WO2018001335A1 - Nbi-98854的晶型及其制备方法和用途 - Google Patents

Nbi-98854的晶型及其制备方法和用途 Download PDF

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WO2018001335A1
WO2018001335A1 PCT/CN2017/090926 CN2017090926W WO2018001335A1 WO 2018001335 A1 WO2018001335 A1 WO 2018001335A1 CN 2017090926 W CN2017090926 W CN 2017090926W WO 2018001335 A1 WO2018001335 A1 WO 2018001335A1
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nbi
solid
crystalline form
crystal form
ray powder
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PCT/CN2017/090926
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English (en)
French (fr)
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陈敏华
张炎锋
邹坡
刘凯
王金秋
张晓宇
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苏州科睿思制药有限公司
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Priority to EP17819332.2A priority Critical patent/EP3473623B1/en
Priority to US16/311,754 priority patent/US10442800B2/en
Priority to ES17819332T priority patent/ES2811048T3/es
Priority to CN201780029517.5A priority patent/CN109153676B/zh
Publication of WO2018001335A1 publication Critical patent/WO2018001335A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring 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
    • A61K31/435—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
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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 relates to the field of pharmaceutical crystal technology.
  • it relates to the crystalline form of NBI-98854, its preparation method and use.
  • Valbenazine (NBI-98854), developed by Neurocrine, is a novel, highly selective VMAT2 inhibitor that regulates the release of dopamine during nerve conduction but has no effect on other monoamines, thus reducing the side effects of "off-target". NBI-98854 is able to maintain a low sustained concentration of active drug in the plasma and brain, thereby minimizing side effects caused by excessive reduction of monoamine. NBI-98854 has been approved by the FDA on April 11, 2017 for the treatment of tardive dyskinesia.
  • NBI-98854 is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4 6,6,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, the structure of which is as shown in formula (I):
  • Polymorphism or polymorphism is a peculiar property of certain molecular and molecular compositions.
  • the same molecules may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties such as solubility and stability. , thermal properties, mechanical properties, purification capabilities, X-ray diffraction patterns, infrared absorption spectra, Raman spectroscopy and solid state nuclear magnetic.
  • One or more analytical assays can be used to distinguish between different crystal forms of the same molecule or combination of molecules.
  • New crystalline forms of pharmaceutically active ingredients have been found to produce more processing advantages or to provide materials with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processed, easy to purify or as an intermediate crystal form that facilitates conversion to other crystal forms. New crystalline forms of certain pharmaceutically useful compounds can also help improve the performance of the drug. It expands the formulation of raw materials that can be used in the formulation, such as improved dissolution, improved shelf life, easier processing, and the like.
  • the inventors of the present invention discovered two crystal forms of NBI-98854 during the course of the research.
  • the crystal form solubility and moisture absorbing property of the NBI-98854 provided by the invention are in compliance with medicinal requirements, have good stability, can be stably stored, and avoid crystal transformation during the development process, thereby avoiding drug solubility, dissolution rate, and bioavailability. And changes in efficacy.
  • the preparation process of the crystalline form CS1 and the crystalline form CS2 provided by the invention is simple and reproducible, and the crystal form of the prepared crystal form is good.
  • the crystalline form CS1 is needle-like, and the crystalline form CS2 is in the form of a block, and the dispersibility is good, and there is little agglomeration, and its morphology is suitable for the development of pharmaceutical preparations.
  • the main object of the present invention is to provide a novel crystal form of NBI-98854, a preparation method and use thereof.
  • the present invention provides a crystalline form CS1 of NBI-98854.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at a diffraction angle 2 ⁇ of 9.9 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, and 20.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS1 is 6.0° ⁇ 0.2° and 6.7° ⁇ 0.2° at a diffraction angle 2 ⁇ .
  • One or two or three of 14.2° ⁇ 0.2° have characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CS1 is 6.0° ⁇ 0.2°, 6.7° ⁇ 0.2° at a diffraction angle 2 ⁇ , There are characteristic peaks at 14.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS1 is 16.8° ⁇ 0.2° and 17.5° ⁇ 0.2° at a diffraction angle 2 ⁇ .
  • One or two or three of 22.2° ⁇ 0.2° have characteristic peaks; preferably, the X-ray powder diffraction of the crystalline form CS1 is 16.8° ⁇ 0.2°, 17.5° ⁇ 0.2° at a diffraction angle 2 ⁇ , There are characteristic peaks at 22.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS1 is 6.0° ⁇ 0.2°, 6.7° ⁇ 0.2°, 9.9° ⁇ 0.2°, 14.2° ⁇ 0.2°, 16.8° at the diffraction angle 2 ⁇ . There are characteristic peaks at ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS1 is substantially as shown in FIG.
  • Form CS1 is an anhydrate.
  • the pattern CS1 when differential scanning calorimetry is performed, the pattern CS1 begins to heat up to around 90 ° C and begins to exhibit an endothermic peak, the DSC of which is shown in FIG.
  • the crystalline form CS1 when thermogravimetric analysis is performed, has a mass loss gradient of about 1.6% when heated to 113 ° C, the TGA of which is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS1, the preparation method comprising:
  • Method 1 Dissolving the solid of NBI-98854 in a single ester solvent or a mixed solvent of an alkylnitrile and an aromatic hydrocarbon, and volatilizing at room temperature to obtain a solid;
  • Method 2 Dissolve the solid of NBI-98854 in an isopropanol or alkyl nitrile solvent, add water to the solution, stir at a certain temperature for a period of time, and filter to dry to obtain a solid; the certain temperature is 0 to 35 ° C The period of time is at least 1 day or more.
  • ester of the method 1 is isopropyl acetate; the alkyl nitrile is acetonitrile, and the aromatic hydrocarbon is toluene.
  • the volume ratio of the alkyl nitrile to the aromatic hydrocarbon in Process 1 is from 1/10 to 10/1, more preferably 3/1.
  • the alkyl nitrile of Process 2 is acetonitrile.
  • the reaction temperature of Process 2 is from 0 to 30 ° C, more preferably 5 ° C.
  • reaction time of Process 2 is from 2 to 10 days, more preferably 7 days.
  • the present invention provides a crystalline form CS2 of NBI-98854.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angles 2 ⁇ of 7.4° ⁇ 0.2°, 10.0° ⁇ 0.2°, and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 4.6° ⁇ 0.2°, 9.1° ⁇ 0.2°, and 14.2° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a diffraction angle 2 ⁇ of 4.6° ⁇ 0.2°, 9.1° ⁇ 0.2°, and 14.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 14.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 22.2° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a diffraction angle 2 ⁇ of 14.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 is 4.6 ° ⁇ 0.2 °, 7.4 ° ⁇ 0.2 °, 9.1 ° ⁇ 0.2 °, 10.0 ° ⁇ 0.2 °, 14.2 ° at diffraction angles 2 ⁇ . There are characteristic peaks at ⁇ 0.2°, 14.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.4° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is substantially as shown in FIG.
  • the endothermic peak begins to occur when the form CS2 is heated to around 77 ° C, and its DSC is as shown in FIG.
  • the crystalline form CS2 when thermogravimetric analysis is performed, has a mass loss gradient of about 3.7% when heated to 111 ° C, the TGA of which is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS2, the preparation method comprising:
  • Method 1 The solid of NBI-98854 was dissolved in a mixed solvent of a cyclic ether and water, and volatilized at room temperature to obtain a solid.
  • Method 2 The solid of NBI-98854 was dissolved in a cyclic ether solvent and volatilized at room temperature to give a solid.
  • Method 3 The solid of NBI-98854 is dissolved in methanol, water is added to the solution, stirred at a certain temperature for a period of time, and dried by filtration to obtain a solid; the certain temperature is 0-35 ° C, and the period is at least 1 More than a day.
  • the cyclic ether solvent of Process 1 is tetrahydrofuran.
  • the volume ratio of the cyclic ether solvent to water in Process 1 is from 1/1 to 10/1, more preferably 3/1.
  • the cyclic ether solvent of Process 2 is tetrahydrofuran.
  • bioglass induction can be added to the evaporation method of Method 2.
  • the reaction temperature of Process 3 is from 0 to 30 ° C, more preferably 5 ° C.
  • reaction time of Process 3 is from 2 to 10 days, more preferably 7 days.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a combination of crystalline form CS1, crystalline form CS2 or both of NBI-98854.
  • a therapeutically effective amount of a combination of Form CS1, Form CS2 or both of NBI-98854 is combined with or combined with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, or a pharmaceutical composition or The formulations are prepared in a manner well known in the pharmaceutical art.
  • the present invention provides the use of a crystalline form CS1, a crystalline form CS2 of NBI-98854 or a mixture of both to prepare a pharmaceutical formulation for preventing, delaying or treating delayed dyskinesia.
  • Still another object of the present invention is to provide a use of the crystalline form CS1, the crystalline form CS2 of NBI-98854 or a mixture of both or a pharmaceutical composition thereof for the preparation of a pharmaceutical preparation for treating tardive dyskinesia.
  • Root temperature as used herein is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • the "drying” can be carried out at room temperature or higher. Drying temperatures range from room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C.
  • the drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • bioglass refers to a glass modified with silica.
  • the crystal form CS1 and the crystal form CS2 of the NBI-98854 provided by the invention have the solubility and the wettability in accordance with the medicinal requirements, have good stability, can be stably stored, and prevent the crystal from being crystallized during the development process, thereby avoiding the solubility and dissolution rate of the drug. Bioavailability and changes in efficacy.
  • the preparation process of the crystalline form CS1 and the crystalline form CS2 provided by the invention is simple and heavy After re-amplification, the prepared crystal form has good crystallinity.
  • the crystalline form CS1 is needle-like, and the crystalline form CS2 is in the form of a block, and the dispersibility is good, and there is little agglomeration, and its morphology is suitable for the development of pharmaceutical preparations.
  • Figure 2 is a differential scanning calorimetry analysis of the crystalline form CS1 in Example 1.
  • Figure 8 is a differential scanning calorimetry analysis of the crystalline form CS2 in Example 5.
  • Figure 12 is a DVS diagram of the crystal form CS1 in the embodiment 8.
  • Figure 13 is a DVS diagram of the crystalline form CS2 in Example 9.
  • Fig. 14 is a comparison chart of XRPD before and after the stability test of the crystalline form CS1 of Example 10 (the upper graph is the starting crystal form, the middle graph is placed at 25 ° C / 60% RH condition for 1 month, and the lower graph is placed at 40 ° C / 75% RH condition after 1 month)
  • Figure 15 is a comparison chart of XRPD before and after the stability test of the crystalline form CS2 in Example 11 (the upper graph is the starting crystal form, the middle graph is placed at 25 ° C / 60% RH for 1 month, and the lower graph is placed at 40 ° C /75%RH condition 1 month later)
  • Figure 16 is a PLM diagram of the crystal form CS1 in the embodiment 12.
  • Figure 17 is a PLM diagram of the crystalline form CS2 in the embodiment 12.
  • 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 dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • Time (minutes) % Mobile Phase B 0.0 10 2.0 10 15.0 80 20.0 80 20.1 10 25.0 10
  • NBI-98854 used in the following examples can be obtained according to the method described in the literature of CN101553487B.
  • a solid of 4.3 mg of NBI-98854 was weighed into a 1.5 mL glass vial, and 0.5 mL of a mixed solvent of acetonitrile and toluene (3:1, v:v) was added, and the solid was dissolved to obtain a clear solution. Slowly volatilize at room temperature to give a solid.
  • the solid obtained in this example was a crystalline form CS1.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 1, the XRPD pattern thereof is shown in Fig. 1, the DSC image is shown in Fig. 2, and the TGA image is shown in Fig. 3.
  • NBI-98854 solid 4.5 mg was weighed into a 1.5 mL glass vial, 0.5 mL of isopropyl acetate was added, and the solid was dissolved to obtain a clear solution. Slowly volatilize at room temperature to give a solid.
  • the solid obtained in this example was a crystalline form CS1.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 2, and the XRPD pattern thereof is shown in Fig. 4.
  • NBI-98854 solid 8.4 mg was weighed into a 1.5 mL glass vial, 30 ⁇ L of acetonitrile was added, and the solid was dissolved to obtain a clear solution. Under magnetic stirring, 0.3 mL of water was added. Stirring was continued for 7 days at 5 ° C and filtered to dryness to give a solid.
  • the solid obtained in this example was a crystalline form CS1.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 3, and the XRPD pattern thereof is shown in Fig. 5.
  • a solid of 8.5 mg of NBI-98854 was weighed into a 1.5 mL glass vial, 50 ⁇ L of isopropanol was added, and the solid was dissolved to obtain a clear solution. Under magnetic stirring, 0.3 mL of water was added. Stirring was continued for 7 days at 5 ° C and filtered to dryness to give a solid.
  • the solid obtained in this example was a crystalline form CS1.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 4, and the XRPD pattern thereof is shown in Fig. 6.
  • NBI-98854 solid 4.5 mg was weighed into a 1.5 mL glass vial, 0.5 mL of tetrahydrofuran was added, and the solid was dissolved to obtain a clear solution. 0.2 mg of bioglass was added and slowly evaporated at room temperature to give a solid.
  • the solid obtained in this example was a crystalline form CS2.
  • X-ray powder diffraction data of the solid obtained in this example As shown in Table 5, the XRPD pattern is shown in Fig. 7.
  • the DSC is shown in Figure 8, and the TGA is shown in Figure 9.
  • NBI-98854 solid 4.5 mg was weighed into a 1.5 mL glass vial, and 0.5 mL of a mixed solvent of tetrahydrofuran and water (3:1, v:v) was added, and the solid was dissolved to obtain a clear solution. Slowly volatilize at room temperature to give a solid.
  • the solid obtained in this example was a crystalline form CS2.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 6, and the XRPD pattern thereof is shown in Fig. 10.
  • NBI-98854 solid 7.8 mg was weighed into a 1.5 mL glass vial, 30 ⁇ L of methanol was added, and the solid was dissolved to obtain a clear solution. Under magnetic stirring, 0.3 mL of water was added. Stirring was continued for 7 days at 5 ° C and filtered to dryness to give a solid.
  • the solid obtained in this example was a crystalline form CS2.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 7, and its XRPD pattern is shown in Fig. 11.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystal form CS1 of the present invention is placed under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH for one month, and each sample is taken at the end of one month to detect the crystal form change, and the high-performance liquid phase is used.
  • the chemical purity was determined by chromatography (HPLC).
  • the test results are shown in Table 8.
  • the XRPD comparison chart is shown in Figure 14 (the upper graph is the starting crystal form, and the middle image is placed at 25 ° C / 60% RH for 1 month, The figure below shows the condition of being placed at 40 ° C / 75% RH for 1 month).
  • the crystalline form CS2 of the present invention is placed under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH for one month, and each sample is taken at the end of one month to detect the crystal form change, and the high-performance liquid phase is used.
  • the chemical purity was determined by chromatography (HPLC).
  • the test results are shown in Table 9.
  • the XRPD comparison chart is shown in Figure 15 (the top image is the starting crystal form, and the middle image is placed at 25 ° C / 60% RH condition for 1 month, The figure below shows the condition of being placed at 40 ° C / 75% RH for 1 month).
  • Example 12 Morphology test of crystalline form CS1 and crystalline form CS2
  • the crystal form CS1 and the form CS2 of the present invention were subjected to a polarizing microscope.
  • the crystal form CS1 was needle-like, and the crystal form CS2 was in a block shape, and the dispersibility was good, and there was little agglomeration.
  • the photographing of the polarizing microscope shows that the morphology of the crystalline form CS1 and the crystalline form CS2 of the present invention is suitable for the development of pharmaceutical preparations.

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Abstract

一种NBI-98854（结构如式I所示）的晶型及其制备方法和用途，所述的NBI-98854晶型分别命名为晶型CS1、晶型CS2，可用于制备治疗迟发型运动障碍药物。所述的NBI-98854晶型的溶解度、引湿性符合药用要求，稳定性好，能稳定储存，避免药物在开发过程中发生转晶，从而避免药物溶解度、溶出率、生物利用度以及药效的改变。为含NBI-98854药物制剂的制备提供了新的更好地选择，对于药物开发具有非常重要的意义。

Description

NBI-98854的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及NBI-98854的晶型及其制备方法和用途。
背景技术
Valbenazine(NBI-98854)由Neurocrine公司研发，是一种新型高选择性的VMAT2抑制剂，调节神经传导过程中多巴胺的释放，但对其他单胺没有影响，因此减少了“脱靶”导致的副作用。NBI-98854能够在血浆和脑内保持较低的持久的活性药物浓度，从而尽可能降低单胺过度减少而导致的副作用。NBI-98854已经于2017年4月11日获得FDA批准，用于治疗迟发性运动障碍。NBI-98854的化学名称为(S)-2-氨基-3-甲基-丁酸(2R，3R，11bR)-3-异丁基-9，10-二甲氧基-1，3，4，6，7，11b-六氢-2H-吡啶并[2，1-a]异喹啉-2-基酯，其结构如式(I)所示：
Figure PCTCN2017090926-appb-000001
多晶型或者多晶现象是某些分子和分子组合物的特有性质，相同的分子可能因不同的排列形式而形成不同晶体，而这些晶体具有不同的晶体结构和物理性质，如溶解度、稳定性、热性质、机械性质、纯化能力、X射线衍射图谱、红外吸收图谱、拉曼光谱和固态核磁等。一种或多种分析检测方式可用于区分同一分子或分子组合物的不同晶型。
发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势或提供具有更好理化特性的物质，比如更好的生物利用度、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。某些药学上有用的化合物的新晶型也可以帮助改善药物的性能。它扩大了制剂学上可选用的原料型态，例如改善溶出度、改善储藏期限、更容易加工等。
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。专利CN101553487B公开了NBI-98854的分子结构，但并未提及化合物的固体或晶体形式。并且，现有技术中也没有NBI-98854的晶型公开。因此，研 究NBI-98854的晶型很有必要。
本发明的发明人在研究过程中发现了NBI-98854的两种晶型。并且，本发明提供的NBI-98854的晶型溶解度、引湿性符合药用要求，稳定性好，能稳定储存，避免药物在开发过程中发生转晶，从而避免药物溶解度、溶出率、生物利用度以及药效的改变。而且本发明提供的晶型CS1、晶型CS2的制备工艺简单、可重复放大，制备得到的晶型结晶度好。晶型CS1呈针状，晶型CS2呈块状，且分散性较好，少有团聚现象，其形貌适合药物制剂的开发。
发明内容
针对现有技术的不足，本发明的主要目的是提供NBI-98854的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供NBI-98854的晶型CS1。
使用Cu-Kα辐射，所述晶型CS1的X-射线粉末衍射在衍射角2θ为9.9°±0.2°、18.1°±0.2°、20.3°±0.2°处有特征峰。
进一步地，所述晶型CS1的X-射线粉末衍射在衍射角2θ为6.0°±0.2°、6.7°±0.2°、
14.2°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型CS1的X-射线粉末衍射在衍射角2θ为6.0°±0.2°、6.7°±0.2°、14.2°±0.2°处有特征峰。
进一步地，所述晶型CS1的X-射线粉末衍射在衍射角2θ为16.8°±0.2°、17.5°±0.2°、
22.2°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型CS1的X-射线粉末衍射在衍射角2θ为16.8°±0.2°、17.5°±0.2°、22.2°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型CS1的X-射线粉末衍射在衍射角2θ为6.0°±0.2°、6.7°±0.2°、9.9°±0.2°、14.2°±0.2°、16.8°±0.2°、17.5°±0.2°、18.1°±0.2°、20.3°±0.2°、22.2°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射图基本如图1所示。
非限制性地，在本发明的一个具体实施方案中，晶型CS1是无水物。
非限制性地，在本发明的一个具体实施方案中，当进行差示扫描量热分析时，晶型CS1加热至90℃附近时开始出现吸热峰，其DSC如附图2所示。
非限制性地，在本发明的一个具体实施方案中，当进行热重分析时，晶型CS1加热至113℃时，具有约1.6％的质量损失梯度，其TGA如附图3所示。
根据本发明的目的，本发明还提供所述晶型CS1的制备方法，所述制备方法包括:
方法1:将NBI-98854的固体溶于单一酯类溶剂或烷基腈和芳香烃的混合溶剂中，于室温下挥发得到固体；或
方法2：将NBI-98854的固体溶于异丙醇或烷基腈类溶剂中，向溶液中添加水，在一定温度下搅拌一段时间，过滤干燥得到固体；所述一定温度为0～35℃，所述一段时间为至少1天以上。
进一步地，方法1所述酯类为乙酸异丙酯；所述烷基腈为乙腈，所述芳香烃为甲苯。
更进一步地，方法1所述烷基腈与芳香烃的体积比为1/10～10/1，更优选为3/1。
优选地，方法2所述烷基腈为乙腈。
优选地，方法2所述反应温度为0～30℃，更优选为5℃。
优选地，方法2所述反应时间为2～10天，更优选为7天。
根据本发明的目的，本发明提供NBI-98854的晶型CS2。
使用Cu-Kα辐射，所述晶型CS2的X-射线粉末衍射在衍射角2θ为7.4°±0.2°、10.0°±0.2°、18.4°±0.2°处有特征峰。
进一步地，所述晶型CS2的X-射线粉末衍射在衍射角2θ为4.6°±0.2°、9.1°±0.2°、14.2°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型CS2的X-射线粉末衍射在衍射角2θ为4.6°±0.2°、9.1°±0.2°、14.2°±0.2°处有特征峰。
进一步地，所述晶型CS2的X-射线粉末衍射在衍射角2θ为14.8°±0.2°、17.2°±0.2°、22.2°±0.2°中的一处或两处或三处有特征峰；优选得，所述晶型CS2的X-射线粉末衍射在衍射角2θ为14.8°±0.2°、17.2°±0.2°、22.2°±0.2°处有特征峰。
在一个优选地实施方案中，所述晶型CS2的X-射线粉末衍射在衍射角2θ为4.6°±0.2°、7.4°±0.2°、9.1°±0.2°、10.0°±0.2°、14.2°±0.2°、14.8°±0.2°、17.2°±0.2°、18.4°±0.2°、22.2°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS2的X射线粉末衍射图基本如附图7所示。
非限制性地，在本发明的一个具体实施方案中，当进行差示扫描量热分析时，晶型CS2加热至77℃附近时开始出现吸热峰，其DSC如附图8所示。
非限制性地，在本发明的一个具体实施方案中，当进行热重分析时，晶型CS2加热至111℃时，具有约3.7％的质量损失梯度，其TGA如附图9所示。
根据本发明的目的，本发明还提供所述晶型CS2的制备方法，所述制备方法包括:
方法1：将NBI-98854的固体溶于环醚类和水的混合溶剂中，于室温下挥发得到固体。
方法2：将NBI-98854的固体溶于环醚类溶剂中，于室温下挥发得到固体。
方法3：将NBI-98854的固体溶于甲醇中，向溶液中添加水，在一定温度下搅拌一段时间，过滤干燥得到固体；所述一定温度为0～35℃，所述一段时间为至少1天以上。
优选地，方法1所述环醚类溶剂为四氢呋喃。
优选地，方法1所述环醚类溶剂与水的体积比为1/1～10/1，更优选为3/1。
优选地，方法2所述环醚类溶剂为四氢呋喃。
优选地，方法2的挥发方法中可加入生物玻璃诱导。
优选地，方法3所述反应温度为0～30℃，更优选为5℃。
优选地，方法3所述反应时间为2～10天，更优选为7天。
本发明的另一个目的是提供一种包含有效治疗量的NBI-98854的晶型CS1、晶型CS2或两者的混合和药用辅料的药用组合物。一般是将治疗有效量的NBI-98854的晶型CS1、晶型CS2或两者的混合与一种或多种药用辅料混合或组合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。
本发明提供NBI-98854的晶型CS1、晶型CS2或两者的混合在制备预防、延缓或治疗迟发性运动障碍的药物制剂的用途。
本发明的又一个目的是提供NBI-98854的晶型CS1、晶型CS2或两者的混合或其药用组合物用于制备治疗迟发性运动障碍药物制剂中的用途。
在本发明的晶型CS1、晶型CS2的制备方法中：
本文所述“室温”不是精确的温度值，是指10-30℃温度范围。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
所述“干燥”可以在室温或更高的温度下进行。干燥温度室温～约60℃，或者到40℃，或者到50℃。干燥时间可以为2～48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“生物玻璃”是指：经氧化硅修饰的玻璃。
本发明提供的NBI-98854的晶型CS1、晶型CS2溶解度、引湿性符合药用要求，稳定性好，能稳定储存，避免药物在开发过程中发生转晶，从而避免药物溶解度、溶出率、生物利用度以及药效的改变。而且本发明提供的晶型CS1、晶型CS2的制备工艺简单、可重 复放大，制备得到的晶型结晶度好。晶型CS1呈针状，晶型CS2呈块状，且分散性较好，少有团聚现象，其形貌适合药物制剂的开发。
附图说明
图1实施例1中晶型CS1的X射线粉末衍射图
图2实施例1中晶型CS1的差示扫描量热分析图
图3实施例1中晶型CS1的热重分析图
图4实施例2中晶型CS1的X射线粉末衍射图
图5实施例3中晶型CS1的X射线粉末衍射图
图6实施例4中晶型CS1的X射线粉末衍射图
图7实施例5中晶型CS2的X射线粉末衍射图
图8实施例5中晶型CS2的差示扫描量热分析图
图9实施例5中晶型CS2的热重分析图
图10实施例6中晶型CS2的X射线粉末衍射图
图11实施例7中晶型CS2的X射线粉末衍射图
图12实施例8中晶型CS1的DVS图
图13实施例9中晶型CS2的DVS图
图14实施例10晶型CS1稳定性试验前后的XRPD对比图(上图为起始晶型，中图为放置在25℃/60％RH条件1个月后，下图为放置在40℃/75％RH条件1个月后)
图15实施例11中晶型CS2稳定性试验前后的XRPD对比图(上图为起始晶型，中图为放置在25℃/60％RH条件1个月后，下图为放置在40℃/75％RH条件1个月后)
图16实施例12中晶型CS1的PLM图
图17实施例12中晶型CS2的PLM图
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
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
DVS：动态水分吸附
PLM：偏光显微镜
采集数据所用的仪器及方法：
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 PCTCN2017090926-appb-000002
：1.540598；Kα2
Figure PCTCN2017090926-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
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
高效液相色谱(HPLC)数据采自于安捷伦1100，所用检测器为二极管阵列检测器(DAD)。本发明所述的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18 150×4.6mm,5μm
2、流动相：A：0.1％的三氟乙酸水溶液
           B：0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
时间(分钟) ％流动相B
0.0 10
2.0 10
15.0 80
20.0 80
20.1 10
25.0 10
3、流速：1.0mL/min
4、进样量：10μL
5、检测波长：230nm
6、柱温：40℃
7、稀释剂：50％乙腈
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用的NBI-98854的固体可根据CN101553487B文献所记载的方法制备获得。
实施例1 晶型CS1的制备方法
称取4.3mg的NBI-98854的固体置于1.5mL的玻璃小瓶中，加入0.5mL乙腈和甲苯(3:1,v:v)的混合溶剂，固体溶解得到澄清溶液。在室温下缓慢挥发得到固体。
经检测，本实施例得到的固体为晶型CS1。本实施例所得固体的X射线粉末衍射数据如表1所示，其XRPD图如图1所示，DSC图像如图2所示，TGA图像如图3所示。
表1
衍射角2θ d值 强度％
6.00 14.74 94.30
6.74 13.11 76.17
8.37 10.56 27.55
9.94 8.90 100.00
12.03 7.36 8.26
13.52 6.55 30.81
14.21 6.23 73.04
14.41 6.15 29.48
15.30 5.79 4.25
16.40 5.41 6.89
16.81 5.27 31.44
17.16 5.17 6.92
17.55 5.05 28.19
18.10 4.90 91.19
19.88 4.47 37.92
20.28 4.38 80.56
22.23 4.00 28.09
22.77 3.91 6.29
23.93 3.72 25.12
24.81 3.59 5.60
25.37 3.51 6.18
26.00 3.43 8.96
26.35 3.38 9.50
27.03 3.30 3.85
28.18 3.17 4.57
29.09 3.07 4.04
31.10 2.88 4.58
35.64 2.52 2.50
36.70 2.45 3.35
实施例2 晶型CS1的制备方法
称取4.5mg的NBI-98854固体置于1.5mL的玻璃小瓶中，加入0.5mL的乙酸异丙酯，固体溶解得到澄清溶液。在室温下缓慢挥发得到固体。
经检测，本实施例得到的固体为晶型CS1。本实施例所得固体的X射线粉末衍射数据如表2所示，其XRPD图如图4所示。
表2
衍射角2θ d值 强度％
6.00 14.73 87.47
6.74 13.11 73.27
8.38 10.55 25.58
9.94 8.90 100.00
12.02 7.37 7.78
13.51 6.55 29.33
14.21 6.23 70.36
14.42 6.14 30.73
15.31 5.79 5.65
16.40 5.41 6.87
16.81 5.27 28.36
17.17 5.16 6.82
17.56 5.05 20.28
18.10 4.90 69.43
19.88 4.47 26.84
20.27 4.38 65.85
20.97 4.24 4.40
22.24 4.00 21.03
22.72 3.91 5.66
23.90 3.72 17.19
24.81 3.59 3.53
25.34 3.51 5.35
26.01 3.43 6.23
26.34 3.38 8.39
27.06 3.29 1.83
28.28 3.16 3.08
29.07 3.07 3.59
29.67 3.01 2.19
30.44 2.94 1.85
31.10 2.88 4.11
35.57 2.52 2.79
36.86 2.44 1.17
实施例3 晶型CS1的制备方法
称取8.4mg的NBI-98854固体加入到1.5mL的玻璃小瓶中，加入30μL的乙腈，固体溶解得到澄清溶液。磁力搅拌下，加入0.3mL的水。5℃下继续搅拌7天，过滤干燥得到固体。
经检测，本实施例得到的固体为晶型CS1。本实施例所得固体的X射线粉末衍射数据如表3所示，其XRPD图如图5所示。
表3
衍射角2θ d值 强度％
5.99 14.75 69.88
6.73 13.13 67.24
8.38 10.55 18.15
9.93 8.91 74.89
11.98 7.38 6.50
13.49 6.56 30.17
14.20 6.24 59.88
16.79 5.28 26.15
17.17 5.16 14.93
17.55 5.05 42.03
18.14 4.89 100.00
19.89 4.46 51.03
20.27 4.38 82.10
20.94 4.24 8.32
22.23 4.00 35.13
22.82 3.90 10.90
23.98 3.71 27.67
24.80 3.59 8.91
25.32 3.52 6.90
26.01 3.43 9.66
26.45 3.37 14.10
28.34 3.15 4.06
29.74 3.00 3.82
30.40 2.94 2.68
31.11 2.87 6.21
35.58 2.52 4.51
实施例4 晶型CS1的制备方法
称取8.5mg的NBI-98854的固体置于1.5mL的玻璃小瓶中，加入50μL的异丙醇，固体溶解得到澄清溶液。磁力搅拌下，加入0.3mL的水。5℃下继续搅拌7天，过滤干燥得到固体。
经检测，本实施例得到的固体为晶型CS1。本实施例所得固体的X射线粉末衍射数据如表4所示，其XRPD图如图6所示。
表4
衍射角2θ d值 强度％
6.00 14.73 100.00
6.75 13.09 69.68
8.39 10.54 19.54
9.95 8.89 73.36
11.33 7.81 4.14
12.04 7.35 6.39
13.54 6.54 17.11
14.22 6.23 65.68
14.43 6.14 27.75
16.40 5.41 5.75
16.83 5.27 24.37
17.60 5.04 19.42
18.09 4.90 67.12
19.91 4.46 24.64
20.27 4.38 51.73
22.27 3.99 18.34
22.88 3.89 6.97
23.94 3.72 19.30
24.84 3.58 4.88
25.34 3.51 6.40
26.36 3.38 9.68
实施例5 晶型CS2的制备方法
称取4.5mg的NBI-98854固体置于1.5mL的玻璃小瓶中，加入0.5mL的四氢呋喃，固体溶解得到澄清溶液。并加入0.2mg的生物玻璃，在室温下缓慢挥发得到固体。
经检测，本实施例得到的固体为晶型CS2。本实施例所得固体的X射线粉末衍射数据 如表5所示，其XRPD图如图7所示。DSC如图8所示，TGA如图9所示。
表5
衍射角2θ d值 强度％
4.56 19.39 56.67
7.37 11.99 100.00
9.15 9.67 44.79
9.71 9.11 20.18
10.02 8.83 56.22
13.30 6.65 13.62
13.76 6.44 25.72
14.22 6.23 51.43
14.81 5.98 40.78
15.08 5.88 24.42
16.74 5.30 4.41
17.18 5.16 18.01
17.79 4.99 18.41
18.39 4.82 46.48
20.15 4.41 19.35
21.49 4.14 5.72
22.13 4.02 12.08
23.98 3.71 1.81
26.20 3.40 14.38
26.84 3.32 10.81
27.78 3.21 2.99
29.55 3.02 2.46
实施例6 晶型CS2的制备方法
称取4.5mg的NBI-98854固体置于1.5mL玻璃小瓶中，加入0.5mL的四氢呋喃和水(3:1,v:v)的混合溶剂，固体溶解得到澄清溶液。在室温下缓慢挥发得到固体。
经检测，本实施例得到的固体为晶型CS2。本实施例所得固体的X射线粉末衍射数据如表6所示，其XRPD图如图10所示。
表6
衍射角2θ d值 强度％
4.58 19.29 59.45
7.37 11.99 100.00
9.14 9.68 73.31
9.72 9.10 21.72
10.01 8.83 58.75
13.30 6.66 13.21
13.74 6.44 41.62
14.22 6.23 43.81
14.82 5.98 35.04
15.08 5.87 22.54
17.18 5.16 16.90
17.78 4.99 20.48
18.38 4.83 62.46
18.60 4.77 28.56
19.36 4.58 9.13
19.76 4.49 9.22
20.15 4.41 14.32
22.27 3.99 32.18
22.66 3.92 11.80
23.93 3.72 4.92
26.22 3.40 9.94
26.82 3.32 9.82
27.74 3.22 5.71
31.75 2.82 2.31
33.86 2.65 2.09
实施例7 晶型CS2的制备方法
称取7.8mg的NBI-98854固体置于1.5mL的玻璃小瓶中，加入30μL甲醇，固体溶解得到澄清溶液。磁力搅拌下，加入0.3mL水。5℃下继续搅拌7天，过滤干燥得到固体。
经检测，本实施例得到的固体为晶型CS2。本实施例所得固体的X射线粉末衍射数据如表7所示，其XRPD图如图11所示。
表7
衍射角2θ d值 强度％
4.55 19.41 100.00
7.37 11.99 56.74
9.14 9.68 58.34
10.01 8.83 36.49
13.27 6.67 6.74
13.75 6.44 33.22
14.23 6.23 25.12
14.79 5.99 19.19
17.17 5.17 11.39
17.60 5.04 23.13
18.38 4.83 62.21
18.58 4.77 47.35
19.33 4.59 16.57
19.78 4.49 14.27
20.12 4.41 11.93
22.24 4.00 37.86
22.61 3.93 15.50
23.97 3.71 6.49
26.18 3.40 14.11
26.85 3.32 6.57
27.63 3.23 5.06
实施例8 晶型CS1的引湿性试验
称取14.3mg的晶型CS1置于DVS仪器中，经历一个0％-95％-0％相对湿度变化的循环，DVS图如图12所示，80％相对湿度时有0.08％的增重，属于几乎无引湿性。
实施例9 晶型CS2的引湿性试验
称取8.6mg的晶型CS2置于DVS仪器中，经历一个40％-95％-0-95％相对湿度变化的循环，DVS图如图13所示，80％相对湿度时有0.56％的增重，引湿性低，便于药物的储存和运输。
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例10 晶型CS1的稳定性试验
将本发明的晶型CS1分别放置于25℃/60％RH和40℃/75％RH的条件下1个月，并在1个月末各取样一次，检测晶型变化情况，并使用高效液相色谱(HPLC)测试化学纯度，试验结果如表8所示，XRPD对比图如图14所示(上图为起始晶型，中图为放置在25℃/60％RH条件1个月后，下图为放置在40℃/75％RH条件1个月后)。
表8
Figure PCTCN2017090926-appb-000004
结果表明，晶型CS1放置在25℃/60％RH和40℃/75％RH条件下1个月，晶型保持不变，且纯度未见显著变化，表明晶型CS1具有良好的稳定性。
实施例11 晶型CS2的稳定性试验
将本发明的晶型CS2分别放置于25℃/60％RH和40℃/75％RH的条件下1个月，并在1个月末各取样一次，检测晶型变化情况，并使用高效液相色谱(HPLC)测试化学纯度，试验结果如表9所示，XRPD对比图如图15所示(上图为起始晶型，中图为放置在25℃/60％RH条件1个月后，下图为放置在40℃/75％RH条件1个月后)。
表9
Figure PCTCN2017090926-appb-000005
结果表明，晶型CS1放置在25℃/60％RH和40℃/75％RH条件下1个月，晶型保持不变，且纯度未见显著变化，表明晶型CS1具有良好的稳定性。
实施例12 晶型CS1、晶型CS2的形态测试
对本发明的晶型CS1、晶型CS2进行偏光显微镜拍摄，结果如图16和图17所示，晶型CS1呈针状，晶型CS2呈块状，且分散性较好，少有团聚现象。偏光显微镜的拍摄图表明，本发明晶型CS1、晶型CS2的形貌适合药物制剂的开发。
本领域技术人员可以理解，在本说明书的教导之下，可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。

Claims (12)

  1. 一种NBI-98854的晶型CS1，其特征在于，其X射线粉末衍射图在2theta值为9.9°±0.2°、18.1°±0.2°、20.3°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2theta值为6.0°±0.2°、6.7°±0.2°、14.2°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射图在2theta值为16.8°±0.2°、17.5°±0.2°、22.2°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种权利要求1所述的晶型CS1的制备方法，其特征在于，所述方法包括：
    1)将NBI-98854的固体溶于单一酯类溶剂或烷基腈和芳香烃的混合溶剂中，于室温下挥发得到固体；或
    2)将NBI-98854的固体溶于异丙醇或烷基腈类溶剂中，向溶液中添加水，在一定温度下搅拌一段时间，过滤干燥得到固体；所述一定温度为0～35℃，所述一段时间为至少1天。
  5. 根据权利要求4所述的制备方法，1)中所述烷基腈为乙腈，所述芳香烃为甲苯；所述烷基腈与芳香烃的体积比为1/10～10/1；2)中所述烷基腈为乙腈；所述反应温度为0～30℃；所述反应时间为2～10天。
  6. 一种NBI-98854的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为7.4°±0.2°、10.0°±0.2°、18.4°±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型CS2，其特征还在于，其X射线粉末衍射图在2theta值为4.6°±0.2°、9.1°±0.2°、14.2°±0.2°中的一处或两处或三处具有特征峰。
  8. 根据权利要求6所述的晶型CS2，其特征还在于，其X射线粉末衍射图在2theta值为14.8°±0.2°、17.2°±0.2°、22.2°±0.2°中的一处或两处或三处具有特征峰。
  9. 一种权利要求6所述的晶型CS2，其特征在于，所述制备方法包括：
    1)将NBI-98854的固体溶于环醚类和水的混合溶剂中，于室温下挥发得到固体；或
    2)将NBI-98854的固体溶于环醚类溶剂中，于室温下挥发得到固体；或
    3)将NBI-98854的固体溶于甲醇中，向溶液中添加水，在一定温度下搅拌一段时间，过滤干燥得到固体；所述反应温度为0～35℃；所述反应时间为至少1天。
  10. 根据权利要求9所述的制备方法，其特征在于，1)中所述环醚类溶剂为四氢呋喃；所述环醚类溶剂与水的体积比为1/1～10/1；2)中所述环醚类溶剂为四氢呋喃；3)中所述反应温度为0～30℃；所述反应时间为2～10天。
  11. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1所述的晶型CS1，或权利要求6所述的晶型CS2，或二者的任意混合及药学上可接受的载体、稀释剂或赋形剂。
  12. 权利要求1所述的晶型CS1，或权利要求6所述的晶型CS2，或二者的任意混合在生产用于制备治疗迟发性运动障碍的药物中的用途。
PCT/CN2017/090926 2016-06-29 2017-06-29 Nbi-98854的晶型及其制备方法和用途 WO2018001335A1 (zh)

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