WO2018149327A1 - 一种卡格列净无定型的制备方法 - Google Patents

一种卡格列净无定型的制备方法 Download PDF

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WO2018149327A1
WO2018149327A1 PCT/CN2018/075417 CN2018075417W WO2018149327A1 WO 2018149327 A1 WO2018149327 A1 WO 2018149327A1 CN 2018075417 W CN2018075417 W CN 2018075417W WO 2018149327 A1 WO2018149327 A1 WO 2018149327A1
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preparation
solvent
oil
amorphous form
mass
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PCT/CN2018/075417
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French (fr)
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钱刚
周燕宝
张林祥
张文灵
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浙江华海药业股份有限公司
浙江华海致诚药业有限公司
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Priority to EP18754385.5A priority Critical patent/EP3584247B1/en
Priority to CN201880006020.6A priority patent/CN110431137A/zh
Priority to US16/486,985 priority patent/US11008357B2/en
Publication of WO2018149327A1 publication Critical patent/WO2018149327A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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  • the invention relates to the field of medical chemistry, in particular to a method for preparing an amorphous form of capeglial.
  • Cagliflozin is a selective type 2 sodium glucose cotransporter (SGLT2) inhibitor developed by Johnson & Johnson, USA, and is mainly used for the treatment of patients with type II diabetes who are ineffective by exercise or control diet. It was listed in the US in March 2013 with FDA approval. This product can lower blood sugar by decomposing glucose and excreting it through the kidney. In addition to good glycemic control, the most striking effect of calglipide is weight loss and few hypoglycemia events, which has a very broad prospect.
  • SGLT2 sodium glucose cotransporter
  • Cagliflozin belongs to a water-insoluble compound, and its research on crystal form is of great significance.
  • the earliest report of the cardiglipone crystal form is the patent WO2008069327A1 of Mitsubishi Pharmaceutical Co., Ltd. of Japan, which reports a cardighepsine hemihydrate having an X-ray diffraction pattern of about 4.36°, 13.54°, 16.00°, The 2 theta angles of 19.32° and 20.80° ⁇ 0.2° have characteristic diffraction.
  • the TGA analysis of the hydrate crystal form had a water content of 1.7%. This crystal form is obtained by curing in an ethyl acetate/diethyl ether/water or acetone/water mixed solvent system.
  • the patent also discloses the calformin amorphous, but the preparation method thereof is not disclosed.
  • Patent CN101801371 discloses another crystal form having characteristic diffraction at 2 ⁇ angles of 10.9°, 15.5°, 17.3°, 18.8° and 20.3° ⁇ 0.2° in an X-ray powder diffraction pattern. This crystal form was obtained by crystallization in an ethyl acetate/n-heptane/water mixed solvent system.
  • Patents CN103980261, CN103980262, and CN103936725 respectively disclose the calcined crystal forms A, B, and C and the respective preparation methods, which are all prepared by using a mixed solvent system.
  • Patent CN103889429 discloses a process for the preparation of a non-stereotype of cardinol, prepared by adding n-heptane to a heated solution of cardinolone toluene.
  • Patent CN104119323 discloses a method for preparing an amorphous form of kaffeta, which is prepared by adding a solution of a cardinal beneign solvent to a poor solvent, since the method is blasting out, the particles are relatively small, Static electricity, easy to coalesce.
  • Patent CN105541817A discloses a method for preparing an amorphous form of calglipide, which is prepared by heat curing by melt curing.
  • Patent WO2014195966 discloses a method for preparing an amorphous form of capeglietate by dissolving cardiglipin in one or more organic solvents to form a solution, followed by spray drying or distillation.
  • the structural formula of cavigliflozin contains 1- ⁇ -D-glucopyranosyl group
  • the cardigrexate has the property of being difficult to crystallize in solution, and most of the crystal form preparation processes require a seed crystal-inducing method.
  • almost all the crystal preparation processes use a mixed solvent system, and the solvent is used in a large amount, and the solvent recycling is quite difficult, which has a great negative impact on the environment.
  • the object of the present invention is to provide a method for preparing an amorphous form of a cardinal, which is simple in preparation, easy to recover in a solvent, high in yield, simple in equipment, and suitable for industrial production.
  • the invention is realized by the following technical solutions: a method for preparing an amorphous form of cardage, the steps are as follows:
  • the cardinol is added to an organic solvent to dissolve, and then distilled to obtain an oil; an anti-solvent is added to the oil, and the solid is stirred, cooled, filtered, and dried to obtain an an amorphous form of calpaglid.
  • the organic solvent is selected from the group consisting of ethyl acetate, toluene, ethanol, methanol, acetone, dichloromethane, tetrahydrofuran, methyl tert-butyl ether or isopropyl ether, preferably selected from ethyl acetate. , ethanol or methyl tert-butyl ether.
  • the mass to volume ratio of the cardinol and the organic solvent is 1 g: (0.5 to 20) ml, preferably 1 g: (1 to 5) ml;
  • the dissolution temperature is -10 to 120 ° C, preferably 30 to 80 ° C;
  • the mass of the obtained oil is 1.0-1.3 times, preferably 1.05-1.1 times, of the mass of the cardigels. If the benign solvent residue in the oil is too high, the curing time of the product will be prolonged until it is not cured; if the benign solvent is too low, industrial production is difficult to achieve, and the benign solvent is too low, which may cause the product to stick to the wall and lose the yield.
  • the anti-solvent is selected from n-hexane, cyclohexane or n-heptane; preferably selected from cyclohexane or n-heptane.
  • the mass-to-volume ratio of the cardinide to the anti-solvent is 1 g: (1 to 20) ml, preferably 1 g: (3 to 6) ml.
  • the temperature at which the anti-solvent or the stirring is added in the preparation method provided by the present invention is 0 to 50 ° C, preferably 10 to 30 ° C.
  • the temperature reduction described in the preparation method provided by the present invention is specifically: cooling to -20 to 20 ° C, preferably -10 to 10 ° C.
  • the drying temperature described in the production method provided by the present invention is 10 to 40 ° C, preferably 20 to 30 ° C.
  • the X-ray powder diffraction pattern has the characteristics as shown in FIG. 1 without any crystallization peak, and only has a diffuse peak at 10° to 30°;
  • the calcite-free amorphous DSC has an endothermic peak between 40 and 50 ° C and a peak at 47 ° C (endothermic peak).
  • the present invention provides a beneficial technical effect of preparing a method for preparing a non-determined form of carbendazim:
  • the preparation method of the invention has small product loss and high yield, and can be as high as 95%;
  • the method provided by the invention does not mix and use the solvent, the solvent is easy to recover, the three wastes are small, and the environmental hazard is small;
  • the method provided by the invention has small solvent ratio and low cost
  • the preparation process of the invention has good reproducibility, simple operation and easy commercialization and large production.
  • the cardage obtained according to the method of the invention has an amorphous shape, stable quality and good fluidity, and is suitable for preparation of a preparation.
  • Figure 1 is an X-ray powder diffraction pattern of a Cappelligin amorphous form prepared in Example 1 of the present invention.
  • Example 2 is a differential scanning calorimetry diagram of a Cappellis amorphous form prepared in Example 1 of the present invention.
  • Fig. 3 is a comparison diagram of infrared spectra of the calformin amorphous form prepared in Example 1 of the present invention.
  • Fig. 4 is a photomicrograph of a polarized microscope of Kglipexine prepared in Example 1 of the present invention.
  • Fig. 5 is a photomicrograph of a polarized microscope of kalbergex obtained by a mixed solvent method according to Example 1 of CN104119323.
  • the kalbergex starting material (referred to as cetareid) used in the following examples was prepared by referring to WO 2005012326.
  • X-ray powder diffraction (XRD) instrument Panaco, Netherlands X'pert Pro type: Radiation source: copper target Scanning at room temperature: voltage: 45kv, current: 40mA, initial 2 ⁇ : 2000°, scanning range: 3.000 to 50.0000°, step size: 0.017°, measurement time: 50.2 sec/step;
  • DSC Differential Scanning Calorimetry
  • Infrared spectrophotometry (FTIR) analytical instrument American Nicolet is5 Fourier transform infrared spectrometer: potassium bromide tableting method, resolution: 4.0cm -1 .
  • Polarized microscope Olympus CX41, objective lens 4 times, eyepiece 10 times.
  • yield (prepared mass of glibenclamide, mass of calcareous net raw material) ⁇ 100%.
  • Fig. 1 is an X-ray powder diffraction pattern of the Cappellis amorphous form obtained in Example 1. As can be seen from Fig. 1, the diffraction pattern is a typical amorphous substance.
  • Fig. 2 is a DSC spectrum of the calformin-free amorphous form obtained in Example 1. As can be seen from Fig. 2, there is an endothermic peak at 47 °C.
  • FIG. 3 is a comparison diagram of the infrared spectrum of the calglipide amorphous form prepared in Example 1 of the present invention and the cavigliflozin hemihydrate disclosed in Chinese Patent No. CN101573368A, and the apparent difference between the characteristic peaks between the two can be seen from the figure. .
  • Fig. 4 is a photograph of a polarized light microscopy of a non-type of kalepside prepared according to Example 1 of the present invention. It can be seen from the figure that the shape of the product is irregular.
  • Example 5 The difference between Example 5 and Example 4 was that toluene was used in the organic solvent, and the volume was 10 ml; the amount of n-hexane was 20 ml. The yield was 95.6%.
  • Example 6 The difference between Example 6 and Example 4 was that tetrahydrofuran was used in the organic solvent, and the volume was 100 ml; the amount of n-hexane was 120 ml, and the yield was 95.7%.
  • Example 7 The difference between Example 7 and Example 4 was that dichloromethane was used in an organic solvent in a volume of 400 ml; n-hexane was used in an amount of 400 ml, and the yield was 96.0%.
  • Example 8 The difference between Example 8 and Example 7 was that the mass of the oil obtained by distillation was 26 g, and the yield was 95.40%.
  • the inventors have selected and more practically used the rapid evaporation solvent curing, mixed solvent method and other related methods.
  • the prepared amorphous samples were compared and the results were as follows:

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Abstract

一种卡格列净无定型的制备方法，该制备方法包括以下步骤：将卡格列净加入有机溶剂中溶解，然后蒸馏至一定质量的油状物后；向所述油状物中加入反溶剂，搅拌析出固体，降温、过滤、烘干，得卡格列净无定型。该制备方法具备溶剂倍率低、收率高、操作简单、易于回收、三废少、重现性好，得到的产品质量稳定，流动性好，适合用于制剂制备等特点，易于商业化大生产，具有很高的推广和应用价值。

Description

一种卡格列净无定型的制备方法
本申请要求于2017年02月20日提交中国专利局、申请号为201710089871.9发明名称为“一种卡格列净无定型的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药化学领域，具体涉及一种卡格列净无定型的制备方法。
背景技术
卡格列净(Canagliflozin)，化学名(1S)-1,5-脱氢-1-C-[3-[[5-(4-氟苯基)-2-噻吩基]甲基]-4-甲基苯基]-D-葡萄糖醇，其化学结构式为：
Figure PCTCN2018075417-appb-000001
卡格列净是美国Johnson & Johnson公司研发的一种选择性2型钠葡萄糖协同转运蛋白(SGLT2)抑制剂，主要用于通过运动或控制饮食无效的II型糖尿患者的治疗。2013年3月经FDA批准在美国上市。本品能通过将葡萄糖分解后经肾脏排出体外的方式来降低血糖，除了良好的血糖控制，卡格列净最引人瞩目的是减肥作用及很少的低血糖事件，具有非常广阔的前景。
近年来，陆续有文献报道卡格列净存在同质多晶现象，这是一些分子和分子配合物的特性。卡格列净属于一种水难溶性化合物，对其晶型的研究具有重要的意义。
最早报道卡格列净晶型的是日本三菱制药株式会社的专利WO2008069327A1，该专利报道了一种卡格列净半水合物，其X-射线衍射图在大约4.36°、13.54°、16.00°、19.32°和20.80°±0.2°的2θ角具有特征衍射。该水合物晶型的TGA分析含水量为1.7％。该晶型通过在乙酸乙酯/二***/水或者丙酮/水混合溶剂体系中固化而得。同时该专利还公开了卡格列净无定型，但 未公开其制备方法。
专利CN101801371公开了另一种晶型，其在X-射线粉末衍射图谱中具有10.9°、15.5°、17.3°、18.8°和20.3°±0.2°的2θ角具有特征衍射。该晶型通过在乙酸乙酯/正庚烷/水混合溶剂体系中析晶而得。
专利CN103980261、CN103980262、CN103936725分别公开了卡格列净晶型A、B、C及各自的制备方法，均采用混合溶剂体系进行制备。专利CN103889429公开了一种卡格列净无定型的制备方法，通过向加热的卡格列净甲苯溶液中加入正庚烷来制备。
专利CN104119323公开了一种卡格列净无定型的制备方法，通过将卡格列净良性溶剂的溶液加入至不良溶剂中固化来制备，由于该方法是爆发析晶出来的，颗粒比较小，有静电，容易聚结。
专利CN105541817A公开了一种卡格列净无定型的制备方法，通过热处理熔融固化来制备。
专利WO2014195966公开了一种卡格列净无定型的制备方法，通过将卡格列净溶解在一种或多种有机溶剂中形成溶液，然后通过喷雾干燥或蒸馏等方法来制备。
由于卡格列净的结构式中含有1-β-D-吡喃葡萄糖基，使得卡格列净具有在溶液中难以结晶的特性，大部分晶型制备工艺均需采用加入晶种诱导的方法。同时几乎所有的晶型制备工艺均使用了混合溶剂体系，且溶剂使用量大，溶剂回收利用相当困难，对环境有着极大负面影响。
发明内容
本发明的目的在于提供一种卡格列净无定型的制备方法，该无定型物制备方法简便、溶剂易于回收，收率高，设备要求简单，适合工业化生产。
本发明通过以下技术方案实现：一种卡格列净无定型的制备方法，步骤如下：
将卡格列净加入有机溶剂中溶解，然后蒸馏以得到油状物；向所述油状物中加入反溶剂，搅拌析出固体，降温、过滤及烘干，得卡格列净无定型。
本发明提供的制备方法中，所述的有机溶剂选自乙酸乙酯、甲苯、乙醇、甲醇、丙酮、二氯甲烷、四氢呋喃、甲基叔丁基醚或异丙醚，优选选自乙酸乙酯、乙醇或甲基叔丁基醚。
本发明提供的制备方法中，所述的卡格列净与有机溶剂的质量体积比为1g：(0.5～20)ml，优选为1g：(1～5)ml；
本发明提供的制备方法中，所述的溶解温度为-10～120℃，优选30～80℃；
本发明提供的制备方法中，所得油状物的质量为卡格列净质量的1.0-1.3倍，优选为1.05-1.1倍。如果油状物中良性溶剂残留过高将导致产品固化时间延长、直至不固化；良性溶剂过低，工业化生产实现比较困难、且良性溶剂过低易导致产品粘壁、损失收率。
本发明提供的制备方法中，所述的反溶剂选自正己烷、环己烷或正庚烷；优选选自环己烷或正庚烷。
本发明提供的制备方法中，所述的卡格列净与反溶剂的质量体积比为1g：(1～20)ml，优选为1g：(3～6)ml。
本发明提供的制备方法中所述加入反溶剂或搅拌的温度为0～50℃，优选10～30℃。
本发明提供的制备方法中所述的降温具体为：降温至-20～20℃，优选为-10～10℃。
本发明提供的制备方法中所述的烘干的温度为10～40℃，优选为20～30℃。
本发明提供的一种卡格列净无定型的制备方法优选的技术方案为：
将卡格列净加入有机溶剂中，加热至30～80℃溶解；溶解完毕，在30～80℃下将卡格列净溶液蒸馏以得到油状物，控制油状物为卡格列净质量的1.05-1.1倍，向所述油状物中加入反溶剂，10～30℃搅拌析出固体，降温至-10～10℃，过滤，在20～30℃烘干，得卡格列净无定型。
根据本发明的制备方法得到的卡格列净无定型，其X-射线粉末衍射图具有如图1所示的特征，没有任何结晶峰，仅在10°～30°显示有一漫散峰；所述的卡格列净无定型的DSC如图2所示，在40～50℃之间有一吸热峰，在47℃ 达到峰值(吸热峰)。
与现有技术相比，本发明提供一种制备卡格列净无定型的制备方法有益的技术效果是：
1、本发明制备方法产品损失小，收率高，可以高达95％；
2、本发明提供的方法，没有将溶剂混合使用，溶剂易回收，三废少，环境危害小；
3、本发明提供的方法，使用的溶剂倍率小，成本低廉；
4、本发明的制备工艺重现性好，操作简单，易于商业化大生产。
5、根据本发明的方法得到的卡格列净无定型，质量稳定，流动性好，适合用于制剂制备。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明实施例1制备的卡格列净无定型的X-射线粉末衍射图。
图2为本发明实施例1制备的卡格列净无定型的差示扫描量热图。
图3为本发明实施例1制备的卡格列净无定型的红外光谱对比图。
图4为本发明实施例1制备的卡格列净无定型的偏光显微镜照片。
图5为根据CN104119323实施例1采用混合溶剂方法得到的卡格列净无定型的偏光显微镜照片。
具体实施方式
为了进一步了解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。
原料和通用测试方法：
以下实施例中所用的卡格列净原料(简称卡格列净)参考WO 2005012326制备得到。
X-射线粉末衍射(XRD)仪器：荷兰帕纳科X’pert Pro型：辐射源：铜靶
Figure PCTCN2018075417-appb-000002
在室温条件下扫描：电压：45kv，电流：40mA，起始2θ：2000°，扫描范围：3.0000～50.0000°，步长：0.017°，测量时间：50.2秒/步；
差示扫描量热法分析(DSC)仪器：瑞士梅特勒-托利多DSC1型，30～300℃范围，加热速率：10℃/min，氮气流速：40ml/min。
红外分光光度法(FTIR)分析仪器：美国Nicolet is5傅里叶变红外光谱仪：溴化钾压片法，分辨率：4.0cm -1。
偏光显微镜：奥林巴斯CX41，物镜4倍，目镜10倍。
收率的计算公式：收率＝(制备的格列净无定型的质量/卡格列净原料的质量)×100％。
实施例1：
向反应瓶中加入卡格列净20g和60ml乙酸乙酯，控温35～45℃搅拌至溶清，控温35～45℃减压蒸馏至余重21.0g，得油状物。向反应瓶中滴加正庚烷100ml，滴加完毕，10～20℃保温2小时。保温完毕，降温至0℃，过滤，滤饼20℃真空烘干，出料，得19.2g卡格列净无定型，为白色粉末状固体，收率为96.0％。蒸馏回收的乙酸乙酯、母液中的正庚烷经过简单除水后可以直接套用。
图1是实施例1得到的卡格列净无定型的X-射线粉末衍射图，从图1中可以看出，该衍射图谱是典型的无定型物质。
图2是实施例1得到的卡格列净无定型的DSC图谱，从图2中可以看到，在47℃有吸热峰。
图3为本发明实施例1制备的卡格列净无定型与中国专利CN101573368A公开的卡格列净半水合物的红外光谱对比图，从图中可以看出两者之间特征 峰的明显差异。
图4为本发明实施例1制备的卡格列净无定型的偏光显微镜照片，从图中可以看出产品的形态呈不规则状。
实施例2：
向反应瓶中加入卡格列净20g和20ml乙酸乙酯，控温60～70℃搅拌至溶清，控温75～85℃减压蒸馏至余重21.2g，得油状物。向反应瓶中滴加环己烷80ml，滴加完毕，20～30℃保温2小时。保温完毕，降温至5℃，过滤，滤饼30℃真空烘干，出料，得19.1g卡格列净无定型，为白色粉末状固体，收率为95.5％。
实施例3：
向反应瓶中加入卡格列净20g和20ml乙醇，控温65～70℃搅拌至溶清，控温45～55℃减压蒸馏至余重22.0g，得油状物。向反应瓶中滴加环己烷60ml，滴加完毕，15～25℃保温2小时。保温完毕，降温至10℃，过滤，滤饼30℃烘干，出料，得19.4g卡格列净无定型，为白色粉末状固体，收率为97.0％。
实施例4：
向反应瓶中加入卡格列净20g和30ml甲基叔丁基醚，控温30～40℃搅拌至溶清，控温50～60℃蒸馏至余重21.7g，得油状物。向反应瓶中滴加正己烷80ml，滴加完毕，20～30℃保温3小时。保温完毕，降温至0℃，过滤，滤饼25℃真空烘干，出料，得19.2g卡格列净无定型，为白色粉末状固体，收率为96.0％。
实施例5
实施例5与实施例4的区别在有机溶剂选用甲苯，体积是10ml；正己烷的用量为20ml。收率为95.6％。
实施例6
实施例6与实施例4的区别在有机溶剂选用四氢呋喃，体积是100ml；正己烷的用量为120ml，收率为95.7％。
实施例7
实施例7与实施例4的区别在有机溶剂选用二氯甲烷，体积是400ml；正己烷的用量为400ml，收率为96.0％。
实施例8
实施例8与实施例7的区别在于蒸馏所得油状物的质量为26g，收率为95.40％。
为了说明本发明的卡格列净无定型与一般无定型制备方法所制备出无定型有所区别，本发明人选取了与通过以上较为实用的快速蒸发溶剂固化、混合溶剂方法及其它相关方法所制得的无定型进行了比较，比较结果如下：
Figure PCTCN2018075417-appb-000003
Figure PCTCN2018075417-appb-000004
“--”表示该项在文献中未记载。
上述试验结果表明，本发明的卡格列净无定型的稳定性明显优于快速挥发溶剂固化所制得的无定型；本发明的卡格列净无定型的制备方法收率高于混合溶剂的方法，并且将图5与图4进行对比可以看出，本发明的方法制得的无定型的形态与混合溶剂方法制得的无定型的形态差异明显，本发明制得的产品颗粒更大，流动性较好，可见，由本发明的方法所得产品的形态与混 合溶剂方法相比在包装、烘干等过程中有明显优势。而CN105541817A实施例1所得到的产品的产率虽然高，但是其成块状，需要进行粉碎才能得到适合使用的产品；工艺更加繁琐。
本发明提出的一种卡格列净无定型的制备方法已通过实施例进行了描述，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卡格列净无定型制备方法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，它们都被视为包括在本发明的精神、范围和内容中。

Claims (10)

  1. 一种卡格列净无定型的制备方法，其特征在于，该制备方法包括以下步骤：
    将卡格列净加入有机溶剂中溶解，然后蒸馏以得到油状物；向所述油状物中加入反溶剂，搅拌析出固体，降温、过滤及烘干，得卡格列净无定型。
  2. 根据权利要求1所述的制备方法，其特征在于，所述的卡格列净无定型的X-射线粉末衍射图没有结晶峰，并且仅仅在10°～30°显示有一漫散峰，优选如附图1所示；所述的卡格列净无定型的DSC扫描在40～50℃之间有一吸热峰。
  3. 根据权利要求1或2所述的制备方法，其特征在于：所述的有机溶剂选自乙酸乙酯、甲苯、乙醇、甲醇、丙酮、二氯甲烷、四氢呋喃、甲基叔丁基醚及异丙醚中的一种或其组合，优选选自乙酸乙酯、乙醇及甲基叔丁基醚中的一种或其组合。
  4. 根据权利要求1～3中任一项所述的制备方法，其特征在于，所述的卡格列净与有机溶剂的质量体积比为1g：(0.5～20)ml，优选为1g：(1～5)ml。
  5. 根据权利要求1～4中任一项所述的制备方法，其特征在于，所述溶解的温度为-10～120℃，优选30～80℃。
  6. 根据权利要求1～5中任一项所述的制备方法，其特征在于，所述油状物的质量为卡格列净质量的1.0～1.3倍，优选为1.05～1.1倍。
  7. 根据权利要求1～6中任一项所述的制备方法，其特征在于，所述的反溶剂选自正己烷、环己烷及正庚烷中的一种或其组合，优选选自环己烷或正庚烷。
  8. 根据权利要求1～7中任一项所述的制备方法，其特征在于，所述的卡格列净与反溶剂的质量体积比为1g：(1～20)ml，优选为1g：(3～6)ml。
  9. 根据权利要求1～8中任一项所述的制备方法，其特征在于，所述加入反溶剂或搅拌的温度为0～50℃，优选10～30℃；所述的降温具体为：降温 至-20～20℃，优选为-10～10℃；所述的烘干的温度为10～40℃，优选为20～30℃。
  10. 如权利要求1-9中任一项所述的卡格列净无定型的制备方法，其特征在于，该制备方法包括以下步骤：
    将卡格列净加入有机溶剂中，加热至30～80℃溶解；溶解完毕，在30～80℃下将卡格列净溶液蒸馏以得到油状物，控制油状物为卡格列净质量的1.05-1.1倍，向所述油状物中加入反溶剂，10～30℃搅拌析出固体，降温至-10～10℃，过滤，在20～30℃烘干，得卡格列净无定型。
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