WO2017202264A1 - 达格列净新晶型及其制备方法和用途 - Google Patents

达格列净新晶型及其制备方法和用途 Download PDF

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WO2017202264A1
WO2017202264A1 PCT/CN2017/085295 CN2017085295W WO2017202264A1 WO 2017202264 A1 WO2017202264 A1 WO 2017202264A1 CN 2017085295 W CN2017085295 W CN 2017085295W WO 2017202264 A1 WO2017202264 A1 WO 2017202264A1
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dapagliflozin
solvent
preparation
crystal
crystal form
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PCT/CN2017/085295
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English (en)
French (fr)
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李响
何雷
余俊
王进家
杜祖银
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江苏豪森药业集团有限公司
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Application filed by 江苏豪森药业集团有限公司 filed Critical 江苏豪森药业集团有限公司
Priority to MX2018013729A priority Critical patent/MX2018013729A/es
Priority to CN201780013982.XA priority patent/CN108699020B/zh
Priority to JP2018560220A priority patent/JP7007300B2/ja
Priority to US16/302,332 priority patent/US10464915B2/en
Priority to BR112018071991-9A priority patent/BR112018071991A2/pt
Priority to EP17802110.1A priority patent/EP3466939B1/en
Priority to ES17802110T priority patent/ES2864153T3/es
Priority to KR1020187034862A priority patent/KR20190010578A/ko
Publication of WO2017202264A1 publication Critical patent/WO2017202264A1/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
    • C07H7/04—Carbocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 pharmaceutical crystal forms, and particularly relates to dapagliflozin crystal E and a preparation method and use thereof.
  • Diabetes is a group of endocrine-metabolic diseases that are marked by high blood sugar. Sugar, protein, fat and secondary water and electrolyte metabolism disorders caused by absolute or relative insufficient secretion of insulin. It can involve chronic damage, dysfunction, and even many fatal complications in various systems of the body, especially the eyes, kidneys, heart, blood vessels, and nerves. With the aging of the world's population, diabetes has become a common and frequently-occurring disease, and it is a disease that seriously endangers human health. According to research data, the number of diabetic patients worldwide has increased from 150 million in 2000 to 280 million. It is estimated that there will be nearly 500 million diabetic patients worldwide by 2030.
  • SGLT Sodium-glucose cotransporter
  • SGLT includes SGLT1 and SGLT2, in which SGLT1 is expressed in the distal S3 segment of the small intestine and renal proximal convoluted tubules, and absorbs about 10% of the sugar; SGLT2 is mainly expressed in the pre-spleen SI segment of the renal proximal convolvulus, more than 90% Glucose reabsorption is the responsibility of SGLT2. Therefore, inhibition of SGLT, particularly inhibition of SGLT2, can further inhibit the reabsorption of sugar, thereby allowing the sugar to be excreted in the urine, thereby reducing the concentration of sugar in the blood.
  • Dapagliflozin is an inhibitor developed by Bristol-Myers Squibb/AstraZeneca for the treatment of type 2 diabetes (sodium-glucose cotransporter-2 (SGLT-2)).
  • Dapagliflozin chemical name: 2-chloro-5-( ⁇ -D-glucopyranose-1- Base 4'-ethoxydiphenylmethane, the chemical structure of which is as follows:
  • the patent WO2013079501A discloses a new crystal form of Daggliflozin disclosed in Daglipide containing crystal forms A and B, WO2015117538A and CN104829573A, respectively, and the crystal forms disclosed in the above patents are not crystalline forms of solvent compounds, but The DSC melting point test found that the melting point of the above crystal form was too low, and both were less than 35 ° C. The local temperature was too high during the tableting process, which caused the active material to melt, which was not conducive to the production of the drug.
  • Another object of the present invention is to provide a process for the preparation of dapagliflozin Form E.
  • Still another object of the present invention is to provide dapagliflozin Form E as an active ingredient, and a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, and its use as an SGLT-2 inhibitor.
  • the present invention provides a crystalline form E of dapagliflozin having an X-ray powder diffraction pattern with a 2 ⁇ value of 3.5 ⁇ 0.2, 4.1 ⁇ 0.2, 5.1 ⁇ 0.2, 7.3 ⁇ 0.2, 14.0 ⁇ 0.2, 14.8 ⁇ 0.2, 19.1. There are characteristic peaks at ⁇ 0.2 and 21.8 ⁇ 0.2.
  • the crystalline form E of dapagliflozin of the present invention has an X-ray powder diffraction pattern with a value of 2 ⁇ of 3.5 ⁇ 0.2, 4.1 ⁇ 0.2, 5.1 ⁇ 0.2, 6.6 ⁇ 0.2, 7.3 ⁇ 0.2, 8.0 ⁇ 0.2, 9.0 ⁇ 0.2, 9.4 ⁇ 0.2, 10.3 ⁇ 0.2, 10.9 ⁇ 0.2, 13.0 ⁇ 0.2, 14.0 ⁇ 0.2, 14.8 ⁇ 0.2, 15.7 ⁇ 0.2, 16.5 ⁇ 0.2, 18.2 ⁇ 0.2, 19.1 ⁇ 0.2, 21.0 ⁇ 0.2 and 21.8 ⁇ There is a characteristic peak at 0.2.
  • a typical example of the crystalline form E of dapagliflozin of the present invention has There is an XRPD pattern as shown in Figure 1.
  • the invention also provides a preparation method of dapagliflozin crystal form E, comprising the following steps:
  • the mass to volume ratio of dapagliflozin to the ester solvent in the step (1) is from 1:2 to 10, preferably from 1:2.5 to 10, more preferably from 1:4 to 5.
  • the ester solvent described in the step (1) is generally an ester solvent having 2 to 6 carbon atoms, preferably an ester solvent having 3 to 5 carbon atoms, more preferably ethyl formate, ethyl acetate or acetic acid. Propyl ester.
  • the mass-to-volume ratio of dapagliflozin to poor solvent in the step (2) is from 1:20 to 70, preferably from 1:22.5 to 50, more preferably from 1:30 to 40.
  • the poor solvent described in the step (2) is generally a liquid alkane solvent or an ether solvent, preferably a liquid alkane solvent, more preferably n-hexane, n-heptane or n-octane.
  • the temperature reduction described in the step (2) means that the temperature of the solution is lowered to below 0 ° C, preferably to 0 ° C to -20 ° C.
  • the seed crystal described in the step (3) can be prepared by the following method, which comprises: adding dapagliflozin to the reactor, adding an ester solvent to the room temperature at room temperature, cooling, cooling, standing, and then adding the solid, adding n-Heptane was used as an anti-solvent, stirred, and filtered to obtain a solid which can be used as a seed crystal.
  • the ester solvent is generally an ester solvent containing 2 to 6 carbon atoms, preferably an ester solvent having 3 to 5 carbon atoms, more preferably ethyl formate, ethyl acetate or n-propyl acetate.
  • the seed crystals described in the step (3) are prepared by the following method, which comprises: adding dapagliflozin to the reactor, and adding an ester solvent having a volume twice the mass of dapagliflozin at room temperature to dissolve. To the clear, then the temperature was lowered to -20 ° C, and allowed to stand. After 2 days, a solid was precipitated, and n-heptane having a volume of 5 times the mass of dapagliflozin was added, stirred for 24 hours, and filtered to obtain a solid which can be used as a seed crystal.
  • the solvent removal in the step (4) is carried out under vacuum and heating.
  • the inventors have found that vacuum and heating can speed up the solvent removal to achieve industrial production, especially in the case of heating, the solvent removal rate is very remarkable.
  • the temperature at which the solvent is removed is generally selected from 25 ° C to 80 ° C, preferably from 40 ° C to 70 ° C, more preferably from 50 ° C to 60 ° C.
  • the solvent is removed in a period of usually from 1 hour to 48 hours, preferably from 20 hours to 24 hours.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising glibenclamide Form E as an active ingredient together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition can be applied to mammals, including humans, baboons, dogs, and administered in the form of, for example, tablets, capsules, granules, injections, intranasal or dermal patches.
  • the dapagliflozin Form E of the present invention may be used alone or in combination with one or more other anti-diabetic agents, anti-hyperglycemic agents, and/or other disease treating agents.
  • the dapagliflozin Form E of the present invention is used with other therapeutic agents, it can be administered in the same dosage form or in separate oral dosage forms or injections.
  • Daphrequine crystal form E is a crystal form of a solvent-free compound, that is, a crystal form of a solvent molecule other than a drug molecule in the crystal lattice, so that the crystal form of the drug is safer and more pure, and the safety of the drug is improved. It has a more obvious effect on the therapeutic effect of diabetes. Further, the melting point of Form E reaches 70 ° C, which is comparable to the crystal form of the existing non-solvent compound.
  • Daglippine crystal form E has good high temperature stability and light stability, which is beneficial to the processing, transportation and storage of drugs;
  • Daglipepsin crystal form E has a small solid particle size, a narrower particle size distribution range, better fluidity, is conducive to the processing of the drug, and avoids the occurrence of more serious aggregation and clumping.
  • Figure 1 is an X-ray powder diffraction pattern of dapagliflozin Form E.
  • Figure 2 is a TGA diagram of dapagliflozin Form E.
  • Figure 3 is a DSC chart of Daphrequine Form E.
  • Figure 4 is an X-ray powder diffraction pattern of Daphrequine Form E after compression.
  • Example 2 In a similar manner to Example 1, ethyl acetate was replaced with isopropyl acetate to prepare a seed crystal containing isopropyl acetate.
  • the experimental results show that the Daglippine Form E sample can be stable for at least 30 days under high temperature (40 ° C) and illumination (5000 lux).
  • the experimental results show that the Daglipepsin Form E sample can be stable for at least 6 months at a temperature of 25 °C.
  • the crystal form prepared in the eighth embodiment of the present invention is directly compressed by a tableting machine, and the control pressure is 10KN. It can be seen from the map 4 that the crystal form E of the present invention does not undergo crystal transformation, indicating that the crystal form of the present invention is stable under the tabletting conditions. of.
  • Preparation process Adding dapagliflozin Form E, microcrystalline cellulose, lactose, crospovidone to the mixer, rotating at 10 rpm for 30 min; using dry granulation mechanism, adding silica and hard Magnesium citrate, rotating at 10 rpm, mixed for 5 min.
  • the mixed material was compressed using a rotary tablet press.
  • the pressed tablets were coated with a high-efficiency coating machine, and the bed temperature was 40 to 45 °C.
  • the specific process steps are as follows:
  • the dapagliflozin tablets prepared after tableting were determined by XPRD, and the characteristic peaks were consistent by pattern comparison, indicating that crystal form E did not undergo crystal transformation. At 40 ° C and 60% relative humidity, the crystal form remained consistent after 3 months and 6 months of long-term placement, and no crystal transformation occurred.

Abstract

本发明公开了达格列净新晶型及其制备方法和用途，具体是2-氯-5-(β-D-吡喃葡萄糖-1-基)-4'-乙氧基二苯甲烷的晶型E及其制备方法，以及含有治疗有效量的该晶型的药物组合物和其在治疗II型糖尿病中的应用。

Description

达格列净新晶型及其制备方法和用途 技术领域
本发明属于药物晶型技术领域，具体涉及达格列净晶体E及其制备方法和用途。
背景技术
糖尿病是一组内分泌-代谢疾病，以高血糖为其共同标志。因胰岛素绝对或相对分泌不足所造成的糖、蛋白质、脂肪和继发的水、电解质代谢紊乱。它可以涉及全身各个***特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍，甚至诱发许多致命性并发症。随着世界人口的老龄化，糖尿病已成为一种常见病、多发病，是一种严重危害人类健康的疾病。研究数据表明，全球糖尿病患者已由2000年的1.5亿增加到2.8亿，预计到2030年全球将有近5亿糖尿病患者。
人体在正常状态下，调节并控制葡萄糖代谢平衡的是葡萄糖转运体。钠-葡萄糖协同转运蛋白(SGLT)为一种已知的葡萄糖转运体。SGLT包括SGLT1和SGLT2,其中SGLT1表达于小肠和肾近曲小管较远端的S3节段中，吸收约10％的糖；SGLT2主要表达于肾近曲小管前SI节段中，90％以上的葡萄糖重吸收由该处的SGLT2负责。因此抑制SGLT，特别是抑制SGLT2可以进而抑制糖的重吸收，从而使糖经尿排出，降低血液中糖的浓度。
达格列净(Dapagliflozin)，是由Bristol-Myers Squibb/AstraZeneca开发的用于治疗II型糖尿病(钠—葡萄糖协同转运蛋白-2(SGLT-2)的抑制剂。
2010年12月，Bristol-Myers Squibb/AstraZeneca向EMA提交申请，2012年04月，欧洲人用药务委员会推荐批准达格列净用于治疗II型糖尿病的申请。
2010年12月，Bristol-Myers Squibb/AstraZeneca向FDA提交NDA申请，2012年01月，FDA发出回应函，要求增加临床数据。
达格列净(Dapagliflozin)，化学名：2-氯-5-(β-D-吡喃葡萄糖-1- 基)-4’-乙氧基二苯甲烷，其化学结构如下：
Figure PCTCN2017085295-appb-000001
一般而言，为了原料药和制剂生产的可操作性，药物保存的稳定性和提高药物疗效的目的，需要将药物制成晶体的状态。
有关达格列净晶型方面的报道，到目前为止，仅有原研晶型专利(CN101479287)报道了9种晶型：为达格列净溶剂化合物和达格列净氨基酸络合物，具体内容如下：
Figure PCTCN2017085295-appb-000002
Figure PCTCN2017085295-appb-000003
众所周知，药物晶体以溶剂化物或者是络合物形式存在时，在原料药中，除去具有治疗效果的有效成分(即API)外，还存在与药物治疗效果无关的一些物质，这些物质往往是对人体有害的；在制剂处方研究方面，以溶剂化物或者是络合物形式存在的药物中，由于存在非API成分，往往对制剂的原辅料相容性、原辅料配比、制剂的重量等造成影响。因此，一般情况下以溶剂化物形式和以络合物形式存在的药物晶型是不适合用于药物制剂开发。
另外，专利WO2013079501A公开了达格列净含水晶型A和B，WO2015117538A和CN104829573A分别公开了的一种新得达格列净晶型，以上专利公开的晶型均不是溶剂化合物晶型，但是经DSC熔点检测发现，上述晶型的熔点过低，均小于35℃，在压片过程中因局部温度过高，导致活性物质熔化，不利于药品的生产。
发明内容
本发明的目的在于提供一种达格列净的新晶型E。
本发明的另一个目的在于提供达格列净晶型E的制备方法。
本发明还有一个目的在于提供达格列净晶型E作为有效成分，以及含有一种或多种药学上可接受的赋形剂的药物组合物，及其作为SGLT-2抑制剂的应用。
本发明的目的是通过如下技术方案实现的：
本发明提供了一种达格列净的晶型E，其X射线粉末衍射图谱在2θ值为3.5±0.2，4.1±0.2，5.1±0.2，7.3±0.2，14.0±0.2，14.8±0.2，19.1±0.2和21.8±0.2处具有特征峰。
优选地，本发明所述达格列净的晶型E，其X射线粉末衍射图谱在2θ值为3.5±0.2，4.1±0.2，5.1±0.2，6.6±0.2，7.3±0.2，8.0±0.2，9.0±0.2，9.4±0.2，10.3±0.2，10.9±0.2，13.0±0.2，14.0±0.2，14.8±0.2，15.7±0.2，16.5±0.2，18.2±0.2，19.1±0.2，21.0±0.2和21.8±0.2处具有特征峰。
进一步优选地，本发明所述达格列净的晶型E的一个典型实例具 有如图1所示的XRPD图谱。
本发明还提供了一种达格列净晶型E的制备方法，包括以下步骤：
(1)将达格列净置于酯类溶剂或酯类与其它溶剂的混合溶剂中，形成溶液；
(2)通过降温或者加入不良溶剂或者同时采用降温和加入不良溶剂使溶液达到饱和；
(3)加入晶种，搅拌析出固体，过滤；
(4)将所得固体脱除溶剂转化为晶型E。
其中，步骤(1)中所述达格列净与酯类溶剂的质量体积比为1：2～10，优选1：2.5～10，更优选1：4～5。
步骤(1)中所述的酯类溶剂一般为含有2～6个碳原子的酯类溶剂，优选含有3～5个碳原子的酯类溶剂，更优选甲酸乙酯、乙酸乙酯或乙酸正丙酯。
步骤(2)中所述达格列净与不良溶剂的质量体积比为1：20～70，优选1：22.5～50，更优选1：30～40。
步骤(2)中所述的不良溶剂一般为液态烷烃溶剂或醚类溶剂，优选液态烷烃溶剂，更优选正己烷、正庚烷、正辛烷。
步骤(2)中所述的降温是指将溶液的温度降至0℃以下，优选降温至0℃～-20℃。
步骤(3)中所述的晶种可以通过以下方法制备得到的，具体包括：将达格列净加入反应器中，室温加入酯类溶剂溶解至清，降温，静置，析出固体后，添加正庚烷作为反溶剂，搅拌，过滤得到可作为晶种使用的固体。所述的酯类溶剂一般为含有2～6个碳原子的酯类溶剂，优选含有3～5个碳原子的酯类溶剂，更优选甲酸乙酯、乙酸乙酯或乙酸正丙酯。
优选地，步骤(3)中所述的晶种是通过以下方法制备得到的，具体包括：将达格列净加入反应器中，室温加入体积为达格列净质量2倍的酯类溶剂溶解至清，然后降温至-20℃，静置，2天后析出固体，添加体积为达格列净质量5倍的正庚烷，搅拌24小时，过滤得到可作为晶种使用的固体。
步骤(4)中所述脱除溶剂是在真空和加热条件下进行。本发明人研究发现，真空和加热可以加快脱除溶剂的速度，以实现工业化生产，特别是在加热的情况下，脱除溶剂的速度十分显著。
进一步地，脱除溶剂的温度一般选择25℃～80℃，优选40℃～70℃，更优选50℃～60℃。
进一步地，脱除溶剂的时间一般在1小时～48小时，优选20小时～24小时。
本发明还提供了一种药物组合物，该药物组合物中含有格列净晶型E作为有效成分以及一种或多种药学上可接受的赋形剂。该药物组合物可以应用在哺乳类，包含人类、猿、狗，以例如片剂、胶囊、颗粒、注射剂、鼻内给药或皮肤贴剂的剂型形式进行给药。
本发明所述达格列净晶型E可单独使用或与一种或多种的其它抗糖尿病剂、抗高血糖剂、和/或其他疾病治疗剂组合使用。当本发明所述达格列净晶型E与其他治疗剂一起使用时，可以相同剂型或分开的口服剂型或注射给药。
与现有技术相比，本发明的有益效果为：
1)达格列净晶型E为无溶剂化合物晶型，即在晶格中除了药物分子外不包含其它的溶剂分子的晶型，使得药物晶型更加安全纯净，提高了用药的安全性，在糖尿病治疗效果上具有更加明显的作用效果。并且晶型E的熔点达到70℃，相比于现有非溶剂化合物的晶型，能够满足制药的要求。
2)达格列净晶型E具有良好的高温稳定性和光照稳定性，有利于药物的加工、运输和存储；
3)达格列净晶型E的固体粒径小，有着更窄的粒径分布范围，具有更好的流动性，有利于药物加工成型，避免存在较严重的聚集成块、抱团等现象。
附图说明
图1为达格列净晶型E的X射线粉末衍射图。
图2为达格列净晶型E的TGA图。
图3为达格列净晶型E的DSC图。
图4为达格列净晶型E经压片后的X射线粉末衍射图。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但并不用来限制本发明的范围。
实施例1晶种制备
称取1g达格列净加入反应器中，室温条件下加入2.0mL乙酸乙酯，将样品溶解至清，然后降温至-20℃，静置，2天后析出固体，向上述反应器中添加5ml正庚烷，搅拌24小时，将悬浊液过滤得到含有乙酸乙酯的固体，该固体即可作为晶种使用。
实施例2晶种制备
采用与实施例1类似的方法，将乙酸乙酯替换为甲酸乙酯，制备得到含有甲酸乙酯的晶种。
实施例3晶种制备
采用与实施例1类似的方法，将乙酸乙酯替换为乙酸异丙酯，制备得到含有乙酸异丙酯的晶种。
实施例4
称取10g达格列净加入反应器中，室温条件下加入25.0mL乙酸乙酯将样品溶解至清，然后向反应器中添加25.0ml正庚烷，体系浑浊，加入实施例1获得的晶种，搅拌4小时后加200ml正庚烷继续搅拌24小时，将悬浊液过滤得到固体，50℃真空干燥24小时得到固体晶型E。
实施例5
称取500g达格列净加入反应器中，室温条件下加入2.0L乙酸乙酯将样品溶解至清，然后向反应器中添加2.3L正庚烷，体系浑浊，加入实施例1获得的晶种，搅拌4小时后加12.7L正庚烷继续搅拌24小时，将悬浊液过滤得到固体，60℃真空干燥24小时得到固体晶型E。
实施例6
称取25g达格列净加入反应器中，室温条件下加入100.0mL甲 酸乙酯将样品溶解至清，然后向反应器中添加100.0ml正庚烷，体系浑浊，加入实施例2获得的晶种，搅拌4小时后加1.5L正庚烷继续搅拌24小时，将悬浊液过滤得到固体，50℃真空干燥24小时得到固体晶型E。
实施例7
称取10g达格列净加入反应器中，室温条件下加入40.0mL乙酸异丙酯将样品溶解至清，然后向反应器中添加40.0ml正庚烷，体系浑浊，加入实施例3获得的晶种，搅拌4小时后加460ml正庚烷继续搅拌24小时，将悬浊液过滤得到固体，60℃真空干燥24小时得到固体晶型E。
实施例8
称取20g达格列净加入反应器中，室温条件下加入50.0mL乙酸正丙酯将样品溶解至清，然后向反应器中添加50.0ml正庚烷，体系浑浊，加入实施例3获得的晶种，搅拌5小时后加750ml正庚烷继续搅拌24小时，将悬浊液过滤得到固体，60℃真空干燥12小时得到固体晶型E。
实施例9
称取20g达格列净加入反应器中，室温条件下加入50.0mL乙酸正丙酯将样品溶解至清，然后向反应器中添加50.0ml正庚烷，体系浑浊，加入实施例3获得的晶种，搅拌5小时后加750ml正庚烷继续搅拌24小时，将悬浊液过滤得到固体，30℃真空干燥48小时，经XPRD比对，仅有少量的溶剂化物转化为晶型E。
实施例10晶种制备
采用与实施例1类似的方法，将乙酸乙酯替换为乙醇，制备得到含有乙醇的晶种。
实施例11
称取20g达格列净加入反应器中，室温条件下加入50.0mL乙醇将样品溶解至清，然后向反应器中添加50.0ml正庚烷，体系浑浊，加入实施例10获得的晶种，搅拌5小时后加750ml正庚烷继续搅拌24小时，将悬浊液过滤得到固体，60℃真空干燥24小时得，经XPRD 比对，未能制备得到晶型E。
实施例12晶型E的稳定性研究
在研究过程中，对达格列净晶型E样品进行了影响因素试验和加速试验，实验内容和结果如下：
(1)影响因素试验内容和结果：
Figure PCTCN2017085295-appb-000004
实验结果表明，达格列净晶型E样品在高温(40℃)和光照(5000勒克斯)的条件下能够至少稳定存在30天。
(2)加速试验内容和结果
Figure PCTCN2017085295-appb-000005
实验结果表明，达格列净晶型E样品在温度25℃条件下至少可以稳定存在6个月。
影响因素试验和加速试验结果表明达格列净晶型E的稳定性可以满足药用要求。
实施例13压片试验
本发明实施例8制备的晶型经过压片机直接压片，控制压力在10KN，通过图谱4可以看出本发明晶型E未发生转晶，表明本发明晶型在压片条件下是稳定的。
实施例14制备达格列净片
按照以下处方制备达格列净片剂：
组分 g/1000片
达格列净晶型E 10
微晶纤维素 105
乳糖 100
交联聚维酮 25
二氧化硅 5
硬脂酸镁 5
薄膜包衣预混剂(胃溶型) 5～10
制备工艺：将达格列净晶型E、微晶纤维素、乳糖、交联聚维酮加入到混合器中，转速10rpm，混合30min；使用干法制粒机制粒，再加入二氧化硅和硬脂酸镁，转速10rpm，混合5min。混合后物料使用旋转压片机压片。压得素片使用高效包衣机包衣，片床温度40～45℃。具体各工艺步骤结果如下：
Figure PCTCN2017085295-appb-000006
压片后制备的达格列净片经XPRD测定，通过图谱比对，特征峰一致，表明晶型E未发生转晶。在40℃、相对湿度60％条件下，经3个月和6个月的长期放置，晶型保持一致，未发生转晶。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (12)

  1. 一种达格列净的晶型E，其特征在于，其X射线粉末衍射图谱在2θ值为3.5±0.2，4.1±0.2，5.1±0.2，7.3±0.2，14.0±0.2，14.8±0.2，19.1±0.2，和21.8±0.2处具有特征峰。
  2. 根据权利要求1所述达格列净的晶型E，其特征在于，其X射线粉末衍射图谱在2θ值为3.5±0.2，4.1±0.2，5.1±0.2，6.6±0.2，7.3±0.2，8.0±0.2，9.0±0.2，9.4±0.2，10.3±0.2，10.9±0.2，13.0±0.2，14.0±0.2，14.8±0.2，15.7±0.2，16.5±0.2，18.2±0.2，19.1±0.2，21.0±0.2和21.8±0.2处具有特征峰。
  3. 根据权利要求1所述达格列净的晶型E，其特征在于，其X射线粉末衍射图谱基本如图1。
  4. 一种达格列净的晶型E的制备方法，包括以下步骤：
    1)将达格列净置于酯类溶剂或酯类与其它溶剂的混合溶剂中，形成溶液；
    2)通过降温或者加入不良溶剂或者同时采用降温和加入不良溶剂使溶液达到饱和；
    3)加入晶种，搅拌析出固体，过滤；
    4)将所得固体脱除溶剂转化为晶型E。
  5. 根据权利要求4所述的制备方法，其特征在于，步骤1)中所述达格列净与酯类溶剂的质量体积比为1：2～10，优选1：2.5～10，更优选1：4～5。
  6. 根据权利要求4所述的制备方法，其特征在于，步骤1)中所述的酯类溶剂一般为含有2～6个碳原子的酯类溶剂，优选含有3～5个碳原子的酯类溶剂，更优选甲酸乙酯、乙酸乙酯或乙酸正丙酯。
  7. 根据权利要求4所述的制备方法，其特征在于，步骤2)中所述达格列净与不良溶剂的质量体积比为1：20～70，优选1：22.5～50，更优选1：30～40。
  8. 根据权利要求4所述的制备方法，其特征在于，步骤2)中所述的不良溶剂为液态烷烃溶剂或醚类溶剂，优选液态烷烃溶剂，更优选正己烷、正庚烷、正辛烷。
  9. 根据权利要求4所述的制备方法，其特征在于，步骤4)中所述脱除溶剂是在真空和加热条件下进行。
  10. 根据权利要求4所述的制备方法，其特征在于，步骤4)中所述脱除溶剂的温度为25℃～80℃，优选40℃～70℃，更优选50℃～60℃。
  11. 一种药物组合物，包含有效量的权利要求1-3任一项所述的达格列净晶型E以及一种或多种药学上可接受的赋形剂。
  12. 权利要求1-3任一项所述的达格列净晶型E或权利要求11所述的药物组合物在治疗II型糖尿病的药中的应用。
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