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WO2019001325A1 - Forme cristalline xv de lésinurad et son procédé de préparation - Google Patents

Forme cristalline xv de lésinurad et son procédé de préparation Download PDF

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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
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Prior art keywords
crystal form
preparation
present
temperature
crystal
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PCT/CN2018/092075
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English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
王金秋
黄春香
张晓宇
杨朝惠
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苏州科睿思制药有限公司
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Publication of WO2019001325A1 publication Critical patent/WO2019001325A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention concerne une nouvelle forme cristalline de lésinurad, un procédé de préparation correspondant, une composition pharmaceutique contenant la forme cristalline et l'utilisation de cette forme cristalline dans la préparation d'un inhibiteur du transporteur de l'acide urique, ainsi qu'une préparation pharmaceutique destinée au traitement de l'hyperuricémie. La nouvelle forme cristalline de lésinurad de la présente invention possède au moins une propriété améliorée par rapport à celles de l'état de la technique, possédant une grande valeur dans l'optimisation et la mise au point de ce médicament à l'avenir.
PCT/CN2018/092075 2017-06-28 2018-06-21 Forme cristalline xv de lésinurad et son procédé de préparation WO2019001325A1 (fr)

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CN201710507676.3 2017-06-28

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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

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