WO2016155631A1 - 托吡司他的新晶型及其制备方法 - Google Patents

托吡司他的新晶型及其制备方法 Download PDF

Info

Publication number
WO2016155631A1
WO2016155631A1 PCT/CN2016/077887 CN2016077887W WO2016155631A1 WO 2016155631 A1 WO2016155631 A1 WO 2016155631A1 CN 2016077887 W CN2016077887 W CN 2016077887W WO 2016155631 A1 WO2016155631 A1 WO 2016155631A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
preparation
present
compound
ray powder
Prior art date
Application number
PCT/CN2016/077887
Other languages
English (en)
French (fr)
Inventor
陈敏华
张炎锋
刘凯
张晓宇
Original Assignee
苏州晶云药物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州晶云药物科技有限公司 filed Critical 苏州晶云药物科技有限公司
Priority to JP2017550772A priority Critical patent/JP6767382B2/ja
Publication of WO2016155631A1 publication Critical patent/WO2016155631A1/zh

Links

Images

Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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 chemical medicine, in particular to a crystal form A of 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole and a preparation method thereof.
  • Topirastat chemical name 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, was developed by Fuji Pharmaceutical Co., Ltd. A xanthine oxidoreductase (XOR) inhibitor. Topirastat was approved for marketing in Japan on June 28, 2013 for the treatment of gout and hyperuricemia.
  • the chemical structure of the drug is as shown in formula (I):
  • 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.
  • tropics also has polymorphism.
  • the original research company protected the three crystal forms of tropisestat, crystal form I, crystal form II and hydrate crystal form, but the patent does not involve the hygroscopicity, stability and other physicochemical properties of the three crystal forms.
  • Form I is well water soluble
  • 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. Based on this, it is necessary to further carry out the polymorphic screening of the compound of the formula (1), and develop a crystal-free type with good stability, low wettability and suitable for industrial production, and provide more and better choices for the subsequent development of the drug.
  • the inventors of the present invention discovered a new crystal form of the compound of the formula (1) during the research, which has good stability, solubility and wettability in accordance with pharmaceutical requirements.
  • the crystal 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 10.2 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, and 27.3 ° ⁇ 0.2 °.
  • the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern is one or two in a 2theta value of 15.7° ⁇ 0.2°, 21.6° ⁇ 0.2°, 24.5° ⁇ 0.2°. Or three with characteristic peaks.
  • the crystal form A provided by the present invention is characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 15.7 ° ⁇ 0.2 °, 21.6 ° ⁇ 0.2 °, and 24.5 ° ⁇ 0.2 °.
  • the crystal form A provided by the present invention is characterized in that the X-ray powder diffraction pattern has a characteristic peak at one or two of the 2theta values of 15.5 ° ⁇ 0.2 ° and 20.6 ° ⁇ 0.2 °.
  • the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 15.5 ° ⁇ 0.2 ° and 20.6 ° ⁇ 0.2 °.
  • the crystal form A provided by the present invention has an X-ray powder diffraction pattern including 2theta values of 10.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, 27.3° ⁇ 0.2°, 15.7° ⁇ 0.2°, 21.6° ⁇ 0.2. Characteristic peaks at °, 24.5 ° ⁇ 0.2 °, 15.5 ° ⁇ 0.2 °, and 20.6 ° ⁇ 0.2 °.
  • crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern thereof. Basically shown in Figure 1.
  • the crystal form A provided by the present invention is characterized in that when differential scanning calorimetry is performed, an endothermic peak begins to appear near the temperature of 326 ° C, and the differential scanning calorimetry diagram is basically as shown in FIG. 2 . Show.
  • Another object of the present invention is to provide a process for the preparation of Form A, which comprises dissolving a powder of the compound of the formula (I) in a mixed solvent system of one or more solvents, stirring, cooling, crystallization and volatilization. A crystallization method of crystallization, antisolvent addition or reverse antisolvent addition is obtained.
  • the solvent system is preferably a ketone solvent or a mixed solvent system of a ketone solvent and an alkyl nitrile.
  • the ketone solvent is more preferably 1-methylpyrrolidone; the alkylnitrile is more preferably acetonitrile.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A of a compound of formula (I) and a pharmaceutically acceptable adjuvant.
  • a therapeutically effective amount of Form A of a compound of Formula (I) is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is well known in the pharmaceutical arts. The way to prepare.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release;
  • dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agents, patches; dosage forms suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • Type has unexpectedly low hygroscopicity and stability in water or aqueous ethanol solution, therefore, it is especially suitable for preparation into tablets, suspensions, capsules, disintegrating tablets, immediate release, sustained release and controlled release tablets; further Preference is given to tablets, suspensions and capsules.
  • a pharmaceutically acceptable excipient in the above pharmaceutical composition, in the case of a solid oral dosage form including but not limited to: a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, Calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, poly Ethylene glycol or the like; a disintegrating agent such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; a lubricant such as stearic acid , magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; complex forming agents, such as
  • the coating is applied to the tablet, for example to provide a shellac barrier coating, a sugar coating or a polymeric coating, a polymer in the coating layer such as hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl Cellulose, methacrylic polymer, hydroxypropyl cellulose or starch may also include anti-adherents such as silica, talc, opacifiers such as titanium dioxide, colorants such as iron oxide-based colorants.
  • suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, and the like; aqueous or nonaqueous sterile suspensions may be employed Containing suspending agents and thickeners; excipients suitable for aqueous suspensions include synthetic or natural gums such as gum arabic, arborvitae, alginate, dextran, sodium carboxymethylcellulose, methylcellulose , polyvinylpyrrolidone or gelatin.
  • the excipients of the aqueous or non-aqueous sterile injectable solutions are usually sterile water, physiological saline or aqueous dextrose, and may contain buffers, antioxidants, and A microbial agent and a solute capable of making the pharmaceutical composition isotonic with blood.
  • Each excipient must be acceptable, compatible with the other ingredients in the formulation, and not deleterious to the patient.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art.
  • Form A of the present invention is admixed with one or more pharmaceutically acceptable excipients, optionally with one or more other pharmaceutically active ingredients.
  • tablets, capsules, granules can be prepared by a process such as mixing, granulating, tableting or filling capsules; powders are prepared by mixing finely divided pharmaceutically active ingredients and excipients; solution and syrup
  • the agent can be prepared by dissolving the pharmaceutically active ingredient in a suitably flavored water or aqueous solution; the suspension can be prepared by dispersing the pharmaceutically active ingredient in a pharmaceutically acceptable carrier.
  • wet granulation process for solid preparations which is exemplified by wet granulation of tablets by mixing dry solids such as active ingredients, fillers, binders, etc., with a wetting agent such as water or alcohol Wet, the wetted solid is made into agglomerates or granules, and wet granulation is continued until the desired uniform particle size is obtained, followed by drying of the granulated product. The resulting dried granules are then mixed with a disintegrant, a lubricant, an anti-adhesive, etc., and compressed in a tablet machine; alternatively, coated with a suitable coating powder.
  • a wet granulation process for solid preparations which is exemplified by wet granulation of tablets by mixing dry solids such as active ingredients, fillers, binders, etc., with a wetting agent such as water or alcohol Wet, the wetted solid is made into agglomerates or granules, and wet granulation is
  • the crystalline form A of the compound of the formula (I) provided by the present invention can be used as a xanthine oxidase inhibitor, and the crystal form of the present invention can regulate the activity of xanthine oxidase by the amount administered.
  • Form A can be used to treat a xanthine oxidase-associated disease or condition in an individual (e.g., a patient) by administering a therapeutically effective amount or a therapeutically effective amount of a crystalline form of a compound of the invention or a pharmaceutical composition thereof, in need thereof. The individual is treated.
  • the crystalline form A of the compound of the formula (I) provided by the present invention can also be used for the treatment of hyperuricemia and gout caused by hyperuricemia.
  • the crystal form A provided by the invention has good stability and low wettability, and can well avoid the occurrence of crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and efficacy.
  • the crystal form A provided by the invention has high solubility and meets the requirements of bioavailability and efficacy.
  • the "patent crystal form” refers to the crystal form of the prior art WO2014017515.
  • an effective therapeutic amount or “therapeutically effective amount” as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or showing a disease or condition of the disease, condition or disorder; and (3) improving the disease A disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a disease or condition of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease.
  • Preventing the disease, condition or disorder in the individual (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • polymorph refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound.
  • the phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs. It is known that a pharmaceutical compound having such a polymorph has an influence on pharmacological activity, solubility, bioavailability, stability, and the like due to its physicochemical properties. Therefore, in the case where a compound which is useful as a drug has a polymorph, it is desirable to produce a crystal compound having high usefulness from these polymorphs.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • the X-ray powder diffraction pattern was characterized by peak position and peak intensity.
  • crystal or “crystal form” as used herein refers to the characterization of the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized The experimental error in the instrument depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Figure 1 is an XRPD pattern of Form A
  • Figure 2 is a DSC diagram of Form A
  • Figure 3 is a 1 H-NMR chart of Form A
  • Figure 4 is a DVS diagram of Form A
  • Figure 5 is a comparison of XRPD before and after DVS of Form A.
  • Figure 6 is an XRPD overlay of Form A and 15 days placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH (from top to bottom, starting form A, 5 ° C, 25) °C/60% RH, placed at 15 °C / 75% RH for 15 days XRPD)
  • Figure 7 is an XRPD overlay of Form A and 30 days placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH (from top to bottom, starting form A, 5 ° C, 25) °C/60% RH, placed at 15 °C / 75% RH for 15 days XRPD)
  • Figure 8 is an XRPD overlay of Form A and 90 days placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH (from top to bottom, starting form A, 5 ° C, 25) °C/60% RH, placed at 15 °C / 75% RH for 15 days XRPD)
  • Figure 9 is an XRPD pattern of the solid obtained after the crystal form A was equilibrated for 1 hour (from the top to the bottom, the starting form A, 5 ° C, 25 ° C, 50 ° C after 1 hour of equilibrium XRPD pattern)
  • Figure 10 is an XRPD pattern of the solid obtained after the equilibrium of the crystalline Form I for 1 hour (from the top to the bottom, the starting form I, 5 ° C, 25 ° C, 50 ° C after 1 hour of equilibrium XRPD)
  • Figure 11 is a diagram showing the transition relationship between the crystalline form I and the crystalline form A.
  • 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:
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1.
  • the X-ray powder diffraction data of the crystal form obtained in this example includes, but is not limited to, Table 1 data. Its DSC chart is shown in Fig. 2, and its 1 H NMR chart is shown in Fig. 3.
  • 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 A of the present invention has a weight gain of 1.00% after being equilibrated at 80% humidity, and is slightly hygroscopic. This property indicates that the crystal form is not susceptible to humidity or deliquescence, facilitating its long-term storage placement.
  • the crystal form since the crystal form has low wettability, no special drying conditions are required in the preparation process, the preparation and post-treatment processes are simplified to some extent, and industrialization is easy. Since the moisture content of the crystal form remains basically unchanged under different humidity conditions, the storage conditions are not critical, which greatly reduces material storage and quality control. The cost of the system has a strong economic value.
  • the crystal form A and the patent crystal form II sample prepared in Example 1 were respectively treated with SGF (simulated gastric juice), pH 5.0 FeSSIF (simulated intestinal juice in the fed state), pH 6.5 FaSSIF (simulated intestinal juice in the fasting state) and pure
  • SGF simulated gastric juice
  • pH 5.0 FeSSIF simulated intestinal juice in the fed state
  • pH 6.5 FaSSIF simulated intestinal juice in the fasting state
  • the water was made into a saturated solution at room temperature, and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours, and 24 hours.
  • HPLC high performance liquid chromatography
  • the new crystal form A of the present invention has higher solubility than the patent crystal form II after 4 hours and 24 hours.
  • SGF simulated gastric juice
  • pH 5.0 FeSSIF simulated intestinal juice in the fed state
  • the solubility of crystal form A is about 1.3 times that of the patent crystal form II
  • at pH 6.5 FaSSIF the simulated intestinal juice in the fasting state
  • the solubility of crystal form A is about 3 times that of the patent crystal form II, and the solubility is remarkably improved, thereby contributing to the improvement of bioavailability.
  • Figure 9, 10 is an XRPD pattern of the solid obtained after the equilibrium of Form A and Form I for 1 hour ( Figure 9: XRPD pattern of crystal form A before equilibrium from top to bottom, 5 ° C, 25 ° C, 50 ° C The XRPD pattern was equilibrated for 1 hour; Figure 10: XRPD pattern of the pre-equilibration Form I from top to bottom, XRPD pattern at 5 ° C, 25 ° C, and equilibrated for 1 hour at 50 ° C).
  • Form A is always more stable than Form I when it is greater than 5 °C.

Abstract

本发明涉及5-(2-氰基-4-吡啶基)-3-(4-吡啶基)-1,2,4-三唑的新晶型及其制备方法。本发明提供的新晶型可用于治疗痛风和高尿酸血症，本发明提供的新晶型稳定性好，工艺提纯效果显著，且溶解度、引湿性符合药用要求。本发明提供的晶型A具有利于工业生产的有利性能，对未来药物的优化和开发具有重要价值。

Description

托吡司他的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及5-(2-氰基-4-吡啶基)-3-(4-吡啶基)-1,2,4-三唑的晶型A及其制备方法。
背景技术
托吡司他，化学名称为5-(2-氰基-4-吡啶基)-3-(4-吡啶基)-1,2,4-三唑，是由日本富士药品株式会社研发的一种黄嘌呤氧化还原酶(XOR)抑制剂。托吡司他于2013年6月28日在日本批准上市，用于治疗痛风及高尿酸血症。该药物的化学结构如式(Ⅰ)所示：
Figure PCTCN2016077887-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、稳定性等方面有显着的差异，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。
据研究，托吡司他同样存在多晶型现象。原研公司在专利WO2014017515A1中保护了托吡司他的三个晶型，晶型I、晶型II、水合物晶型，但专利中并未涉及三种晶型的吸湿性，稳定性等物化性质，仅仅提到晶型I水溶性良好， 而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。基于此，有必要进一步进行式(1)化合物的多晶型筛选，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。
本发明的发明人在研究过程中发现了式(1)化合物的一种新晶型，该晶型稳定性良好，溶解度，引湿性符合药用要求。
发明内容
本发明的一个目的是提供式(Ⅰ)化合物的一种新晶型，命名为晶型A。
本发明提供的晶型A，其特征在于，其X射线粉末衍射图在2theta值为10.2°±0.2°、17.0°±0.2°、27.3°±0.2°处具有特征峰。
进一步的，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15.7°±0.2°、21.6°±0.2°、24.5°±0.2°中的一处或两处或三处具有特征峰。
更进一步的，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15.7°±0.2°、21.6°±0.2°、24.5°±0.2°处具有特征峰。
进一步的，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15.5°±0.2°、20.6°±0.2°中的一处或两处具有特征峰。
更进一步的，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15.5°±0.2°、20.6°±0.2°处具有特征峰。
优选的，本发明提供的晶型A，其X射线粉末衍射图包括在2theta值为10.2°±0.2°、17.0°±0.2°、27.3°±0.2°、15.7°±0.2°、21.6°±0.2°、24.5°±0.2°、15.5°±0.2°、20.6°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图 基本如图1所示。
更进一步的，本发明提供的晶型A，其特征在于，当进行差示扫描量热分析时，加热至326℃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。
本发明的另一个目的是提供晶型A的制备方法，其特征在于，将式(Ⅰ)化合物的粉末溶于一种或多种溶剂的混合溶剂体系中，通过混悬搅拌、降温结晶、挥发结晶、反溶剂添加或反向反溶剂添加的结晶方法得到。
更进一步的，所述溶剂体系优选酮类溶剂或酮类溶剂与烷基腈的混合溶剂体系。
更进一步的，所述酮类溶剂更优选1-甲基吡咯烷酮；所述烷基腈更优选乙腈。
本发明的另一个目的是提供一种包含有效治疗量的式(Ⅰ)化合物的晶型A和药用辅料的药用组合物。一般是将治疗有效量的式(Ⅰ)化合物的晶型A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。
上述药物组合物可制成一定的剂型，通过适合的途径给药。例如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。优选地，由于本发明的晶 型具有出人意料的低吸湿性和在水中或乙醇水溶液中的稳定性，因此，尤其适合制备成片剂、混悬剂、胶囊剂、崩解片、即释、缓释和控释片剂；进一步优选为片剂、混悬剂和胶囊剂。
上述药物组合物中药学上可接受的赋形剂，在固体口服剂型的情况下，包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。任选地，对片剂涂覆包衣层，例如提供虫胶隔离包衣、糖衣或聚合物包衣，包衣层中的聚合物例如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、甲基丙烯酸类聚合物、羟丙基纤维素或淀粉，还可以包括抗粘着剂如二氧化硅、滑石粉，乳浊剂如二氧化钛，着色剂如氧化铁类着色剂。在液体口服剂型的情况下，合适的赋形剂包括水、油类、醇类、二醇类、调味剂、防腐剂、稳定剂、着色剂等；水或非水的无菌混悬剂可含有悬浮剂和增稠剂；适用于水性混悬剂的赋形剂包括合成胶或天然胶例如阿拉伯树胶、苍耳树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。在胃肠外给药剂型的情况下，水或非水的无菌注射溶液的赋形剂通常为无菌水、生理盐水或葡萄糖水溶液，可以含有缓冲剂、抗氧化剂、抑 菌剂和能够使该药物组合物与血液等渗的溶质。每一种赋形剂必须是可接受的，能与配方中的其他成分兼容并且对于患者无害。
所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备药物组合物时，将本发明晶型A与一种或多种药学上可接受的赋形剂相混合，任选地与一种或多种其他的药物活性成分相混合。例如，片剂、胶囊剂、颗粒剂可以通过混合、制粒、压片或填充胶囊等工艺来制备；粉剂通过将研细到合适大小的药物活性成分及赋形剂混合来制备；溶液和糖浆剂可通过将药物活性成分溶解于适当调味的水或水性溶液中来制备；混悬剂可通过将药物活性成分分散于药学上可接受的载体中来制备。
特别提及的是固体制剂的湿法制粒工艺，以片剂的湿法制粒为例，制备工艺是：混合活性成分、填充剂、粘合剂等干固体，用润湿剂例如水或醇润湿，将该润湿的固体制成凝聚物或颗粒剂，继续湿法制粒，直到获得所要求的均匀粒径，随后干燥该颗粒产物。然后将得到的干燥颗粒与崩解剂、润滑剂、抗粘着剂等混合，在制片机中压片；可选地，用适当的包衣粉进行包衣。
本发明提供的式(I)化合物晶型A可以用作黄嘌呤氧化酶抑制剂，本发明的晶型可通过给药量来调节黄嘌呤氧化酶的活性。晶型A可用于治疗个体(例如患者)的黄嘌呤氧化酶相关性疾病或病症，其通过将治疗有效量或治疗有效剂量的本发明的化合物晶型或其药物组合物给药于需要这种治疗的个体而进行。本发明提供的式(I)化合物晶型A还可以用于治疗高尿酸血症以及高尿酸血症引起的痛风。
本发明的有益效果为：
本发明提供的晶型A稳定性良好，且引湿性低，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A具有较高的溶解度，满足生物利用度和药效要求。
在本发明的晶型A的制备方法中：所述“专利晶型”指现有技术WO2014017515中的晶型。
本文所使用的术语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本文所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
本文所使用的术语“多晶型”是指相同化合物的不同晶型且包括但不限于包含相同化合物的水合物及溶剂合物的其它固态分子形式。同一种药物分子形成多种晶型的现象称为药物多晶型，药物多晶型是固体药物中普遍存在的现象。已知具有这样的多晶型的药物化合物由于其物理化学性质不同而对药理活性、溶解性、生物利用度及稳定性等带来影响。因此，在作为药品有用的化合物存在多晶型的情况下，希望从这些多晶型中制造有用性高的晶型化合物。
本文所使用的术语“X射线粉末衍射图”是指实验观测到的衍射图或源自其的参数。通过峰位置及峰强度表征X射线粉末衍射图。
本发明所使用的术语“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，本发明所讨论的理化性质可以被表征，其 中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
附图说明
图1为晶型A的XRPD图
图2为晶型A的DSC图
图3为晶型A的1H-NMR图
图4为晶型A的DVS图
图5为晶型A的DVS前后XRPD对比图
图6为晶型A与放置在5℃，25℃/60％RH，40℃/75％RH条件下15天的XRPD叠图(从上到下依次为起始晶型A，5℃，25℃/60％RH，40℃/75％RH条件下放置15天的XRPD图)
图7为晶型A与放置在5℃，25℃/60％RH，40℃/75％RH条件下30天的XRPD叠图(从上到下依次为起始晶型A，5℃，25℃/60％RH，40℃/75％RH条件下放置15天的XRPD图)
图8为晶型A与放置在5℃，25℃/60％RH，40℃/75％RH条件下90天的XRPD叠图(从上到下依次为起始晶型A，5℃，25℃/60％RH，40℃/75％RH条件下放置15天的XRPD图)
图9为晶型A平衡1小时后所得固体的XRPD图(从上到下依次为起始晶型A，5℃，25℃，50℃平衡1小时后的XRPD图)
图10为专利晶型I平衡1小时后所得固体的XRPD图(从上到下依次为起始晶型I，5℃，25℃，50℃平衡1小时后的XRPD图)
图11为专利晶型I和晶型A的转变关系图
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。
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
1H NMR：核磁共振氢谱
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 PCTCN2016077887-appb-000002
：1.540598；Kα2
Figure PCTCN2016077887-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
实施例1
式(Ⅰ)化合物晶型A的制备方法：
将7.4mg式(Ⅰ)化合物游离碱溶解于0.18mL的1-甲基吡咯烷酮中，搅拌溶液，并将2.0mL的乙腈滴加到上述溶液中，室温条件下，继续搅拌1小时，过滤，所得固体经检测为晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表1所示。其XRPD图如图1。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1数据。其DSC图如图2，其1H NMR图如图3所示。
表1 晶型A的X射线粉末衍射数据
2theta d间隔 强度％
10.25 8.63 100.00
15.46 5.73 31.94
15.64 5.67 24.54
17.03 5.21 48.83
20.63 4.31 46.88
21.56 4.12 12.54
23.56 3.78 2.96
24.51 3.63 22.32
27.27 3.27 27.26
28.10 3.18 8.42
34.77 2.58 2.43
实施例2
式(Ⅰ)化合物晶型A的制备方法：
将7.4mg式(Ⅰ)化合物游离碱溶解于0.18mL的1-甲基吡咯烷酮中，搅拌条件下将此溶液滴加至2.0mL的乙腈中，室温条件下，继续搅拌1小时，过滤，所得固体经检测为晶型A。
本实施例得到的晶型A的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
2theta d间隔 强度％
10.26 8.63 100.00
13.32 6.65 3.75
15.47 5.73 37.53
15.65 5.66 26.03
17.03 5.21 56.34
19.14 4.64 1.04
20.63 4.30 52.42
21.58 4.12 14.49
22.28 3.99 1.85
23.50 3.79 3.57
24.53 3.63 21.85
25.17 3.54 3.86
27.27 3.27 25.98
28.08 3.18 6.88
31.24 2.86 3.03
34.74 2.58 2.05
37.63 2.39 1.59
实施例3
式(Ⅰ)化合物晶型A的引湿性实验：
在25℃条件下，取本发明晶型A约10mg进行动态水分吸附(DVS)测试其引湿性。实验结果如表3所示，晶型A的DVS图如图4所示，DVS前后XRPD对比图如图5所示，其中上图为DVS前，下图为DVS后。
表3
Figure PCTCN2016077887-appb-000004
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J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％
结果表明，本发明的晶型A在80％湿度下平衡后增重1.00％，属于略有引湿性。该性质表明该晶型不易受湿度影响或潮解，方便其长期贮存放置。另一方面，由于该晶型引湿性较低，在制备过程中无需特殊的干燥条件，一定程度上简化了制备与后处理工艺，易于工业化。由于该晶型在不同湿度条件下水分含量基本保持不变，对储存条件要求不苛刻，大大降低了物料储存以及质量控 制方面的成本，具有很强的经济价值。
实施例4
式(Ⅰ)化合物晶型A与专利晶型II溶解度对比研究：
将实施例1中制备得到的晶型A与专利晶型II样品分别用SGF(模拟胃液),pH5.0 FeSSIF(模拟进食状态下肠液),pH6.5 FaSSIF(模拟空腹状态下肠液)和纯水室温下配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表4所示。
表4 晶型A与专利晶型溶解度对比研究
Figure PCTCN2016077887-appb-000005
通过上述对比结果可以看出，在SGF,FaSSIF和FeSSIF中放置1个小时后，4个小时后和24个小时后本发明的新晶型A与专利晶型II相比，溶解度更高，在SGF(模拟胃液)和pH5.0 FeSSIF(模拟进食状态下肠液)的条件下，晶型A的溶解度约为专利晶型II的1.3倍左右，而在pH6.5 FaSSIF(模拟空腹状态下肠液)的条件下，晶型A的溶解度约为专利晶型II的3倍左右，溶解度显着提高，进而有助于生物利用度的提高。
实施例5
式(Ⅰ)化合物晶型A的稳定性及纯度研究
将本发明制得的新的晶型A放置于5℃，25℃/RH60％，40℃/RH为75％的条件下90天，分别于15天、30天和90天各取样一次，分别检测样品的晶型XRPD变化，并通过HPLC测得其化学纯度，试验结果显示晶型A具有良好的物理稳定性及较高的化学纯度，纯度数据结果如表5所示，图6，7，8分别表示晶型A放置于5℃，25℃/RH60％，40℃/RH为75％的条件下15天、30天和90天的XRPD结果(图6：从上到下依次为起始晶型A，5℃，25℃/60％RH，40℃/75％RH条件下放置15天的XRPD图；图7：从上到下依次为起始晶型A，5℃，25℃/60％RH，40℃/75％RH条件下放置30天的XRPD图；图8：从上到下依次为起始晶型A，5℃，25℃/60％RH，40℃/75％RH条件下放置90天的XRPD图)。
表5 晶型A的稳定性(纯度％)
  5℃/(％) 25℃/60％RH(％) 40℃/75％RH(％)
起始 99.83 99.83 99.83
15天 99.92 99.90 99.88
30天 99.91 99.88 99.87
90天 99.91 99.86 99.82
结果表明，式(I)化合物晶型A在5℃，长期稳定(25℃/60％RH)及加速稳定(40℃/75％RH)条件下，放置过程中样品稳定，并且纯度几乎不变。上述试验结果表明，本发明提供的式(I)化合物的晶型A具有良好的稳定性及较高的纯度。
实施例6
取适量式(Ⅰ)化合物晶型A和专利晶型I加入适量甲基异丁基酮(MIBK)配成悬浊液，分别置于5℃，25℃，50℃下平衡1小时，离心，液体用高效液 相色谱法测浓度，固体用XRPD测试，结果如表6所示。图9，10分别为晶型A和晶型I平衡1小时后所得固体的XRPD图(图9：从上至下依次为平衡前晶型A的XRPD图，5℃，25℃，50℃下平衡1小时的XRPD图；图10：从上至下依次为平衡前晶型I的XRPD图，5℃，25℃，50℃下平衡1小时的XRPD图)。
表6 晶型A和专利晶型I的平衡溶解度数据
起始晶型 溶剂 温度/℃ 浓度/mg/mL 最终晶型
晶型A MIBK 5 0.17 晶型A
晶型A MIBK 25 0.22 晶型A
晶型A MIBK 50 0.39 晶型A
专利晶型I MIBK 5 0.17 专利晶型I
专利晶型I MIBK 25 0.25 专利晶型I
专利晶型I MIBK 50 0.42 专利晶型I
基于上表晶型I和晶型A的溶解度和温度的数据，根据范霍夫方程所绘制的晶型I和晶型A的转化关系图，如图11。经转化关系研究，晶型A在大于5℃时总是比晶型I更稳定。

Claims (11)

  1. 一种式(I)化合物的晶型A，
    Figure PCTCN2016077887-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为10.2°±0.2°、17.0°±0.2°、27.3°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为15.7°±0.2°、21.6°±0.2°、24.5°±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或2任一项所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为15.5°±0.2°、20.6°±0.2°中的一处或两处具有特征峰。
  4. 根据权利要求1-3任一项所述的晶型A，其特征在于，其X射线粉末衍射图基本上与图1一致。
  5. 一种如权利要求1-4任一项所述的式(I)化合物晶型A的制备方法，其特征在于，将式(I)化合物的粉末溶于一种或多种溶剂的溶剂体系中，通过混悬搅拌、降温结晶、挥发结晶、反溶剂添加或反向反溶剂添加的结晶方法得到。
  6. 根据权利要求5所述的制备方法，所述溶剂体系为酮类溶剂或酮类溶剂与烷基腈的混合溶剂体系。
  7. 根据权利要求6所述的制备方法，所述酮类溶剂为1-甲基吡咯烷酮。
  8. 根据权利要求6所述的制备方法，所述烷基腈为乙腈。
  9. 一种药物组合物，所述药用组合物包含有效量的权利要求1-4任一项所述的晶型A及药学上可接受的药用辅料。
  10. 根据权利要求9所述的药物组合物，其特征在于，所述的晶型A可用于制备治疗痛风和高尿酸血症药物制剂。
  11. 权利要求1-4中任一项所述的晶型A在治疗痛风和高尿酸血症的用途。
PCT/CN2016/077887 2015-03-30 2016-03-30 托吡司他的新晶型及其制备方法 WO2016155631A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2017550772A JP6767382B2 (ja) 2015-03-30 2016-03-30 トピロキソスタットの新規結晶形及びその製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510144393.8 2015-03-30
CN201510144393 2015-03-30

Publications (1)

Publication Number Publication Date
WO2016155631A1 true WO2016155631A1 (zh) 2016-10-06

Family

ID=56231376

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/077887 WO2016155631A1 (zh) 2015-03-30 2016-03-30 托吡司他的新晶型及其制备方法

Country Status (3)

Country Link
JP (2) JP6767382B2 (zh)
CN (1) CN105693699B (zh)
WO (1) WO2016155631A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115308347A (zh) * 2022-09-01 2022-11-08 江苏知原药业股份有限公司 一种托吡司特中氮氧化物杂质的分析方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014017515A1 (ja) * 2012-07-25 2014-01-30 株式会社富士薬品 ４－［５－（ピリジン－４－イル）－１ｈ－１，２，４－トリアゾール－３－イル］ピリジン－２－カルボニトリルの結晶多形およびその製造方法
CN104961730A (zh) * 2015-06-18 2015-10-07 山东金城医药化工股份有限公司 托吡司他新晶型及其制备方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001051919A2 (en) * 2000-01-07 2001-07-19 Transform Pharmaceuticals, Inc. High-throughput formation, identification, and analysis of diverse solid-forms
EP1471065B1 (en) * 2002-01-28 2008-02-27 Fuji Yakuhin Co., Ltd. Novel 1,2,4-triazole compound
CN1826335A (zh) * 2003-07-24 2006-08-30 株式会社富士药品 1,2,4－三唑化合物的制造方法以及其中间体
JP2005041802A (ja) * 2003-07-25 2005-02-17 Fujiyakuhin Co Ltd １，２，４−トリアゾール化合物の製造方法
MX362102B (es) * 2012-07-25 2019-01-04 Fujiyakuhin Co Ltd Método para producir 4-[5-(piridin-4-il)-1h-1,2,4-triazol-3-il]pir idina-2-carbonitrilo e intermediario del mismo.
CN103724329B (zh) * 2013-12-23 2015-02-18 济南百诺医药科技开发有限公司 4-[5-(吡啶-4-基)-1h-[1,2,4]三唑-3-基]吡啶-2-甲腈的制备方法
CN104151297B (zh) * 2014-08-27 2016-03-16 王庆本 4-[5-(吡啶-4-基)-1h-[1，2，4]三唑-3-基]吡啶-2-甲腈的制备方法
CN104230891B (zh) * 2014-08-27 2016-03-30 于宗光 一种托匹司他的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014017515A1 (ja) * 2012-07-25 2014-01-30 株式会社富士薬品 ４－［５－（ピリジン－４－イル）－１ｈ－１，２，４－トリアゾール－３－イル］ピリジン－２－カルボニトリルの結晶多形およびその製造方法
CN104961730A (zh) * 2015-06-18 2015-10-07 山东金城医药化工股份有限公司 托吡司他新晶型及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115308347A (zh) * 2022-09-01 2022-11-08 江苏知原药业股份有限公司 一种托吡司特中氮氧化物杂质的分析方法
CN115308347B (zh) * 2022-09-01 2023-09-08 江苏知原药业股份有限公司 一种托吡司特中氮氧化物杂质的分析方法

Also Published As

Publication number Publication date
JP2019089822A (ja) 2019-06-13
JP6767382B2 (ja) 2020-10-14
CN105693699A (zh) 2016-06-22
CN105693699B (zh) 2019-06-18
JP2018510173A (ja) 2018-04-12

Similar Documents

Publication Publication Date Title
AU2014239995B2 (en) Salt of omecamtiv mecarbil and process for preparing salt
WO2018196687A1 (zh) 乐伐替尼甲磺酸盐的新晶型及其制备方法
US10377757B2 (en) Crystal form of JAK inhibitor and preparation method thereof
WO2018184185A1 (zh) 奥扎莫德加成盐晶型、制备方法及药物组合物和用途
EP3279201B1 (en) Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor
WO2016155578A1 (zh) 达格列净的新晶型及其制备方法
WO2018103726A1 (zh) 一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途
WO2015176591A1 (zh) 贝曲西班盐及其制备方法和用途
WO2017025045A1 (zh) 3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法
WO2021143954A2 (zh) 一种氟伐替尼或其甲磺酸盐的晶型及其制备方法
WO2018133705A1 (zh) Gft-505的晶型及其制备方法和用途
US20190100519A1 (en) Hydrochloride salt crystal of drug for treating or preventing jak-associated disease and preparation method thereof
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
WO2016155631A1 (zh) 托吡司他的新晶型及其制备方法
WO2015003571A1 (zh) 达拉菲尼甲磺酸盐的新晶型及其制备方法
US11512078B2 (en) Addition salt of S1P1 receptor agonist and crystal form thereof, and pharmaceutical composition
WO2016078587A1 (zh) Lu AE58054的盐酸盐晶型A及其制备方法和用途
WO2019134455A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2018024236A1 (zh) 一种jak1选择性抑制剂的新晶型及其制备方法和用途
US10266523B2 (en) Crystaline forms of N-[6-(cis-2,6-dimethylmorpholine-4-yl)pyridine-3-yl]-2-Methyl-4′-(trifluoromethoxy) [1,1′-biphenyl]-3-Methanamide monophosphate, and process of preparation thereof
KR101928987B1 (ko) 신규한 고순도 미라베그론의 결정질 일수화물, 이의 제조방법 또는 용도
WO2017076358A1 (zh) 咪唑基联苯基化合物盐的新晶型及其制备方法
WO2018157741A1 (zh) Sb-939的盐的晶型及其制备方法和用途
WO2015096119A1 (zh) 氯卡色林盐及其晶体、其制备方法和用途
WO2017152846A1 (zh) 2-[(2r)-2-甲基-2-吡咯烷基]-1h-苯并咪唑-7-甲酰胺二盐酸盐的晶型a及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16771386

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017550772

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16771386

Country of ref document: EP

Kind code of ref document: A1