WO2016201905A1 - 一种头孢呋辛钠的新型工业结晶方法及其制剂 - Google Patents

一种头孢呋辛钠的新型工业结晶方法及其制剂 Download PDF

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WO2016201905A1
WO2016201905A1 PCT/CN2015/095810 CN2015095810W WO2016201905A1 WO 2016201905 A1 WO2016201905 A1 WO 2016201905A1 CN 2015095810 W CN2015095810 W CN 2015095810W WO 2016201905 A1 WO2016201905 A1 WO 2016201905A1
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cefuroxime sodium
crystallization
extraction
cefuroxime
tank
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PCT/CN2015/095810
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English (en)
French (fr)
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陶灵刚
郝红勋
王静康
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海南灵康制药有限公司
天津大学
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Priority to US15/306,084 priority Critical patent/US20170158711A1/en
Publication of WO2016201905A1 publication Critical patent/WO2016201905A1/zh

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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
    • A61K9/0012—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
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0403—Solvent extraction of solutions which are liquid with a supercritical fluid
    • B01D11/0411—Solvent extraction of solutions which are liquid with a supercritical fluid the supercritical fluid acting as solvent for the solvent and as anti-solvent for the solute, e.g. formation of particles from solutions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • B01D9/0054—Use of anti-solvent
    • 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
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D2009/0086—Processes or apparatus therefor
    • B01D2009/009—Separation of organic compounds by selective or extractive crystallisation with the aid of auxiliary substances forming complex or molecular compounds, e.g. with ureum, thioureum or metal salts
    • B01D2009/0095—Separation of organic compounds by selective or extractive crystallisation with the aid of auxiliary substances forming complex or molecular compounds, e.g. with ureum, thioureum or metal salts with the aid of other complex forming substances than ureum, thioureum or metal salts
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the invention relates to a novel industrial crystallization technology of cefuroxime sodium, belonging to the technical field of medicine.
  • Cefuroxime sodium English name Cefuroxime Sodium, also known as cefuroxime, cefuroxime, Chinese alias: (6R, 7R)-7-[2-furyl (methoxyimino) acetylamino]-3-amino Sodium acyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylate. Molecular weight: 446.36. Molecular formula: C 16 H 15 N 4 NaO 8 S, chemical structural formula:
  • the cefuroxime sodium is a white, off-white or yellowish powder or a crystalline powder; odorless, bitter; hygroscopic.
  • This product is soluble in water, slightly soluble in methanol, insoluble in ethanol or chloroform, in a solution containing 10mg per 1ml, the specific rotation is +55° to +65°; measured by spectrophotometry at 274nm The absorbance was measured at the wavelength, and the absorption coefficient (E1 cm1%) was 390 to 425.
  • Cefuroxime sodium is the best second-generation cephalosporin with the advantages of first-generation and third-generation cephalosporins, not only has strong antibacterial activity against Gram-positive cocci, but also certain Gram-negative bacteria. It also has good antibacterial activity, especially in the treatment of mixed infection of Gram-positive and Gram-negative bacteria. Due to its broad spectrum of antibacterial activity, wide distribution in the body, high tissue concentration and low toxicity, cefuroxime sodium is suitable for respiratory infection, urinary tract infection, ENT infection, skin and soft tissue infection, gynecological infection, gonorrhea, sepsis, meningitis and Internal and external surgical infections, etc.
  • Cefuroxime sodium is not only used for anti-infective treatment during surgery, but also has obvious effects in postoperative anti-infective treatment and surgical prevention of infection. Cefuroxime sodium is not metabolized by the liver in the body, so it is not toxic to the liver; it is excreted from the urine by the kidneys in the original form, so it has almost no toxic side effects on the kidneys, so its medication is very safe, and it has good pharmacokinetics for newborns. And security. The above advantages of the drug make it the first choice for mixed infection with Gram-negative bacteria or Gram-negative bacteria.
  • cefuroxime sodium was proposed by Glax Company of the United Kingdom and was prepared by 7-step reaction of 7-aminocephalosporanic acid, mainly due to the introduction of protective groups of amino and carboxyl groups in the intermediate step, but the final deprotection was required.
  • Base The yield is low and there are many impurities.
  • cefuroxime sodium has poor stability and needs to be sealed and refrigerated at 2-8 °C. It is easy to appear solid color deepening when stored or transported improperly. When tested according to pharmacopoeia standards, the color of the solution often fails.
  • the clinically used cefuroxime sodium product Due to the influence of the raw material synthesis process and the nature of the drug itself, the clinically used cefuroxime sodium product has serious problems such as unstable quality and poor color grade. Thereby affecting the quality of the product, resulting in the formulation product is not clear, the turbidity is unqualified, and the stability of the preparation is lowered.
  • the invention aims to solve the problem that the existing cefuroxime sodium has many impurities and deep color, and aims to simplify the process and improve the efficiency, and provides a method and a device for crystallization of cefuroxime sodium which can be industrialized by the technology and equipment.
  • the refined cefuroxime sodium product color meets the quality requirements, the product quality is high, the stability is good, and the dissolution rate is fast.
  • the present invention also provides cefuroxime sodium prepared by the technology and equipment, and a sterile powder injection containing the cefuroxime sodium.
  • the technical essence of the refined cefuroxime sodium according to the present invention is a method for preparing high-purity cefuroxime sodium from crude cefuroxime sodium.
  • the purity of cefuroxime sodium can be increased to more than 99% by one crystallization.
  • the technical scheme of the invention is based on the principle of supercritical fluid extraction technology and traditional crystallization technology, firstly preparing cefuroxime sodium into a cefuroxime sodium solution in a dissolution tank, and extracting the organic solvent in the cefuroxime sodium solution by using a supercritical fluid. The impurities dissolved in the organic solvent are also extracted together; the cefuroxime sodium solution is crystallized and separated in the crystallization tank by adjusting the pressure and temperature.
  • the invention is characterized in that the organic solvent and the solute in the multi-mixed system are extracted by the supercritical fluid, and the solubility characteristics of the substance component in the organic solvent and the supercritical fluid are changed to precipitate the solute crystal. Thereby, one-time crystallization of the effective substance is achieved, and a high-purity product is obtained.
  • the technology of the invention integrates extraction, adsorption, crystallization and drying, and has the advantages of high separation efficiency, no solvent residual toxicity, and the active component is not easily broken down by decomposition.
  • the extraction pressure of the technical solution of the present invention is 15-40 Mpa, the extraction temperature is 40-60 ° C, the extraction time is 5-20 minutes, the crystallization pressure is 0.5-5 MPa, the crystallization temperature is 20-30 ° C, and the crystallization time is 20-40 minutes.
  • the drawing shows the process schematic of the method.
  • the apparatus mainly includes a working medium gas cylinder, a compressor, a heat exchanger, an extraction tank, a crystallization tank, and the like.
  • the working medium is supercharged to form a supercritical fluid.
  • the working medium may be CO 2 , an alkane, an olefin or the like, preferably CO 2 .
  • the solvent used for dissolving cefuroxime sodium is composed of a single component or a plurality of components such as alcohols, aldehydes, esters, ketones, ethers, and water.
  • the solvent used should be chosen such that its partition coefficient in the supercritical CO 2 fluid is greater than the partition coefficient of cefuroxime sodium.
  • An aqueous ethanol solution is preferred, and an aqueous ethanol solution having a concentration of 50% to 80% is more preferred.
  • the extraction cell is used to form a multi-component system of solvent, working medium and cefuroxime sodium by pressurization.
  • the surface of the extraction tank is coated with materials such as activated carbon or macroporous adsorption resin to enhance the adsorption and selectivity of impurities in the solution.
  • the crystallization pond is used to separate the solvent, the working medium, and the extracted cefuroxime sodium by reduced pressure.
  • the quick interface has a device capable of sterilizing and filtering.
  • the extraction tank and the crystallization tank are under respective temperature and pressure conditions, and the supercritical fluid and the cefuroxime sodium solution are extracted and adsorbed in the extraction tank; the crystallization separation and distillation are realized in the multi-system in the crystallization tank. After the system is cooled and the pressure is balanced, high purity cefuroxime sodium is collected from the crystallization tank.
  • the present invention provides a method for crystallizing cefuroxime sodium, which comprises the steps of:
  • the solvent used in the crystallization separation in the present technology is a supercritical fluid, and the extraction technology of the supercritical fluid is unified with the conventional crystallization separation technology, and the extraction, adsorption, crystallization, and drying are integrated. Under the joint action of supercritical fluid, solvent, extraction tank and crystallization tank, the cefuroxime sodium is further purified and purified, and the obtained product has high purity and high yield, which greatly simplifies the enrichment and crystallization process of the substance.
  • the novel industrial crystallization technique of the present invention is somewhat more apparent than the conventional recrystallization recrystallization method. Under the same temperature conditions, the crystallization time of the method of the invention is short and the crystallization efficiency is high.
  • the target product obtained by primary crystal precipitation of the present invention has high purity.
  • the method is simple in process, and does not require complex energy-consuming and time-consuming processes such as column chromatography. At the same time, the yield is higher than that of the conventional process, and the crude raw material is crystallized once, the purity of cefuroxime sodium is over 99%, and the crystallization efficiency is more than 80%, which is suitable for large-scale production.
  • cefuroxime sodium purified by the novel industrial crystallization technology of the invention solves the problem that the existing cefuroxime sodium has many impurities and The problem of dark color and poor stability, the obtained cefuroxime sodium satisfies the requirements of injection, and can be used for preparing sterile powder for injection.
  • Figure 1 shows a schematic diagram of the apparatus of the present method, wherein 1 is a temperature controlled heater, 2 is an extraction tank, 3 is a crystallization tank, 4 is a stirrer, 5 is a sensor, 6 is a digital monitor, 7 is a quick interface, 8
  • 1 is a temperature controlled heater
  • 2 is an extraction tank
  • 3 is a crystallization tank
  • 4 is a stirrer
  • 5 is a sensor
  • 6 is a digital monitor
  • 7 is a quick interface
  • 9 is a high pressure pump
  • 10 is a cylinder
  • 11 is a gas collector
  • 12 is a polystyrene insulator.
  • the purity of the cefuroxime sodium sample was determined by high performance liquid chromatography.
  • the chromatographic conditions were:
  • Injection volume 20 ⁇ l.
  • the cefuroxime sodium prepared in Example 1 was measured by the funnel method to determine the mobility.
  • cefuroxime sodium crystal powder prepared by the novel industrial crystallization technology and equipment of the cefuroxime sodium of the invention has high yield and high purity, and all the inspection indexes are in compliance with regulations, and are suitable for It is prepared into sterile powder injection and has good industrial application value.

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Abstract

本发明公开了一种头孢呋辛钠的新型工业结晶技术，采用超临界流体萃取技术与传统的结晶技术相结合的方式实现头孢呋辛钠的重结晶。在整个结晶系统内，在特定的温度和压力条件下，在超临界流体、溶剂、萃取池、结晶池的共同作用下，完成萃取、吸附、结晶和干燥的过程，实现头孢呋辛钠的重结晶。本方法分离效率高，杂质少，大大提高了制剂产品质量。

Description

一种头孢呋辛钠的新型工业结晶方法及其制剂 技术领域
本发明涉及一种头孢呋辛钠的新型工业结晶技术，属于医药技术领域。
背景技术
头孢呋辛钠，英文名称Cefuroxime Sodium，又称头孢呋肟，头孢呋新，中文别称：(6R，7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-氨基甲酰氧甲基-8-氧代-5-硫杂-1-氮杂二环[4.2.0]辛-2-烯-2-甲酸钠。分子量：446.36。分子式：C16H15N4NaO8S，化学结构式：
Figure PCTCN2015095810-appb-000001
头孢呋辛钠为白色、类白色或微黄色粉末或结晶性粉末；无臭，味苦；有引湿性。本品在水中易溶，在甲醇中略溶，在乙醇或氯仿中不溶，在每1ml中含10mg的溶液中，比旋度为+55°至+65°；采用照分光光度法测定，在274nm的波长处测定吸收度，吸收系数(E1cm1％)为390～425。
头孢呋辛钠是具备第一代与第三代头孢菌素优点的最优秀的二代头孢菌素，不但对革兰氏阳性球菌有较强的抗菌活性，而且对某些革兰氏阴性细菌也有很好的抗菌活性，尤其在革兰氏阳性与革兰氏阴性细菌混合感染的治疗中，更是优先选用的药物。头孢呋辛钠由于抗菌谱广、体内分布广、组织浓度高、毒性低，适用于呼吸道感染、泌尿系统感染、耳鼻喉感染、皮肤和软组织感染、妇产科感染、淋病、败血症、脑膜炎和内外手术感染等。头孢呋辛钠不仅用于手术中的抗感染治疗，而且在术后抗感染治疗和手术预防感染中疗效非常明显。头孢呋辛钠在体内不被肝脏代谢，故对肝脏无毒性；以原形经肾脏从尿液中排泄，故对肾脏几乎无毒副作用，所以其用药非常安全，对新生儿有良好的药动学和安全性。该药的上述优点使其成为革兰氏阴性菌或革兰氏阴阳性菌混合感染的首选用药。
头孢呋辛钠最初的制备路线由英国的Glax公司提出，由7-氨基头孢烷酸经过8步反应制备，主要是由于在中间步骤引入了氨基和羧基的保护基团，但需要最终脱去保护基， 收率较低，杂质多。随后出现了许多其它制备方法，如由7-ACA先与SMIF-C1反应生成7-[(z)-2-呋喃基-2-甲氧亚胺乙酰氨基]-3-乙酰氧甲基-3-头孢烷7-FCA)，再用氢氧化钠水解生成7-FHCA，而后与三氯乙酰异氰酸酯反应生成头孢呋辛酸，最后经过成盐过程转化为头孢呋辛钠。此方法水解收率较高，但是酰氯反应活性太高，易发生较多的副反应，产物色泽较深。此外，头孢呋辛钠稳定性较差，需在2～8℃条件下密封冷藏，储存或运输不当容易出现固体颜色加深，按照药典标准检验时，经常出现溶液的颜色不合格的问题。
由于原料合成工艺合药物本身性质的影响，目前临床上使用的头孢呋辛钠产品，存在着质量不稳定、产品色级差等严重问题。从而影响产品质量，造成制剂产品不澄清，浊度不合格，并且降低了制剂的稳定性。
头孢呋辛钠的重结晶工艺众多文献都有报道，如：英国专利GB2012270、中国专利CN101054386、中国专利CN101967156，但这些方法都采用传统的溶析结晶方法，操作复杂，后期处理繁琐，易引入新的杂质，在大生产中受到很大的限制。
因此，迫切需要寻求更佳的方案来解决现有技术中存在的问题。
发明内容
本发明的目的在于解决现有头孢呋辛钠存在杂质多、颜色深的问题，旨在简化工艺、提高效率，提供一种可供工业化的头孢呋辛钠结晶方法与设备，通过该技术与设备精制的头孢呋辛钠产品颜色符合质量要求，产品质量高、稳定性好，溶解速度快。同时，本发明还提供了该技术与设备制得的头孢呋辛钠，含有该头孢呋辛钠的无菌粉针剂。
本发明所述的精制头孢呋辛钠的技术实质是由头孢呋辛钠粗品制备高纯度头孢呋辛钠的方法，本方法经一次结晶，头孢呋辛钠的纯度可提高到99％以上。
本发明的技术方案是根据超临界流体萃取技术与传统的结晶技术原理，首先在溶解池内将头孢呋辛钠制备成头孢呋辛钠溶液，利用超临界流体萃取头孢呋辛钠溶液中的有机溶剂，同时溶于有机溶剂的杂质也一并萃取；通过调节压力和温度，在结晶池中对头孢呋辛钠溶液进行结晶分离。
本发明的特征在于利用超临界流体萃取多元混合系中的有机溶剂与溶质，改变物质成分在有机溶剂与超临界流体中的溶解特性，使溶质结晶析出。从而实现有效物质的一次性结晶，获得高纯度产品。
本发明的技术集萃取、吸附、结晶、干燥于一体，具有分离效率高、无溶剂残留毒性、活性成分不易被分解破坏等优点。
本发明的技术方案所述的萃取压力15～40Mpa，萃取温度40～60℃，萃取时间5～20分钟，结晶压力0.5～5Mpa、结晶温度20～30℃，结晶时间20～40分钟。
附图所示为本方法的工艺原理图。
图中所示，所述的设备主要包括工作介质气瓶、压缩机、热交换器、萃取池、结晶池等。
图中所示，工作介质经处理增压后形成超临界流体。工作介质可以是CO2、烷烃、烯 烃等，优选CO2。
溶解头孢呋辛钠所使用的溶剂是由醇类、醛类、酯类、酮类、醚类及水等单组份或多组分构成。
所使用的溶剂应选择其在超临界CO2流体中的分配系数大于头孢呋辛钠的分配系数的溶剂。优选乙醇水溶液，更优选为浓度50％～80％的乙醇水溶液。
萃取池用于通过加压形成溶剂、工作介质及头孢呋辛钠的多元混合体系。萃取池表面涂覆活性炭或大孔吸附树脂等材料，增强对溶液中杂质的吸附性和选择性。
结晶池用于通过减压分离溶剂、工作介质以及萃取出的头孢呋辛钠。
萃取池和结晶池之间设有可以自由开闭的快速接口，快速接口内部设有能够除菌过滤的装置。
当系统工作时，萃取池和结晶池均处于各自的温度和压力条件下，超临界流体和头孢呋辛钠溶液在萃取池内完成萃取、吸附；在结晶池内多元体系实现结晶分离和蒸馏。待系统降温、平衡压力后，自结晶池中收集高纯度头孢呋辛钠。
作为优选的实施方案，本发明提供了一种头孢呋辛钠结晶方法，其包括以下步骤：
(1)称取头孢呋辛钠粗品置于萃取池中，加入50～80％乙醇水的混合溶剂，控制温度40～60℃，搅拌使其溶解；
(2)用高压液体泵泵入CO2流体至15～40Mpa，搅拌，并保持该压力和温度5～20分钟，关闭高压泵；
(3)向结晶池中放置晶种，提升萃取池的高度至30cm，开启两池体的快速接口，使萃取池中的液体进入结晶池，关闭快速接口；
(4)调节结晶池内的压力为0.5～5Mpa，温度20～30℃，保持此温度和压力20～40分钟；
(5)待系统降温，卸压后，通过减压干燥，得高纯度的头孢呋辛钠结晶品。
本技术中结晶分离所使用的溶剂为超临界流体，将超临界流体的萃取技术与传统的结晶分离技术统一起来，集萃取、吸附、结晶、干燥于一体。在超临界流体、溶剂、萃取池、结晶池的共同作用下，使头孢呋辛钠实现进一步结晶提纯，所得产品纯度高、收率高，大大简化了物质的富集、结晶工艺。
本发明的新型工业结晶析出的技术与传统的溶析重结晶法相比有点明显。相同温度条件下，本发明方法的结晶时间较短，结晶效率高。本发明一次结晶沉析所得到的目标产品的纯度较高。本法工艺简单，无需上柱色谱等复杂耗能、耗时工艺。同时，其收率也较传统工艺高，原料粗品经一次结晶，头孢呋辛钠的纯度超过99％，结晶效率大于80％，适合大规模生产。
头孢呋辛钠的结晶效率(％)＝[结晶产物的重量(g)*含量(％)]/[投料量(g)*含量(％)]*100％
本发明的新型工业结晶技术所精制的头孢呋辛钠，解决了现有头孢呋辛钠杂质多、颜 色深、稳定性差的问题，所得头孢呋辛钠满足注射剂的要求，可用于制备成注射用无菌粉末.
附图说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1所示为本方法的装置示意图，其中1为温控加热器，2为萃取池，3为结晶池，4为搅拌器，5为传感器，6为数字监控器，7为快速接口，8为冷却系统，9为高压泵，10为钢瓶，11为气体收集器，12为聚苯乙烯绝缘器。
具体实施方式
以下实施例是对本发明的进一步说明，但绝不是对本发明范围的限制。下面参照实施例进一步详细阐述本发明，但是本领域技术人员应当理解，本发明并不限于这些实施例以及使用的制备方法。而且，本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰，但这些都将包括在本发明的范围内。
头孢呋辛钠纯度的检测方法：
用高效液相色谱仪检测头孢呋辛钠样品的纯度，色谱条件为：
填充剂：辛烷基硅烷键合硅胶
流动相：pH3.4醋酸盐缓冲液(取醋酸钠0.68g，冰醋酸5.8g，加水稀释成1000ml，用冰醋酸调节pH值至3.4)-乙腈(85:15)；
检测波长：273nm；
进样量：20μl。
实施例1
(1)称取纯度为93.4％的头孢呋辛钠粗品5.43kg置于萃取池中，加入50％乙醇水的混合溶剂50kg，控制温度40℃，搅拌使其溶解；
(2)用高压液体泵泵入CO2流体至15Mpa，搅拌，并保持该压力和温度5分钟，关闭高压泵；
(3)向结晶池中放置晶种，提升萃取池的高度至30cm，开启两池体的快速接口，使萃取池中的液体进入结晶池，关闭快速接口；
(4)调节结晶池内的压力为0.5Mpa，温度20℃，保持此温度和压力20分钟；
(5)待系统降温，卸压后，通过减压干燥，得高纯度的头孢呋辛钠结晶品4.52kg，经无菌分装，得头孢呋辛钠无菌粉。
(6)经HPLC法测定，头孢呋辛钠的纯度为99.5％，结晶率88.7％。
实施例2
(1)称取纯度为93.4％的头孢呋辛钠粗品5.66kg置于萃取池中，加入80％乙醇水的混合溶剂60kg，控制温度60℃，搅拌使其溶解；
(2)用高压液体泵泵入CO2流体至40Mpa，搅拌，并保持该压力和温度20分钟，关闭高压泵；
(3)向结晶池中放置晶种，提升萃取池的高度至30cm，开启两池体的快速接口，使萃取池中的液体进入结晶池，关闭快速接口；
(4)调节结晶池内的压力为5Mpa，温度30℃，保持此温度和压力40分钟；
(5)待系统降温，卸压后，通过减压干燥，得高纯度的头孢呋辛钠结晶品4.66kg，经无菌分装，得头孢呋辛钠无菌粉。
(6)经HPLC法测定，头孢呋辛钠的纯度为99.6％，结晶率87.8％。
实施例3
(1)称取纯度为93.4％头孢呋辛钠粗品6.97kg置于萃取池中，加入70％乙醇水的混合溶剂70kg，控制温度50℃，搅拌使其溶解；
(2)用高压液体泵泵入CO2流体至30Mpa，搅拌，并保持该压力和温度10分钟，关闭高压泵；
(3)向结晶池中放置晶种，提升萃取池的高度至30cm，开启两池体的快速接口，使萃取池中的液体进入结晶池，关闭快速接口；
(4)调节结晶池内的压力为1Mpa，温度25℃，保持此温度和压力30分钟；
(5)待系统降温，卸压后，通过减压干燥，得高纯度的头孢呋辛钠结晶品5.65kg，经无菌分装，得头孢呋辛钠无菌粉。
(6)经HPLC法测定，头孢呋辛钠的纯度为99.9％，结晶率86.7％。
实施例4
(1)称取纯度为93.4％的头孢呋辛钠粗品4.47kg置于萃取池中，加入75％乙醇水的混合溶剂50kg，控制温度55℃，搅拌使其溶解；
(2)用高压液体泵泵入CO2流体至20Mpa，搅拌，并保持该压力和温度15分钟，关闭高压泵；
(3)向结晶池中放置晶种，提升萃取池的高度至25cm，开启两池体的快速接口，使萃取池中的液体进入结晶池，关闭快速接口；
(4)调节结晶池内的压力为4Mpa，温度25℃，保持此温度和压力35分钟；
(5)待系统降温，卸压后，通过减压干燥，得高纯度的头孢呋辛钠结晶品3.85kg，经无菌分装，得头孢呋辛钠无菌粉。
(6)经HPLC法测定，头孢呋辛钠的纯度为99.7％，结晶率91.9％。
对比例1
(1)取纯度为93.4％的头孢呋辛钠粗品1.44kg，置于反应釜中，加入20kg水，控制温度60℃搅拌使其溶解；
(2)向上述溶液中加入丙酮，同时降低温度至室温，室温静置6小试；
(3)通过减压干燥得头孢呋辛钠结晶品0.67kg；
(4)经HPLC法测定，头孢呋辛钠的纯度为95.2％，结晶率47.4％。
试验例1
将实施例1制备的头孢呋辛钠精品采用漏斗法进行休止角测定，以考察其流动性
试验方法：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。结果如下表：
表1头孢呋辛钠流动性试验结果
检测项 高度H 半径r 休止角θ
第一次 30mm 61.5mm 25.9°
第二次 30mm 61.2mm 26.1°
第三次 30mm 60.9mm 26.2°
平均值 30mm 61.3mm 26.1°
结论：一般而言，粉体或颗粒的休止角＜30°时，流动性较好，上述头孢呋辛钠结晶粉末休止角为θ＝26.1°，小于30°，说明流动性良好，适合于分装为无菌粉针剂。
试验例2
参照《中国药典2010版2部》头孢呋辛钠原料质量标准对实施例1～4和对比例1的头孢呋辛钠的结晶粉末进行质量研究，结果如下：
表2头孢呋辛钠质量研究结果
Figure PCTCN2015095810-appb-000002
结论：实施例1～4的头孢呋辛钠结晶粉末各项检测指标均符合规定，而对比例1的头孢呋辛钠结晶粉末溶液的颜色、有关物质、头孢呋辛聚合物和含量不符合规定，因此应用本技术制备的头孢呋辛钠结晶粉末满足《中国药典2010版2部》对头孢呋辛钠的质量要求。
工业实用性
由上述实施例以及实验例的结果可知，本发明的头孢呋辛钠新型工业结晶技术及设备所制备的头孢呋辛钠结晶粉末收率高、纯度高，各项检查指标均符合规定，适合于制备成无菌粉针剂，具有良好的工业应用价值。
以上通过具体实施方式和实施例对本发明进行了详细说明，不过应理解，这些说明并不对本发明的范围构成任何限制，在不偏离本发明的精神和保护范围的情况下，可以对本发明的技术方案及其实施方式进行多种修饰、改进和替换，这些均因落入本发明的保护范围内。

Claims (7)

  1. 一种头孢呋辛钠的新型工业结晶技术，其特征在于采用超临界流体萃取技术与传统的结晶技术相结合的方式实现头孢呋辛钠的重结晶，将头孢呋辛钠用溶剂溶解，利用超临界流体萃取头孢呋辛钠溶液中的有机溶剂与溶质，通过调节温度和压力，改变物质成分在有机溶剂与超临界流体中的溶解特性，使头孢呋辛钠结晶析出。
  2. 根据权利要求1所述的头孢呋辛钠新型工业结晶技术，其特征在于包括该技术与设备制得的头孢呋辛钠，含有该头孢呋辛钠的无菌粉针剂。
  3. 根据权利要求1～2所述的头孢呋辛钠新型工业结晶技术，其特征在于采用超临界流体萃取对头孢呋辛钠溶液进行结晶分离，萃取压力15～40Mpa，萃取温度40～60℃，萃取时间5～20分钟，结晶压力0.5～5Mpa、结晶温度20～30℃，结晶时间20～40分钟。
  4. 根据权利要求1～3所述的头孢呋辛钠新型工业结晶技术，其特征在于所述的溶解头孢呋辛钠所用的溶剂是由醇类、醛类、酯类、酮类、醚类及水等单组份或多组分构成，优选乙醇水溶液，更优选为浓度50％～80％的乙醇水溶液。
  5. 根据权利要求1～4所述的头孢呋辛钠新型工业结晶技术，其特征在于形成超临界流体所用的工作介质可以是CO2、烷烃、烯烃等，优选CO2。
  6. 根据权利要求1～5所述的头孢呋辛钠新型工业结晶技术，其特征在于所述的设备主要包括工作介质气瓶、压缩机、热交换器、溶解池、结晶池等。
  7. 根据权利要求6所述的头孢呋辛钠新型工业结晶技术，其特征在于溶解池表面涂覆活性炭或大孔吸附树脂等材料，萃取池内设有搅拌装置，溶解池和结晶池之间设有可以自由开闭的快速接口，快速接口内部设有能够除菌过滤的装置。
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