relates to a novel crystal form of a sodium cefmenudate compound and a preparation method thereof.
  • the chemical name of sodium cefamandole nafate is 7-D-(2-formyloxyphenylacetamide)-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl] 8-Oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylate having a molecular formula of C 19 H 18 N 6 NaO 6 S 2 and a molecular weight of 512.50.
  • the structural formula is as shown in formula (I).
  • Cefmenidran sodium was developed by Lilly Corporation of the United States in 1972 and first marketed in 1978. The injectable is commercially available under the trade name MANDOL.
  • Sodium cefmenudate is a second-generation semi-synthetic cephalosporin with strong bactericidal effect. It has certain advantages of both first-generation and third-generation cephalosporins. It is stable to ⁇ -lactamase and has low nephrotoxicity. The blood drug concentration is high, the tissue permeability is good, and the antibacterial spectrum is wide.
  • ceftime sodium has a strong effect on Gram-negative bacteria, and has strong effects on Clostridium oxysporum, meningococcal, gonococcal, Escherichia coli, Klebsiella pneumoniae, influenza bacillus and Proteus. Especially for Haemophilus, it is clinically used for pulmonary infection, urinary tract infection, biliary tract infection, skin and soft tissue infection, bone and joint infection, sepsis, abdominal infection, etc. caused by sensitive bacteria. It has low adverse reactions and good tolerance and is a safe and effective antibacterial drug.
  • the present invention invents a novel crystal form of a cefomen poly(sodium) compound having a melting range of 150-180 ° C and a peak at 165 ⁇ 2 ° C (the melting range of a common crystal form is 90-100 ° C), improve the thermal stability of the product, the product is not easy to deteriorate when stored.
  • the appearance of the new crystal form is thick rod, while the traditional stable crystal form is fine needle shape, so the new crystal product has better fluidity and higher bulk density, which significantly improves the packaging and transportation of the product. Sex.
  • the DSC analysis of the crystal of the sodium cefmenudate compound showed an endothermic peak at 165 ⁇ 2 ° C, as shown in FIG. 2 .
  • the crystal of the sodium cefmenudate compound has a crystal appearance as shown in FIG.
  • the method for preparing the crystal of the cefmenoxime sodium compound according to the present invention comprises: adding solid sodium cefomen polyester to an organic solvent to prepare a suspension of 0.04 to 0.3 g/ml, and stirring and suspending the suspension at 40 to 50 ° C for a period of time. Then, the temperature is lowered to 5-15 ° C at a certain cooling rate for a period of time, and the obtained suspension is filtered by suction, and the obtained filter cake is a wet product of ceftime polyester sodium, and dried wet crystal product of cefmenoxime sodium to constant weight. A final new product of sodium cefmenudate sodium is obtained.
  • the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, isoamyl alcohol, n-pentanol, ethyl acetate, 1,4-dioxane Or a mixed solution of one or several of acetone.
  • the agitation rate of the suspension in the process is from 600 to 1200 rpm.
  • the stirring time before the suspension is cooled is 5 to 10 hours.
  • the stirring time after the suspension is cooled is 5 to 10 hours.
  • the cooling rate of the suspension in the method is 0.2 to 2 ° C / min.
  • the drying conditions in the method are carried out at 20 to 70 ° C under normal pressure for 6 to 12 hours.
  • the method has the following beneficial effects: the operation step is simple and easy to operate, and the energy consumption is small.
  • the prepared product has a melting range of 160-170 ° C, good thermal stability, and is more conducive to long-term preservation; purity is higher than 99%, yield is higher than 90%, product purity and color after storage for 100 days under normal temperature and dry conditions The shape has not changed.
  • the product is easy to comminute and easy to add to the dosage form of the pharmaceutical composition, as well as low cost and easier to implement on a commercial industrial scale.
  • the new crystalline form of the sodium cefmenudate compound obtained by the method has higher melting point than the reported crystalline form, better thermal stability, no degradation change for a long time; better crystal habit, higher bulk density, flow
  • the property is better, the particle size distribution is more uniform, and it is more favorable for the post-treatment of the product, and has great advantages in the pharmaceutical preparation; at the same time, the product has high purity and high process yield.
  • the toxicity of the new crystalline form of cefamenodiate sodium obtained by the present invention indicates that the toxicity is lower than that of the existing sodium cefmenudate.
  • Figure 1 X-ray powder diffraction pattern of a new crystalline form of a cefmenudate sodium compound
  • Figure 2 DSC analysis of a new crystalline form of a cefmenudate sodium compound
  • Figure 3 Micrograph of a new crystalline form of a sodium cefmenudate compound
  • the new crystalline product obtained by the method has a melting point higher than the common crystal form by about 69 ° C, has higher thermal stability, and has no degradation change for a long time, outside the product.
  • the view (see Figure 3) is a thick rod with a product purity of 99.2% and a process yield of 92.8%.
  • the new crystalline product obtained by the method has a melting point higher than the common stable crystal form by about 71 ° C, has high thermal stability, and has no degradation change for a long time, and the product appearance is a thick rod, and the product purity is 99.1%, and the process yield is high. 92%.
  • the new crystalline product obtained by the method has a melting point higher than the common stable crystal form by about 69 ° C, has high thermal stability, and has no degradation change for a long time, and the product appearance is a thick rod, the product purity is 99.6%, and the process yield is 92.8%.
  • the new crystalline product obtained by the method has a melting point higher than the common stable crystal form by about 72 ° C, has high thermal stability, and has no degradation change for a long time, and the appearance of the product is thick rod, the product purity is 99.4%, and the process yield is 93.5%.
  • the new crystalline product obtained by the method has a melting point higher than the common stable crystal form by about 70 ° C, has high thermal stability, and has no degradation change for a long time, and the product appearance is a thick rod, and the product purity is 99.1%, and the process yield is high. 92.5%.
  • the new crystalline product obtained by the method has a melting point higher than the common stable crystal form by about 68 ° C, has high thermal stability, and has no degradation change for a long time, and the product appearance is a thick rod, and the product purity is 99.3%, and the process yield is high. 94.2%.
  • mice were divided into 4 groups according to body weight, 10 mice in each group, and the mice were administered intravenously, subcutaneously and intraperitoneally at 5200, 4400, 3850, 3350, 7000, 5700, 4500, 3380 mg/kg.
  • the median lethal doses of LD 50 of mice injected intravenously, subcutaneously, and intraperitoneally were 4216 mg/kg, 7256 mg/kg, and 4500 mg/kg, respectively, and the LD 50 value of intravenous injection in rats was 3425 mg/kg.
  • Rabbits were intravenously injected with cefomen sodium, 0.4 to 2.1 g each, at intervals of 15 min, and blood pressure and ECG changes were recorded. After anesthesia, the rabbits were given intravenous sodium cefmenodide. The blood pressure dropped by 0-37 mmHg, the breathing deepened, and the ECG and heart rate did not change significantly. When the drug dose reached 4800mg/kg, the blood pressure decreased significantly, the breathing was inhibited, and the electrocardiogram showed prolonged P-R interval, ST segment depression, and ventricular arrhythmia. When the dose increased, the rabbit died.
  • Rabbits were divided into 2 groups, 4 in each group. Intravenous injection of cefmenoxime sodium 250 mg/kg per day for 15 consecutive days. The control group was injected with 5 ml of normal saline per day. The results showed that the concentration of renal tissue of sodium cefmenudate was increased, but the nephrotoxicity was low.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种头孢孟多酯钠化合物的新晶型及其制备方法，所述方法为：将头孢孟多酯钠固体加入有机溶剂中，配制成0.04～0.3g/ml的悬浮液，在40～50℃下搅拌悬浮一段时间，然后以一定的降温速率降温至5～15℃搅拌一段时间，抽滤所得的悬浮液，得到滤饼，干燥该头孢孟多酯钠湿晶体产品至恒重。所述晶型的外观为粗棒状。

Description

头孢孟多酯钠化合物新晶型及其制剂和制备方法 技术领域
本发明属于医药分离技术领域，特别涉及一种头孢孟多酯钠化合物的新晶型及其制备方法。
背景技术
头孢孟多酯钠(Cefamandole nafate)的化学名为7-D-(2-甲酰氧苯乙酰胺)-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-甲酸钠盐，分子式为C19H18N6NaO6S2，分子量为512.50。结构式如式(I)。
Figure PCTCN2015095229-appb-000001
头孢孟多酯钠是由美国Lilly公司1972年研制开发，于1978年首次上市，注射剂商品名为MANDOL。头孢孟多酯钠是一种杀菌作用强的第2代半合成头孢菌素，兼有第1代和第3代头孢菌素的某些优点，对β－内酰胺酶较稳定，肾毒性低，血药浓度高，组织渗透性好，抗菌谱广。头孢孟多酯钠的主要特点是对革兰阴性菌作用强，对厌气梭状芽孢杆菌、脑膜炎球菌、淋球菌、大肠杆菌、肺炎杆菌、流感杆菌及吲哚阳性变形杆菌等作用较强，特别是对嗜血杆菌属最有效，临床上用于敏感菌所致的肺部感染、尿路感染、胆道感染、皮肤软组织感染、骨和关节感染以及败血症、腹腔感染等，其在临床上不良反应少、耐受性好，是一种安全、有效的抗菌药物。
近年来，为了提高头孢孟多酯钠化合物的稳定性，提高其生物利用度，研究人员对头孢孟多酯钠化合物的多晶型及其药物组合物进行了大量研究，目前发表的专利文献报道包括CN201210284600.6、CN201010257886.X、CN201010199235.X、CN201310021764.4等。中国专利CN201010257886.X和中国专利CN201010199235.X都是制备成的水合物， 但含有结晶水的物质往往在制剂过程中出现结晶水不稳定的缺陷，如中国专利CN201010257886.X的长期试验和加速试验的稳定性显著下降，中国专利CN201010199235.X所要求保护的制剂中加入了苯甲酸钠，而苯甲酸钠作为一种防腐剂存在安全隐患，已经在一些国家禁用。中国专利201210284600.6公开的头孢孟多酯钠的化合物并没有解决溶解性的问题，不溶性微粒较多，在制剂中添加了大量碳酸钠，或者添加了利多卡因、还原性谷胱甘肽和谷氨酸钠，而利多卡因和还原性谷胱甘肽均为有活性的药物，一起使用存在不确定的安全隐患。
发明内容
为了解决这些问题，本发明专利发明了一种头孢孟多酯钠化合物的新晶型，该新晶型的熔程为150-180℃，峰值在165±2℃(常见晶型的熔程在90-100℃)，提高了产品的热稳定性，产品在储存时不易变质。同时，新晶型的外观为粗棒状，而传统稳定晶型为细小的针状，因此新晶型产品具有更好的流动性和更高的堆密度，这显著改善了产品的包装与运输方便性。
本发明公开了一种新的头孢孟多酯钠化合物的的晶型，其X-射线粉末衍射图谱在衍射角2θ＝4.0±0.2，4.7±0.2，6.2±0.2，7.5±0.2，9.9±0.2，10.8±0.2，14.5±0.2，15.8±0.2，16.3±0.2，17.4±0.2，18.1±0.2，19.2±0.2，20.1±0.2，21.4±0.2，22.2±0.2，22.8±0.2，23.9±0.2，24.9±0.2，30.1±0.2，34.1±0.2度处有特征峰，如图1所示。
所述的头孢孟多酯钠化合物的晶体，其DSC分析结果显示，在165±2℃有吸热峰，如图2所示。
所述的头孢孟多酯钠化合物的晶体，其晶体外形如图3所示。
本发明所述的头孢孟多酯钠化合物晶体的制备方法：将头孢孟多酯钠固体加入有机溶剂中，配制成0.04～0.3g/ml的悬浮液，在40～50℃下搅拌悬浮一段时间，然后以一定的降温速率降温至5～15℃搅拌一段时间，抽滤所得的悬浮液,得到的滤饼即为头孢孟多酯钠湿产物，干燥头孢孟多酯钠湿晶体产品至恒重得到最终头孢孟多酯钠新晶型产品。
所述有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、异戊醇、正戊醇、乙酸乙酯、1,4-二氧六环或丙酮的一种或其几种的混合溶液。
所述方法中悬浮液的搅拌速率是每分钟600～1200r。
所述方法中悬浮液降温前的搅拌时间是5～10h。
所述方法中悬浮液降温后的搅拌时间是5～10h。
所述方法中悬浮液的降温速率是0.2～2℃/min.
所述方法中干燥条件是在20～70℃、常压的条件下进行6～12h。
所述方法具有以下有益效果：操作步骤简单易操作、耗能少。制备出的产品熔程在160-170℃,热稳定性好，更利于长期保存；纯度高于99％、收率高于90％，产品在常温、干燥条件下储存100天后，产品纯度、颜色、形态未发生变化。产品易于粉碎和易于加入药物组合物的剂型，以及成本低，更易于商业产业化规模实施。
所述方法得到的头孢孟多酯钠化合物的新晶型较已报道晶型的熔点更高，热稳定性更好，长时间放置无降解变化；产品晶习更好，堆密度更高，流动性更好，粒度分布更均匀，更有利于产品的后处理，在药物制剂中有很大的优势；同时产品纯度高、过程收率高。
本发明获得的头孢孟多酯钠新晶型化合物的毒性反应表明，其毒性比现有的头孢孟多酯钠有所降低。
附图说明
图1：头孢孟多酯钠化合物的新晶型的X-射线粉末衍射图；
图2：头孢孟多酯钠化合物的新晶型的DSC分析图；
图3：头孢孟多酯钠化合物的新晶型的显微镜照片；
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：
将干燥的头孢孟多酯钠固体0.40g加入10mL的1,4-二氧六环中形成悬浮液，在600r/min的搅拌速率下搅拌该悬浮液，且将悬浮液加热到40℃，恒定温度，搅拌悬浮液5h，然后以0.2℃/min的速率将悬浮液降温至5℃，恒定温度，搅拌悬浮液5h，真空抽滤晶浆，将产物在20℃、常压下干燥6h至恒重，得到头孢孟多酯钠新晶型产品。产品的X－射线粉末衍射图谱(可参见图1)在衍射角2θ＝4.01，4.66，6.18，7.47，9.95，10.70,14.56，15.82,16.26，17.40，18.05，19.26，20.15，21.45，22.25，22.78，24.00，24.94，30.17，34.16度处有特征峰，DSC(可参见图2)在164℃有吸热峰。该方法得到的新晶型产品其熔点比常见的晶型高约69℃，具有更高的热稳定性，长时间放置无降解变化，产品外 观(可参见图3)为粗棒状，产品纯度99.2％,过程收率92.8％。
实施例2：
将干燥的头孢孟多酯钠固体0.43g加入4mL的甲醇中形成悬浮液，在800r/min的搅拌速率下搅拌该悬浮液，且将悬浮液加热到45℃，恒定温度，搅拌悬浮液8h，然后以1℃/min的速率将悬浮液降温至10℃，恒定温度，搅拌悬浮液9h，真空抽滤晶浆，将产物在40℃、常压下干燥10h至恒重，得到头孢孟多酯钠晶体产品。产品的X－射线粉末衍射图谱在衍射角2θ＝4.04，4.70，6.22，7.48，9.90，10.80,14.66，15.72,16.22，17.38，18.02，19.20，20.08，21.38，22.12，22.82，23.88，24.92，30.32，34.16度处有特征峰，DSC分析图在166℃有吸热峰。该方法得到的新晶型产品其熔点比常见的稳定晶型高约71℃，具有很高的热稳定性，长时间放置无降解变化，产品外观为粗棒状，产品纯度99.1％,过程收率92％。
实施例3：
将干燥的头孢孟多酯钠固体0.50g加入10mL的乙酸乙酯中形成悬浮液，在1000r/min的搅拌速率下搅拌该悬浮液，且将悬浮液加热到48℃，恒定温度，搅拌悬浮液9h，然后以1℃/min的速率将悬浮液降温至15℃，恒定温度，搅拌悬浮液8h，真空抽滤晶浆，将产物在60℃、常压下干燥10h至恒重，得到头孢孟多酯钠晶体产品。产品的X－射线粉末衍射图谱在衍射角2θ＝4.10，4.76，6.28，7.54，9.98，10.61,14.46，15.62,16.30，17.46，18.08，19.28，20.16，21.48，22.26，22.84，24.00，24.98，30.26，34.22度处有特征峰，DSC分析图在164℃有吸热峰。该方法得到的新晶型产品其熔点比常见的稳定晶型高约69℃，具有很高的热稳定性，长时间放置无降解变化，产品外观为粗棒状，产品纯度99.6％,过程收率92.8％。
实施例4：
将干燥的头孢孟多酯钠固体0.60g加入4mL的丙酮中形成悬浮液，在1000r/min的搅拌速率下搅拌该悬浮液，且将悬浮液加热到50℃，恒定温度，搅拌悬浮液8h，然后以0.5℃/min的速率将悬浮液降温至12℃，恒定温度，搅拌悬浮液10h，真空抽滤晶浆，将产物在50℃、常压下干燥8h至恒重，得到头孢孟多酯钠晶体产品。产品的X－射线粉末衍射图谱在衍射角2θ＝4.02，4.68，6.20，7.46，9.90，10.90,14.66，15.92,16.50，17.36， 18.00，19.20，20.08，21.40，22.18，22.78，23.90，24.88，30.16，34.14度处有特征峰，DSC分析图在167℃有吸热峰。该方法得到的新晶型产品其熔点比常见的稳定晶型高约72℃，具有很高的热稳定性，长时间放置无降解变化，产品外观为粗棒状，产品纯度99.4％,过程收率93.5％。
实施例5：
将干燥的头孢孟多酯钠固体5.00g加入25mL的1,4-二氧六环与乙醇混合溶液中形成悬浮液，其中1,4-二氧六环与乙醇的体积比为2:3，在1200r/min的搅拌速率下搅拌该悬浮液，且将悬浮液加热到50℃，恒定温度，搅拌悬浮液7h，然后以1.5℃/min的速率将悬浮液降温至10℃，恒定温度，搅拌悬浮液9h，真空抽滤晶浆，将产物在45℃、常压下干燥7h至恒重，得到头孢孟多酯钠晶体产品。产品的X－射线粉末衍射图谱在衍射角2θ＝4.08，4.74，6.26，7.52，9.94，10.60,14.35，15.60，16.26，17.42，18.08，19.26，20.12，21.40，22.26，22.90，23.96，24.96，30.30，34.20度处有特征峰，DSC分析图在165℃有吸热峰。该方法得到的新晶型产品其熔点比常见的稳定晶型高约70℃，具有很高的热稳定性，长时间放置无降解变化，产品外观为粗棒状，产品纯度99.1％,过程收率92.5％。
实施例6：
将干燥的头孢孟多酯钠固体3.00g加入10mL的丙酮与1,4-二氧六环混合溶液中形成悬浮液，其中丙酮与1,4-二氧六环的体积比为1:1，在1200r/min的搅拌速率下搅拌该悬浮液，且将悬浮液加热到50℃，恒定温度，搅拌悬浮液10h，然后以2℃/min的速率将悬浮液降温至15℃，恒定温度，搅拌悬浮液10h，真空抽滤晶浆，将产物在70℃、常压下干燥12h至恒重，得到头孢孟多酯钠晶体产品。产品的X－射线粉末衍射图谱在衍射角2θ＝4.10，4.74，6.26，7.52，9.96，10.65,14.65，15.72，16.28，17.42，18.08，19.28，20.16，21.50，22.18，22.90，24.00，24.98，30.32，34.26度处有特征峰，DSC分析图在163℃有吸热峰。该方法得到的新晶型产品其熔点比常见的稳定晶型高约68℃，具有很高的热稳定性，长时间放置无降解变化，产品外观为粗棒状，产品纯度99.3％,过程收率94.2％。
毒性反应实验：
对本发明获得的头孢孟多酯钠新晶型化合物进行如下毒性反应实验(以实施例1获得的头孢孟多酯钠化合物晶型为例)：
小鼠按体重分成4组，每组10只，以5200、4400、3850、3350、7000、5700、4500、3380mg/kg给予小鼠静注、皮下和腹腔给药。小鼠静脉注射、皮下注射、腹腔注射的半数致死量LD50分别为4216mg/kg、7256mg/kg和4500mg/kg，大鼠静脉注射的半数致死量LD50值为3425mg/kg。
家兔静注头孢孟多酯钠，每次0.4～2.1g，间隔15min，记录血压和心电图变化。家兔经过麻醉后，静脉注射头孢孟多酯钠，血压下降0～37mmHg，呼吸加深加快，心电图和心率未见明显改变。当药物剂量达到4800mg/kg时，血压下降明显，呼吸被抑制，心电图出现P-R间期延长、ST段压低、室性心律失常。剂量再加大时，家兔出现死亡。
家兔分为2组，每组4只，每天分别静脉注射头孢孟多酯钠250mg/kg，连续15天，对照组每天注射生理盐水5ml。结果显示，头孢孟多酯钠的肾组织浓度虽升高，但肾毒性较低。
本发明公开和提出的头孢孟多酯钠化合物的晶型及其制备方法，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 (10)

  1. 一种头孢孟多酯钠化合物的晶体，其特征在于其X-射线粉末衍射在衍射角2θ＝4.0±0.2，4.7±0.2，6.2±0.2，7.5±0.2，9.9±0.2，10.8±0.2，14.5±0.2，15.8±0.2，16.3±0.2，17.4±0.2，18.1±0.2，19.2±0.2，20.1±0.2，21.4±0.2，22.2±0.2，22.8±0.2，23.9±0.2，24.9±0.2，30.1±0.2，34.1±0.2度处有特征峰。
  2. 如权利要求1所述的头孢孟多酯钠化合物的晶体，其特征是在165±2℃处有DSC吸热峰。
  3. 如权利要求1或2所述的头孢孟多酯钠化合物的晶体的制备方法，其特征是：将头孢孟多酯钠固体加入有机溶剂中，配制成0.04～0.3g/ml的悬浮液，在40～50℃下搅拌悬浮液，然后以降温至5～15℃搅拌，抽滤所得的悬浮液,得到的滤饼即为头孢孟多酯钠湿产物，干燥头孢孟多酯钠湿晶体产品至恒重得到头孢孟多酯钠新晶型产品。
  4. 如权利要求3所述的制备方法，其特征是所述有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、仲丁醇、异戊醇、正戊醇、乙酸乙酯、1,4-二氧六环或丙酮的一种或其几种的混合溶液。
  5. 如权利要求3所述的制备方法，其特征是悬浮液的搅拌速率是每分钟600～1200r。
  6. 如权利要求3所述的制备方法，其特征是悬浮液降温前的搅拌时间是5～10h。
  7. 如权利要求3所述的制备方法，其特征是悬浮液降温后的搅拌时间是5～10h。
  8. 如权利要求3所述的制备方法，其特征是悬浮液的降温速率是0.2～2℃/min.
  9. 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20～70℃、常压的条件下进行6～12h
  10. 如权利要求1所述的头孢孟多酯钠化合物的晶体，其特征是所述的头孢孟多酯钠作为一种用于治疗、预防或延缓敏感菌所致的各种感染的有效成分药物的用途。
PCT/CN2015/095229 2014-12-16 2015-11-20 头孢孟多酯钠化合物新晶型及其制剂和制备方法 WO2016095660A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/305,661 US20170050982A1 (en) 2014-12-16 2015-11-20 New crystalline form of cefamandole sodium compound, formulation and preparation method thereof
US15/687,359 US9834567B1 (en) 2014-12-16 2017-08-25 Crystalline form of cefamandole nafate compound, preparation and preparing method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410784492.8A CN104530086B (zh) 2014-12-16 2014-12-16 头孢孟多酯钠化合物的新晶型及其结晶制备方法
CN201410784492.8 2014-12-16

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/305,661 A-371-Of-International US20170050982A1 (en) 2014-12-16 2015-11-20 New crystalline form of cefamandole sodium compound, formulation and preparation method thereof
US15/687,359 Continuation-In-Part US9834567B1 (en) 2014-12-16 2017-08-25 Crystalline form of cefamandole nafate compound, preparation and preparing method thereof

Publications (1)

Publication Number Publication Date
WO2016095660A1 true WO2016095660A1 (zh) 2016-06-23

Family

ID=52845752

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/095229 WO2016095660A1 (zh) 2014-12-16 2015-11-20 头孢孟多酯钠化合物新晶型及其制剂和制备方法

Country Status (3)

Country Link
US (1) US20170050982A1 (zh)
CN (1) CN104530086B (zh)
WO (1) WO2016095660A1 (zh)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104829631A (zh) * 2015-05-08 2015-08-12 天津大学 一种头孢孟多酯钠的新晶型及其结晶制备方法
CN104844625A (zh) * 2015-05-08 2015-08-19 天津大学 头孢孟多酯钠的一种新晶型及其结晶制备方法
CN104844626A (zh) * 2015-05-08 2015-08-19 天津大学 头孢孟多酯钠的新晶型及其结晶制备方法
CN107915750B (zh) * 2017-11-28 2019-09-24 华北制药河北华民药业有限责任公司 一种头孢孟多酯钠粉针制剂的制备方法
CN110734455A (zh) * 2018-07-20 2020-01-31 罗欣药业(上海)有限公司 一种头孢孟多酯钠新晶型及其制备方法
CN113754717A (zh) * 2021-10-15 2021-12-07 南京高新工大生物技术研究院有限公司 一种还原型谷胱甘肽α型晶体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4006138A (en) * 1975-04-11 1977-02-01 Eli Lilly And Company Crystalline form of sodium O-formylcefamandole
CN103044453A (zh) * 2013-01-22 2013-04-17 湖北济生医药有限公司 头孢孟多酯钠化合物及其药物组合物
CN103145736A (zh) * 2013-03-29 2013-06-12 四川省惠达药业有限公司 一种含有头孢孟多酯钠化合物的药物组合物
CN104829631A (zh) * 2015-05-08 2015-08-12 天津大学 一种头孢孟多酯钠的新晶型及其结晶制备方法
CN104844625A (zh) * 2015-05-08 2015-08-19 天津大学 头孢孟多酯钠的一种新晶型及其结晶制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947415A (en) * 1974-12-23 1976-03-30 Eli Lilly And Company Cefamandole derivatives
US4035361A (en) * 1976-03-17 1977-07-12 Eli Lilly And Company Bis-trimethylsilyl cefamandole and process therefor
US4168376A (en) * 1978-06-05 1979-09-18 Eli Lilly And Company Process for crystalline sodium cefamandole
US8586781B2 (en) * 1998-04-02 2013-11-19 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
CN101914106B (zh) * 2010-08-20 2012-12-19 湖北济生医药有限公司 头孢孟多酯钠水合物及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4006138A (en) * 1975-04-11 1977-02-01 Eli Lilly And Company Crystalline form of sodium O-formylcefamandole
CN103044453A (zh) * 2013-01-22 2013-04-17 湖北济生医药有限公司 头孢孟多酯钠化合物及其药物组合物
CN103145736A (zh) * 2013-03-29 2013-06-12 四川省惠达药业有限公司 一种含有头孢孟多酯钠化合物的药物组合物
CN104829631A (zh) * 2015-05-08 2015-08-12 天津大学 一种头孢孟多酯钠的新晶型及其结晶制备方法
CN104844625A (zh) * 2015-05-08 2015-08-19 天津大学 头孢孟多酯钠的一种新晶型及其结晶制备方法

Also Published As

Publication number Publication date
CN104530086B (zh) 2015-12-09
CN104530086A (zh) 2015-04-22
US20170050982A1 (en) 2017-02-23

Similar Documents

Publication Publication Date Title
WO2016095660A1 (zh) 头孢孟多酯钠化合物新晶型及其制剂和制备方法
KR20110010753A (ko) 트레프로스티닐 일수화물
BR122019021689B1 (pt) composto, composição farmacêutica, método para a preparação do composto e uso do composto
NZ541991A (en) Ferric organic compounds, uses thereof and methods of making same
CN109942546B (zh) 喹诺酮嘧啶类化合物及其制备方法和应用
MX2011005117A (es) Composiciones antimicrobianas.
WO2015007181A1 (zh) 5-溴-2-（α-羟基戊基）苯甲酸钠盐的不同晶型及其制备方法
WO2021227146A1 (zh) N-[8-(2-羟基苯甲酰基)氨基]辛酸一钾晶型化合物、制备方法及用途
KR101700734B1 (ko) 아미노산과 카르복실산을 포함한 게르마늄의 착체 및 이를 제조하는 방법
US9834567B1 (en) Crystalline form of cefamandole nafate compound, preparation and preparing method thereof
KR20110026311A (ko) 엔테카비어의 신규한 염
CN102977101A (zh) 多尼培南一水合物、其药物组合物、其制备方法和用途
WO2022228352A1 (zh) 一种五环三萜类化合物结晶及其制备方法
WO2015158202A1 (zh) 一种噁唑烷酮类抗生素的晶型及制备方法、组合物和用途
CN102204916A (zh) 一种含头孢美唑钠化合物的药物组合物及其制备方法
WO2020258660A1 (zh) 盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物
CN110393720A (zh) 曲索芬头孢曲松钠药物制剂治疗免疫机能低下患者感染的新适应症
CN109851611B (zh) 磺胺嘧啶类化合物及其制备方法和应用
CN103304580B (zh) 一种盐酸头孢吡肟化合物、其制备方法及其药物组合物
WO2020244148A1 (zh) 多拉菌素晶型a、晶型b及其制备方法
CN102351881B (zh) 一种稳定的盐酸左氧氟沙星化合物
CN102190656A (zh) 含有五元杂环的噁唑烷酮抗菌素
CN104109128A (zh) 卡博替尼苹果酸盐及其制备方法
CN1261439C (zh) 头孢克肟钠药物化合物及其制备方法和应用
CN102002054B (zh) 一种吡唑类化合物及其制备方法和用途

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: 15869168

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15305661

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15869168

Country of ref document: EP

Kind code of ref document: A1