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WO2019011337A1 - Crystal form of qaw-039, preparation method and use thereof - Google Patents

Crystal form of qaw-039, preparation method and use thereof Download PDF

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Publication number
WO2019011337A1
WO2019011337A1 PCT/CN2018/095694 CN2018095694W WO2019011337A1 WO 2019011337 A1 WO2019011337 A1 WO 2019011337A1 CN 2018095694 W CN2018095694 W CN 2018095694W WO 2019011337 A1 WO2019011337 A1 WO 2019011337A1
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Prior art keywords
crystalline form
preparation
crystal form
compound
present
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French (fr)
Chinese (zh)
Inventor
陈敏华
张炎锋
王金秋
钱佳乐
张晓宇
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmaceutical Suzhou Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of QAW-039 and a preparation method and use thereof.
  • QAW-039 (Fevipiprant) is a potential prostaglandin D2 receptor 2 (DP2/CRTh2) antagonist for the treatment of asthma, atopic dermatitis and allergic rhinitis, developed by Novartis.
  • DP2/CRTh2 prostaglandin D2 receptor 2
  • QAW-039 has achieved positive results in clinical trials, reducing eosinophils that play a role in airway inflammation, safely and effectively reducing eosinophilic airway inflammation in patients with moderate or severe asthma, and improving patients.
  • the lung function and quality of life are expected to be innovative asthma drugs in recent decades.
  • the present inventors have found crystalline forms CS5 and CS6 of the compound (I) excellent in properties.
  • the crystal form of the present invention is at least one of stability, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility, fluidity, and processability, purification, formulation production, and the like. There are advantages, especially low wetting, good stability, high dissolution, and strong developability of the preparation, which provides a new and better choice for the development of drugs containing QAW-039, which is of great significance.
  • 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 also provides the crystal form CS5 of the compound (I) (hereinafter referred to as "crystal form CS5").
  • the X-ray powder diffraction of the crystal form CS5 has a characteristic peak at a diffraction angle 2 ⁇ value of 13.6 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °, 21.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 20.2° ⁇ 0.2°, and 22.7° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 4.7° ⁇ 0.2°, 20.2° ⁇ 0.2°, and 22.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS5 has one, or two, or three places in the diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 24.6° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 24.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS5 has a diffraction angle 2 ⁇ of 13.6° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.5° ⁇ 0.2°, 4.7° ⁇ 0.2°, and 20.2° ⁇ 0.2°. Any of 22.7° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.6° ⁇ 0.2°, 24.6° ⁇ 0.2°, 16.1° ⁇ 0.2°, 23.5° ⁇ 0.2°, 26.2° ⁇ 0.2°, 27.5° ⁇ 0.2° There are three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or 13 characteristic peaks.
  • the X-ray powder diffraction pattern of Form CS5 is as shown in FIG.
  • the present invention further provides a method for preparing a crystalline form CS5, which comprises: dissolving a raw material of the compound (I) in an alcohol solvent system, stirring and crystallization, separating and drying to obtain .
  • the alcohol solvent is preferably methanol, or ethanol, or propanol, or any mixture thereof, and the crystallization time is preferably from 1 to 15 days;
  • the alcohol solvent is preferably a mixed solvent of methanol and ethanol, and the crystallization time is preferably 5 days;
  • volume ratio of methanol to ethanol is preferably from 1:3 to 3:1, more preferably from 1:1.
  • the crystal form CS5 provided by the invention has the following beneficial effects:
  • the crystalline form CS5 provided by the invention has high solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystalline form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, and achieves an ideal Drug bioavailability and efficacy.
  • the crystalline form CS5 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 present invention also provides the crystal form CS6 of the compound (I) (hereinafter referred to as "crystal form CS6").
  • the X-ray powder diffraction of the crystal form CS6 has a characteristic peak at a diffraction angle 2 ⁇ value of 10.1 ⁇ 0.2°, 15.5° ⁇ 0.2°, and 20.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 12.2° ⁇ 0.2°, 27.3° ⁇ 0.2°, and 30.3° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS6 has characteristic peaks at diffraction angle 2 ⁇ values of 12.2 ° ⁇ 0.2 °, 27.3 ° ⁇ 0.2 °, and 30.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS6 has a diffraction angle 2 ⁇ value of 10.1 ⁇ 0.2°, 15.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 12.2° ⁇ 0.2°, 27.3° ⁇ 0.2°, There are characteristic peaks at any 3, or 4, or 5, or 6 of 30.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form CS6 is as shown in FIG.
  • the present invention also provides a method for preparing a crystal form CS6, which comprises: dissolving a compound (I) as a raw material in a mixed system of a ketone and an alcohol solvent, and adding a high polymer. After evaporation, it is obtained.
  • the ketone solvent is preferably acetone, or methyl ethyl ketone, or a mixture thereof, and the alcohol solvent is preferably methanol, or ethanol, or isopropanol, or any mixture thereof, the ketone
  • the volume ratio of the solvent-like solvent to the alcohol solvent (v:v) is preferably from 1:15 to 15:1, the crystallization time is preferably from 1 to 15 days, and the high polymer is composed of equal-mass polycaprolactone, Polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose and sodium alginate;
  • the ketone solvent is preferably acetone
  • the alcohol solvent is preferably ethanol
  • the volume ratio (v:v) of the ketone solvent to the alcohol solvent is preferably 1:3, and the crystallization time is It is preferably 5 days.
  • the crystal form CS6 provided by the invention has the following beneficial effects:
  • the crystal form CS6 provided by the present invention has good stability.
  • the crystalline bulk drug provided by the invention has good physical and chemical stability.
  • the crystalline form CS6 did not change at 25 ° C / 60% relative humidity for at least 3 months, its chemical purity was above 99%, and the chemical purity remained basically unchanged during the placement process.
  • the crystalline form provided by the present invention has good physical and chemical stability in the formulation.
  • the crystalline form CS6 of the present invention is mixed with an adjuvant to form a pharmaceutical preparation, and is allowed to stand at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for at least 3 months, and the crystal form of the present invention remains unchanged in the preparation.
  • the crystalline bulk drug and preparation have good physical and chemical stability. During the storage and formulation process, the crystalline form CS6 will not be converted into other crystal forms, and the chemical purity of the crystalline form CS6 remains basically unchanged during storage. In order to ensure the quality of the drug substance and preparation is consistent and controllable.
  • the crystalline form CS6 provided by the present invention has low wettability, and after weight equilibration at 80% relative humidity, the weight gain is about 1.17%, which is slightly wettability.
  • Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity also affects the preparation, storage and post-treatment of the drug.
  • the low moisture absorbing crystal form has strict requirements on storage conditions, reduces material storage and quality control costs, and has strong economic value.
  • the crystalline form CS6 provided by the invention has good solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystalline form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the human body, and achieves an ideal medicine. Bioavailability and efficacy.
  • the crystalline form CS6 of the present invention also has good dissolution and dissolution rates.
  • Dissolution is a prerequisite for absorption.
  • Good in vitro dissolution makes the absorption of the drug higher, and the in vivo exposure characteristics are better, thereby improving the bioavailability and improving the efficacy of the drug; a good in vitro dissolution rate allows the drug to be administered after the drug is administered. The highest concentration can be reached quickly in the plasma, thus ensuring rapid drug action.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS5, CS6 of the present invention or any mixture thereof, and at least one pharmaceutically acceptable carrier , diluent or excipient.
  • crystalline form CS5, CS6 or any combination thereof provided by the present invention for the preparation of a pharmaceutical preparation of a prostaglandin D2 receptor 2 antagonist.
  • the present invention provides the use of the crystalline forms CS5 and CS6 or any combination thereof in the preparation of a pharmaceutical preparation for the treatment of asthma and/or atopic dermatitis and/or allergic rhinitis.
  • the compound (I) as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of formula (I) as a starting material is in the form of a solid powder.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • 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. In fact, 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 forms CS5 and CS6 of the present invention are pure, unitary, and are 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.
  • Figure 1 is an XRPD pattern of a crystal form CS5 obtained according to Example 1 of the present invention.
  • Example 2 is a DSC chart of a crystal form CS5 obtained according to Example 1 of the present invention.
  • Figure 3 is a TGA diagram of a crystalline form CS5 obtained in accordance with Example 1 of the present invention.
  • Example 4 is an XRPD pattern of a crystal form CS5 obtained according to Example 2 of the present invention.
  • Figure 5 is a PSD diagram of a crystalline form CS5 of the present invention.
  • Figure 6 is an XRPD pattern of a crystalline form CS6 obtained according to Example 3 of the present invention.
  • Figure 7 is a 1 H NMR chart of the crystalline form CS6 obtained according to Example 3 of the present invention.
  • Figure 8 is a DSC chart of a crystalline form CS6 obtained according to Example 3 of the present invention.
  • Figure 9 is a TGA diagram of a crystalline form CS6 obtained in accordance with Example 3 of the present invention.
  • Figure 10 is a DVS diagram of the crystalline form CS6 of the present invention.
  • Figure 11 is an XRPD pattern of the crystalline form CS6 of the present invention placed at 25 ° C / 60% relative humidity for 6 months (the top view is before placement and the lower figure is after placement).
  • Figure 12 is an in vitro dissolution profile of a crystalline form CS6 tablet of the present invention.
  • the invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention.
  • PSD particle size distribution
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • HPLC high performance liquid chromatography
  • HPLC high performance liquid chromatography
  • 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. This test uses a wet method and the 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.
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the QAW-039 used in the following examples was prepared according to the prior art, for example according to the preparation method disclosed in WO2005123731A1.
  • the DSC of the crystalline form CS5 obtained in this example showed an endothermic peak near the temperature of 95 ° C, and the endothermic peak was the dehydration endothermic peak of the crystalline form CS5.
  • the TGA of the form CS5 obtained in this example is as shown in Fig. 3, and has a weight loss of about 10.2% when heated to around 140 °C.
  • Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • the crystalline form CS5 of the present invention was dissolved in a saturated solution of SGF, FaSSIF, FeSSIF and water, respectively, and after 1 hour of equilibrium, the content of the sample in the saturated solution (microgram/ml) was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the nuclear magnetic resonance spectrum is shown in Fig. 7.
  • the DSC of the crystalline form CS6 obtained in this example showed an endothermic peak near the temperature of 46 ° C, and the endothermic peak was the dehydration endothermic peak of the crystalline form CS6.
  • the TGA of the crystalline form CS6 obtained in this example is as shown in Fig. 9, and has a weight loss of about 5.5% when heated to around 140 °C.
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystalline form CS6 of the present invention has no change in crystal form and the chemical purity remains substantially unchanged after being left for 3 months under the condition of 25 ° C / 60% relative humidity, indicating that the crystalline form CS2 of the present invention has good physical and chemical stability.
  • Example 8 Dynamic solubility of crystalline form CS6
  • Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • the crystalline form CS6 of the present invention was dissolved in a saturated solution of SGF, FaSSIF, FeSSIF and water, respectively, and after 1 hour of equilibrium, the content of the sample in the saturated solution (microgram/ml) was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the crystalline form CS6 of the invention has good solubility in SGF, FeSSIF, FaSSIF and pure water, which provides a good solution for the good dissolution of the crystal form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, which is ideal. Drug bioavailability and efficacy.
  • the crystalline form CS6, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate (the contents of the respective components shown in Table 9 below) of the compound (I) were weighed and mixed for 2 minutes. It was pressed into a piece by a manual tableting machine, and a circular die of 6 mm in diameter was pressed at a pressure of 5 KN ⁇ 1 KN, and the tablet weight was 75 mg ⁇ 1 mg. Packed in 35cc HDPE bottles (one per bottle), each bottle contains 1g desiccant and sealed with a sealing machine. The crystal form of the active ingredient was not changed before and after preparation of the preparation.
  • the tablets prepared above were allowed to stand under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 3 months, and the crystal form did not change in the tablets containing the crystalline form CS6.
  • the results are shown in Table 10 below, indicating that the crystalline form CS6 has good stability in the formulation.
  • Example 10 In vitro dissolution and in vitro dissolution rate of crystalline CS6
  • the tablets containing the crystalline form CS6 obtained in Example 9 were tested for dissolution in vitro, and the dissolution was measured according to the Chinese Pharmacopoeia 2015 edition 0931 dissolution and release assay conditions, as follows:
  • Dissolution method paddle method
  • the in vitro dissolution of the crystalline form CS6 is shown in Table 11 below, and it is shown in Fig. 12 that the tablet having the crystalline form of the present invention as an active ingredient has a good dissolution rate and a dissolution rate.

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Abstract

涉及化合物(I)的晶型及其制备方法和用途，含有该晶型的药物组合物，以及该晶型在制备前列腺素D2受体2拮抗剂和治疗哮喘或过敏性皮炎或过敏性鼻炎药物制剂中的用途。所述晶型引湿性低、稳定性好、溶出度高、制剂可开发性强，为含化合物(I)的药物开发提供了新的更好的选择。A crystalline form relating to the compound (I), a preparation method and use thereof, a pharmaceutical composition containing the crystal form, and a preparation of a prostaglandin D2 receptor 2 antagonist and a medicament for treating asthma or atopic dermatitis or allergic rhinitis Use in the formulation. The crystal form has low wettability, good stability, high dissolution rate and strong developability of the preparation, and provides a new and better choice for drug development containing the compound (I).

Description

QAW-039的晶型及其制备方法和用途Crystal form of QAW-039 and preparation method and use thereof 技术领域Technical field

本发明涉及药物晶体技术领域。具体而言，涉及QAW-039的晶型及其制备方法和用途。The invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of QAW-039 and a preparation method and use thereof.

背景技术Background technique

QAW-039(Fevipiprant)是一种潜在的治疗哮喘、过敏性皮炎和过敏性鼻炎的前列腺素D2受体2(DP2/CRTh2)拮抗剂，由诺华研发。QAW-039在临床试验中取得了积极的效果，减少在气道炎症中起作用的嗜酸性粒细胞，可以安全有效地降低中度或重度哮喘患者的嗜酸性粒细胞气道炎症反应，改善患者的肺功能和生活质量，有望成为近几十年来的创新型哮喘药物。QAW-039 (Fevipiprant) is a potential prostaglandin D2 receptor 2 (DP2/CRTh2) antagonist for the treatment of asthma, atopic dermatitis and allergic rhinitis, developed by Novartis. QAW-039 has achieved positive results in clinical trials, reducing eosinophils that play a role in airway inflammation, safely and effectively reducing eosinophilic airway inflammation in patients with moderate or severe asthma, and improving patients. The lung function and quality of life are expected to be innovative asthma drugs in recent decades.

QAW-039的化学名称为：[1-(4-((甲烷)磺酰基)-2-三氟甲基苯甲基)-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基]乙酸(以下称为“化合物(I)”)，其结构式如下：The chemical name of QAW-039 is: [1-(4-((methane)sulfonyl)-2-trifluoromethylbenzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine -3-yl]acetic acid (hereinafter referred to as "compound (I)"), the structural formula is as follows:

Figure PCTCN2018095694-appb-000001
Figure PCTCN2018095694-appb-000001

目前无化合物(I)的晶型信息公开，因此，需要开发化合物(I)的晶型，寻找适合药用的优势晶型，以适于药物的工业化生产要求。本发明人发现了性质优良的化合物(I)的晶型CS5和CS6。本发明的晶型在稳定性、熔点、溶解度、体内外溶出、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、制剂生产等方面中的至少一方面上存在优势，特别是引湿性低、稳定性好、溶出度高、制剂可开发性强，为含QAW-039的药物开发提供了新的更好的选择，具有非常重要的意义。At present, no crystal form information of the compound (I) is disclosed, and therefore, it is necessary to develop a crystal form of the compound (I) to find a favorable crystal form suitable for medicinal use, which is suitable for industrial production requirements of a drug. The present inventors have found crystalline forms CS5 and CS6 of the compound (I) excellent in properties. The crystal form of the present invention is at least one of stability, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility, fluidity, and processability, purification, formulation production, and the like. There are advantages, especially low wetting, good stability, high dissolution, and strong developability of the preparation, which provides a new and better choice for the development of drugs containing QAW-039, which is of great significance.

发明内容Summary of the invention

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。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.

根据本发明的目的，本发明还提化合物(I)的晶型CS5(以下称作“晶型CS5”)。According to the object of the present invention, the present invention also provides the crystal form CS5 of the compound (I) (hereinafter referred to as "crystal form CS5").

一方面，使用Cu-Kα辐射，所述晶型CS5的X射线粉末衍射在衍射角2θ值为13.6°±0.2°、 19.6°±0.2°、21.5°±0.2°处有特征峰。On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CS5 has a characteristic peak at a diffraction angle 2θ value of 13.6 ° ± 0.2 °, 19.6 ° ± 0.2 °, 21.5 ° ± 0.2 °.

进一步地，所述晶型CS5的X射线粉末衍射在衍射角2θ值为4.7°±0.2°、20.2°±0.2°、22.7°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS5的X射线粉末衍射在衍射角2θ值为4.7°±0.2°、20.2°±0.2°、22.7°±0.2°处均有特征峰。Further, the X-ray powder diffraction of the crystalline form CS5 has characteristics at one, or two, or three of the diffraction angle 2θ values of 4.7°±0.2°, 20.2°±0.2°, and 22.7°±0.2°. peak. Preferably, the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2θ values of 4.7°±0.2°, 20.2°±0.2°, and 22.7°±0.2°.

更进一步地，所述晶型CS5的X射线粉末衍射在衍射角2θ值为8.4°±0.2°、10.6°±0.2°、24.6°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS5的X射线粉末衍射在衍射角2θ值为8.4°±0.2°、10.6°±0.2°、24.6°±0.2°处均有特征峰。Further, the X-ray powder diffraction of the crystal form CS5 has one, or two, or three places in the diffraction angle 2θ value of 8.4°±0.2°, 10.6°±0.2°, and 24.6°±0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystalline form CS5 has characteristic peaks at diffraction angle 2θ values of 8.4°±0.2°, 10.6°±0.2°, and 24.6°±0.2°.

另一方面，所述晶型CS5的X射线粉末衍射在衍射角2θ值为13.6°±0.2°、19.6°±0.2°、21.5°±0.2°、4.7°±0.2°、20.2°±0.2°、22.7°±0.2°、8.4°±0.2°、10.6°±0.2°、24.6°±0.2°、16.1°±0.2°、23.5°±0.2°、26.2°±0.2°、27.5°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处、或13处有特征峰。On the other hand, the X-ray powder diffraction of the crystalline form CS5 has a diffraction angle 2θ of 13.6°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 4.7°±0.2°, and 20.2°±0.2°. Any of 22.7°±0.2°, 8.4°±0.2°, 10.6°±0.2°, 24.6°±0.2°, 16.1°±0.2°, 23.5°±0.2°, 26.2°±0.2°, 27.5°±0.2° There are three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or 13 characteristic peaks.

非限制性的，在本发明的另一个具体实施方案中，晶型CS5的X射线粉末衍射谱图如附图1所示。Without limitation, in another embodiment of the invention, the X-ray powder diffraction pattern of Form CS5 is as shown in FIG.

根据本发明的目的，本发明还提供晶型CS5的制备方法，其特征在于，所述方法包括：将化合物(I)原料溶解在醇类溶剂体系中，搅拌析晶后，分离、干燥而获得。According to the object of the present invention, the present invention further provides a method for preparing a crystalline form CS5, which comprises: dissolving a raw material of the compound (I) in an alcohol solvent system, stirring and crystallization, separating and drying to obtain .

进一步地，所述醇类溶剂优选为甲醇、或乙醇、或丙醇、或它们的任意混合，所述析晶时间优选为1-15天；Further, the alcohol solvent is preferably methanol, or ethanol, or propanol, or any mixture thereof, and the crystallization time is preferably from 1 to 15 days;

更进一步地，所述醇类溶剂优选为甲醇和乙醇的混合溶剂，所述析晶时间优选为5天；Further, the alcohol solvent is preferably a mixed solvent of methanol and ethanol, and the crystallization time is preferably 5 days;

更进一步地，所述甲醇和乙醇的体积比(v:v)优选为1:3-3:1，更优选为1:1。Further, the volume ratio of methanol to ethanol (v:v) is preferably from 1:3 to 3:1, more preferably from 1:1.

本发明提供的晶型CS5具有以下有益效果：The crystal form CS5 provided by the invention has the following beneficial effects:

1)本发明提供的晶型CS5在模拟生物介质和纯水中具有较高的溶解度，为制剂中晶型的良好溶出提供保障，有利于制剂中活性成分在人体内的有效吸收，达到理想的药物生物利用度和药效。1) The crystalline form CS5 provided by the invention has high solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystalline form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, and achieves an ideal Drug bioavailability and efficacy.

2)本发明的晶型CS5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。2) The crystalline form CS5 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.

根据本发明的目的，本发明还提供化合物(I)的晶型CS6(以下称作“晶型CS6”)。According to the object of the present invention, the present invention also provides the crystal form CS6 of the compound (I) (hereinafter referred to as "crystal form CS6").

一方面，使用Cu-Kα辐射，所述晶型CS6的X射线粉末衍射在衍射角2θ值为10.1°±0.2°、15.5°±0.2°、20.1°±0.2°处有特征峰。On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CS6 has a characteristic peak at a diffraction angle 2θ value of 10.1±0.2°, 15.5°±0.2°, and 20.1°±0.2°.

进一步地，所述晶型CS6的X射线粉末衍射在衍射角2θ值为12.2°±0.2°、27.3°±0.2°、30.3°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS6的X射线粉末衍射 在衍射角2θ值为12.2°±0.2°、27.3°±0.2°、30.3°±0.2°处均有特征峰。Further, the X-ray powder diffraction of the crystalline form CS6 has characteristics at one, or two, or three of the diffraction angle 2θ values of 12.2°±0.2°, 27.3°±0.2°, and 30.3°±0.2°. peak. Preferably, the X-ray powder diffraction of the crystalline form CS6 has characteristic peaks at diffraction angle 2θ values of 12.2 ° ± 0.2 °, 27.3 ° ± 0.2 °, and 30.3 ° ± 0.2 °.

另一方面，所述晶型CS6的X射线粉末衍射在衍射角2θ值为10.1°±0.2°、15.5°±0.2°、20.1°±0.2°、12.2°±0.2°、27.3°±0.2°、30.3°±0.2°中的任意3处、或4处、或5处、或6处有特征峰。On the other hand, the X-ray powder diffraction of the crystalline form CS6 has a diffraction angle 2θ value of 10.1±0.2°, 15.5°±0.2°, 20.1°±0.2°, 12.2°±0.2°, 27.3°±0.2°, There are characteristic peaks at any 3, or 4, or 5, or 6 of 30.3 ° ± 0.2 °.

非限制性地，在本发明的一个具体实施方案中，晶型CS6的X射线粉末衍射谱图如附图5所示。Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form CS6 is as shown in FIG.

根据本发明的目的，本发明还提晶型CS6的制备方法，其特征在于，所述方法包括：将化合物(I)原料溶于酮类和醇类溶剂的混合体系中，并加入高聚物，后挥发得到。According to the object of the present invention, the present invention also provides a method for preparing a crystal form CS6, which comprises: dissolving a compound (I) as a raw material in a mixed system of a ketone and an alcohol solvent, and adding a high polymer. After evaporation, it is obtained.

进一步地，所述酮类溶剂优选为丙酮、或甲基乙基酮、或它们的混合，所述醇类溶剂优选为甲醇、或乙醇、或异丙醇、或它们的任意混合，所述酮类溶剂与醇类溶剂的体积比(v:v)优选为1:15-15:1，所述析晶时间优选为1-15天，所述高聚物由等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成；Further, the ketone solvent is preferably acetone, or methyl ethyl ketone, or a mixture thereof, and the alcohol solvent is preferably methanol, or ethanol, or isopropanol, or any mixture thereof, the ketone The volume ratio of the solvent-like solvent to the alcohol solvent (v:v) is preferably from 1:15 to 15:1, the crystallization time is preferably from 1 to 15 days, and the high polymer is composed of equal-mass polycaprolactone, Polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose and sodium alginate;

更进一步地，所述酮类溶剂优选为丙酮，所述醇类溶剂优选为乙醇，所述酮类溶剂与醇类溶剂的体积比(v:v)优选为1:3，所述析晶时间优选为5天。Further, the ketone solvent is preferably acetone, and the alcohol solvent is preferably ethanol, and the volume ratio (v:v) of the ketone solvent to the alcohol solvent is preferably 1:3, and the crystallization time is It is preferably 5 days.

本发明提供的晶型CS6具有以下有益效果：The crystal form CS6 provided by the invention has the following beneficial effects:

1)本发明提供的晶型CS6具有良好的稳定性。1) The crystal form CS6 provided by the present invention has good stability.

本发明提供的晶型原料药具有良好的物理、化学稳定。晶型CS6在25℃/60％相对湿度下至少放置3个月晶型未发生变化，其化学纯度在99％以上，且在放置过程中化学纯度基本保持不变。The crystalline bulk drug provided by the invention has good physical and chemical stability. The crystalline form CS6 did not change at 25 ° C / 60% relative humidity for at least 3 months, its chemical purity was above 99%, and the chemical purity remained basically unchanged during the placement process.

本发明提供的晶型在制剂中具有良好的物理、化学稳定性。本发明的晶型CS6与辅料混合做成药物制剂后，在25℃/60％相对湿度和40℃/75％相对湿度下至少放置3个月，制剂中本发明的晶型保持不变。The crystalline form provided by the present invention has good physical and chemical stability in the formulation. The crystalline form CS6 of the present invention is mixed with an adjuvant to form a pharmaceutical preparation, and is allowed to stand at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for at least 3 months, and the crystal form of the present invention remains unchanged in the preparation.

晶型原料药和制剂具有良好的物理、化学稳定性，在存储和制剂工艺过程中，晶型CS6不会转变成其它晶型，且在储存过程中，晶型CS6的化学纯度基本保持不变，从而保证原料药和制剂的质量一致可控。The crystalline bulk drug and preparation have good physical and chemical stability. During the storage and formulation process, the crystalline form CS6 will not be converted into other crystal forms, and the chemical purity of the crystalline form CS6 remains basically unchanged during storage. In order to ensure the quality of the drug substance and preparation is consistent and controllable.

2)本发明提供的晶型CS6具有低的引湿性，在80％相对湿度下平衡后增重约1.17％，属于略有引湿性。2) The crystalline form CS6 provided by the present invention has low wettability, and after weight equilibration at 80% relative humidity, the weight gain is about 1.17%, which is slightly wettability.

引湿性会影响药物的稳定性、加工时的流动性和均匀性等，最终影响药物制剂的质量。引湿性还会影响药物的制备、储存与后处理工艺。低引湿性晶型对储存条件要求不苛刻，降低了物料储存以及质量控制成本，具有很强的经济价值。Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity also affects the preparation, storage and post-treatment of the drug. The low moisture absorbing crystal form has strict requirements on storage conditions, reduces material storage and quality control costs, and has strong economic value.

3)本发明提供的晶型CS6在模拟生物介质和纯水中具有良好的溶解度，为制剂中晶型的良好溶出提供保障，有利于制剂中活性成分在人体内的有效吸收，达到理想的药物生物利用度和药效。3) The crystalline form CS6 provided by the invention has good solubility in simulated biological medium and pure water, and provides a good solution for the good dissolution of the crystalline form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the human body, and achieves an ideal medicine. Bioavailability and efficacy.

4)本发明晶型CS6还具有良好的溶出度和溶出速率。本发明晶型CS6为活性成分的片剂，在pH＝6.8磷酸盐缓冲溶液介质中，60分钟时的溶出度达到89.6％，有利于其在体内的良好吸收，达到理想的生物利用度。4) The crystalline form CS6 of the present invention also has good dissolution and dissolution rates. The tablet of the invention wherein the crystalline form CS6 is an active ingredient has a dissolution rate of 89.6% at 60 minutes in a phosphate buffer solution medium of pH=6.8, which is favorable for good absorption in the body and achieves desired bioavailability.

溶出是吸收的前提条件，良好的体外溶出度使得药物的吸收程度较高，在体内暴露特性更好，从而提高生物利用度，提高药物的疗效；良好的体外溶出速率使得药物在给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。Dissolution is a prerequisite for absorption. Good in vitro dissolution makes the absorption of the drug higher, and the in vivo exposure characteristics are better, thereby improving the bioavailability and improving the efficacy of the drug; a good in vitro dissolution rate allows the drug to be administered after the drug is administered. The highest concentration can be reached quickly in the plasma, thus ensuring rapid drug action.

根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的本发明的晶型CS5、CS6或它们的任意混合，以及至少一种药学上可接受的载体、稀释剂或赋形剂。According to the purpose of the present invention, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS5, CS6 of the present invention or any mixture thereof, and at least one pharmaceutically acceptable carrier , diluent or excipient.

进一步地，本发明提供的晶型CS5、CS6或它们的任意混合在制备前列腺素D2受体2拮抗剂药物制剂中的用途。Further, the use of the crystalline form CS5, CS6 or any combination thereof provided by the present invention for the preparation of a pharmaceutical preparation of a prostaglandin D2 receptor 2 antagonist.

更进一步地，本发明提供的晶型CS5和CS6或它们的任意混合在制备治疗治疗哮喘和/或过敏性皮炎和/或过敏性鼻炎药物制剂中的用途。Further, the present invention provides the use of the crystalline forms CS5 and CS6 or any combination thereof in the preparation of a pharmaceutical preparation for the treatment of asthma and/or atopic dermatitis and/or allergic rhinitis.

根据本发明，作为原料的所述化合物(I)指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述式(I)化合物为固体粉末形式。According to the invention, the compound (I) as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the compound of formula (I) as a starting material is in the form of a solid powder.

本发明中，“晶体”或“多晶型”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。In the present invention, "crystal" or "polymorph" means confirmed by the X-ray diffraction pattern characterization 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. 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. In fact, 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. In addition, 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. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that 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.

在一些实施方案中，本发明的晶型CS5和CS6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。In some embodiments, the crystalline forms CS5 and CS6 of the present invention are pure, unitary, and are substantially free of any other crystalline form. In the present invention, "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.

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。It should be noted that the numerical values and numerical ranges recited in the present invention are not to be construed as narrowly construed as a numerical value or a numerical range per se. It will be understood by those skilled in the art that they may vary depending on the specific technical environment without departing from the spirit of the invention. On the basis of the principle, there are fluctuations around specific numerical values. In the present invention, such a floating range which can be foreseen by those skilled in the art is often expressed by the term "about".

附图说明DRAWINGS

图1为根据本发明实施例1所得晶型CS5的XRPD图。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRPD pattern of a crystal form CS5 obtained according to Example 1 of the present invention.

图2为根据本发明实施例1所得晶型CS5的DSC图。2 is a DSC chart of a crystal form CS5 obtained according to Example 1 of the present invention.

图3为根据本发明实施例1所得晶型CS5的TGA图。Figure 3 is a TGA diagram of a crystalline form CS5 obtained in accordance with Example 1 of the present invention.

图4为根据本发明实施例2所得晶型CS5的XRPD图。4 is an XRPD pattern of a crystal form CS5 obtained according to Example 2 of the present invention.

图5为本发明晶型CS5的PSD图。Figure 5 is a PSD diagram of a crystalline form CS5 of the present invention.

图6为根据本发明实施例3所得晶型CS6的XRPD图。Figure 6 is an XRPD pattern of a crystalline form CS6 obtained according to Example 3 of the present invention.

图7为根据本发明实施例3所得晶型CS6的 1HNMR图。 Figure 7 is a 1 H NMR chart of the crystalline form CS6 obtained according to Example 3 of the present invention.

图8为根据本发明实施例3所得晶型CS6的DSC图。Figure 8 is a DSC chart of a crystalline form CS6 obtained according to Example 3 of the present invention.

图9为根据本发明实施例3所得晶型CS6的TGA图。Figure 9 is a TGA diagram of a crystalline form CS6 obtained in accordance with Example 3 of the present invention.

图10为本发明晶型CS6的DVS图。Figure 10 is a DVS diagram of the crystalline form CS6 of the present invention.

图11为本发明晶型CS6在25℃/60％相对湿度条件下放置6个月前后的XRPD图(上图为放置前，下图为放置后)。Figure 11 is an XRPD pattern of the crystalline form CS6 of the present invention placed at 25 ° C / 60% relative humidity for 6 months (the top view is before placement and the lower figure is after placement).

图12为本发明晶型CS6片剂的体外溶出曲线。Figure 12 is an in vitro dissolution profile of a crystalline form CS6 tablet of the present invention.

具体实施方式Detailed ways

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。The invention is further defined by the following examples which describe in detail the preparation and use of the crystalline forms of the invention.

本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:

XRPD：X射线粉末衍射XRPD: X-ray powder diffraction

DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry

TGA：热重分析TGA: Thermogravimetric Analysis

DVS：动态水分吸附DVS: Dynamic moisture adsorption

HPLC：高效液相色谱HPLC: high performance liquid chromatography

1HNMR：核磁共振氢谱 1 H NMR: Nuclear Magnetic Resonance Spectroscopy

PSD：粒径分布PSD: particle size distribution

采集数据所用的仪器及方法：Instruments and methods used to collect data:

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：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:

X射线反射参数：Cu,KαX-ray reflection parameters: Cu, Kα

Kα1

Figure PCTCN2018095694-appb-000002
：1.540598；Kα2
Figure PCTCN2018095694-appb-000003
：1.544426 Kα1
Figure PCTCN2018095694-appb-000002
:1.540598;Kα2
Figure PCTCN2018095694-appb-000003
:1.544426

Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50

电压：45仟伏特(kV)Voltage: 45 volts (kV)

电流：40毫安培(mA)Current: 40 milliamps (mA)

扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees

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：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:

扫描速率：如无特别说明为10℃/minScanning rate: 10°C/min unless otherwise specified

保护气体：N 2 Protective gas: N 2

本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

扫描速率：10℃/minScan rate: 10 ° C / min

保护气体：N 2 Protective gas: N 2

本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：The dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture adsorber are as follows:

温度：25℃Temperature: 25 ° C

载气，流速：N 2,200毫升/分钟 Carrier gas, flow rate: N 2 , 200 ml / min

单位时间质量变化：0.002％/分钟Unit time quality change: 0.002% / minute

相对湿度范围：0％RH-95％RHRelative humidity range: 0%RH-95%RH

测试晶型化学纯度的HPLC仪器参数：HPLC instrument parameters for testing crystal purity:

高效液相色谱(HPLC)数据采集来自于安捷伦1260，所用检测器为紫外可变波长检测器(VWD)。本发明所述的HPLC方法参数如下：High performance liquid chromatography (HPLC) data acquisition was performed on an Agilent 1260 detector using a UV variable wavelength detector (VWD). The HPLC method parameters of the present invention are as follows:

色谱柱：Xbridge C8,150×4.6mm,3.5μmColumn: Xbridge C8, 150 x 4.6 mm, 3.5 μm

流动相：A:0.1％TFA in H 2O Mobile phase: A: 0.1% TFA in H 2 O

B:0.1％TFA in acetonitrileB: 0.1% TFA in acetonitrile

洗脱梯度：Elution gradient:

Time(min)Time(min) ％B%B 0.00.0 1515 20.020.0 8080 25.025.0 8080 26.026.0 1515 32.032.0 1515

流速：1.0mL/minFlow rate: 1.0mL/min

进样量：5μLInjection volume: 5μL

柱温：40℃Column temperature: 40 ° C

稀释剂：ACN:H 2O＝1:1 Thinner: ACN: H 2 O = 1:1

测试溶解度的HPLC仪器参数：HPLC instrument parameters for testing solubility:

高效液相色谱(HPLC)数据采集来自于安捷伦1260，所用检测器为紫外可变波长检测器(VWD)。本发明所述的HPLC方法参数如下：High performance liquid chromatography (HPLC) data acquisition was performed on an Agilent 1260 detector using a UV variable wavelength detector (VWD). The HPLC method parameters of the present invention are as follows:

色谱柱：Xbridge C18,150×4.6mm,5μmColumn: Xbridge C18, 150 x 4.6 mm, 5 μm

流动相：A:0.1％TFA in H 2O Mobile phase: A: 0.1% TFA in H 2 O

B:0.1％TFA in acetonitrileB: 0.1% TFA in acetonitrile

洗脱梯度：Elution gradient:

Time(min)Time(min) ％B%B 0.00.0 4040 8.08.0 4040

流速：1.0mL/minFlow rate: 1.0mL/min

进样量：5μLInjection volume: 5μL

柱温：40℃Column temperature: 40 ° C

稀释剂：ACN:H 2O＝1:1 Thinner: ACN: H 2 O = 1:1

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：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. This test uses a wet method and the dispersion medium is Isopar G. The method parameters of the laser particle size analyzer are as follows:

Figure PCTCN2018095694-appb-000004
Figure PCTCN2018095694-appb-000004

*：流速60％为65毫升/秒的60％。*: The flow rate is 60% of 60% of 65 ml/sec.

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。 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.

除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是精确的温度值，是指10-30℃温度范围。The following examples were operated at room temperature unless otherwise stated. The "room temperature" is not an accurate temperature value and refers to a temperature range of 10-30 °C.

以下实施例中所使用到的QAW-039是根据现有技术制备得到，例如根据WO2005123731A1中公开的制备方法得到。The QAW-039 used in the following examples was prepared according to the prior art, for example according to the preparation method disclosed in WO2005123731A1.

实施例1：晶型CS5的制备方法Example 1: Preparation method of crystalline form CS5

将108.1mg的化合物(I)加至2.0mL体积比为1:1的甲醇和乙醇的混合溶剂中，室温下搅拌5天，分离所得固体并真空干燥得到本发明的晶型CS5。其XRPD数据如图1、表1所示。108.1 mg of the compound (I) was added to 2.0 mL of a mixed solvent of methanol and ethanol in a volume ratio of 1:1, and stirred at room temperature for 5 days, and the obtained solid was separated and dried in vacuo to obtain the crystalline form CS5 of the present invention. Its XRPD data is shown in Figure 1 and Table 1.

本实施例所得晶型CS5的DSC如图2所示，加热至95℃附近开始出现一个吸热峰，该吸热峰为晶型CS5的脱水吸热峰。As shown in FIG. 2, the DSC of the crystalline form CS5 obtained in this example showed an endothermic peak near the temperature of 95 ° C, and the endothermic peak was the dehydration endothermic peak of the crystalline form CS5.

本实施例所得晶型CS5的TGA如附图3所示，加热至140℃附近时具有约10.2％的失重。The TGA of the form CS5 obtained in this example is as shown in Fig. 3, and has a weight loss of about 10.2% when heated to around 140 °C.

表1Table 1

衍射角2θDiffraction angle 2θ d值d value 强度％strength% 4.744.74 18.6318.63 48.8348.83 8.378.37 10.5610.56 41.6541.65 10.5910.59 8.358.35 22.1922.19 12.6512.65 7.007.00 9.649.64 12.9212.92 6.856.85 20.6420.64 13.6013.60 6.516.51 90.2890.28

14.7114.71 6.026.02 6.366.36 16.0916.09 5.515.51 21.2321.23 17.7317.73 5.005.00 8.308.30 19.5819.58 4.534.53 63.9363.93 20.1620.16 4.404.40 73.9173.91 21.5021.50 4.134.13 100.00100.00 21.9521.95 4.054.05 14.1814.18 22.6722.67 3.923.92 26.0126.01 23.5323.53 3.783.78 22.9822.98 24.1724.17 3.683.68 19.7019.70 24.5824.58 3.623.62 27.2327.23 26.1926.19 3.403.40 24.9524.95 27.5227.52 3.243.24 24.1824.18 27.9927.99 3.193.19 25.8225.82 29.8229.82 3.003.00 10.3810.38 31.8331.83 2.812.81 14.8914.89 32.7632.76 2.732.73 4.554.55 34.0734.07 2.632.63 3.373.37 36.3736.37 2.472.47 5.865.86

实施例2：晶型CS5的制备方法Example 2: Preparation method of crystal form CS5

将39.4mg的化合物(I)加至0.4mL体积比为1:1的甲醇和乙醇的混合溶剂中，5℃下搅拌16小时，分离所得固体并干燥得到本发明的晶型CS5。其XRPD数据如图4、表2所示。39.4 mg of the compound (I) was added to 0.4 mL of a mixed solvent of methanol and ethanol in a volume ratio of 1:1, and stirred at 5 ° C for 16 hours, and the obtained solid was separated and dried to obtain the crystalline form CS5 of the present invention. Its XRPD data is shown in Figure 4 and Table 2.

表2Table 2

衍射角2θDiffraction angle 2θ d值d value 强度％strength% 4.764.76 18.5718.57 33.0133.01 8.388.38 10.5510.55 36.2936.29 10.6010.60 8.358.35 20.1020.10 12.6812.68 6.986.98 11.3711.37 12.9112.91 6.866.86 21.0721.07 13.6113.61 6.516.51 87.9987.99 14.6914.69 6.036.03 5.715.71 16.0816.08 5.515.51 20.5920.59 17.7017.70 5.015.01 6.876.87 19.5419.54 4.544.54 46.2246.22

19.7219.72 4.504.50 25.6125.61 20.1620.16 4.404.40 55.8155.81 21.5021.50 4.134.13 100.00100.00 21.9221.92 4.054.05 12.5712.57 22.6222.62 3.933.93 19.5619.56 23.1723.17 3.843.84 6.246.24 23.5723.57 3.783.78 20.4620.46 24.2324.23 3.673.67 12.5812.58 24.6124.61 3.623.62 27.9227.92 25.7425.74 3.463.46 6.546.54 26.2126.21 3.403.40 21.8221.82 27.5127.51 3.243.24 16.3516.35 27.9527.95 3.193.19 16.1316.13 29.8429.84 2.992.99 8.808.80 31.8131.81 2.812.81 8.508.50 32.6932.69 2.742.74 4.074.07 34.0334.03 2.632.63 2.152.15 36.3436.34 2.472.47 4.184.18 39.1739.17 2.302.30 2.402.40

实施例3：晶型CS5的动态溶解度Example 3: Dynamic solubility of crystalline form CS5

胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The solubility measured in such media is much closer to the solubility in the human environment.

取本发明的晶型CS5，分别溶于SGF、FaSSIF、FeSSIF和水配制成的饱和溶液，平衡1小时后用高效液相色谱(HPLC)测试饱和溶液中样品的含量(微克/毫升)。晶型CS5的溶解度实验结果如表3所示。The crystalline form CS5 of the present invention was dissolved in a saturated solution of SGF, FaSSIF, FeSSIF and water, respectively, and after 1 hour of equilibrium, the content of the sample in the saturated solution (microgram/ml) was measured by high performance liquid chromatography (HPLC). The results of the solubility test of the crystalline form CS5 are shown in Table 3.

表3晶型CS5在SGF、FeSSIF、FaSSIF和水中的溶解度Table 3 Solubility of Form CS5 in SGF, FeSSIF, FaSSIF and Water

Figure PCTCN2018095694-appb-000005
Figure PCTCN2018095694-appb-000005

结果表明，本发明晶型CS5在SGF，FeSSIF，FaSSIF和纯水中具有较高的溶解度。The results show that the crystalline form CS5 of the present invention has a high solubility in SGF, FeSSIF, FaSSIF and pure water.

实施例4：晶型CS5的PSDExample 4: PSD of Form CS5

取10-30mg本发明的晶型CS5，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。Take 10-30 mg of the crystalline form CS5 of the present invention, then add 10 mL of Isopar G (containing 0.2% lecithin), mix the sample to be tested uniformly, and then add it to the SDC sample introduction system to make the sample amount indication map reach a suitable position and start the experiment. The particle size distribution is tested to obtain an average particle diameter calculated by volume, a particle size distribution (volume distribution) of 10%, and a particle size distribution (volume distribution) of 50%. path. The particle size distribution (volume distribution) accounts for 90% of the corresponding particle size and crystal size distribution map.

结果如表4所示，PSD图如图5所示。结果表明，晶型CS5具有均一的粒径分布。The results are shown in Table 4, and the PSD diagram is shown in Fig. 5. The results show that the crystalline form CS5 has a uniform particle size distribution.

表4晶型CS5的PSD数据Table 4 PSD data of crystal form CS5

晶型Crystal form MV/μmMV/μm D(10)/μmD(10)/μm D(50)/μmD(50)/μm D(90)/μmD(90)/μm CS5CS5 17.0417.04 5.485.48 12.1412.14 27.1927.19

注：Note:

MV：按照体积计算的平均粒径MV: average particle size by volume

D10：表示粒径分布中(体积分布)占10％所对应的粒径D10: indicates the particle size distribution (volume distribution) accounts for 10% of the particle size

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D50: indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.

D90：表示粒径分布中(体积分布)占90％所对应的粒径D90: indicates the particle size distribution (volume distribution) accounts for 90% of the particle size

实施例5：晶型CS6的制备方法Example 5: Preparation method of crystalline form CS6

将约9.0mg的化合物(I)溶解于0.6mL体积比为1:3的丙酮和乙醇的混合溶剂中，过滤后加入等质量的由聚己内酯、聚氧乙烯、聚甲基丙烯酸甲酯、羟乙基纤维素和海藻酸钠组成的高聚物，于室温下挥发约5天析出固体。经检测，所得固体为晶型CS6。其XRPD数据如图6、表5所示。About 9.0 mg of the compound (I) was dissolved in 0.6 mL of a mixed solvent of acetone and ethanol in a volume ratio of 1:3, and after filtration, an equal amount of polycaprolactone, polyoxyethylene, polymethyl methacrylate was added. A polymer composed of hydroxyethyl cellulose and sodium alginate was volatilized at room temperature for about 5 days to precipitate a solid. Upon examination, the obtained solid was crystalline form CS6. Its XRPD data is shown in Figure 6 and Table 5.

核磁共振氢谱谱图如图7所示，核磁数据为： 1H NMR(400MHz,DMSO)δ8.26(s,1H),8.13(d,J＝4.7Hz,1H),8.04(d,J＝7.9Hz,1H),7.95(d,J＝7.7Hz,1H),7.11(dd,J＝7.8,4.7Hz,1H),6.49(d,J＝8.2Hz,1H),5.76(s,2H),3.72(s,2H),3.28(s,3H),2.28(s,3H)。 The nuclear magnetic resonance spectrum is shown in Fig. 7. The nuclear magnetic data are: 1 H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 8.04 (d, J) = 7.9 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 7.8, 4.7 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H), 5.76 (s, 2H) ), 3.72 (s, 2H), 3.28 (s, 3H), 2.28 (s, 3H).

本实施例所得晶型CS6的DSC如图8所示，加热至46℃附近开始出现一个吸热峰，该吸热峰为晶型CS6的脱水吸热峰。As shown in Fig. 8, the DSC of the crystalline form CS6 obtained in this example showed an endothermic peak near the temperature of 46 ° C, and the endothermic peak was the dehydration endothermic peak of the crystalline form CS6.

本实施例所得晶型CS6的TGA如图9所示，加热至140℃附近时具有约5.5％的失重。The TGA of the crystalline form CS6 obtained in this example is as shown in Fig. 9, and has a weight loss of about 5.5% when heated to around 140 °C.

表5table 5

衍射角2θDiffraction angle 2θ d值d value 强度％strength% 6.186.18 14.3014.30 0.790.79 10.0810.08 8.788.78 53.8653.86 12.2412.24 7.237.23 4.124.12

15.4715.47 5.735.73 50.3150.31 18.3818.38 4.834.83 1.411.41 20.1020.10 4.424.42 100.00100.00 20.9520.95 4.244.24 1.491.49 21.4021.40 4.154.15 0.870.87 22.1322.13 4.024.02 0.920.92 22.6922.69 3.923.92 0.960.96 25.4825.48 3.503.50 0.420.42 26.2026.20 3.403.40 0.530.53 27.2927.29 3.273.27 3.923.92 28.8428.84 3.103.10 0.510.51 30.2530.25 2.952.95 2.872.87 32.2032.20 2.782.78 0.390.39 33.4533.45 2.682.68 0.760.76 35.6535.65 2.522.52 1.061.06 37.0237.02 2.432.43 0.670.67

实施例6：晶型CS6的引湿性Example 6: Wetting property of crystalline form CS6

称取本发明晶型CS6约10mg进行动态水分吸附(DVS)测试其引湿性，结果如表6所示，80％相对湿度下晶型CS6增重量仅为1.17％，属于略有引湿性，DVS图如图10所示。About 10 mg of the crystalline form CS6 of the present invention was weighed and subjected to dynamic moisture adsorption (DVS) to test its wettability. As shown in Table 6, the weight gain of the crystalline form CS6 was only 1.17% at 80% relative humidity, which was slightly wetted, DVS. The figure is shown in Figure 10.

表6Table 6

晶型Crystal form 80％相对湿度下增重量Weight gain at 80% relative humidity 引湿性Humidity CS6CS6 1.17％1.17% 略有引湿性Slightly hygroscopic

结果表明，本发明晶型CS6具有低的引湿性。The results show that the crystalline form CS6 of the present invention has low wettability.

关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，相对湿度为80％±2％)：Defining the characteristics of wettability and the definition of wettability weight gain (Chinese Pharmacopoeia 2015 General Principles 9103 Guidelines for Drug Wetness Test, Experimental Conditions: 25 °C ± 1 °C, Relative Humidity 80% ± 2%):

潮解：吸收足量水分形成液体Deliquescence: absorb enough water to form a liquid

极具引湿性：引湿增重不小于15.0％Very hygroscopic: the wetting weight gain is not less than 15.0%

有引湿性：引湿增重小于15.0％但不小于2.0％Humidity: Wet weight gain is less than 15.0% but not less than 2.0%

略有引湿性：引湿增重小于2.0％但不小于0.2％Slightly hygroscopic: wet weight gain is less than 2.0% but not less than 0.2%

无或几乎无引湿性：引湿增重小于0.2％No or almost no wettability: wetting gain is less than 0.2%

实施例7：晶型CS6的稳定性Example 7: Stability of Form CS6

取本发明晶型CS6的样品置于25℃/60％相对湿度下敞口放置，测试放置前后的晶型和 化学纯度的变化，结果如表7所示：The sample of the crystalline form CS6 of the present invention was placed open at 25 ° C / 60% relative humidity, and the change in crystal form and chemical purity before and after the test was tested. The results are shown in Table 7:

表7Table 7

Figure PCTCN2018095694-appb-000006
Figure PCTCN2018095694-appb-000006

本发明晶型CS6在25℃/60％相对湿度条件下，放置3个月前后晶型未发生改变且化学纯度基本保持不变，说明本发明晶型CS2具有良好的物理、化学稳定性。The crystalline form CS6 of the present invention has no change in crystal form and the chemical purity remains substantially unchanged after being left for 3 months under the condition of 25 ° C / 60% relative humidity, indicating that the crystalline form CS2 of the present invention has good physical and chemical stability.

实施例8：晶型CS6的动态溶解度Example 8: Dynamic solubility of crystalline form CS6

胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release. The solubility measured in such media is much closer to the solubility in the human environment.

取本发明的晶型CS6，分别溶于SGF、FaSSIF、FeSSIF和水配制成的饱和溶液，平衡1小时后用高效液相色谱(HPLC)测试饱和溶液中样品的含量(微克/毫升)。晶型CS5的溶解度实验结果如表8所示。The crystalline form CS6 of the present invention was dissolved in a saturated solution of SGF, FaSSIF, FeSSIF and water, respectively, and after 1 hour of equilibrium, the content of the sample in the saturated solution (microgram/ml) was measured by high performance liquid chromatography (HPLC). The solubility test results of the crystal form CS5 are shown in Table 8.

表8晶型CS6在SGF、FeSSIF、FaSSIF和水中的溶解度Table 8 Solubility of Form CS6 in SGF, FeSSIF, FaSSIF and Water

Figure PCTCN2018095694-appb-000007
Figure PCTCN2018095694-appb-000007

结果表明，本发明晶型CS6的在SGF，FeSSIF，FaSSIF和纯水中具有良好的溶解度，为制剂中晶型的良好溶出提供保障，有利于制剂中活性成分在人体内的有效吸收，达到理想的药物生物利用度和药效。The results show that the crystalline form CS6 of the invention has good solubility in SGF, FeSSIF, FaSSIF and pure water, which provides a good solution for the good dissolution of the crystal form in the preparation, and is beneficial to the effective absorption of the active ingredient in the preparation in the preparation, which is ideal. Drug bioavailability and efficacy.

实施例9：晶型CS6的制剂Example 9: Formulation of Form CS6

1.化合物(I)片剂的制备：1. Preparation of Compound (I) Tablets:

称取化合物(I)的晶型CS6、微晶纤维素、交联羧甲基纤维素钠和硬脂酸镁(各组分含量如下表9所示)，混合2分钟。用手动压片机压制成片，直径6mm圆形冲模，压力5KN±1KN，片重75mg±1mg。用35cc HDPE瓶包装(每瓶一片)，每瓶含有1g干燥剂，用封口机封口。经检测，制剂制备前后，活性成分的晶型未发生变化。The crystalline form CS6, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate (the contents of the respective components shown in Table 9 below) of the compound (I) were weighed and mixed for 2 minutes. It was pressed into a piece by a manual tableting machine, and a circular die of 6 mm in diameter was pressed at a pressure of 5 KN ± 1 KN, and the tablet weight was 75 mg ± 1 mg. Packed in 35cc HDPE bottles (one per bottle), each bottle contains 1g desiccant and sealed with a sealing machine. The crystal form of the active ingredient was not changed before and after preparation of the preparation.

表9Table 9

片剂成分Tablet ingredients 质量(mg/片)Quality (mg/piece) 质量比(％)Mass ratio (%) 晶型CS6Crystal form CS6 1515 2020 微晶纤维素Microcrystalline cellulose 55.555.5 7474 交联羧甲基纤维素钠Croscone sodium 3.753.75 55 硬脂酸镁Magnesium stearate 0.750.75 11 合计total 7575 100100

2.晶型CS6在制剂中的稳定性：2. Stability of crystalline CS6 in the formulation:

取上述制备的片剂在25℃/60％相对湿度和40℃/75％相对湿度条件下放置3个月，经检测，在含晶型CS6的片剂中，晶型未发生变化。结果如下表10所示，说明晶型CS6在制剂中具有很好的稳定性。The tablets prepared above were allowed to stand under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 3 months, and the crystal form did not change in the tablets containing the crystalline form CS6. The results are shown in Table 10 below, indicating that the crystalline form CS6 has good stability in the formulation.

表10晶型CS6在制剂中的稳定性Table 10 Stability of crystalline form CS6 in the formulation

Figure PCTCN2018095694-appb-000008
Figure PCTCN2018095694-appb-000008

实施例10：晶型CS6的体外溶出度与体外溶出速率Example 10: In vitro dissolution and in vitro dissolution rate of crystalline CS6

对实施例9获得的含晶型CS6的片剂测试体外溶出情况，溶出度的测定按照中国药典2015年版0931溶出度与释放度测定法，条件如下：The tablets containing the crystalline form CS6 obtained in Example 9 were tested for dissolution in vitro, and the dissolution was measured according to the Chinese Pharmacopoeia 2015 edition 0931 dissolution and release assay conditions, as follows:

溶出介质：pH＝6.8磷酸盐缓冲溶液Dissolution medium: pH=6.8 phosphate buffer solution

溶出方法：桨法Dissolution method: paddle method

介质体积：900mLMedia volume: 900mL

转速：75rpmSpeed: 75rpm

介质温度：37℃Medium temperature: 37 ° C

晶型CS6的体外溶出情况如下表11，图12所示，表明以本发明晶型为活性成分的片剂具有良好的溶出度和溶出速率。The in vitro dissolution of the crystalline form CS6 is shown in Table 11 below, and it is shown in Fig. 12 that the tablet having the crystalline form of the present invention as an active ingredient has a good dissolution rate and a dissolution rate.

表11Table 11

Figure PCTCN2018095694-appb-000009
Figure PCTCN2018095694-appb-000009

Figure PCTCN2018095694-appb-000010
Figure PCTCN2018095694-appb-000010

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。The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (15)

一种化合物(I)的晶型CS6，其特征在于，其X射线粉末衍射在衍射角2θ值为10.1°±0.2°、15.5°±0.2°、20.1°±0.2°、12.2°±0.2°处有特征峰。A crystal form CS6 of the compound (I) characterized in that the X-ray powder diffraction is at a diffraction angle 2θ of 10.1±0.2°, 15.5°±0.2°, 20.1°±0.2°, 12.2°±0.2°. There are characteristic peaks. 一种化合物(I)晶型CS6的制备方法，其特征在于，所述方法为：将化合物(I)溶于酮类和醇类溶剂的混合体系中，并加入高聚物，后挥发得到。A method for preparing a compound (I) crystal form CS6, which is characterized in that the compound (I) is dissolved in a mixed system of a ketone and an alcohol solvent, and a high polymer is added, followed by volatilization. 根据权利要求2所述的制备方法，所述酮类溶剂为丙酮、或甲基乙基酮、或它们的任意混合，所述醇类溶剂为甲醇、或乙醇、或异丙醇、或它们的任意混合，所述酮类溶剂与醇类溶剂的体积比(v:v)为1:15-15:1，所述析晶时间为1-15天，所述高聚物由等质量的聚己内酯，聚氧乙烯，聚甲基丙烯酸甲酯，羟乙基纤维素和海藻酸钠组成。The method according to claim 2, wherein the ketone solvent is acetone, or methyl ethyl ketone, or any mixture thereof, and the alcohol solvent is methanol, or ethanol, or isopropanol, or Optionally, the volume ratio (v:v) of the ketone solvent to the alcohol solvent is 1:15-15:1, the crystallization time is 1-15 days, and the high polymer is composed of equal mass Caprolactone, polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose and sodium alginate. 根据权利要求3所述的制备方法，所述酮类溶剂为丙酮，所述醇类溶剂为乙醇，所述酮类溶剂与醇类溶剂的体积比(v:v)为1:3，所述析晶时间为5天。The preparation method according to claim 3, wherein the ketone solvent is acetone, the alcohol solvent is ethanol, and the volume ratio (v:v) of the ketone solvent to the alcohol solvent is 1:3. The crystallization time was 5 days. 一种化合物(I)的晶型CS5，其特征在于，其X射线粉末衍射在衍射角2θ值为13.6°±0.2°、19.6°±0.2°、21.5°±0.2°处有特征峰。A crystal form CS5 of the compound (I) characterized in that the X-ray powder diffraction has a characteristic peak at a diffraction angle 2θ of 13.6 ° ± 0.2 °, 19.6 ° ± 0.2 °, and 21.5 ° ± 0.2 °. 根据权利要求5所述的晶型CS5，其特征还在于，其X射线粉末衍射在衍射角2θ值为4.7°±0.2°、20.2°±0.2°、22.7°±0.2°中的一处或多处有特征峰。The crystal form CS5 according to claim 5, wherein the X-ray powder is diffracted in one or more of diffraction angle 2θ values of 4.7 ° ± 0.2 °, 20.2 ° ± 0.2 °, and 22.7 ° ± 0.2 °. There are characteristic peaks. 根据权利要求5所述的晶型CS5，其特征还在于，其X射线粉末衍射在衍射角2θ值为8.4°±0.2°、10.6°±0.2°、24.6°±0.2°中的一处或多处有特征峰。The crystal form CS5 according to claim 5, wherein X-ray powder diffraction is one or more of diffraction angle 2θ values of 8.4 ° ± 0.2 °, 10.6 ° ± 0.2 °, and 24.6 ° ± 0.2 °. There are characteristic peaks. 一种化合物(I)晶型CS5的制备方法，其特征在于，所述方法为：将化合物(I)溶解在醇类溶剂体系中，搅拌析晶后，分离、干燥而获得。A method for producing a compound (I) crystal form CS5, which is obtained by dissolving a compound (I) in an alcohol solvent system, stirring and crystallization, separating and drying. 根据权利要求8所述的制备方法，所述醇类溶剂为甲醇、或乙醇、或丙醇或它们的任意混合，所述析晶时间为1-15天。The preparation method according to claim 8, wherein the alcohol solvent is methanol, or ethanol, or propanol or any mixture thereof, and the crystallization time is 1 to 15 days. 根据权利要求9所述的制备方法，所述醇类溶剂为甲醇和乙醇的混合溶剂，所述析晶时间为5天。The preparation method according to claim 9, wherein the alcohol solvent is a mixed solvent of methanol and ethanol, and the crystallization time is 5 days. 根据权利要求10所述的制备方法，所述甲醇和乙醇的体积比(v:v)为1:3-3:1。The production method according to claim 10, wherein the volume ratio (v:v) of methanol to ethanol is 1:3 to 3:1. 根据权利要求11所述的制备方法，所述甲醇和乙醇的体积比(v:v)为1:1。The production method according to claim 11, wherein the volume ratio (v:v) of methanol to ethanol is 1:1. 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CS6、权利要求5中所述的晶型CS5或它们的任意混合及药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form CS6 of claim 1, the crystalline form CS5 of claim 5, or any combination thereof and a pharmaceutically acceptable carrier, Diluent or excipient. 权利要求1中所述的晶型CS6、权利要求5中所述的晶型CS5或它们的任意混合在生产用于制备前列腺素D2受体2拮抗剂药物制剂中的用途。Use of the crystalline form CS6 of claim 1, the crystalline form CS5 of claim 5, or any mixture thereof, for the manufacture of a pharmaceutical formulation for the preparation of a prostaglandin D2 receptor 2 antagonist. 权利要求1中所述的晶型CS6、权利要求5中所述的晶型CS5或它们的任意混合在生产 用于制备治疗哮喘和/或过敏性皮炎和/或过敏性鼻炎药物制剂中的用途。Use of the crystalline form CS6 as claimed in claim 1, the crystalline form CS5 of claim 5, or any mixture thereof, for the manufacture of a pharmaceutical preparation for the treatment of asthma and/or atopic dermatitis and/or allergic rhinitis .
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