WO2016124125A1 - (R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型 - Google Patents

(R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型 Download PDF

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WO2016124125A1
WO2016124125A1 PCT/CN2016/073102 CN2016073102W WO2016124125A1 WO 2016124125 A1 WO2016124125 A1 WO 2016124125A1 CN 2016073102 W CN2016073102 W CN 2016073102W WO 2016124125 A1 WO2016124125 A1 WO 2016124125A1
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hydrochloride salt
salt form
ray powder
powder diffraction
diffraction pattern
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PCT/CN2016/073102
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English (en)
French (fr)
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陈敏华
张炎锋
刘凯
张晓宇
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苏州晶云药物科技有限公司
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    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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

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  • the present invention relates to the field of chemical medicine, in particular to a new crystalline form of the hydrochloride salt of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and Preparation.
  • Drug polymorphism refers to the presence of two or more different crystalline forms of a drug. Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.
  • Encenicline hydrochloride is present in a polymorphic form.
  • EnVivo Pharmaceuticals, Inc. in the patent CN103221411A, discloses two hydrate crystalline forms of Encelicline hydrochloride, Form I and Form II, but the crystalline form I and Form II are unstable, and humidity has a great influence on them.
  • No other pharmaceutical company has disclosed a new polymorph of Encnicline hydrochloride.
  • the present invention provides two novel crystalline forms of the hydrochloride salt of the compound of formula (I), designated as the hydrochloride salt form A and the hydrochloride salt, respectively.
  • Form B the crystal form provided by the invention has favorable properties such as good stability, low moisture absorption, process developability and easy handling, and has simple preparation method and low cost, and has the optimization and development of the drug in the future. Important value.
  • the hydrochloride salt form A provided by the present invention is characterized in that its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 16.60 ° ⁇ 0.2 °, 19.90 ° ⁇ 0.2 °, 23.58 ° ⁇ 0.2 °.
  • the present invention provides a hydrochloride salt form A, which is characterized in that the X-ray powder diffraction pattern has a 2theta value of 13.40° ⁇ 0.2°, 22.50° ⁇ 0.2°, and 19.16° ⁇ 0.2°. There are characteristic peaks at two or three places; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 13.40 ° ⁇ 0.2 °, 22.50 ° ⁇ 0.2 °, 19.16 °. There is a characteristic peak at ⁇ 0.2°.
  • the present invention provides a hydrochloride salt form A, which is characterized in that the X-ray powder diffraction pattern has a 2theta value of 14.23° ⁇ 0.2°, 24.98° ⁇ 0.2°, and 27.65° ⁇ 0.2°. There are characteristic peaks at two or three places; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 14.23 ° ⁇ 0.2 °, 24.98 ° ⁇ 0.2 °, 27.65 °. There is a characteristic peak at ⁇ 0.2°.
  • the present invention provides a hydrochloride salt form A, which is characterized in that its X-ray powder diffraction pattern is substantially as shown in FIG.
  • the hydrochloride salt form A provided by the present invention is characterized in that when differential scanning calorimetry is performed, an endothermic peak begins to appear near heating at 285 ° C, and the differential scanning calorimetry diagram is substantially as shown in FIG. 2 . Show.
  • the hydrochloride salt form A provided by the present invention is characterized in that, when subjected to thermogravimetric analysis, it has a weight loss gradient of about 2.1% when heated to 180 ° C, and its thermogravimetric analysis chart is basically as shown in FIG. 3 .
  • the present invention provides a hydrochloride salt form A, characterized in that Form A is an anhydrate.
  • Another object of the present invention is to provide a method for preparing a hydrochloride salt form A, characterized in that a powder of the compound of the formula (I) and hydrochloric acid are added to an organic solvent system, suspended and stirred, and the solid is collected at 150 ° C. Drying at -200 ° C, the solid obtained after cooling is the hydrochloride salt form A.
  • the organic solvent is preferably a halogenated hydrocarbon.
  • halogenated hydrocarbon is preferably chloroform.
  • Another object of the present invention is to provide a method for preparing a hydrochloride salt form A, characterized in that a hydrochloride of the compound of the formula (I) is added to an organic solvent system and stirred at 50 ° C to 100 ° C for separation. Solid, the resulting solid is the hydrochloride salt form A.
  • the organic solvent is preferably an ester.
  • ester is preferably ethyl acetate.
  • Another object of the invention is to provide the hydrochloride salt form B of the compound of formula (I).
  • the hydrochloride salt form B provided by the present invention is characterized in that the X-ray powder diffraction pattern has a 2theta value of 14.10° ⁇ 0.2°, 18.03° ⁇ 0.2°, 20.10° ⁇ 0.2°, 23.70° ⁇ 0.2°. Characteristic peaks.
  • the present invention provides a hydrochloride salt form B, which is characterized in that the X-ray powder diffraction pattern is one of 2theta values of 19.51° ⁇ 0.2°, 17.04° ⁇ 0.2°, and 24.81° ⁇ 0.2°. There are characteristic peaks at two or three places; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 19.51° ⁇ 0.2°, 17.04° ⁇ 0.2°, 24.81°. There is a characteristic peak at ⁇ 0.2°.
  • the present invention provides a hydrochloride salt form B, which is characterized in that the X-ray powder diffraction pattern has a 2theta value of 4.42° ⁇ 0.2°, 18.47° ⁇ 0.2°, 25.56° ⁇ 0.2°. There are characteristic peaks at two or three places; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 4.42° ⁇ 0.2°, 18.47° ⁇ 0.2°, 25.56° at 2theta. There is a characteristic peak at ⁇ 0.2°.
  • hydrochloride salt form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern thereof is substantially as shown in FIG.
  • the hydrochloride salt form B provided by the present invention is characterized in that the differential scanning calorimetry chart is substantially as shown in FIG.
  • the hydrochloride salt form B provided by the present invention is characterized in that, when subjected to thermogravimetric analysis, it has a weight loss gradient of about 6.9% when heated to 180 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG. 6 .
  • Another object of the present invention is to provide a method for preparing a hydrochloride salt form B, characterized in that a hydrochloride powder of the compound of the formula (I) is added to a certain ratio of a mixed solvent of pure water and an organic solvent to be insoluble. The precipitate is precipitated and stirred for 30 minutes or more, and the solid is collected to be the hydrochloride salt form B.
  • the hydrochloride powder of the compound of the formula (I) is the hydrochloride salt form A.
  • stirring time is preferably 48 hours or more.
  • the ratio of the pure water to the organic solvent is between 1:19 and 1:4.
  • the ratio of the pure water to the organic solvent is between 1:15 and 1:4.
  • the ratio of the pure water to the organic solvent is between 1:8 and 1:4.
  • the ratio of the pure water to the organic solvent is between 1:15 and 1:12.
  • the organic solvent is an alcohol solvent.
  • the alcohol solvent is preferably methanol.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a hydrochloride salt form A or a hydrochloride salt form B or a mixture thereof and a pharmaceutically acceptable adjuvant.
  • a therapeutically effective amount of the hydrochloride salt Form A or the hydrochloride salt form B of the compound of formula (I) or a mixture thereof is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation.
  • the pharmaceutical compositions or formulations are prepared in a manner well known in the pharmaceutical art.
  • the hydrochloride salt crystal form A or the hydrochloride crystal of the compound of the formula (I) Form B or a mixture thereof can be used for the preparation of a medicament for the treatment of Alzheimer's or schizophrenia.
  • the crystal form provided by the present invention has good stability. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form provided by the invention has low wettability, is not easily affected by high humidity and deliquesces, and is convenient for long-term storage and placement of the medicine.
  • Figure 1 is an XRPD pattern of the hydrochloride salt form A
  • FIG. 1 is a DSC chart of the hydrochloride salt form A
  • FIG. 3 is a TGA diagram of the hydrochloride salt form A
  • Figure 4 is an XRPD pattern of the hydrochloride salt form B
  • FIG. 5 is a DSC chart of the hydrochloride salt form B
  • FIG. 6 is a TGA diagram of the hydrochloride salt form B
  • Figure 7 is a comparison of the XRPD of the hydrochloride salt form B placed at 25 ° C / 60% relative humidity (a picture shows the XRPD pattern before placement, b picture shows the XRPD pattern after two weeks of placement, and c shows the placement of one XRPD chart after the month)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the X-ray powder diffraction data of the hydrochloride salt form A obtained in this example includes, but is not limited to, Table 1 data. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.
  • the hydrochloride salt form A of the compound of the formula (I) prepared in Example 1 was added to 0.2 mL of a mixed solvent of pure water and methanol in a volume ratio of 7:93 until insoluble matter appeared, and then 10.0 mg of the patent CN103221411A was added.
  • the hydrochloride solid was stirred at room temperature for 48 hours.
  • the X-ray powder diffraction data of the crystal form obtained in this example includes, but is not limited to, Table 3 data. Its XRPD diagram is shown in Figure 4, its DSC diagram is shown in Figure 5, and its TGA diagram is shown in Figure 6.
  • the hydrochloride salt form A of the compound of the formula (I) prepared in Example 1 was added to 0.2 mL of a mixed solvent of pure water and methanol in a volume ratio of 4:21 until insoluble matter appeared, and then 10.0 mg of the patent CN103221411A was added.
  • the hydrochloride solid was stirred at room temperature for 48 hours.
  • the X-ray powder diffraction data of the crystal form obtained in this example includes, but is not limited to, Table 4 data.
  • the crystal form B prepared by the invention was placed in a constant temperature and humidity chamber at 25 ° C / 60% relative humidity, and placed for 14 days and 30 days, respectively, and the XRPD was sampled and measured.
  • the experimental results are shown in Table 5, and the XRPD results are as follows.
  • Figure 7 shows.
  • the crystal form I disclosed in 10.0 mg of the patent CN103221411A was mixed with a solvent to form a suspension, and the crystal form II disclosed in the patent CN103221411A was added thereto, and placed at 50 ° C and 80 ° C, respectively, magnetically stirred at a rate of 500 rpm, and centrifuged. Solid test XRPD. The results are shown in Table 6.
  • the crystal form I disclosed in 10.0 mg of the patent CN103221411A was mixed with a solvent to form a suspension, and the crystal form II disclosed in the patent CN103221411A was added thereto, and magnetically stirred at 25 ° C at a rate of 500 rpm, and centrifuged to obtain a solid test XRPD.
  • Table 7 The results are shown in Table 7.

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Abstract

本发明涉及(R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐新晶型及其制备方法。本发明提供的晶型具有良好的稳定性、较低的引湿性、工艺可开发和易处理性等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

(R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型 技术领域
本发明涉及化学医药领域，特别是涉及(R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型及其制备方法。
背景技术
(R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺(Encenicline)，如式(I)化合物所示，是由拜耳医药保健公司首先研发，后授权给英维沃(EnVivo)制药公司和田边三菱(Mitsubishi Tanabe)制药公司开发。该药用于治疗阿尔茨海默氏症和精神分裂症，目前处于临床III期阶段，临床使用的是Encenicline的盐酸盐。
Figure PCTCN2016073102-appb-000001
药物多晶型(drug polymorphism)是指药物存在有两种或两种以上的不同晶型物质状态。多晶型现象在药物中广泛存在。同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。
Encenicline盐酸盐存在多晶型形式，目前，仅英维沃(EnVivo)制药公司在专利CN103221411A公开了Encenicline盐酸盐的的两种水合物晶型，晶型I和晶型II，但晶型I和晶型II不稳定，湿度对其影响很大。尚无其他制药公司公开Encenicline盐酸盐新的多晶型。
基于此，有必要进一步进行Encenicline盐酸盐的多晶型研究和筛选，开发出稳定性好、引湿性低、适合工业化生产的无水晶型，为药物的后续开发提供更多更好的选择。
发明内容
本发明提供式(I)化合物的盐酸盐的两种新晶型，分别命名为盐酸盐晶型A和盐酸盐 晶型B，本发明提供的晶型具有良好的稳定性、较低的引湿性、工艺可开发和易处理性等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
具体的，本发明的一个目的是提供式(I)化合物的盐酸盐晶型A。
本发明提供的盐酸盐晶型A，其特征在于，其X射线粉末衍射图在2theta值为16.60°±0.2°、19.90°±0.2°、23.58°±0.2°处具有特征峰。
更进一步的，本发明提供的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图在2theta值为13.40°±0.2°、22.50°±0.2°、19.16°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为13.40°±0.2°、22.50°±0.2°、19.16°±0.2°处具有特征峰。
更进一步的，本发明提供的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图在2theta值为14.23°±0.2°、24.98°±0.2°、27.65°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为14.23°±0.2°、24.98°±0.2°、27.65°±0.2°处具有特征峰。
更进一步的，本发明提供的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图基本如图1所示。
本发明提供的盐酸盐晶型A，其特征在于，当进行差示扫描量热分析时，在加热至285℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示。
本发明提供的盐酸盐晶型A，其特征在于，当进行热重分析时，在加热至180℃时，具有约2.1％的重量损失梯度，其热重分析图基本如图3所示。
本发明提供的盐酸盐晶型A，其特征在于，晶型A是无水合物。
本发明的另一个目的是提供盐酸盐晶型A的制备方法，其特征在于，将式(I)化合物的粉末与盐酸加入到有机溶剂体系内，混悬搅拌，收集固体，并在150℃-200℃条件下干燥，冷却后所得固体即为盐酸盐晶型A。
更进一步的，所述有机溶剂优选卤代烃。
更进一步的，所述卤代烃优选氯仿。
本发明的另一个目的是提供盐酸盐晶型A的制备方法，其特征在于，将式(I)化合物的盐酸盐加入到有机溶剂体系内，在50℃-100℃条件下搅拌，分离固体，所得固体即为盐酸盐晶型A。
更进一步的，所述有机溶剂优选酯类。
更进一步的，所述酯类优选乙酸乙酯。
本发明的另一个目的是提供式(I)化合物的盐酸盐晶型B。
本发明提供的盐酸盐晶型B，其特征在于，其X射线粉末衍射图在2theta值为14.10°±0.2°、18.03°±0.2°、20.10°±0.2°、23.70°±0.2°处具有特征峰。
更进一步的，本发明提供的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为19.51°±0.2°、17.04°±0.2°、24.81°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为19.51°±0.2°、17.04°±0.2°、24.81°±0.2°处具有特征峰。
更进一步的，本发明提供的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为4.42°±0.2°、18.47°±0.2°、25.56°±0.2°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为4.42°±0.2°、18.47°±0.2°、25.56°±0.2°处具有特征峰。
更进一步的，本发明提供的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图基本如图4所示。
本发明提供的盐酸盐晶型B，其特征在于，其差示扫描量热分析图基本如图5所示。
本发明提供的盐酸盐晶型B，其特征在于，当进行热重分析时，在加热至180℃时，具有约6.9％的重量损失梯度，其热重分析图基本如图6所示。
本发明的另一个目的是提供盐酸盐晶型B的制备方法，其特征在于，将式(I)化合物的盐酸盐粉末加入到一定比例的纯水与有机溶剂的混合溶剂中至有不溶物析出，混悬搅拌30分钟以上，收集固体，即为盐酸盐晶型B；优选的，所述式(I)化合物的盐酸盐粉末为所述的盐酸盐晶型A。
更进一步的，所述搅拌时间优选48小时以上。
更进一步的，所述纯水与有机溶剂的比例介于1：19至1：4之间。
更进一步的，所述纯水与有机溶剂的比例介于1：15至1：4之间。
更进一步的，所述纯水与有机溶剂的比例介于1：8至1：4之间。
更进一步的，所述纯水与有机溶剂的比例介于1：15至1：12之间。
更进一步的，所述有机溶剂是醇类溶剂。
更进一步的，所述醇类溶剂优选甲醇。
本发明的另一个目的是提供一种包含有效治疗量的式(I)化合物的盐酸盐晶型A或盐酸盐晶型B或其混合物和药用辅料的药用组合物。一般是将治疗有效量的式(I)化合物的盐酸盐晶型A或盐酸盐晶型B或其混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
更进一步的，本发明所述的药用组合物中，式(I)化合物的盐酸盐晶型A或盐酸盐晶 型B或其混合物可用于制备治疗阿尔茨海默症或精神分裂症药物制剂中的用途。
本发明的有益效果为：
本发明提供的晶型具有良好的稳定性。能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变。
本发明提供的晶型引湿性较低，不易受高湿度影响而潮解，方便药物的长期贮存放置。
附图说明
图1为盐酸盐晶型A的XRPD图
图2为盐酸盐晶型A的DSC图
图3为盐酸盐晶型A的TGA图
图4为盐酸盐晶型B的XRPD图
图5为盐酸盐晶型B的DSC图
图6为盐酸盐晶型B的TGA图
图7为盐酸盐晶型B放置在25℃/60％相对湿度条件下的XRPD对比图(a图为放置前的XRPD图，b图为放置两周后的XRPD图，c图为放置一个月后的XRPD图)
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Kα1
Figure PCTCN2016073102-appb-000002
1.540598；Kα2
Figure PCTCN2016073102-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
实施例1
式(I)化合物盐酸盐的晶型A的制备方法：
将202.2mg式(I)化合物溶于5mL氯仿中，逐滴加入1当量的盐酸溶液(盐酸浓度为12mol/L)，室温下搅拌30分钟，滤去氯仿，将所得固体置于180℃的烘箱中30分钟，室温下冷却，所得固体即为盐酸盐晶型A。
本实施例得到的盐酸盐晶型A的X射线粉末衍射数据包括但不限于表1数据。其XRPD图如图1，其DSC图如图2，其TGA图如图3。
表1晶型A的X射线粉末衍射数据
Figure PCTCN2016073102-appb-000004
Figure PCTCN2016073102-appb-000005
实施例2
式(I)化合物盐酸盐的晶型A的制备方法：
向10.7mg的专利CN103221411A公开的式(I)化合物盐酸盐固体中加入0.5ml的乙酸乙酯，置于1.5ml的玻璃小瓶中，再向小瓶中加入式(I)化合物盐酸盐固体9.9mg，在80℃下搅拌72小时，离心，干燥所得固体即为盐酸盐晶型A。
本实施例得到的盐酸盐晶型A的X射线粉末衍射数据如表2所示。
表2晶型A的X射线粉末衍射数据
Figure PCTCN2016073102-appb-000006
Figure PCTCN2016073102-appb-000007
实施例3
式(I)化合物盐酸盐的晶型B的制备方法：
将实施例1制备得到的式(I)化合物的盐酸盐晶型A加入0.2mL纯水与甲醇体积比为7:93的混合溶剂中直至出现不溶物，再加入10.0mg的专利CN103221411A公开的盐酸盐固体，室温下搅拌48小时。
本实施例得到的晶型的X射线粉末衍射数据包括但不限于表3数据。其XRPD图如图4，其DSC图如图5，其TGA图如图6。
表3晶型B的X射线粉末衍射数据
Figure PCTCN2016073102-appb-000008
Figure PCTCN2016073102-appb-000009
实施例4
式(I)化合物盐酸盐的晶型B的制备方法：
将实施例1制备得到的式(I)化合物的盐酸盐晶型A加入0.2mL纯水与甲醇体积比为4:21的混合溶剂中直至出现不溶物，再加入10.0mg的专利CN103221411A公开的盐酸盐固体，室温下搅拌48小时。
本实施例得到的晶型的X射线粉末衍射数据包括但不限于表4数据。
表4晶型A的X射线粉末衍射数据
Figure PCTCN2016073102-appb-000010
Figure PCTCN2016073102-appb-000011
实施例5
式(Ⅰ)化合物盐酸盐晶型B的自身稳定性研究：
将本发明制备得到的晶型B置于25℃/60％相对湿度的恒温恒湿箱中，分别放置14天和30天，取样测定其XRPD，实验结果见表5所示，其XRPD结果如图7所示。
表5
Figure PCTCN2016073102-appb-000012
结果表明，式(I)化合物盐的新晶型B在25℃，60％相对湿度条件下，30天晶型保持不变，上述试验结果表明，本发明提供的式(I)化合物盐的晶型B具有良好的稳定性。
实施例6
本发明中盐酸盐晶型A与专利CN103221411A公开的晶型I和II的稳定性对比研究：
取10.0mg专利CN103221411A公开的晶型I与溶剂混合配成悬浮液，向其中加入专利CN103221411A公开的晶型II，分别置于50℃和80℃以500转每分钟的速率磁力搅拌，离心，取固体测试XRPD。其结果如表6所示。
表6
编号 温度 溶剂 起始晶型 最终晶型
1 50℃ 乙酸乙酯 晶型I+晶型II 晶型A
2 80℃ 乙酸乙酯 晶型I+晶型II 晶型A
结果表明，在高温条件下，无水晶型A比现有晶型稳定。
实施例7
本发明中盐酸盐晶型B与专利CN103221411A公开的晶型I和II的稳定性对比研究：
取10.0mg专利CN103221411A公开的晶型I与溶剂混合配成悬浮液，向其中加入专利CN103221411A公开的晶型II，置于25℃以500转每分钟的速率磁力搅拌，离心，取固体测试XRPD。其结果如表7所示。
表7
编号 温度 溶剂 相对湿度 起始晶型 最终晶型
1 25℃ 纯水：甲醇＝7:93 21％ 晶型I+晶型II 晶型B
2 25℃ 纯水：甲醇＝4:21 40％ 晶型I+晶型II 晶型B
结果表明，在室温下一定的湿度范围内，水与有机溶剂的混合溶剂中，晶型B比现有晶型稳定。

Claims (28)

  1. 一种式(I)化合物的盐酸盐晶型A，
    Figure PCTCN2016073102-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为16.60°±0.2°、19.90°±0.2°、23.58°±0.2°处具有特征峰。
  2. 根据权利要求1所述的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图在2theta值为13.40°±0.2°、22.50°±0.2°、19.16°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求2所述的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图在2theta值为13.40°±0.2°、22.50°±0.2°、19.16°±0.2°处具有特征峰。
  4. 根据权利要求1-3任一项所述的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图在2theta值为14.23°±0.2°、24.98°±0.2°、27.65°±0.2°中的一处或两处或三处具有特征峰。
  5. 根据权利要求4所述的盐酸盐晶型A，其特征还在于，其X射线粉末衍射图在2theta值为14.23°±0.2°、24.98°±0.2°、27.65°±0.2°处具有特征峰。
  6. 根据权利要求1所述的盐酸盐晶型A，其特征在于，其X射线粉末衍射图基本上与图1一致。
  7. 根据权利要求1-6中任一项所述的盐酸盐晶型A，其特征在于：所述晶型A为无水物。
  8. 一种权利要求1-7中任一项所述的盐酸盐晶型A的制备方法，其特征在于，包括将式(I) 化合物的粉末与盐酸加入到有机溶剂体系内，混悬搅拌，收集固体，并在150℃-200℃条件下干燥，冷却后所得固体即为盐酸盐晶型A。
  9. 根据权利要求8所述的盐酸盐晶型A的制备方法，其特征在于所述有机溶剂为卤代烃。
  10. 根据权利要求9所述的盐酸盐晶型A的制备方法，其特征在于，所述卤代烃优选氯仿。
  11. 一种权利要求1-7中任一项所述的盐酸盐晶型A的制备方法，其特征在于，将式(I)化合物的盐酸盐加入到有机溶剂体系内，在50℃-100℃条件下搅拌，分离固体，所得固体即为盐酸盐晶型A。
  12. 根据权利要求11所述的盐酸盐晶型A的制备方法，其特征在于所述有机溶剂优选酯类。
  13. 根据权利要求12所述的盐酸盐晶型A的制备方法，其特征在于所述酯类优选乙酸乙酯。
  14. 一种式(I)化合物的盐酸盐晶型B，其特征在于，其X射线粉末衍射图在2theta值为14.10°±0.2°、18.03°±0.2°、20.10°±0.2°、23.70°±0.2°处具有特征峰。
  15. 根据权利要求14所述的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为19.51°±0.2°、17.04°±0.2°、24.81°±0.2°中的一处或两处或三处具有特征峰。
  16. 据权利要求15所述的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为19.51°±0.2°、17.04°±0.2°、24.81°±0.2°处具有特征峰。
  17. 根据权利要求14-16任一项所述的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为4.42°±0.2°、18.47°±0.2°、25.56°±0.2°中的一处或两处或三处具有特征峰。
  18. 根据权利要求17所述的盐酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为4.42°±0.2°、18.47°±0.2°、25.56°±0.2°处具有特征峰。
  19. 根据权利要求14所述的盐酸盐晶型B，其特征在于，其X射线粉末衍射图基本上与图4一致。
  20. 一种权利要求14-19中任一项所述的盐酸盐晶型B的制备方法，其特征在于，包括将式(I)化合物的盐酸盐粉末加入到一定比例的纯水与有机溶剂的混合溶剂中至有不溶物析出， 混悬搅拌，收集固体，即为盐酸盐晶型B。
  21. 根据权利要求20所述的盐酸盐晶型B的制备方法，其特征在于，所述有机溶剂是醇类。
  22. 根据权利要求21所述的盐酸盐晶型B的制备方法，其特征在于，所述醇类优选甲醇。
  23. 根据权利要求20-22任一项所述的盐酸盐晶型B的制备方法，其特征在于，所述纯水与有机溶剂的比例介于1：19至1：4之间。
  24. 根据权利要求23所述的盐酸盐晶型B的制备方法，其特征在于，所述纯水与有机溶剂的比例介于1：15至1：4之间。
  25. 根据权利要求24所述的盐酸盐晶型B的制备方法，其特征在于，所述纯水与有机溶剂的比例介于1：8至1：4之间。
  26. 根据权利要求24所述的盐酸盐晶型B的制备方法，其特征在于，所述纯水与有机溶剂的比例介于1：15至1：12之间。
  27. 一种药用组合物，所述药用组合物包含有效量的权利要求1-7任意一项所述的盐酸盐晶型A或权利要求14-19任意一项所述的盐酸盐晶型B或二者的混合物及药学上可接受的赋形剂。
  28. 权利要求1-7任意一项所述的盐酸盐晶型A或权利要求14-19任意一项所述的盐酸盐晶型B或二者的混合物在生产用于制备治疗阿尔茨海默症或精神分裂症药物制剂中的用途。
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