WO2016011783A1 - 一种制备球形硫酸氢氯吡格雷i晶型的方法 - Google Patents

一种制备球形硫酸氢氯吡格雷i晶型的方法 Download PDF

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WO2016011783A1
WO2016011783A1 PCT/CN2014/095926 CN2014095926W WO2016011783A1 WO 2016011783 A1 WO2016011783 A1 WO 2016011783A1 CN 2014095926 W CN2014095926 W CN 2014095926W WO 2016011783 A1 WO2016011783 A1 WO 2016011783A1
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clopidogrel
hydrogen sulfate
clopidogrel hydrogen
preparing
spherical
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PCT/CN2014/095926
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English (en)
French (fr)
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龚俊波
王�琦
王静康
尹秋响
侯宝红
宋晓鹏
谭端明
廖丽婷
邸子渊
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天津大学
深圳信立泰药业股份有限公司
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Priority to US15/302,944 priority Critical patent/US9815848B2/en
Priority to PCT/CN2014/095926 priority patent/WO2016011783A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
    • 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 pharmaceutical synthesis, and in particular relates to a method for preparing a spherical crystal form of clopidogrel hydrogen sulfate.
  • Clopidogrel hydrogen sulfate (CAS: 135046-48-9) is a clopidogrel sulfate, English name Clopidogrel Hydrogen Sulfate, chemical name: (s)- ⁇ -(2-chlorophenyl)-6,7 - Dihydrothieno[3,2-c]pyridine-5(4H)acetic acid methyl ester hydrogensulfate.
  • Clopidogrel hydrogen sulfate is an anti-platelet aggregation agent. The product was developed by the French pharmaceutical company Sanofi-Aventis and first marketed in the United Kingdom and the United States in 1998. Clopidogrel hydrogen sulfate entered China in 2001 and is used clinically to prevent atherothrombotic thrombosis. .
  • the domestic clopidogrel hydrogen sulfate preparation products mainly include Plavix of Sanofi-Aventis and Taijia of Shenzhen Xinlitai Pharmaceutical Co., Ltd.
  • type II crystals are thermodynamically stable crystals, and the dissolution properties of the corresponding preparations are slightly poor; while type I crystals are thermodynamically unstable crystals.
  • clopidogrel hydrogen sulfate preparation products mostly use type I crystal, while clopidogrel hydrogen sulfate type I crystal is unstable to moist heat, so the conventional wet granulation-tableting method is not suitable for clopidogrel hydrogen sulfate preparation.
  • the preparation process of dry pressing tablets is currently commonly used.
  • the clopidogrel hydrogen sulfate powder has strong static electricity and viscosity, which makes it easy to stick in the dry preparation process, which leads to the production failure, although the adhesion can be improved by adding a lubricant, but another report has been reported.
  • Conventional alkaline lubricants such as magnesium stearate have a great influence on the stability of the active ingredient, while most other conventional lubricants such as stearic acid have a sticking phenomenon due to a lower melting point.
  • the solvent system used in the process is a 2-butanol-cyclohexane system, and cyclohexane belongs to the second type of solvent listed in relevant laws and regulations (such as "Guidelines for the Study of Residual Solvents of Chemical Drugs").
  • relevant laws and regulations such as "Guidelines for the Study of Residual Solvents of Chemical Drugs”
  • the residue is strictly required; and the mixed solvent also brings inconvenience to the recycling of the solvent.
  • one of the key technical factors of the process is that the cyclohexane sulfate solution needs to be slowly added to the solvent system under cooling conditions, which makes the process complicated, and cyclohexane may be discolored due to the addition of concentrated sulfuric acid, which affects product quality.
  • the process takes a long time, and the long reaction time has the risk of crystal transformation on the one hand and the product bulk density on the other hand.
  • Patent WO2011083955 discloses a preparation method of clopidogrel hydrogen sulfate spherulites, wherein Example 5 uses a solvent system to prepare spherulites in a 2-butanol-water system, but in the solvent used in the process, the boiling point of water is higher. It takes a long time to dry at a higher temperature; in addition, the presence of water is also detrimental to the formation of the target crystal form, and the yield of the process is only 53%, which is at a lower level. In the comparative example 1, the patent also studied the influence of the amount of water in the solvent system on the morphology of the product.
  • the object of the present invention is to overcome the disadvantages of the prior art and to provide a novel process for the preparation of spherical clopidogrel hydrogen sulfate crystal form I by using a single 2-butanol as a solvent by controlling the sulfuric acid used for salt formation. Concentration, addition mode and addition rate, while shortening the process time, the clopidogrel hydrogen sulfate was precipitated from the solution system in a spherical shape, and the obtained clopidogrel hydrogen sulfate was consistent with the solvent residue, bulk density and fluidity. The need for a formulation process.
  • a method for preparing a spherical form of clopidogrel hydrogen sulfate I comprising the steps of:
  • step (2) maintaining the temperature range of step (1), adding a clopidogrel hydrogen sulfate crystal form with a mass ratio of clopidogrel free base of 1 to 10 wt%, and maintaining the temperature for 4 to 8 hours;
  • the sulfuric acid addition time is the key to the realization of the scheme, and the Chinese patent CN201180072203.6 slowly drops the cyclohexane sulfate solution in 8-10 hours (Example 1), and the phenomenon from the repeated experiment can be It is observed that the method first forms a quasi-emulsion droplet in a solution system and then coalesces into a spherical crystal. For this method, when the sulfuric acid is added for a long time, the formed clopidogrel hydrogen sulfate crystal form has a transition with time.
  • spherical I-type crystals which may be
  • the faster rate of sulfuric acid addition is beneficial to the formation of higher supersaturation of the solution, increasing the nucleation and growth rate of the crystal, and rapidly nucleating and growing into a relatively dense sphere, and the resulting clopidogrel hydrogen sulfate is spherical I.
  • the crystal density, morphology and morphology of the crystals are in line with the subsequent formulation process requirements, and the yield is relatively high.
  • the experiment also found that under the premise of ensuring that the product is a spherical single crystal form, as the sulfuric acid addition time is extended, the product bulk density is correspondingly decreased, and the morphology tends to deteriorate.
  • the sulfuric acid control is added over a period of 20 minutes, both the bulk density and the spherical morphology are good. More preferably, when the sulfuric acid control is added within 10 minutes, the factors such as comprehensive bulk density and morphology are optimally evaluated.
  • the method of adding the sulfuric acid is a method commonly used in the art, such as constant addition, addition in portions, and the like.
  • the time required for the preparation of a batch of products by the method of the present invention is also greatly shortened. Specifically, the time required for the preparation of the process of the present invention is less than 10 hours, while the prior art is generally 20 to 30 hours.
  • the molar ratio of sulfuric acid to clopidogrel free base is from 0.8 to 1.1:1, preferably from 0.95 to 1.05:1; the purity of the clopidogrel base is preferably 95% or more.
  • the sulfuric acid is added to the system after dilution, and the concentration of the 2-butanol sulfate solution is 0.5 to 2.0 mol/L.
  • the sulfuric acid is 2-
  • the concentration of the butanol solution is 0.6-1.0 mol/L; the concentration of the free alkali solution has a certain influence on the product, although increasing the concentration can improve the yield to some extent, but we find that the excessive concentration is easy in the crystallization process.
  • the crystal transformation occurs, and the bulk density of the obtained product also tends to decrease, and the obtained product does not meet the requirements of the subsequent preparation; and the too low concentration crystal nucleation and slow growth, and the yield is low.
  • the inventors have found that when the concentration of the free alkali solution is 0.02 to 0.1 g/mL, preferably 0.040 to 0.065 g/mL, it is advantageous for the formation of spherical crystals.
  • the step (1) can be carried out under the temperature range of 0 to 35 ° C, and the preferred operating temperature is 10 to 30 ° C.
  • the addition of a certain amount of seed crystals contributes to the formation of spherical crystals
  • the seed crystal used in the present invention is clopidogrel hydrogen sulfate type I crystal.
  • the inventors have found that when the amount of seed crystals is controlled to be from 1 to 10% by weight, preferably from 1 to 5% by weight, based on the mass ratio to clopidogrel free base, it is possible to contribute to a stable and uniform precipitation of crystals in a spherical form.
  • the step (2) can maintain the temperature range of the step (1) at 0-35 °C.
  • the properties of clopidogrel hydrogen sulfate have their special characteristics.
  • the performance of crystal transformation is too high at too high temperature, and the obtained products are mostly mixed crystal forms; while the too low temperature is not conducive to crystal nucleation and growth.
  • the yield is also low, making the production cost too high.
  • the temperature should be controlled between 10 and 30 ° C; more preferably, in order to optimize product morphology, bulk density and yield, the temperature may fluctuate during the production process, and may optionally be gradually reduced, You can choose to reduce the segmentation. For example, after maintaining a certain temperature for a certain period of time, lower the temperature and further crystallization. For example, it can be carried out in two steps: tempering at 20-30 °C for 2-4 h, then cooling to 10-20 °C to continue stirring and crystallization. .
  • the method of the invention adopts a single 2-butanol as a solvent, and 2-butanol is a third type of solvent listed in relevant laws and regulations (such as "Guidelines for the Study of Residual Solvents of Chemical Drugs", etc.), and has a relative residue for the residue.
  • relevant laws and regulations such as "Guidelines for the Study of Residual Solvents of Chemical Drugs", etc.
  • the coating of the solvent during the crystal growth process is greatly reduced, so that the subsequent The solvent removal process is relatively simple, and the solvent residue is relatively easy to meet the requirements of the subsequent production process.
  • the clopidogrel free base in the foregoing technical scheme can be prepared from the corresponding clopidogrel salt, and the steps are as follows:
  • the clopidogrel salt is preferably a mixture obtained by mixing one or more of hydrogensulfate, camphorsulfonate, and hydrochloride in an arbitrary ratio, which is well known to those skilled in the art.
  • the purity of the clopidogrel salt is above 95%;
  • the organic solvent is a solvent which is immiscible with water, preferably dichloromethane, chloroform.
  • One or more of ethyl acetate and the like are mixed in a mixture at an arbitrary ratio.
  • the dehydrating agent is a dehydrating agent commonly used by those skilled in the art such as anhydrous magnesium sulfate, anhydrous sodium sulfate, and the like.
  • a method for preparing a spherical form of clopidogrel hydrogen sulfate I comprising the steps of:
  • step (4) maintaining the temperature range of step (4), adding a clopidogrel hydrogen sulfate crystal form with a clopidogrel free base mass ratio of 1 to 10 wt%, and maintaining the temperature for 4 to 8 hours;
  • the method comprises the steps of preparing clopidogrel free base and clopidogrel hydrogen sulfate type I spherulites, wherein all technical features, ranges, references and related preferred ranges in the steps are the same as the preparation of spherical clopidogrel hydrogen sulfate.
  • the crystal form of I and the scheme for preparing clopidogrel free base correspond to the same.
  • the clopidogrel hydrogen sulfate crystal prepared by the method of the invention has a regular spherical morphology and can be visually observed by conventional observation methods such as scanning electron microscopy (SEM), microscopy, and the like. Through further detection of the morphology, it is found that the particle size distribution of the spherulitic product can reach 40um ⁇ d (0.1) ⁇ 60um, 60um ⁇ d (0.5) ⁇ 90um, 90um ⁇ d (0.9) ⁇ 150um, and the particle size distribution is very uniform. The crystals of this morphology can improve the performance of the formulation and the dissolution rate of the product to some extent.
  • the clopidogrel hydrogen sulfate prepared by the method of the present invention has a value of 9.22 ⁇ 0.02°, 10.90 ⁇ 0.02°, 11.58 ⁇ 0.02°, 13.84 ⁇ 0.02°, 14.40 ⁇ 0.02° at 2 ⁇ . , 14.82 ⁇ 0.02°, 15.54 ⁇ 0.02°, 23.16 ⁇ 0.02°, there is a diffraction peak.
  • the spherical crystal of clopidogrel hydrogen sulfate prepared by the method of the invention is clopidogrel hydrogen sulfate I crystal form. .
  • the crystal form of the spherical crystal can also be subjected to conventional detection methods in the art, such as differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR), and the like.
  • the spherical crystal of clopidogrel hydrogen sulfate prepared by the method of the invention meets the requirements of the subsequent preparation process. Specifically, the spherical crystal achieves the preset purpose of improving fluidity and reducing static electricity.
  • the fluidity is represented by the powder angle of repose, and the powder fluidity is determined by a conventional detection method in the art, such as an fixed funnel method; the electrostatic phenomenon can be expressed by the bulk density, and the powder is measured by a conventional detection method such as a graduated tapping method in the art. Bulk density.
  • the obtained spherical crystal has high fluidity and bulk density, which can meet the requirements of subsequent high-demand preparation processes (such as direct compression).
  • Figure 1 shows the XRPD spectrum of clopidogrel hydrogen sulfate obtained in Example 1
  • Figure 2 shows the DSC spectrum of clopidogrel hydrogen sulfate obtained in Example 1.
  • Figure 4 is a comparison of the XRPD spectrum of clopidogrel hydrogen sulfate obtained in Example 1.
  • Figure 5 is a SEM photograph of clopidogrel hydrogen sulfate obtained in Comparative Example 1.
  • the XRPD spectrum of the obtained product is shown in Fig. 1, the DSC spectrum is shown in Fig. 2, and the SEM photograph is shown in Fig. 3.
  • clopidogrel camphorsulfonate (purity greater than 99.0%) was dispersed in a mixture of 10 L of dichloromethane and 5 L of water, and solid sodium hydrogencarbonate was added until the pH of the aqueous phase was >7. The mixture was allowed to stand for separation, and the organic phase was taken and washed with water (1 L ⁇ 2).
  • the filter cake was washed with ethyl acetate and dried under vacuum at 40 ° C for 1.0 h to obtain 605 g (2-butanol residue ⁇ 0.2%). It is clopidogrel hydrogen sulfate type I spherulites.
  • the product was kept at 25 ° C for 2.5 h, cooled to 15 ° C and kept for 3 h, suction filtered, and the filter cake was washed with ethyl acetate and vacuum dried at 40 ° C for 1.0 h to obtain 608 g of product (2-butanol residue ⁇ 0.2%).
  • the XRPD spectrum is shown in Fig. 4.
  • the SEM photograph of the product is shown in Fig. 5. From Fig. 4, the obtained product is a mixed crystal of clopidogrel hydrogen sulfate type I crystal and type II crystal. From Fig. 5, the product form has begun to appear. It is an irregular sphere.
  • Example 2 Using the same feed ratio and process operation of Example 1, different sulfuric acid addition times were used to study the relationship between the sulfuric acid addition time and the product morphology and crystal form.
  • the sulfuric acid addition time is related to the product morphology and crystal form. Specifically, as the sulfuric acid addition time elongates, the product has a tendency to crystallize and increases with time. When the addition time is extended to 40 minutes or more, the obtained product is a mixed crystal.
  • the spheroidal crystals of clopidogrel hydrogen sulfate obtained in Examples 1 and 2 have a uniform morphology, and in the further detection of the dissolution properties of the preparation prepared by the preparation, it is found that the dissolution rate of the preparation obtained by using the spherulites of the present invention is significantly faster than that of the commercially available one. product.
  • angles of repose of Examples 1 and 2 are generally between 25° and 32°, and it is known that the fluidity of the obtained spherical crystal is much better than that of the powder form product;
  • the bulk density of Examples 1 and 2 was between 0.75 and 0.80 g/ml, which was much larger than that of the powder form product, and it was found that the electrostatic effect of the obtained spherulites was greatly lowered.
  • the spherical crystal obtained by the present invention is more in line with the preparation process common to the prior art of clopidogrel hydrogen sulfate product, and is advantageous for further improvement of the process level.

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Abstract

本发明提供了一种制备球形硫酸氢氯吡格雷I晶型的新方法，采用单一的2-丁醇作为溶剂，通过控制用于成盐的硫酸的浓度、加入方式和加入速度，在缩短工艺时间的同时，使得硫酸氢氯吡格雷以球状稳定从溶液体系中析出，所得硫酸氢氯吡格雷在溶剂残留、堆密度和流动性等方面均符合后续制剂工艺的需要。

Description

一种制备球形硫酸氢氯吡格雷I晶型的方法 技术领域
本发明属于药物合成领域，特别涉及一种制备球形硫酸氢氯吡格雷I晶型的方法。
背景技术
硫酸氢氯吡格雷(CAS:135046-48-9)，是氯吡格雷的硫酸盐，英文名Clopidogrel Hydrogen Sulfate，化学名为：(s)-α-(2-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)乙酸甲酯硫酸氢盐。硫酸氢氯吡格雷是一种抗血小板聚集剂。该产品由法国制药企业赛诺菲-安万特公司研制，并于1998年首次在英国和美国上市，硫酸氢氯吡格雷于2001年进入中国，临床上用于预防动脉粥样硬化血栓形成事件。目前，国内的硫酸氢氯吡格雷制剂产品主要有赛诺菲-安万特公司的波立维(Plavix)和深圳信立泰药业股份有限公司的泰嘉。
Figure PCTCN2014095926-appb-000001
硫酸氢氯吡格雷的主流晶型有I型和II型两种，其中II型晶体为热力学稳定晶体，其对应制剂的溶出性能略差；而I型晶体则为热力学不稳定晶体。
目前市售硫酸氢氯吡格雷制剂产品多采用I型晶体，而硫酸氢氯吡格雷I型晶体对于湿热不稳定，因此常规湿法制粒-压片的方法并不适用于硫酸氢氯吡格雷制剂中，目前常用干法压片的制剂工艺。硫酸氢氯吡格雷粉体具有很强的静电和粘性，使得其在干法制剂工艺中极易发生粘冲从而导致生产无法顺利进行，尽管通过加入润滑剂可以改善粘冲情况，但是另有报道常规的碱性润滑剂诸如硬脂酸镁对有效成分的稳定性影响较大，而其他大多数常规润滑剂诸如硬脂酸等则因为熔点较低，同样会存在粘冲的现象。
将有效成分做成流动性好、无静电现象的粉体/晶体是解决以上问题可行的方案之一，现有技术多采用混合溶剂体系制备球形硫酸氢氯吡格雷I型晶体。
中国专利CN201180072203.6公开了一种球形硫酸氢氯吡格雷I型晶体的制备方法，采用2-丁醇/环己烷体系制备得到粒径分布为：d(0.1)＝52.536μm，d(0.5)＝74.567μm，d(0.9)＝106.074μm的球形结晶，该结晶改善了硫酸氢氯吡格雷的流动性，并且大大减小静电现象。但是，该工艺所用溶剂体系为2-丁醇-环己烷体系，其中环己烷属于相关法律法规(如《化学药物残留溶剂研究的指导原则》等)所列举的第二类溶剂，属于在药物制备过程中需要限制使用的溶剂，对应的，对其残留情况要求较为严格；而混合溶剂也给溶剂的回收利用带来不便。另外，该工艺的关键技术因素之一即为硫酸环己烷溶液需要在冷却条件下缓慢加入溶剂体系中，使得该工艺变得复杂，而且环己烷可能因为浓硫酸加入而变色，影响产品质量；还有，该工艺所需时间较长，而过长的反应时间一方面存在转晶的风险，另一方面也会降低产品堆密度。
专利WO2011083955公开了一种硫酸氢氯吡格雷球晶的制备方法，其中实施例5采用溶剂体系为2-丁醇-水体系制备球晶，但是该工艺方法所用溶剂中，水的沸点较高，在后续需要较长时间、较高温度烘干；另外，水的存在也不利于目的晶型生成，该工艺的收率也仅为53％，处于较低的水平。该专利在对比实施例1还对溶剂体系中水的用量对产品形态的影响做了研究，结果表明当采用单一2-丁醇溶剂体系并不利于球形结晶的形成，其制备得到硫酸氢氯吡格雷的形态为杂乱无章的粉体(如专利附图Figure4所示)。
因此，寻找一种环境友好、成本低、收率高、所得产品性状符合后续制剂工艺的硫酸氢氯吡格雷I型球晶仍然是现有技术未解决的技术问题。
发明内容
本发明的目的在于克服现有技术的缺点，提供一种制备球形硫酸氢氯吡格雷I晶型的新方法，该方法采用单一的2-丁醇作为溶剂，通过控制用于成盐的硫酸的浓度、加入方式和加入速度，在缩短工艺时间的同时，使得硫酸氢氯吡格雷以球状稳定从溶液体系中析出，所得硫酸氢氯吡格雷在溶剂残留、堆密度和流动性等方面均符合后续制剂工艺的需要。
本发明的上述有益效果通过以下技术方案实现。
一种制备球形硫酸氢氯吡格雷I晶型的方法，所述方法包含如下步骤：
(1)将氯吡格雷游离碱溶解在2-丁醇中，得到浓度为0.02～0.1g/mL的游离碱溶液，在0～35℃温度条件下，快速加入0.5～2.0mol/L硫酸的2-丁醇溶液，加入硫酸与 氯吡格雷游离碱的摩尔比为0.8～1.1:1；
(2)保持步骤(1)温度范围，加入与氯吡格雷游离碱质量比为1～10wt％的硫酸氢氯吡格雷I晶型晶种后，保持温度搅拌4～8h；
(3)过滤、洗涤及干燥，得到硫酸氢氯吡格雷I晶型球形晶体；
其特征在于所述步骤(1)中硫酸2-丁醇溶液加入的时间控制在40分钟以内。
所述步骤(1)中，硫酸加入时间是本方案实现的关键，中国专利CN201180072203.6将硫酸环己烷溶液在8-10小时内缓慢滴加(实施例1)，从重复实验的现象可以观察出，该方法首先在溶液体系中形成准乳滴，进而聚结成球状晶体，对于该方法，当硫酸滴加时间较长时，生成的硫酸氢氯吡格雷I晶型随时间延长有转变成II晶型的趋势，并且得到的球形晶体堆密度明显下降；而如果硫酸加入过快，则会出现胶化现象，影响晶体的生成。而发明人惊奇的发现，对于单一的2-丁醇重结晶溶剂体系，其属于不同的结晶过程，具体的，当硫酸控制在40分钟时间内加入时，有利于生成球形I型晶体，可能是较快的硫酸加入速度，有利于溶液形成较高的过饱和度，提高晶体的成核与生长速度，并快速的成核、生长成为相对比较致密的球形，所得硫酸氢氯吡格雷为球状I型晶体，其堆密度和形态等均符合后续制剂工艺要求，产率也相对较高。实验还发现，在保证产品为球状单一晶型的前提下，随着硫酸加入时间的拉长，产品堆密度有相应下降，形态也趋于变劣。优选的，硫酸控制在20分钟时间内加入时，堆密度和球状形态均较好。更优选的，硫酸控制在10分钟时间内加入时，综合堆密度和形态等因素评价最优。所述硫酸的加入方法为本领域常用的方法，如匀速加入、按份加入等。由于硫酸加入时间的缩短，使得本发明所属方法制备一批产品所需的时间也大大缩短，具体的，本发明工艺制备所需时间为10小时以内，而现有技术则普遍在20～30小时；加入硫酸与氯吡格雷游离碱的摩尔比为0.8～1.1:1，优选0.95～1.05:1；所述氯吡格雷碱的纯度优选95％以上。
所述步骤(2)中，由于结晶过程的特殊性，因此硫酸需经稀释后加入体系，所述硫酸2-丁醇溶液的浓度为0.5～2.0mol/L，优选的，所述硫酸2-丁醇溶液的浓度为0.6～1.0mol/L；所述游离碱溶液的浓度对产品有一定影响，尽管提高浓度可以一定程度上提高收率，但我们发现，过高的浓度在结晶过程中容易发生转晶，且所得产品的堆密度也有降低的趋势，所得产品不符合后续制剂需要；而过低的浓度晶体成核及生长缓慢，收率低。发明人发现，当游离碱溶液的浓度为0.02～0.1g/mL时，优选0.040～0.065g/mL时，有利于球形晶体的生成。
所述步骤(1)在0～35℃温度范围条件下可以实现，优选的操作温度为10～30℃。
本发明所述方法中，一定量晶种的加入有助于球形晶体的生成，本发明所用晶种为硫酸氢氯吡格雷I型晶体。发明人发现当晶种量控制在与氯吡格雷游离碱的质量比为1～10wt％，优选1-5wt％时，可以有助于晶体更快的以球形形态稳定均一的析出。
所述步骤(2)可以保持步骤(1)的温度范围，在0-35℃下进行。硫酸氢氯吡格雷的性质具有其特殊性，表现在过高的温度会有晶型转化的风险，所得产品多为混合晶型；而过低的温度则不利于晶体的成核与生长，所得产率也偏低，使得生产成本过高。优选的，应控制温度在10～30℃之间；更优选的，为使产品形态、堆密度及产率达到最优化，所述温度可以在生产过程中有所波动，可以选择逐渐降低，也可以选择分段降低，如在较高温度保持一定时间后，降低温度进一步析晶，如分两步进行：在20～30℃下保温2-4h，后降温至10-20℃继续搅拌析晶。
本发明所述方法采用单一的2-丁醇为溶剂，2-丁醇为相关法律法规(如《化学药物残留溶剂研究的指导原则》等)所列举的第三类溶剂，对于其残留具有相对宽松的要求；另外，由于该球形晶体产品为球形生长机理得到，而并非现有技术方法中的球形聚结机理，因此很大程度减少了晶体生长过程中对溶剂的包覆，使得其后续的溶剂去除工艺较为简单，其溶剂残留也相对容易达到后续生产工艺的要求。
在工业化生产中，前述技术方案中的氯吡格雷游离碱可由对应的氯吡格雷盐制备得到，其步骤如下：
(1)将氯吡格雷盐溶于有机溶剂中；
(2)用碱调节体系的pH值，分相后有机相用少量水洗涤，所得有机相加脱水剂除水；
(3)除水后的有机相真空浓缩得到氯吡格雷游离碱；
所述步骤(1)中：氯吡格雷盐优选自硫酸氢盐、樟脑磺酸盐、盐酸盐中的一种或一种以上以任意比例混合所得的混合物，本领域普通技术人员公知，所述氯吡格雷盐的纯度越高，越有利于球晶的制备，优选的，所述氯吡格雷盐的纯度在95％以上；有机溶剂为与水不互溶的溶剂，优选二氯甲烷、氯仿、乙酸乙酯等的一种或一种以上以任意比例混合所得的混合物。
所述包含氯吡格雷游离碱制备的方案，所述步骤(2)中：使用碱调节pH值的目的在于将硫酸氢氯吡格雷变成氯吡格雷碱，以便使用有机溶剂萃取，该操作可以加水后加入固体碱，也可以使用碱溶液；所述碱可为本领域普通技术人员常用的碱，如碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾等；所述脱水剂为本领域普通技术人员常用的脱水剂如无水硫酸镁、无水硫酸钠等。
为达到工业化连续生产的目的，可以综合前述氯吡格雷游离碱和硫酸氢氯吡格雷I型球晶的制备步骤，进一步得到符合工业化连续生产的方案如下：
一种制备球形硫酸氢氯吡格雷I晶型的方法，所述方法包含如下步骤：
(1)将氯吡格雷盐溶于有机溶剂中；
(2)用碱调节体系的pH值，分相后有机相用少量水洗涤，所得有机相加脱水剂除水；
(3)除水后的有机相真空浓缩得到氯吡格雷游离碱；
(4)将步骤(3)所得到的氯吡格雷游离碱溶解在2-丁醇中，得到浓度为0.02～0.1g/mL的游离碱溶液，在0～35℃温度条件下，快速加入0.5～2.0mol/L硫酸的2-丁醇溶液，加入硫酸与氯吡格雷游离碱的摩尔比为0.8～1.1:1；
(5)保持步骤(4)温度范围，加入与氯吡格雷游离碱质量比为1～10wt％的硫酸氢氯吡格雷I晶型晶种后，保持温度搅拌4～8h；
(6)过滤、洗涤及干燥，得到硫酸氢氯吡格雷I晶型球形晶体；
其特征在于所述步骤(1)中硫酸2-丁醇溶液加入的时间控制在40分钟以内。
该方法包含氯吡格雷游离碱和硫酸氢氯吡格雷I型球晶的制备步骤，其步骤中的所有技术特征、范围、指代的内容及相关优选范围均与前述制备球形硫酸氢氯吡格雷I晶型及制备氯吡格雷游离碱的方案对应相同。
本发明所述方法均可制备得到的硫酸氢氯吡格雷晶体为规则的球形形态，通过常规的观测方法如扫描电镜(SEM)、显微镜等即可直观的看出。通过对形态的进一步检测发现，所述球晶产品的粒度分布可以达到40um≤d(0.1)≤60um，60um≤d(0.5)≤90um，90um≤d(0.9)≤150um，粒度分布非常均一。该形态的晶体可以在一定程度上提高制剂性能以及产品的溶出速率。
通过X-ray粉末衍射法检测发现，本发明所述方法制备得到的硫酸氢氯吡格雷在2θ为9.22±0.02°，10.90±0.02°，11.58±0.02°，13.84±0.02°，14.40±0.02°，14.82±0.02°，15.54±0.02°，23.16±0.02°的位置存在衍射峰，经进一步比对，本发明所述方法制备得到的硫酸氢氯吡格雷球形晶体为硫酸氢氯吡格雷I晶型。所述 球形晶体的晶型还可以采用本领域常规的检测方法，如差热扫描量热仪(DSC)、傅立叶变换红外(FT-IR)等方法。
本发明所述方法制备得到的硫酸氢氯吡格雷球形晶体符合后续制剂工艺要求。具体的，所述球形晶体达到了预设的目的，即改善流动性，降低静电现象。所述流动性由粉体休止角体现，采用本领域常规检测方法如固定漏斗法测定粉体流动性；所述静电现象可由堆密度体现，采用本领域常规的检测方法如量筒敲击法测定粉体堆密度。
本发明相对于现有技术具有如下的优点及有益效果：
1、克服单一溶剂难以制备球状晶体的技术困难，采用单一溶剂2-丁醇制备硫酸氢氯吡格雷I型球形晶体，降低溶剂残留风险与回收成本；
2、所得球形晶体有较高的流动性及堆密度，能够满足后续高要求制剂工艺(如直接压片)的要求。
3、产品制备可实现工业化连续生产。
附图说明
图1实施例1所得硫酸氢氯吡格雷XRPD谱图
图2实施例1所得硫酸氢氯吡格雷DSC谱图
图3实施例1所得硫酸氢氯吡格雷SEM照片
图4对比实施例1所得硫酸氢氯吡格雷XRPD谱图
图5对比实施例1所得硫酸氢氯吡格雷SEM照片
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但发明的实施方式不限于此。
实施例1
取氯吡格雷硫酸氢盐760g(纯度大于99.0％)分散于10L二氯甲烷和5L水的混合液中，加入固体碳酸氢钠至水相pH>7。静置分液，取有机相并用水洗涤(1L×2)，无水硫酸镁除水至溶液澄清。
将有机相过滤、真空旋蒸至质量不再变化，将剩余物溶于10.5L的2-丁醇中，将溶液于25℃下保温。将100ml浓硫酸(181g)分散于2.5L的2-丁醇中在10分钟内加入体系中，将10g I晶型晶种分散于1L的2-丁醇中一并倒入。25℃ 下保温2.5h，降温至15℃继续保温3h，抽滤，滤饼用乙酸乙酯洗涤，40℃真空烘干1.0h，得产品610g(2-丁醇残留<0.2％)。
所得产品XRPD谱图如图1所示，DSC谱图如图2所示，SEM照片如图3所示。
实施例2
取氯吡格雷樟脑磺酸盐1000g(纯度大于99.0％)分散于10L二氯甲烷和5L水的混合液中，加入固体碳酸氢钠至水相pH>7。静置分液，取有机相并用水洗涤(1L×2)，无水硫酸镁除水至溶液澄清。
将有机相过滤、真空旋蒸至质量不再变化，将剩余物溶于10.5L的2-丁醇中，将溶液于25℃下保温。将100ml浓硫酸(181g)分散于2.5L的2-丁醇中在10分钟内加入体系中，将12g I晶型晶种分散于1L的2-丁醇中一并倒入。25℃下保温2.5h，降温至15℃继续保温3h，抽滤，滤饼用乙酸乙酯洗涤，40℃真空烘干1.0h，得产品605g(2-丁醇残留<0.2％)，经检测其为硫酸氢氯吡格雷I型球晶。
对比实施例1
取氯吡格雷硫酸氢盐760g(纯度大于99.0％)分散于10L二氯甲烷和5L水的混合液中，加入固体碳酸氢钠至水相pH>7。静置分液，取有机相并用水洗涤(1L×2)，无水硫酸镁除水至溶液澄清。
将有机相过滤、真空旋蒸至质量不再变化，将剩余物溶于10.5L的2-丁醇中，将溶液于25℃下保温。将100ml浓硫酸(181g)分散于2.5L的2-丁醇中在1h内缓慢滴加入体系中，将10g I晶型晶种分散于1L的2-丁醇中一并倒入。25℃下保温2.5h，降温至15℃继续保温3h，抽滤，滤饼用乙酸乙酯洗涤，40℃真空烘干1.0h，得产品608g(2-丁醇残留<0.2％)，所得产品XRPD谱图如图4所示，产品SEM照片如图5所示，从图4可知所得产品为硫酸氢氯吡格雷I型晶体和II型晶体的混晶，从图5可知产品形态已开始呈现为不规则球形。
实施例3
采用实施例1相同的投料比及工艺操作，采用不同的硫酸加入时间，研究硫酸加入时间与产品形态及晶型之间的关系。
编号 时间(min) 形态 晶型 堆密度
1 15 球形 I型 0.77
2 20 球形 I型 0.76
3 30 球形 I型 0.75
4 40 球形 I型 0.75
5 80 类球形 I/II型混晶 0.68
6 120 类球形 I/II型混晶 0.65
7 180 类球形 I/II型混晶 0.58
可以看出，在其他工艺条件不变的前提下，硫酸加入时间与产品形态及晶型存在一定关联。具体的，随着硫酸加入时间的拉长，产品存在转晶趋势，并随着时间的拉长而增加，当加入时间拉长到40分钟以上时，所得产品即为混晶。
通过实验还观察到：随着硫酸加入时间的拉长，产品堆密度相应下降，形态也会发生改变，表现为均一性变差。当硫酸控制在20分钟时间内加入时，堆密度和形态均较好；当硫酸控制在10分钟时间内加入时，综合产率、堆密度和形态等因素评价最优。
实施例4
采用Malvern-3000粒度分析仪对实施例1～2所得产品的产品形态和均一性进行检测，检测结果如下表所示：
  形态 d(0.1) d(0.5) d(0.9)
实施例1 球状 58.24μm 70.67μm 113.10μm
实施例2 球状 46.46μm 62.48μm 90.60μm
可以看出，实施例1～2所得硫酸氢氯吡格雷球状晶体形态均匀，在进一步对其制备得到的制剂溶出性能的检测中发现，使用本发明球晶所得制剂的溶出速率明显快于市售产品。
实施例5
采用固定漏斗法和量筒敲击法分别检测实施例1～2所得产品的休止角和堆密度，测量结果如下表所示：
  休止角(°) 堆密度(g/ml)
实施例1 28 0.78
实施例2 30 0.77
粉末形态 规则均匀的球形 规则均匀的球形
可以看出，实施例1～2休止角普遍在25°～32°之间，可知所得球形晶体的流动性远优于粉末形态产品；
实施例1～2堆密度在0.75～0.80g/ml之间，远大于粉末形态产品，可知所得球晶的静电效应大大降低。
综上可知，本发明所得球形晶体更符合硫酸氢氯吡格雷产品现有技术通用的制剂工艺，且有利于工艺水平的进一步提高。
通过进一步的放大实验研究得知，实施例1-3中制备球形硫酸氢氯吡格雷I晶型的工艺同样在大规模生产时表现为与实施例规模一致的效果，可知对应的工艺同样适用于规模化生产。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种制备球形硫酸氢氯吡格雷I晶型的方法，所述方法包含如下步骤：
    (1)将氯吡格雷游离碱溶解在2-丁醇中，得到浓度为0.02～0.1g/mL的游离碱溶液，在0～35℃温度条件下，快速加入0.5～2.0mol/L硫酸的2-丁醇溶液，加入硫酸与氯吡格雷游离碱的摩尔比为0.8～1.1:1；
    (2)保持步骤(1)温度范围，加入与氯吡格雷游离碱质量比为1～10wt％的硫酸氢氯吡格雷I晶型晶种后，保持温度搅拌4～8h；
    (3)过滤、洗涤及干燥，得到硫酸氢氯吡格雷I晶型球形晶体；
    其特征在于所述步骤(1)中硫酸2-丁醇溶液加入的时间控制在40分钟以内。
  2. 根据权利要求1所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述步骤(1)中硫酸2-丁醇溶液加入的时间控制在20分钟以内。
  3. 根据权利要求1或2任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述硫酸2-丁醇溶液的浓度为0.6～1.0mol/L。
  4. 根据权利要求1-3任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述游离碱溶液的浓度为0.040～0.065g/mL，加入硫酸与氯吡格雷游离碱的摩尔比为0.95～1.05:1。
  5. 根据权利要求1-4任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述步骤(4)中硫酸2-丁醇溶液加入的时间控制在10分钟以内。
  6. 根据权利要求1-5任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述步骤(1)的温度为10～30℃。
  7. 根据权利要求1-6任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述步骤(2)为在20～30℃下保温2-4h，后降温至10-20℃继续搅拌析晶。
  8. 根据权利要求1-7任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述硫酸氢氯吡格雷I晶型晶种与氯吡格雷游离碱的质量比为1-5wt％。
  9. 根据权利要求1-8任意一项所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述方法进一步包含氯吡格雷碱的制备步骤：
    (1)将氯吡格雷盐溶于有机溶剂中；
    (2)用碱调节体系的pH值，分相后有机相用少量水洗涤，所得有机相加脱水剂除水；
    (3)除水后的有机相真空浓缩得到氯吡格雷游离碱。
  10. 根据权利要求9所述制备球形硫酸氢氯吡格雷I晶型的方法，其特征在于所述步骤(1)中：氯吡格雷盐优选自硫酸氢盐、樟脑磺酸盐、盐酸盐中的一种或一种以上以任意比例混合所得的混合物；所述氯吡格雷盐的纯度在95％以上；所述有机溶剂为二氯甲烷、氯仿、乙酸乙酯中一种或一种以上以任意比例混合所得的混合物；所述步骤(2)中：所述碱为碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾；所述脱水剂为无水硫酸镁、无水硫酸钠。
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