[go: up one dir, main page]

WO2019001325A1 - 雷西纳得的晶型xv及其制备方法 - Google Patents

雷西纳得的晶型xv及其制备方法 Download PDF

Info

Publication number
WO2019001325A1
WO2019001325A1 PCT/CN2018/092075 CN2018092075W WO2019001325A1 WO 2019001325 A1 WO2019001325 A1 WO 2019001325A1 CN 2018092075 W CN2018092075 W CN 2018092075W WO 2019001325 A1 WO2019001325 A1 WO 2019001325A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
preparation
present
temperature
crystal
Prior art date
Application number
PCT/CN2018/092075
Other languages
English (en)
French (fr)
Inventor
陈敏华
张炎锋
王金秋
黄春香
张晓宇
杨朝惠
Original Assignee
苏州科睿思制药有限公司
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 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Publication of WO2019001325A1 publication Critical patent/WO2019001325A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms

Definitions

  • the invention relates to the technical field of pharmaceutical crystal forms, in particular to a crystal form of Resinadine and a preparation method and use thereof.
  • AstraZeneca is an uric acid excretion oral drug that treats gout patients with hyperuricemia by inhibiting the uric acid transporter URAT1 of the renal proximal convoluted tubule.
  • Resina has been approved by the US FDA on December 22, 2015, and its structural formula is as shown in formula (I) (hereinafter referred to as "compound (I)").
  • Patent US8003681B2 and CN101817793B disclose S-triazolyl- ⁇ -mercaptoacetanilide as an HIV reverse transcriptase inhibitor, but it does not disclose a crystalline form of the compound; US8546436B2 and CN103298796B disclose crystalline polymorphic forms of Resina 1 and Form 2; CN104557748A discloses crystal form ⁇ and crystal form ⁇ of Resinadine; CN104447590A discloses Form III, Form IV, Form V, Form VI of Resina.
  • CN104447590A crystal form IV is a methylene chloride solvate
  • form V is tetrahydrofuran.
  • Solvate, Form VI is a chloroform solvate.
  • Dichloromethane, tetrahydrofuran and chloroform are all two types of solvents, which are highly toxic and are prepared into drugs which seriously endanger human health.
  • the crystal form III disclosed by Resinadine Form 1 and Form 2 and CN 104447590A disclosed in CN103298796B is relatively safe and non-toxic.
  • the inventors of the present application have unexpectedly discovered the compound (I) crystalline form XV provided by the present invention in terms of stability, melting point, solubility, dissolution, wettability, bioavailability, on the basis of attempts to prepare different crystal forms.
  • Adhesion, compressibility, fluidity, and processing, purification, in vitro dissolution, formulation production, etc. have advantages in at least one aspect, especially high solubility, good stability, uniform distribution, good purification effect, and Sinad's drug development offers new and better choices and is of great importance.
  • the main object of the present invention is to provide a novel crystalline form of the compound (I), a process for its preparation and use.
  • the present invention provides a crystal form XV of the compound (I) (hereinafter referred to as "crystal form XV").
  • the X-ray powder diffraction of the crystal form XV has a characteristic peak at a diffraction angle 2 ⁇ of 6.3 ° ⁇ 0.2 °, 13.0 ° ⁇ 0.2 °, and 23.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form XV has a characteristic peak at one, or two, or three points of 2 ⁇ of 18.3° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 25.0° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystal form XV has a characteristic peak at a diffraction angle 2 ⁇ of 18.3° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 25.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form XV is also characterized by 1 or 2, or 3 at 2 ⁇ values of 22.9° ⁇ 0.2°, 27.3° ⁇ 0.2°, 28.6° ⁇ 0.2°. Peak; preferably, the X-ray powder diffraction of the Form XV has a characteristic peak at a diffraction angle 2 ⁇ of 22.9° ⁇ 0.2°, 27.3° ⁇ 0.2°, and 28.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form XV is 6.3° ⁇ 0.2°, 13.0° ⁇ 0.2°, 23.3° ⁇ 0.2°, 18.3° ⁇ 0.2°, 21.0° ⁇ 0.2° at the diffraction angle 2 ⁇ . 3, 4, 4, 5, or 6, or 7, or 8, 2, 2, 2, 2, 2, 2, 2 9 characteristic peaks.
  • the form XV of the present invention is an isopropanol solvate, preferably one isopropanol solvate.
  • the X-ray powder diffraction pattern of Form XV is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form XV, comprising: adding a solid of the compound (I) to an isopropanol solvent, then heating at a temperature of 40 ° C to 50 ° C, and filtering. The filtrate was cooled to 35 ° C to 5 ° C, then an anti-solvent was added and crystallization was carried out to obtain a crystal form XV.
  • the cooling may be two steps of cooling, the first step of cooling is to devitrify; the second step of cooling is to increase the yield.
  • the temperature at which the first step is lowered is in the range of 35 to 15 ° C; preferably 30 ° C.
  • the temperature of the second step of cooling is in the range of 20-5 ° C; preferably 5 ° C.
  • the temperature of the second step of cooling is lower than the temperature of the first step of cooling.
  • the anti-solvent is an alkane solvent or water; further, the alkane solvent is n-pentane, n-hexane, n-heptane, n-octane or a mixture thereof; preferably n-heptane.
  • the crystallization time is 12 to 36 hours; preferably 24 hours.
  • the crystalline form XV of the present invention has higher solubility in an acetate buffer solution containing and not containing sodium chloride, and especially in an acetate buffer containing sodium chloride.
  • the solubility is 3-4 times higher than the Form III solubility of Form 1 and Form 2 of CN103298796B and CN104447590A.
  • Solubility is the rate limiting factor of drug bioavailability. Therefore, the significant increase in the solubility of crystal form XV will help to improve the bioavailability of Resinadine drugs, thereby improving the drug-forming properties and efficacy of drugs; At the same time, the dosage of the drug is lowered, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the crystalline form XV of the present invention has higher stability in a mixed solution of isopropyl alcohol and water, and its stability is much higher than that of the forms 1 and 2 of the prior art CN103298796B and the crystal of CN104447590A. Type III.
  • Isopropanol and water are preferred solvents in industrial production because of their low toxicity, no pollution, and low cost.
  • the crystal form is stable in a preferred solvent, and is not easily converted into other compounds and crystal forms, which can ensure its preparation in synthesis and preparation.
  • the crystalline form XV of the present invention has higher solubility in various organic solvents, especially in ethanol, acetonitrile and toluene, and has higher solubility than the forms 1 and 2 of the prior art CN103298796B and CN104447590A.
  • Form III is a crystalline form XV of the present invention.
  • the crystalline form of the drug has a higher solubility in an organic solvent, which allows the crystal form to select more organic solvents during the process development process, and at the same time dissolves the same quality of the drug substance with less organic solvent, and has a low volume effect.
  • the reaction vessel using the same solvent can produce more raw materials, significantly reduce the amount of crystallization solvent, reduce cost, and is environmentally friendly, which is beneficial to process optimization and development.
  • the crystal form XV of the present invention has a uniform particle size distribution. Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control.
  • the crystal form XV of the present invention has a good purification effect.
  • the purity of the raw material is significantly improved by the preparation of the raw material from the raw material.
  • the purity of the raw material used in the present invention is 98.51%.
  • the purity is increased to 99.32%, and the purity is improved by 0.81%.
  • the purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
  • the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
  • the "stirring” described herein is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100. -300 rpm.
  • the "cooling down” is accomplished using conventional methods in the art, such as slow cooling and rapid cooling.
  • Slow cooling is usually carried out at 0.1 ° C / min.
  • Rapid cooling is usually to transfer the sample directly from the environment below room temperature, such as cooling in the refrigerator.
  • the "drying” can be carried out at room temperature or higher. Dry at room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C. 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.
  • the Resinadine and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) and/or its salt as a raw material is in the form of a solid powder.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • 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 relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • 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.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form XV of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the crystalline form XV of the present invention, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • crystalline form XV of the present invention for the preparation of a pharmaceutical preparation for treating hyperuricemia.
  • Example 1 is an XRPD pattern of a Resina obtained crystal form XV obtained in Example 1;
  • Example 2 is a 1 H NMR chart of Resina obtained crystal form XV obtained in Example 1;
  • Example 3 is a DSC chart of the Resina obtained crystal form XV obtained in Example 1;
  • Example 4 is a TGA diagram of a Resina obtained crystal form XV obtained in Example 1;
  • Example 5 is an XRPD pattern of a Resina obtained crystal form XV obtained in Example 2;
  • Example 6 is an XRPD pattern of the Resina obtained crystal form XV obtained in Example 4 (the upper graph is an XRPD pattern of the crystal form XV obtained by stirring at room temperature, and the lower graph is an XRPD pattern of the crystal form XV obtained by stirring at 4 ° C)
  • Example 7 is an XRPD pattern of the Resina obtained crystal form XV obtained in Example 5.
  • Figure 8 is a PSD diagram of a crystalline form XV
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer at a conventional temperature, such as 25 °C.
  • 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 Q200.
  • 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 particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • the particle size distribution results described in the specific embodiments of the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method in which the dispersion medium is Isopar G (containing 0.2% lecithin).
  • Resinadine solid used in the following examples can be prepared according to the method described in the literature of CN 101817793 B or commercially available.
  • Resinadine solid was added to 20.0 mL of isopropanol solvent, and then placed in an oven at 50 ° C for 2 hours at a rate of 500 rpm, and the solution was filtered to a folder at 40 ° C.
  • a crystallizer stir at a rate of 150 rpm for 10 minutes, then cool to a temperature of 1 ° C / minute to 30 ° C, slowly inject 40.0 mL of n-heptane solvent at 30 ° C, solid precipitation, continue The temperature was lowered to 5 ° C at a rate of 0.1 ° C / minute, after about 1 day, filtered, and the resulting solid was dried in a vacuum oven to collect a solid.
  • the DSC of Form XV is shown in Figure 3.
  • An endothermic peak appears near 80 ° C.
  • the endothermic peak is the solvent desolvation near this temperature.
  • the TGA of Form XV, as shown in Figure 4 has a mass loss gradient of about 6.55% when heated to about 95 °C.
  • CN103298796B Form 1 and Form 2 data are from CN103298796B patent text
  • the crystal form XV of the present invention contains and does not contain sodium chloride as compared with the solubility data of Form 1 and Form 2 disclosed in the prior art (CN103298796B pages 21/25 and 23/25).
  • D10 indicates a particle diameter corresponding to 10% of the particle size distribution (volume distribution);
  • D50 indicates the particle size corresponding to the particle size distribution (volume distribution), which is 50%, which is also called the median diameter;
  • D90 indicates a particle diameter corresponding to 90% of the particle size distribution (volume distribution).
  • the crystal form XV of the present invention has an average particle diameter of about 16.9 ⁇ m and has a normal distribution, and has good uniformity and a narrow particle size distribution.
  • Example 8 The crystal form XV purification effect of the present invention
  • the crystal form of the present invention has a strong purification effect.
  • the purity of the raw material is increased from 98.51% to 99.32%, and the purity is increased by 0.81%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种雷西纳得的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备尿酸转运蛋白抑制剂和治疗高尿酸血症药物制剂中的用途。本发明提供的雷西纳得新晶型与现有技术相比具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。

Description

雷西纳得的晶型XV及其制备方法 技术领域
本发明涉及药物晶型技术领域，具体而言，涉及雷西纳得的晶型及其制备方法和用途。
背景技术
2-(5-溴-4-(4-环丙基萘-1-基)-4H-1,2,4-三唑-3-基硫基)乙酸(雷西纳得，Lesinurad)，由阿斯利康(AstraZeneca)研发，是一种促尿酸排泄口服药，通过抑制肾近曲小管的尿酸转运子URAT1而治疗有高尿酸血症的痛风患者。雷西纳得已于2015年12月22日获得美国FDA批准上市，其结构式如式(I)所示(以下称为“化合物(I)”)。
Figure PCTCN2018092075-appb-000001
专利US8003681B2和CN101817793B公开了一种作为HIV逆转录酶抑制剂的S-三唑基α-巯基乙酰苯胺，但是其未公开化合物的结晶形式；US8546436B2和CN103298796B公开了雷西纳得的结晶多晶形式1和形式2；CN104557748A公开了雷西纳得的晶型α和晶型β；CN104447590A公开了雷西纳得的晶型III、晶型IV、晶型V、晶型VI。
发明人经分析发现，CN104557748A公开的晶型β和晶型α与CN104447590A晶型III和晶型IV相同，此外，发明人还发现CN104447590A晶型IV为二氯甲烷溶剂合物，晶型V为四氢呋喃溶剂合物，晶型VI为三氯甲烷溶剂合物。二氯甲烷、四氢呋喃、三氯甲烷均为二类溶剂，毒性大，制备成药物严重危害人体健康。CN103298796B公开的雷西纳得形式1和形式2以及CN104447590A公开的晶型III相对安全且无毒性。
本申请发明人在尝试不同晶型制备方法的基础上，意外的发现了本发明提供的化合物(I)晶型XV，其在稳定性、熔点、溶解度、溶出度、引湿性、生物有效性、黏附性、可压性、流动性以及加工性能、提纯作用、体外溶出、制剂生产等方面中的至少一方面上存在优势，特别是溶解度高、稳定性好、分布均一、提纯效果好，为雷西纳得的药物开发提供了新的更好的选择，具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物(I)的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物(I)的晶型XV(以下称作“晶型XV”)。
使用Cu-Kα辐射，所述晶型XV的X射线粉末衍射在衍射角2θ为6.3°±0.2°、13.0°±0.2°、23.3°±0.2°处有特征峰。
进一步地，所述晶型XV的X射线粉末衍射在2θ为18.3°±0.2°、21.0°±0.2°、25.0°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型XV的X射线粉末衍射在衍射角2θ为18.3°±0.2°、21.0°±0.2°、25.0°±0.2°处有特征峰。
进一步地，所述晶型XV的X射线粉末衍射图还在2θ值为22.9°±0.2°、27.3°±0.2°、28.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型XV的X射线粉末衍射在衍射角2θ为22.9°±0.2°、27.3°±0.2°、28.6°±0.2°处有特征峰。
使用Cu-Kα辐射，所述晶型XV的X射线粉末衍射在衍射角2θ为6.3°±0.2°、13.0°±0.2°、23.3°±0.2°、18.3°±0.2°、21.0°±0.2°、25.0°±0.2°、22.9°±0.2°、27.3°±0.2°、28.6°±0.2°处具有3个、或4个、或5个、或6个、或7个、或8个、或9个特征峰。
进一步地本发明所述晶型XV是异丙醇溶剂合物，优选为1个异丙醇溶剂合物。
非限制性地，在本发明的一个具体实施方案中，晶型XV的X射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明还提供所述晶型XV的制备方法，包括：将化合物(I)的固体加入到异丙醇溶剂中，然后在40℃-50℃的温度下加热，过滤，将滤液降温到35℃-5℃，然后添加反溶剂，析晶得到晶型XV。
进一步地，所述降温可以为两步降温，第一步降温的目的是析晶；第二步降温的目的是增加收率。
更进一步地，第一步降温的温度范围为35-15℃；优选为30℃。
更进一步地，第二步降温的温度范围为20-5℃；优选为5℃。
其中，第二步降温的温度低于第一步降温的温度。
进一步地，反溶剂为烷烃类溶剂或水；更进一步地，所述烷烃类溶剂为正戊烷、正己烷、正庚烷、正辛烷或者它们的混合物；优选为正庚烷。
进一步地，所述析晶时间为12-36小时；优选为24小时。
本发明提供的晶型XV具有以下有益效果：
(1)与现有固体相比，本发明晶型XV在含有及不含有氯化钠的乙酸盐缓冲液中以及水中具有更高的溶解度，特别是在含有氯化钠的乙酸盐缓冲液中，溶解度比现有技术CN103298796B的形式1和形式2以及CN104447590A的晶型III溶解度高3-4倍之多。
溶解度是药物生物利用度的限速因素，因此，晶型XV溶解度的显著提高将有助于提高雷西纳得药物的生物利用度，从而提高药物的成药性及药效；在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(2)与现有固体相比，本发明晶型XV在异丙醇和水的混合溶液中稳定性更高，其稳定性远远高于现有技术CN103298796B的形式1和形式2以及CN104447590A的晶型III。
异丙醇、水因其低毒性、无污染、价格低廉而在工业生产中成为优选溶剂， 晶型在优选溶剂中保持稳定，不易转变成其他化合物及晶型，可以保证其在合成、制剂制备过程中使用优选溶剂而无需特殊的反应条件，在大大降低生产成本的基础上实现绿色环保。
(3)与现有固体相比，本发明晶型XV在多种有机溶剂中溶解度更高，尤其是在乙醇、乙腈和甲苯中，溶解度高于现有技术CN103298796B的形式1和形式2以及CN104447590A的晶型III。
药物晶型在有机溶剂中具有更高的溶解度，这使得晶型在工艺开发过程中，可以选择更多的有机溶剂，同时使用更少的有机溶剂便可溶解相同质量的原料药，体积效应低，采用相同溶剂的反应釜可以生产出更多的原料药，显著减少结晶溶剂的用量，降低成本，环境友好，利于工艺优化和开发。
(4)本发明的晶型XV具有均一的粒径分布。其均匀的粒径有助于简化制剂过程的后处理工艺，如可减少对晶体的研磨，节约成本，也减小研磨中晶型结晶度变化和转晶的风险，提高质量控制。
(5)本发明的晶型XV具有很好的提纯作用。由原料制备成本发明晶型后纯度显著提高，在具体的实施例中，本发明使用的原料纯度为98.51％，经制备得到晶型XV后，纯度提升至99.32％，纯度提升达0.81％。
药物的纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义。药物中的杂质是影响纯度的主要因素，如药物中含有超过限量的杂质，就有可能使理化常数变化，外观性状产生变异，并影响药物的稳定性；杂质增多也使药物含量明显偏低或活性降低，毒副作用显著增加。提纯作用好的晶型在结晶工艺中能够体现出极强的杂质排除能力，使得通过结晶就能得到纯度较高的原料药，有效的克服了药物纯度低带来的药物稳定性低、疗效差、毒性高等缺点。
在本发明晶型XV的制备方法中：
本文所述“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，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“降温”，采用本领域的常规方法完成，例如缓慢降温和快速降温。缓慢降温通常以0.1℃/分钟进行。快速降温通常是将样品从不低于室温的环境直接转移如冰箱中进行降温操作。
所述“干燥”可以在室温或更高的温度下进行。干燥温度室温到约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。
根据本发明，作为原料的所述雷西纳得和/或其盐指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物(I)和/或其盐为固体粉末形式。
本发明中，“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，这里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。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。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，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。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。
在一些实施方案中，本发明的晶型XV是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明雷西纳得的晶型XV，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提的晶型XV在制备尿酸转运蛋白抑制剂药物制剂中的用途。
进一步地，本发明提的晶型XV在制备治疗高尿酸血症的药物制剂中的用途。
附图说明
图1为实施例1制得的雷西纳得晶型XV的XRPD图；
图2为实施例1制得的雷西纳得晶型XV的 1HNMR图；
图3为实施例1制得的雷西纳得晶型XV的DSC图；
图4为实施例1制得的雷西纳得晶型XV的TGA图；
图5为实施例2制得的雷西纳得晶型XV的XRPD图；
图6为实施例4得到的雷西纳得晶型XV的XRPD图(上图为室温下搅拌得到的晶型XV的XRPD图，下图为4℃搅拌得到的晶型XV的XRPD图)
图7为实施例5得到的雷西纳得晶型XV的XRPD图
图8为晶型XV的PSD图；
具体实施方式
对实施例中涉及的测试仪器进行参数描述
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
1HNMR：液态核磁氢谱
PSD：粒度分析
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，测试温度采用常规温度，例如25℃。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
Figure PCTCN2018092075-appb-000002
1.540598；
Figure PCTCN2018092075-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 Q200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℃/分钟；
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℃/分钟；
保护气体：氮气。
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：
Figure PCTCN2018092075-appb-000004
*：流速60％为65毫升/秒的60％。
核磁共振氢谱数据( 1HNMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明实施例3中高效液相色谱(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)。本发明所述的测试纯度的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：
Time(min) ％B
0 40
2 40
5 47
5 60
6 80
7 80
7 40
10 40
3、流速：1.7mL/min
4、进样量：5μL
5、检测波长：230nm
6、柱温：40℃
7、稀释剂：乙腈:水＝1:1
本发明实施例6中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为紫外检测器(VWD)。本发明所述的测试纯度的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：
Time(min) ％B
0 40
2 40
5 47
5 60
6 80
7 80
7 40
10 40
3、流速：1.7mL/min
4、进样量：5μL
5、检测波长：230nm
6、柱温：40℃
7、稀释剂：乙腈
本发明实施例8中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。本发明所述的测试纯度的HPLC方法参数如下：
1、色谱柱：phenomenex Gemini C18 110A,250×4.6mm,3μm
2、流动相：A：(10mM KH 2PO4+0.1％TEA,pH2.5):乙腈＝19:1
           B：乙腈
洗脱梯度如下：
Time(min) ％B
0.0 30
26.0 44
50.0 75
57.0 75
57.5 30
70 30
3、流速：1.0mL/min
4、进样量：5μL
5、检测波长：220nm
6、柱温：40℃
7、稀释剂：乙腈：水＝8:2
本发明中具体实施方式所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含有0.2％卵磷脂)。
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雷西纳得固体可根据CN101817793B文献所记载的方法制备或市售获得。
实施例1 晶型XV的制备方法
将约1.0g的雷西纳得的固体加入到20.0mL的异丙醇溶剂中，然后放置于50℃的烘箱中以500转/分钟的速率搅拌2小时，将该溶液过滤到40℃的夹套结晶器中，并以150转/分钟的速率搅拌10分钟，然后以1℃/分钟的速率降温至30℃，在30℃条件下缓慢注入40.0 mL的正庚烷溶剂，有固体析出，继续以0.1℃/分钟的速率降温至5℃，约1天后，过滤，然后将所得固体放入真空干燥箱中干燥，收集固体。
经检测，所得结晶固体为本发明所述的晶型XV，其X射线粉末衍射数据如表1所示。其XRPD图如图1所示。
本发明晶型XV的液态核磁氢谱如图2所示，数据如下所述： 1HNMR(400MHz,DMSO)δ8.59(d,J＝8.4Hz,1H),7.75(t,J＝7.2Hz,1H),7.70–7.56(m,2H),7.44(d,J＝7.7Hz,1H),7.15(d,J＝8.2Hz,1H),4.36(d,J＝4.1Hz,1H),4.00(d,J＝1.6Hz,2H),3.77(d,J＝3.9Hz,1H),1.15(dd,J＝8.4,2.0Hz,2H),1.04(d,J＝6.1Hz,6H),0.87(dd,J＝9.0,5.4Hz,2H)。其中在1.04和3.77处有多重峰，共7个氢原子，对应于1个异丙醇两类氢的化学位移，由此可见本发明晶型XV为一异丙醇溶剂合物。
晶型XV的DSC如图3所示，在80℃附近出现一个吸热峰，该吸热峰是在该温度附近溶剂合物脱溶剂。
晶型XV的TGA如附图4所示，加热至95℃左右时，具有约6.55％的质量损失梯度。
表1
衍射角2θ d值 强度％
6.33 13.95 51.50
8.99 9.84 12.21
13.02 6.80 100.00
15.10 5.87 18.16
16.19 5.48 15.55
17.47 5.08 19.89
18.31 4.85 40.66
19.07 4.65 17.42
19.93 4.46 16.62
20.99 4.23 47.62
21.94 4.05 15.31
22.88 3.89 31.33
23.23 3.83 56.27
24.35 3.65 25.02
24.97 3.57 35.46
26.38 3.38 28.82
27.29 3.27 26.78
28.61 3.12 24.45
29.45 3.03 23.27
30.49 2.93 33.46
32.30 2.77 4.22
37.22 2.42 7.83
38.26 2.35 6.28
实施例2 晶型XV的制备方法
称取约0.6g的雷西纳得的固体于玻璃小瓶中，并加入10.0mL的异丙醇溶剂，然后放置于50℃的烘箱中以500转/分钟的速率搅拌1小时，将该溶液过滤到40℃的夹套结晶器中，然后以0.3℃/分钟的速率降温至20℃，在20℃条件下缓慢注入20.0mL的H 2O，然后以150转/分钟的速率搅拌约1天后，过滤并对样品进行晶型测试。经检测，所得固体为本发明所述的晶型XV，其X射线粉末衍射数据表2所示，其XRPD图如图5所示。
表2
衍射角2θ d值 强度％
6.34 13.94 86.50
9.04 9.78 10.38
12.66 6.99 8.37
13.02 6.80 100.00
15.20 5.83 5.27
16.20 5.47 8.12
17.53 5.06 15.54
18.34 4.84 31.24
19.12 4.64 16.86
19.36 4.58 13.17
20.01 4.44 10.54
21.02 4.23 19.21
22.65 3.93 17.29
22.90 3.88 13.38
23.34 3.81 28.35
23.73 3.75 8.72
25.03 3.56 16.58
26.22 3.40 16.03
27.37 3.26 14.60
28.65 3.12 9.87
29.48 3.03 9.98
30.55 2.93 12.78
实施例3 晶型XV与CN103298796B中形式1，形式2以及CN104447590A中晶型III 在乙酸盐缓冲液中溶解度对比
分别将CN104447590A中的晶型III以及本发明的晶型XV 25mg与乙酸盐缓冲液(25mM，pH5,4mL)(制备得含有及不含有氯化钠(离子强度调节至＝0.1M))置于玻璃小瓶中，将其密封并置于实验室旋转器上于25℃培育箱中。1天后，过滤试样并藉由HPLC进行分析。结果如表3所示。
表3
Figure PCTCN2018092075-appb-000005
注：CN103298796B形式1和形式2数据来源于CN103298796B专利文本
由上述实验数据可知，同现有技术公开的形式1和形式2的溶解度数据(CN103298796B第21/25页及23/25页)相比，本发明晶型XV在含有及不含有氯化钠的乙酸盐缓冲液中具有更高的溶解度，特别是在含有氯化钠的乙酸盐缓冲液中，溶解度比现有技术中CN103298796B的形式1和形式2以及CN104447590A晶型III溶解度高3-4倍之多。
实施例4 晶型XV与CN104447590A中晶型III的稳定性关系
分别称取约10mg的CN104447590A中晶型III和本发明晶型XV混合于玻璃小瓶中，然后加入0.5mL的异丙醇和水(1:1，v：v)的混合溶液，标记为样品1。用上述同样的方法配置样品2。然后将样品1和样品2分别放置在室温和4℃下以500转/分的转速搅拌，1小时后，收集固体，经XRPD测试，两份固体均为晶型XV。本实施例得到的晶型XV的XRPD图如图6所示(上图为室温下搅拌得到的晶型XV的XRPD图，下图为4℃搅拌得到的晶型XV的XRPD图)，实验结果见表4。
表4
Figure PCTCN2018092075-appb-000006
Figure PCTCN2018092075-appb-000007
上述结果，说明本发明晶型XV在异丙醇和水的混合溶剂中比CN104447590A中晶型III更稳定。
实施例5 晶型XV与CN103298796B中形式2的稳定性关系
分别称取约10mg的CN103298796B中形式2和本发明晶型XV于玻璃小瓶中，然后加入0.3mL的异丙醇和水(1:1，v:v)的混合溶液，然后在4℃下以500转/分的转速搅拌，5小时后，收集固体，经XRPD测试，所得固体为本发明晶型XV。本实施例得到的晶型XV的XRPD图如图7所示，实验结果见表5。
表5
Figure PCTCN2018092075-appb-000008
上述结果，说明本发明晶型XV在异丙醇和水的混合溶剂中比CN103298796B中形式2稳定。
实施例6 晶型XV与CN103298796B形式2以及CN104447590A晶型III在水及有机 溶剂中的溶解度对比
称取适量晶型XV、CN103298796B形式2以及CN104447590A晶型III分别加入1.0ml如表5的不同溶剂中，形成悬浊液，15分钟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6所示。
表6 不同溶剂中晶型的溶解度对比
Figure PCTCN2018092075-appb-000009
通过对比结果可以看出：在水、乙醇、乙腈、以及甲苯中，本发明晶型XV的溶解度比CN103298796B形式2以及CN104447590A晶型III更高。
实施例7 晶型XV的粒径分布
取10-30mg晶型XV，然后加入10mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使样品量指示图达到合适位置，开始实验，进行粒径分布的测试，从而得到按照体积计算的平均粒径、粒径分布中(体积分布)占10％所对应的粒径、粒径分布中(体积分布)占50％所对应的粒径。粒径分布中(体积分布)占90％所对应的粒径以及晶型粒度分布图。具体结果见表7，PSD图见图8。
表7 晶型XV的粒径数据
晶型 MV(μm) SD D10(μm) D50(μm) D90(μm)
晶型XV 16.9 9.5 4.5 11.4 32.3
MV：按照体积计算的平均粒径；
SD：表示标准偏差
D10：表示粒径分布中(体积分布)占10％所对应的粒径；
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径；
D90：表示粒径分布中(体积分布)占90％所对应的粒径。
上述试验结果来看，本发明的晶型XV的平均粒径在16.9μm左右并呈正态分布，具有良好的均一性，粒径分布更窄。
实施例8 本发明晶型XV提纯作用
称取49.2mg的游离酸原料，加入1.0mL的异丙醇溶剂，得到的悬浊液于室温搅拌约24h后，离心过滤，真空干燥约24h得到晶型XV，制备前后样品的纯度变化见表8。
表8
起始纯度 制备得到的晶型XV纯度 纯度变化
98.51％ 99.32％ +0.81％
由上述试验结果可以看出，本发明的晶型具有较强的提纯作用，通过制备晶型XV，原料纯度即由原来的98.51％提升至99.32％，纯度提升0.81％。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (12)

  1. 一种雷西纳得的晶型XV，其特征在于，其X射线粉末衍射图(CuKα辐射)在2θ值为6.3°±0.2°、13.0°±0.2°、23.3°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型XV，其特征在于，其X射线粉末衍射图在2θ值为18.3°±0.2°、21.0°±0.2°、25.0°±0.2°中的一处或多处具有特征峰。
  3. 根据权利要求1所述的晶型XV，其特征在于，其X射线粉末衍射图在2θ值为22.9°±0.2°、27.3°±0.2°、28.6°±0.2°中的一处或多处具有特征峰。
  4. 根据权利要求1所述的晶型XV，其特征在于，所述晶型XV是异丙醇溶剂合物。
  5. 一种雷西纳得晶型XV的制备方法，其特征在于，包括如下步骤:将雷西纳得的固体加入到异丙醇溶剂中，然后在40℃-50℃的温度下加热，过滤，滤液降温到35℃-5℃，然后添加反溶剂，析晶得到晶型XV。
  6. 根据权利要求5所述的制备方法，其特征在于所述降温分两步进行，第一步降温的温度范围为35-15℃，第二步降温的温度范围为20-5℃，所述第二步降温低于第一步降温的温度；
  7. 根据权利要求6所述的制备方法，其特征在于所述第一步降温的温度为30℃，第二步降温的温度为5℃。
  8. 根据权利要求5所述的制备方法，其特征在于所述反溶剂为烷烃类溶剂或水。
  9. 根据权利要求8所述的制备方法，其特征在于所述烷烃类溶剂为正戊烷、正己烷、正庚烷、正辛烷或者它们的混合物。
  10. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1中所述的晶型XV及药学上可接受的载体、稀释剂或赋形剂。
  11. 权利要求1中所述的晶型XV在制备尿酸转运蛋白抑制剂药物制剂中的用途。
  12. 权利要求1中所述的晶型XV在制备治疗高尿酸血症的药物制剂中的用途。
PCT/CN2018/092075 2017-06-28 2018-06-21 雷西纳得的晶型xv及其制备方法 WO2019001325A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710507676.3 2017-06-28
CN201710507676 2017-06-28

Publications (1)

Publication Number Publication Date
WO2019001325A1 true WO2019001325A1 (zh) 2019-01-03

Family

ID=64741033

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/092075 WO2019001325A1 (zh) 2017-06-28 2018-06-21 雷西纳得的晶型xv及其制备方法

Country Status (1)

Country Link
WO (1) WO2019001325A1 (zh)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817793A (zh) * 2004-08-25 2010-09-01 阿迪亚生命科学公司 作为HIV逆转录酶抑制剂的S-三唑基α-巯基乙酰苯胺
CN103298796A (zh) * 2010-12-30 2013-09-11 阿迪亚生命科学公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1,2,4-三唑-3-基硫基)乙酸的多晶型形式及其用途
CN103588716A (zh) * 2013-11-22 2014-02-19 苏州晶云药物科技有限公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1，2，4-三唑-3-基硫基)乙酸的新晶型及其制备方法
CN103755651A (zh) * 2013-12-23 2014-04-30 苏州晶云药物科技有限公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1，2，4-三唑-3-基硫基)乙酸的盐的新晶型及其制备方法
CN104447589A (zh) * 2013-11-20 2015-03-25 广东东阳光药业有限公司 一种尿酸调节剂的制备方法及其中间体
CN104557748A (zh) * 2014-01-25 2015-04-29 广东东阳光药业有限公司 硫代-1,2,4-三唑衍生物的新的固体形态
CN106831620A (zh) * 2016-03-11 2017-06-13 苏州晶云药物科技有限公司 雷西纳得的晶型及其制备方法
CN106866559A (zh) * 2013-12-20 2017-06-20 苏州晶云药物科技有限公司 雷西纳得的共晶及其制备方法
CN106883190A (zh) * 2013-12-02 2017-06-23 苏州晶云药物科技有限公司 雷西纳得的钠盐的晶型及其制备方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817793A (zh) * 2004-08-25 2010-09-01 阿迪亚生命科学公司 作为HIV逆转录酶抑制剂的S-三唑基α-巯基乙酰苯胺
CN103298796A (zh) * 2010-12-30 2013-09-11 阿迪亚生命科学公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1,2,4-三唑-3-基硫基)乙酸的多晶型形式及其用途
CN104447589A (zh) * 2013-11-20 2015-03-25 广东东阳光药业有限公司 一种尿酸调节剂的制备方法及其中间体
CN103588716A (zh) * 2013-11-22 2014-02-19 苏州晶云药物科技有限公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1，2，4-三唑-3-基硫基)乙酸的新晶型及其制备方法
CN104447590A (zh) * 2013-11-22 2015-03-25 苏州晶云药物科技有限公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1,2,4-三唑-3-基硫基)乙酸的晶型及其制备方法
CN106883190A (zh) * 2013-12-02 2017-06-23 苏州晶云药物科技有限公司 雷西纳得的钠盐的晶型及其制备方法
CN106866559A (zh) * 2013-12-20 2017-06-20 苏州晶云药物科技有限公司 雷西纳得的共晶及其制备方法
CN103755651A (zh) * 2013-12-23 2014-04-30 苏州晶云药物科技有限公司 2-(5-溴-4-(4-环丙基萘-1-基)-4h-1，2，4-三唑-3-基硫基)乙酸的盐的新晶型及其制备方法
CN104557748A (zh) * 2014-01-25 2015-04-29 广东东阳光药业有限公司 硫代-1,2,4-三唑衍生物的新的固体形态
CN106831620A (zh) * 2016-03-11 2017-06-13 苏州晶云药物科技有限公司 雷西纳得的晶型及其制备方法

Similar Documents

Publication Publication Date Title
EP3248983B1 (en) Crystal form a of obeticholic acid and preparation method therefor
EP3176173B1 (en) Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
JP6691218B2 (ja) 選択的なｓ１ｐ１受容体アゴニストの新規な結晶形及びその製造方法
EP3337485B1 (en) Crystalline forms of ibrutinib
US20090076272A1 (en) Polymorphs of eszopiclone malate
WO2017152707A1 (zh) 吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用
CN114605406A (zh) Amg510化合物的晶型及其制备方法和用途
WO2017114446A1 (zh) 艾沙度林的新晶型及其制备方法
WO2018157803A1 (zh) 维奈妥拉的晶型及其制备方法
WO2021000687A1 (zh) Pac-1晶型的制备方法
CN112125868B (zh) 一种氢溴酸伏硫西汀晶型及其制备方法、组合物与用途
US20180273499A1 (en) Salts and solid state forms of vortioxetine
TW202404604A (zh) [(1S)-1-[(2S,4R,5R)-5-(5-胺基-2-酮基-噻唑并[4,5-d]嘧啶-3-基)-4-羥基-四氫呋喃-2-基]丙基]乙酸酯之新穎固態形式
US20150150868A1 (en) Aripiprazole-organic acid cocrystal, preparation or composition containing same, and preparation method therefor
WO2017162139A1 (zh) 用于治疗或预防jak相关疾病药物的盐酸盐晶型及其制备方法
WO2019001325A1 (zh) 雷西纳得的晶型xv及其制备方法
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
WO2018137670A1 (zh) 一种病毒蛋白抑制剂药物vx-787的晶型及其制备方法和用途
CA2596754C (en) Crystalline 1h-imidazo[4,5-b]pyridin-5-amine,7-[5-[(cyclohexylmethylamino)-methyl]-1h-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its uses for the treatment of inflammatory, autoimmune and proliferative diseases and disorders
KR102597986B1 (ko) 3-(3,5-디클로로-4-히드록시벤조일)-1,1-디옥소-2,3-디히드로-1,3-벤조티아졸의 결정형 및 염
CA2762652A1 (en) Novel solid materials of {[(2s,5r,8s,11s)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid} and methods for obtaining them
CN110291071B (zh) Sb-939的盐的晶型及其制备方法和用途
CN113149998B (zh) 2-吲哚啉螺环酮类化合物或其盐、溶剂合物的无定形形式或结晶形式
JP6656505B2 (ja) オービットアジン−フマル酸塩、水和物、結晶形及びその調製方法
WO2023202651A1 (en) Polymorphic forms of glutamine antagonist and uses thereof

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: 18824573

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18824573

Country of ref document: EP

Kind code of ref document: A1