WO2024027013A1 - Crystal form ii of elobixibat and preparation method therefor - Google Patents

Crystal form ii of elobixibat and preparation method therefor Download PDF

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WO2024027013A1
WO2024027013A1 PCT/CN2022/124083 CN2022124083W WO2024027013A1 WO 2024027013 A1 WO2024027013 A1 WO 2024027013A1 CN 2022124083 W CN2022124083 W CN 2022124083W WO 2024027013 A1 WO2024027013 A1 WO 2024027013A1
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crystal form
eloxibate
ketones
eloxibat
ray powder
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PCT/CN2022/124083
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French (fr)
Chinese (zh)
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曹铭
陈玉凤
陈道玉
邹洁
张姿微
金飞敏
杨绍波
郑保富
高强
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上海皓元医药股份有限公司
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Priority to CN202280060973.7A priority Critical patent/CN117980295A/en
Publication of WO2024027013A1 publication Critical patent/WO2024027013A1/en

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to the crystal form of eloxibate and belongs to the technical fields of medicine and chemistry.
  • Elobixibat is a drug developed by Albireo AB (trade name: Goofice). It is the world's first approved bile acid transport inhibitor drug. It was approved by PMDA in January 2018 for the treatment of chronic constipation. Compared with traditional intestinal secretagogues and intestinal prokinetic drugs, eloxibate can effectively reduce the hardness of defecation and increase the frequency of defecation, improve the smoothness of defecation and cause less abdominal cramps or pain. The structural formula of this compound is shown below:
  • Patent WO2002050051A1 discloses compounds of formula (1) and preparation methods and pharmaceutical compositions thereof.
  • Patent WO2014174066A1 discloses a crystalline monohydrate IV of eloxibate. Its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ values of 6.3 ⁇ 0.2°, 19.4 ⁇ 0.2°, 10.2 ⁇ 0.2°, 10.5 ⁇ 0.2°, and 9.4 ⁇ 0.2° and 9.5 ⁇ 0.2°; crystal modifications EtOH-1, crystal modification MeOH-1, crystal modification 1-PrOH-1 and crystal modification 2-PrOH-1 of eloxibate are also disclosed.
  • Patent CN112375044A (WO2016062848A1) discloses anhydrous form C, dihydrate crystal form E, anhydrous form F, anhydrous form L and dihydrate crystal form N; among which anhydrous form C and anhydrous form L are highly hygroscopic, It will turn into crystalline hydrate at 30-70% RH. The water and environmental humidity must be strictly controlled during actual production or preparation process.
  • the CN112375044A patent also discloses that the preparation method of the anhydrous form F needs to be prepared through the solid-solid transformation of the solvate. Specifically, the solvate MIBK solvate G or EA solvate H is first prepared, and then the solvate is prepared at a high temperature of 100°C.
  • eloxibate compounds are easy to form solvates. Due to the problem of residual dissolution, these solvates have poor pharmaceutical properties; eloxibate hydrates and anhydrous products often have hygroscopic properties or preparation conditions. Harsh; only the crystalline form F has acceptable hygroscopicity and relatively good stability, but its preparation process is obtained by drying the corresponding MIBK solvate G and EA solvate H at 100°C at high temperature. This method is not conducive to Industrial production and quality control.
  • the invention provides a new crystal form of eloxibate and a preparation method thereof.
  • the crystal form has stable physical and chemical properties and can meet the requirements of low hygroscopicity for medicinal purposes.
  • the preparation method of the crystal form is easy to operate and is conducive to industrial production.
  • the present invention provides an anhydrous crystal form II of eloxibat with good stability (hereinafter also referred to as "crystalline form II") and a preparation method thereof.
  • the present invention provides a crystal form II of eloxibate, the X-ray powder diffraction pattern of which has characteristic peaks at 2 ⁇ values of 9.4 ⁇ 0.2° and 7.8 ⁇ 0.2°.
  • the invention provides a crystal form II of eloxibate, the X-ray powder diffraction pattern of which has characteristic peaks at 2 ⁇ values of 9.4 ⁇ 0.2° and 7.8 ⁇ 0.2° and has one or more of the following characteristic peaks: 3.9 ⁇ 0.2 °, 11.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.1 ⁇ 0.2° and 25.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form II of eloxibate of the present invention also has characteristic peaks at 2 ⁇ values of 3.9 ⁇ 0.2°, 8.8 ⁇ 0.2°, and 19.6 ⁇ 0.2°.
  • the invention provides a crystal form II of eloxibate, the X-ray powder diffraction pattern of which has 2 ⁇ values of 3.9 ⁇ 0.2°, 7.8 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.6
  • the XRPD pattern of crystal form II of the compound of formula I of the present invention is consistent with Figure 1 or Figure 2.
  • the present invention relates to a method for preparing crystalline Form II, comprising the following method:
  • the raw material eloxibat in the method one or two is amorphous eloxibat or another crystal form of eloxibat.
  • the raw material eloxibat is the eloxibat monohydrate crystal form IV reported in WO2014174066A1.
  • other raw materials of eloxibat may also be used, such as other solvates of eloxibat (for example, those reported in WO2014174066A1 or CN112375044A (WO2016062848A1) or crystal forms prepared by other conventional crystallization methods), or may also be used It is amorphous.
  • the mass volume ratio (g: mL) of the mixed solvent of eloxibat and ketones or ketones and liquid alkanes is 1:5 to 100, preferably 1 :15 ⁇ 30.
  • the ketone in method one or two is preferably acetone;
  • the liquid alkane is preferably at least one of pentane, n-hexane or n-heptane, and further preferably n-hexane or n-heptane. At least one.
  • the volume ratio of ketones to liquid alkanes in method one or method two is preferably 2:1 to 1:15; preferably the ketone is acetone and the liquid alkane is n-hexane or n-heptane; The volume ratio of acetone to n-hexane or n-heptane is 2:1 to 1:15, preferably 1:3 to 1:10.
  • drying in the first or second method is preferably carried out under vacuum or normal pressure blast drying at 30-60°C; the preferred drying time is 1-24 hours.
  • step a) of method 1 is to dissolve the raw material eloxibat in ketones or a mixed solvent of ketones and liquid alkanes, and the solution can be heated to dissolve it.
  • the temperature is preferably raised to 50-60°C; the rate of heating and cooling does not have a decisive influence on the formation of crystal form II.
  • it is recommended to heat at a rate of 5 to 30°C/min; specifically, for example, to heat at a rate of 5 to 15°C/min.
  • step b) of method 1 it is recommended to cool down at a rate of 1 to 15°C/min, preferably naturally, to cool to room temperature.
  • the DSC pattern of crystalline Form II of eloxibate of the present invention includes an endothermic peak at 169.5 ⁇ 0.5°C.
  • the eloxibat crystal form II provided above by the present invention is heated from room temperature to 300°C using a thermogravimetric analyzer (TGA) at a heating rate of 10°C/min.
  • TGA thermogravimetric analyzer
  • the temperature is 150°C, there will be no more than 2% weight loss, and more preferably, no more than 1.2% weight loss.
  • Crystalline Form II is the acrystalline form. There is no risk of crystallization due to loss of solvent under reduced pressure and elevated temperature in the non-crystalline form. So only the solvent needs to be removed from the surface.
  • the solid is dried under vacuum at room temperature.
  • the crystal form II of eloxibate provided by the present invention is physically stable at room temperature.
  • the crystal form II does not absorb water molecules to form hydrate crystal form IV or any other hydrate crystal form.
  • the eloxibat crystal form II provided by the present invention is chemically pure and stable at room temperature, and the anhydrate crystal form II is exposed to 40°C/75% RH. Or in a 25°C/92.5%RH environment, the chemical purity of crystalline Form II has no significant change.
  • the eloxibat crystal form II provided by the present invention is slightly hygroscopic at 25°C and 0-90% RH environment, and XRPD shows no crystallization phenomenon.
  • the DVS isotherm of the crystal form II provided by the present invention has no obvious change in moisture (the moisture absorption of 1.1% in Figure 8 is significantly lower than the 5.0%, 0-90% RH of the crystal form C reported in CN112375044A (WO2016062848A1)), and the hygroscopicity
  • the XRPD spectra of the samples after testing are consistent, that is, there is no risk of crystallization during the adsorption and desorption process.
  • the crystal form II of the present invention is more conducive to industrial production; through comparison in Figure 10, there are obvious differences between the crystal form II of the present invention and all reported crystal forms in CN112375044A, and can be identified as different crystal forms.
  • the present invention also provides a medicine for treating constipation, which contains an active ingredient, and the active ingredient includes the crystal form II of the eloxibat crystal as described above; the medicine includes excipients other than the active ingredient, the selection of excipients, and the Preparation, etc. are common choices.
  • pharmaceutical excipients can be selected from: microcrystalline cellulose, D-mannitol, hypromellose, croscarmellose sodium, light anhydrous silicic acid, magnesium stearate , polyethylene glycol 6000, titanium oxide, yellow ferric oxide or carnauba wax, etc.
  • the active ingredient of the medicament of the present invention may only comprise the crystalline form II of eloxibat, and in this case, the crystalline form II of eloxibat is present in an effective amount.
  • the present invention has significantly improved solubility due to crystal form II, more flexible selection of excipients, and higher drug safety.
  • the new anhydrous crystal form of eloxibat crystal form II provided by the present invention not only has good stability, low hygroscopicity, meets pharmaceutical requirements, but also has significantly improved solubility. It is expected that it will have better Ideal drug selection and better bioavailability, as well as helping to increase potency and reduce dosage.
  • Crystal form II of the present invention can be dried under vacuum at 30-60°C without the risk of crystallization due to water loss.
  • Figure 1 is an X-ray powder diffraction (XPRD) pattern of crystal form II obtained in Example 1.1 of the present invention
  • Figure 2 is an X-ray powder diffraction (XPRD) pattern of crystal form II obtained in Example 1.2 of the present invention
  • FIG. 3 is a thermogravimetric analysis (TGA) spectrum of crystal form II obtained in Example 1.1 of the present invention
  • Figure 4 is a differential scanning calorimetry (DSC) spectrum of crystal form II obtained in Example 1.1 of the present invention.
  • Figure 5 is an X-ray powder diffraction comparison chart showing the stability of crystal form II obtained in Example 1.1 of the present invention before and after placement;
  • Figure 6 is an X-ray powder diffraction comparison chart showing the stability of crystal form C obtained in the comparative example of the present invention before and after placement;
  • Figure 7 is an X-ray powder diffraction comparison chart showing the stability of crystal form IV prepared according to the method of WO2014174066A1 before and after placement;
  • Figure 8 is a hygroscopicity test (DVS) chart of crystal form II obtained in Example 1.1 of the present invention.
  • Figure 9 is an X-ray powder diffraction comparison chart before and after the hygroscopicity test of the crystal form II obtained in Example 1.1 of the present invention.
  • Figure 10 is a comparison chart of X-ray powder diffraction of the crystal form II obtained in Example 1.1 of the present invention and the crystal form reported in the prior art.
  • the XPRD spectrum was collected on a Bruker D8 ADVANCE diffractometer.
  • the parameters of the X-ray powder diffraction method are as follows:
  • Tube voltage 40 kilovolts (kV)
  • Tube current 40 milliamps (mA)
  • Slits 2# scattering slit: 1°, 3# anti-scattering slit: 1°, 4# receiving slit: 0.3mm.
  • test tube The contents of the test tube were filtered and poured into a crystallization bowl, which was then vacuum dried at 60°C for 2 hours.
  • the sample was analyzed by XRPD, which showed that the solid form was Form C anhydrate.
  • the XRPD spectrum was compared with the anhydrous Form C disclosed in patent CN112375044A (WO2016062848A1) and was the same crystal form.
  • the X-ray powder diffraction pattern of the obtained solid product is shown in Figure 1.
  • the X-ray powder diffraction pattern of the obtained crystal form II has 2 ⁇ values of 3.9 ⁇ 0.2°, 7.8 ⁇ 0.2°, 9.4 ⁇ 0.2°, and 11.7 ⁇ 0.2 °, 16.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.3 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.1 ⁇ 0.2°, 25.8 ⁇ 0.2° and below: 8.5 ⁇ 0.2°, 8.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.1 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.1 ⁇ 0.2°, 17.1 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.6 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.5 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.6 ⁇ 0.2°, 27.2 ⁇ 0.2°, 27.5 ⁇ 0.2°, 28.4 ⁇ 0.2°, 28.6 ⁇ 0.2°, 29.9 ⁇ 0.2°, There are characteristic
  • the TGA spectrum of the obtained crystal form II is shown in Figure 3.
  • the TGA data shows that the crystal form has a weight loss of approximately 1.02% in the heating range of 0 to 150°C.
  • the DSC image of the obtained crystal form II is shown in Figure 4.
  • the crystal form II has a single melting endotherm peak at 164-200°C. Specifically, Form II has a single absorption peak at 169.5 ⁇ 0.5°C.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the X-ray powder diffraction pattern measured using Cu-K ⁇ rays of the prepared crystals is the same as that of Example 1.1.
  • the target crystal form II of the compound obtained in Example 1.1, the crystal form IV prepared according to the method of WO2014174066A, and the crystal form C obtained in the comparative example were placed under different temperatures and different humidity environments for 3 days or one week, and samples were taken for XRPD comparison. Crystal form, chemical purity measured by HPLC, as shown in Table 1 below:
  • the crystal form II obtained by the present invention and the crystal form IV prepared according to the method of WO2014174066A1 were stored in five different humidity and temperature conditions shown in Table 1 (25°C/60%RH, 40°C /75%RH, 25°C/92.5%RH, room temperature environment (28°C/66%RH) or 25°C/10%RH) for one week, there is no obvious change in the X-ray powder diffraction pattern, indicating that the crystalline form is in the above environment. Can be kept for at least a week.
  • the crystalline Form C exhibits a high degree of stability under five different humidity and temperature conditions shown in Table 1 (25°C/60%RH, 40°C/75%RH, 25°C/92.5%RH, room temperature environment (28°C/ The crystal form has changed after being stored under 66% RH) for three days, and crystallized into the crystal form E published in CN112375044A.
  • Crystalline form II and crystalline form IV still have good stability under high temperature and high humidity conditions.
  • crystalline form II of eloxibate shows excellent stability under both 40°C/75%RH and 25°C/92.5%RH conditions.
  • stability is the stability, with no change in the purity of crystalline Form II of eloxibate.
  • Patent CN112375044A discloses DVS without crystalline form C and crystalline form E. Crystalline form C will transform into crystalline hydrate E at 30-70% RH and absorb about 5% water at 90% humidity. In the actual production or preparation process Water and environmental humidity must be strictly controlled.
  • Patent WO2014174066A1 discloses the DVS of monohydrate crystal form IV. Crystal form IV absorbs about 2.45% water between 0% RH and 10% RH, and absorbs more than 3% water at 90% humidity. In the actual production or preparation process, the Moisture and environmental humidity must be controlled to prevent crystallization.
  • the crystal form II of the present application has good low hygroscopicity compared to the anhydrous form C disclosed in patent CN112375044A (WO2016062848A1) and the monohydrate crystal form IV disclosed in WO2014174066A1.
  • strict humidity control is not required to remain stable. It has low requirements on drug preparation process and storage conditions.
  • the invention provides a crystal form II of eloxibate and a preparation method thereof.
  • the crystal form has stable physical and chemical properties and can meet the requirements of low hygroscopicity for medicinal purposes.
  • the preparation method is easy to operate and can realize industrial production.

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Abstract

A crystal form II of elobixibat. The X-ray powder diffraction pattern of the crystal form II has specific peaks at 2θ values 9.4±0.2° and 7.8±0.2° and has one or more of following characteristic peaks: 3.9±0.2°, 11.7±0.2°, 16.1±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2°, and 25.8±0.2°. The crystal form II is stable and has low hygroscopicity; when exposed to a high-humidity environment of 25°C/92.5%RH, the chemical purity of the crystal form II does not change significantly, and the X-ray powder diffraction pattern of the crystal form likewise does not change; moreover, the crystal form II involves a simple and convenient preparation method, has low requirements with respect to the preparation process and storage conditions, and has high medicinal value.

Description

一种依洛西巴特晶型II及其制备方法A kind of eloxibate crystal form II and its preparation method 技术领域Technical field
本发明涉及依洛西巴特的晶体形式，属于药物和化学技术领域。The present invention relates to the crystal form of eloxibate and belongs to the technical fields of medicine and chemistry.
背景技术Background technique
依洛西巴特(Elobixibat)是由Albireo AB公司研发的药物(商品名：Goofice)，是全球首款获得批准上市的胆汁酸转运抑制药物，2018年1月获PMDA批准，用于治疗慢性便秘。与传统的肠道促分泌药和肠道促动力药相比，依洛西巴特可以有效降低排便的硬度并增加排便次数，提高排便流畅性的同时较少引起腹部痉挛或疼痛。该化合物结构式如下图所示：Elobixibat is a drug developed by Albireo AB (trade name: Goofice). It is the world's first approved bile acid transport inhibitor drug. It was approved by PMDA in January 2018 for the treatment of chronic constipation. Compared with traditional intestinal secretagogues and intestinal prokinetic drugs, eloxibate can effectively reduce the hardness of defecation and increase the frequency of defecation, improve the smoothness of defecation and cause less abdominal cramps or pain. The structural formula of this compound is shown below:
Figure PCTCN2022124083-appb-000001
Figure PCTCN2022124083-appb-000001
专利WO2002050051A1公开了式(1)化合物及其制备方法和药物组合物。Patent WO2002050051A1 discloses compounds of formula (1) and preparation methods and pharmaceutical compositions thereof.
专利WO2014174066A1公开了一种依洛西巴特的结晶单水合物IV，其X射线粉末衍射图谱在2θ值特征峰为6.3±0.2°、19.4±0.2°、10.2±0.2°、10.5±0.2°、9.4±0.2°和9.5±0.2°；还公开了依洛昔巴特的结晶修饰物EtOH-1、结晶修饰物MeOH-1、结晶修饰物1-PrOH-1和结晶修饰物2-PrOH-1。Patent WO2014174066A1 discloses a crystalline monohydrate IV of eloxibate. Its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 6.3±0.2°, 19.4±0.2°, 10.2±0.2°, 10.5±0.2°, and 9.4 ±0.2° and 9.5±0.2°; crystal modifications EtOH-1, crystal modification MeOH-1, crystal modification 1-PrOH-1 and crystal modification 2-PrOH-1 of eloxibate are also disclosed.
专利CN112375044A(WO2016062848A1)公开了无水晶型C、二水合物晶型E、无水晶型F、无水晶型L和二水合物晶型N；其中无水晶型C和无水晶型L吸湿性强，在30～70％RH会转晶水合物，在实际生产或者制剂过程中要严格控制水分及环境湿度。CN112375044A专利中还公开了无水晶型F的制备方法需要通过溶剂合物固-固转变制备得到，具体为先制备成溶剂合物MIBK溶剂合物G或EA溶剂合物 H，再在100℃高温条件下真空干燥才能制备得到，制备工艺要求苛刻，在实际生产过程中难以实现；通过高温干燥制备无水晶型F的过程往往存在样品不均匀的问题，且无法进行中控进而带来一系列混晶的风险，重现性差。Patent CN112375044A (WO2016062848A1) discloses anhydrous form C, dihydrate crystal form E, anhydrous form F, anhydrous form L and dihydrate crystal form N; among which anhydrous form C and anhydrous form L are highly hygroscopic, It will turn into crystalline hydrate at 30-70% RH. The water and environmental humidity must be strictly controlled during actual production or preparation process. The CN112375044A patent also discloses that the preparation method of the anhydrous form F needs to be prepared through the solid-solid transformation of the solvate. Specifically, the solvate MIBK solvate G or EA solvate H is first prepared, and then the solvate is prepared at a high temperature of 100°C. It can only be prepared by vacuum drying under certain conditions. The preparation process is demanding and difficult to achieve in the actual production process. The process of preparing acrystalline form F through high-temperature drying often has the problem of uneven samples, and it cannot be controlled in-process, which leads to a series of mixtures. Risk of crystallization and poor reproducibility.
根据现有报道晶型可见：依洛西巴特化合物容易形成溶剂合物，由于溶残问题，这些溶剂合物成药性差；依洛西巴特水合物和无水物，又多有引湿性或者制备条件苛刻；仅无水晶型F引湿性尚可，稳定性相对较好，但是它的制备工艺是通过相应的MIBK溶剂合物G和EA溶剂合物H在100℃高温干燥获得的，这个方式不利于产业化生产和质量控制。According to the existing reported crystal forms, eloxibate compounds are easy to form solvates. Due to the problem of residual dissolution, these solvates have poor pharmaceutical properties; eloxibate hydrates and anhydrous products often have hygroscopic properties or preparation conditions. Harsh; only the crystalline form F has acceptable hygroscopicity and relatively good stability, but its preparation process is obtained by drying the corresponding MIBK solvate G and EA solvate H at 100°C at high temperature. This method is not conducive to Industrial production and quality control.
本发明提供一种依洛西巴特的新晶型及其制备方法，该晶型理化性质稳定，可满足药用低吸湿要求，且该晶型的制备方法操作简便，有利于实现产业化生产。The invention provides a new crystal form of eloxibate and a preparation method thereof. The crystal form has stable physical and chemical properties and can meet the requirements of low hygroscopicity for medicinal purposes. The preparation method of the crystal form is easy to operate and is conducive to industrial production.
发明内容Contents of the invention
针对以上背景技术，本发明提供了一种具有良好稳定性的依洛昔巴特的无水晶体形式II(下文也称为“晶型II”)及其制备方法。In view of the above background technology, the present invention provides an anhydrous crystal form II of eloxibat with good stability (hereinafter also referred to as "crystalline form II") and a preparation method thereof.
本发明提供了一种依洛西巴特的晶体形式II，其X射线粉末衍射图谱在2θ值为9.4±0.2°及7.8±0.2°处具有特征峰。The present invention provides a crystal form II of eloxibate, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ values of 9.4±0.2° and 7.8±0.2°.
本发明提供了一种依洛西巴特的晶体形式II，其X射线粉末衍射图谱在2θ值9.4±0.2°及7.8±0.2°处具有特征峰且具有一个或多个以下特征峰：3.9±0.2°、11.7±0.2°、16.1±0.2°、17.6±0.2°、18.3±0.2°、19.6±0.2°、20.9±0.2°、22.1±0.2°及25.8±0.2°。The invention provides a crystal form II of eloxibate, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ values of 9.4±0.2° and 7.8±0.2° and has one or more of the following characteristic peaks: 3.9±0.2 °, 11.7±0.2°, 16.1±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2° and 25.8±0.2°.
更进一步地，本发明的依洛西巴特的晶体形式II的X射线粉末衍射图谱在2θ值3.9±0.2°、8.8±0.2°、19.6±0.2°处还具有特征峰。Furthermore, the X-ray powder diffraction pattern of the crystal form II of eloxibate of the present invention also has characteristic peaks at 2θ values of 3.9±0.2°, 8.8±0.2°, and 19.6±0.2°.
本发明提供了一种依洛西巴特的晶体形式II，其X射线粉末衍射图谱在2θ值3.9±0.2°、7.8±0.2°、9.4±0.2°、11.7±0.2°、16.1±0.2°、17.6±0.2°、18.3±0.2°、19.6±0.2°、20.9±0.2°、22.1±0.2°及25.8±0.2°处具有特征峰且具有一个或多个以下特征峰：8.5±0.2°、8.8±0.2°、10.4±0.2°、11.1±0.2°、13.0±0.2°、14.0±0.2°、14.5±0.2°、15.1±0.2°、17.1±0.2°、19.0±0.2°、20.6±0.2°、21.3±0.2°、22.6±0.2°、23.7±0.2°、24.5±0.2°、24.7±0.2°、 26.6±0.2°、27.2±0.2°、27.5±0.2°、28.4±0.2°、28.6±0.2°、29.9±0.2°、30.5±0.2°、31.6±0.2°、32.5±0.2°、33.5±0.2°、34.5±0.2°、35.4±0.2°、37.1±0.2°及38.1±0.2°。The invention provides a crystal form II of eloxibate, the X-ray powder diffraction pattern of which has 2θ values of 3.9±0.2°, 7.8±0.2°, 9.4±0.2°, 11.7±0.2°, 16.1±0.2°, 17.6 There are characteristic peaks at ±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2° and 25.8±0.2° and one or more of the following characteristic peaks: 8.5±0.2°, 8.8±0.2 °, 10.4±0.2°, 11.1±0.2°, 13.0±0.2°, 14.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.1±0.2°, 19.0±0.2°, 20.6±0.2°, 21.3±0.2 °, 22.6±0.2°, 23.7±0.2°, 24.5±0.2°, 24.7±0.2°, 26.6±0.2°, 27.2±0.2°, 27.5±0.2°, 28.4±0.2°, 28.6±0.2°, 29.9±0.2 °, 30.5±0.2°, 31.6±0.2°, 32.5±0.2°, 33.5±0.2°, 34.5±0.2°, 35.4±0.2°, 37.1±0.2° and 38.1±0.2°.
进一步优选地，本发明所述式I化合物的晶体形式II，晶体形式II的XRPD图谱与图1或图2一致。Further preferably, the XRPD pattern of crystal form II of the compound of formula I of the present invention is consistent with Figure 1 or Figure 2.
在另一方面中，本发明涉及用于制备晶体形式II的方法，包含以下方法：In another aspect, the present invention relates to a method for preparing crystalline Form II, comprising the following method:
方法一：method one:
a)将原料依洛昔巴特溶于酮类或酮类与液态烷烃的混合溶剂中；a) Dissolve the raw material eloxibate in ketones or a mixed solvent of ketones and liquid alkanes;
b)搅拌并降温至晶体析出，滤集析出结晶、干燥得到晶体形式II；b) Stir and cool down until crystals precipitate, filter and collect the precipitated crystals, and dry to obtain crystal form II;
方法二：Method Two:
1)在适宜温度(例如10～40℃，优选室温)下，将原料依洛昔巴特于酮类或酮类与液态烷烃的混合溶剂中得到混悬液；1) Dissolve the raw material eloxibat in ketones or a mixed solvent of ketones and liquid alkanes at a suitable temperature (for example, 10 to 40°C, preferably room temperature) to obtain a suspension;
2)搅拌并降温(例如，至0～8℃，优选约5℃)，继续搅拌一定时间(例如12小时以上，优选24～48小时)至晶体完全析出，滤集析出结晶、干燥得到晶体形式II。2) Stir and cool down (for example, to 0-8°C, preferably about 5°C), continue stirring for a certain period of time (for example, more than 12 hours, preferably 24-48 hours) until the crystals are completely precipitated, filter the precipitated crystals, and dry to obtain the crystal form. II.
进一步地，所述方法一或方法二中原料依洛昔巴特是无定形依洛昔巴特或依洛昔巴特的另一晶体形式。在优选实施方式中，原料依洛昔巴特为WO2014174066A1报道的依洛昔巴特单水合物晶体形式IV。此外，也可以采用其他原料依洛昔巴特，例如依洛昔巴特的其他溶剂化物(例如可以是WO2014174066A1或CN112375044A(WO2016062848A1)所报道的那些或者通过其他常规结晶方法制备的晶型)，或者还可以是无定形。Further, the raw material eloxibat in the method one or two is amorphous eloxibat or another crystal form of eloxibat. In a preferred embodiment, the raw material eloxibat is the eloxibat monohydrate crystal form IV reported in WO2014174066A1. In addition, other raw materials of eloxibat may also be used, such as other solvates of eloxibat (for example, those reported in WO2014174066A1 or CN112375044A (WO2016062848A1) or crystal forms prepared by other conventional crystallization methods), or may also be used It is amorphous.
在某些实施方式中，所述方法一或方法二中依洛昔巴特与酮类或酮类与液态烷烃的混合溶剂的质量体积比(g：mL)为1：5～100，优选为1：15～30。In certain embodiments, in the method one or two, the mass volume ratio (g: mL) of the mixed solvent of eloxibat and ketones or ketones and liquid alkanes is 1:5 to 100, preferably 1 :15～30.
在某些实施方式中，所述方法一或方法二中酮类优选为丙酮；液态烷烃优选为戊烷、正己烷或正庚烷中的至少一种，进一步优选正己烷或正庚烷中的至少一种。In certain embodiments, the ketone in method one or two is preferably acetone; the liquid alkane is preferably at least one of pentane, n-hexane or n-heptane, and further preferably n-hexane or n-heptane. At least one.
在某些实施方式中，所述方法一或方法二中所述酮类与液态烷烃 的体积比优选2：1～1：15；优选酮类为丙酮，液态烷烃为正己烷或正庚烷；所述丙酮与正己烷或正庚烷体积比2：1～1：15，优选1：3～1：10。In certain embodiments, the volume ratio of ketones to liquid alkanes in method one or method two is preferably 2:1 to 1:15; preferably the ketone is acetone and the liquid alkane is n-hexane or n-heptane; The volume ratio of acetone to n-hexane or n-heptane is 2:1 to 1:15, preferably 1:3 to 1:10.
在某些实施方式中，所述方法一或方法二中干燥，优选在30～60℃真空或常压鼓风干燥；优选干燥时间1～24小时。In some embodiments, drying in the first or second method is preferably carried out under vacuum or normal pressure blast drying at 30-60°C; the preferred drying time is 1-24 hours.
在某些实施方式中，方法一的步骤a)将原料依洛昔巴特溶于酮类或酮类与液态烷烃的混合溶剂中，可采用溶液升温使之溶解。本发明方法中，优选升温至50～60℃；升温和降温的速率对于晶型II的形成不具有决定性影响。然而，综合产业实施等多方面的考虑，升温建议以5～30℃/min的速率进行加热；具体例如以5～15℃/min的速率进行加热。In certain embodiments, step a) of method 1 is to dissolve the raw material eloxibat in ketones or a mixed solvent of ketones and liquid alkanes, and the solution can be heated to dissolve it. In the method of the present invention, the temperature is preferably raised to 50-60°C; the rate of heating and cooling does not have a decisive influence on the formation of crystal form II. However, based on various considerations such as industrial implementation, it is recommended to heat at a rate of 5 to 30°C/min; specifically, for example, to heat at a rate of 5 to 15°C/min.
在某些实施方式中，方法一的步骤b)中，建议以1～15℃/min的速率降温，优选为自然降温，使其冷却至室温。In certain embodiments, in step b) of method 1, it is recommended to cool down at a rate of 1 to 15°C/min, preferably naturally, to cool to room temperature.
本发明的依洛西巴特的晶体形式II的DSC图谱包括在169.5±0.5℃处的吸热峰。The DSC pattern of crystalline Form II of eloxibate of the present invention includes an endothermic peak at 169.5±0.5°C.
更进一步地，本发明的依洛西巴特的晶体形式II的DSC图谱的吸热峰位置与图4所示基本相同。Furthermore, the endothermic peak position of the DSC spectrum of the crystal form II of eloxibate of the present invention is basically the same as shown in Figure 4.
非限制性地，在本发明的一个具体实施方案中，本发明上述提供的依洛昔巴特晶体形式II，当采用热重分析仪(TGA)10℃/min的加热速率从室温升温到300℃时，150℃之前有不超过2％的失重，更优地，不超过1.2％的失重。晶体形式II是无水晶型。无水晶型没有在减压及升高的温度下失去溶剂从而转晶的风险。因此只需去除表面的溶剂即可。优选地，在室温真空环境下干燥固体。Without limitation, in a specific embodiment of the present invention, the eloxibat crystal form II provided above by the present invention is heated from room temperature to 300°C using a thermogravimetric analyzer (TGA) at a heating rate of 10°C/min. When the temperature is 150℃, there will be no more than 2% weight loss, and more preferably, no more than 1.2% weight loss. Crystalline Form II is the acrystalline form. There is no risk of crystallization due to loss of solvent under reduced pressure and elevated temperature in the non-crystalline form. So only the solvent needs to be removed from the surface. Preferably, the solid is dried under vacuum at room temperature.
非限制性地，在本发明的一个具体实施方案中，本发明提供的依洛昔巴特晶体形式II，在室温环境下物理形态稳定，将无水晶体形式II暴露于来自空气的水分时，晶体形式II不会吸收水分子形成水合物晶体形式IV或其它任意水合物晶型。Without limitation, in a specific embodiment of the present invention, the crystal form II of eloxibate provided by the present invention is physically stable at room temperature. When the anhydrous crystal form II is exposed to moisture from the air, the crystal form II does not absorb water molecules to form hydrate crystal form IV or any other hydrate crystal form.
非限制性地，在本发明的一个具体实施方案中，本发明提供的依洛昔巴特晶体形式II，在室温环境下化学纯度稳定，将无水合物晶体形式II暴露于40℃/75％RH或25℃/92.5％RH环境中，晶体形式II化 学纯度无明显变化。Without limitation, in a specific embodiment of the present invention, the eloxibat crystal form II provided by the present invention is chemically pure and stable at room temperature, and the anhydrate crystal form II is exposed to 40°C/75% RH. Or in a 25°C/92.5%RH environment, the chemical purity of crystalline Form II has no significant change.
非限制性地，在本发明的一个具体实施方案中，本发明提供的依洛昔巴特晶体形式II，在25℃，0～90％RH环境下轻微吸湿，且XRPD显示没有转晶现象。Non-limitingly, in a specific embodiment of the present invention, the eloxibat crystal form II provided by the present invention is slightly hygroscopic at 25°C and 0-90% RH environment, and XRPD shows no crystallization phenomenon.
本发明提供的晶型II的DVS等温线，没有水分的明显变化(图8水分吸收量1.1％明显低于CN112375044A(WO2016062848A1)报道晶型C的5.0％，0～90％RH)，且吸湿性测试后的样品XRPD谱图前后一致，即在吸附解吸附过程中没有转晶风险。本发明晶型II更加有利于工业化生产；经过图10比对，本发明晶体形式II与CN112375044A中所有报道晶型有明显差异，可认定为不同晶型。The DVS isotherm of the crystal form II provided by the present invention has no obvious change in moisture (the moisture absorption of 1.1% in Figure 8 is significantly lower than the 5.0%, 0-90% RH of the crystal form C reported in CN112375044A (WO2016062848A1)), and the hygroscopicity The XRPD spectra of the samples after testing are consistent, that is, there is no risk of crystallization during the adsorption and desorption process. The crystal form II of the present invention is more conducive to industrial production; through comparison in Figure 10, there are obvious differences between the crystal form II of the present invention and all reported crystal forms in CN112375044A, and can be identified as different crystal forms.
本发明还提供一种治疗便秘的药物，包含活性成分，该活性成分包含如上所述的依洛昔巴特晶体的晶体形式II；所述药物包括活性成分之外的辅料，辅料的选择、药物的制备等是常规选择，例如药用辅料可选自：微晶纤维素，D-甘露醇，羟丙甲纤维素，交联羧甲基纤维素钠，轻质无水硅酸，硬脂酸镁，聚乙二醇6000，氧化钛，黄色三氧化二铁或巴西棕榈蜡等。The present invention also provides a medicine for treating constipation, which contains an active ingredient, and the active ingredient includes the crystal form II of the eloxibat crystal as described above; the medicine includes excipients other than the active ingredient, the selection of excipients, and the Preparation, etc. are common choices. For example, pharmaceutical excipients can be selected from: microcrystalline cellulose, D-mannitol, hypromellose, croscarmellose sodium, light anhydrous silicic acid, magnesium stearate , polyethylene glycol 6000, titanium oxide, yellow ferric oxide or carnauba wax, etc.
本发明的药物的活性成分可以仅包含依洛昔巴特的晶体形式II，此时，依洛昔巴特的晶体形式II以有效量存在。与现有的依洛昔巴特的晶型的药物(单水合物)相比，本发明由于晶体形式II具有显著提高的溶解性，辅料选择更灵活，药物安全性更高。The active ingredient of the medicament of the present invention may only comprise the crystalline form II of eloxibat, and in this case, the crystalline form II of eloxibat is present in an effective amount. Compared with the existing crystal form of eloxibat (monohydrate), the present invention has significantly improved solubility due to crystal form II, more flexible selection of excipients, and higher drug safety.
与现有技术相比，本发明提供的依洛昔巴特晶体形式II的无水新晶型，不仅稳定性好，引湿性低，满足药用要求，且同时溶解度有显著提高，期望其具有更理想的药物选择和更好的生物利用度，以及有助于提高药效和降低剂量。Compared with the existing technology, the new anhydrous crystal form of eloxibat crystal form II provided by the present invention not only has good stability, low hygroscopicity, meets pharmaceutical requirements, but also has significantly improved solubility. It is expected that it will have better Ideal drug selection and better bioavailability, as well as helping to increase potency and reduce dosage.
此晶体形式较晶体形式IV具有更灵活的干燥条件，本发明的晶体形式II在30～60℃真空干燥，无失去水而导致转晶的风险。This crystal form has more flexible drying conditions than crystal form IV. Crystal form II of the present invention can be dried under vacuum at 30-60°C without the risk of crystallization due to water loss.
附图说明Description of the drawings
图1为本发明实施例1.1所得晶体形式II的X-射线粉末衍射(XPRD)图谱；Figure 1 is an X-ray powder diffraction (XPRD) pattern of crystal form II obtained in Example 1.1 of the present invention;
图2为本发明实施例1.2所得晶体形式II的X-射线粉末衍射(XPRD)图谱；Figure 2 is an X-ray powder diffraction (XPRD) pattern of crystal form II obtained in Example 1.2 of the present invention;
图3为本发明实施例1.1所得晶体形式II的热重分析(TGA)图谱；Figure 3 is a thermogravimetric analysis (TGA) spectrum of crystal form II obtained in Example 1.1 of the present invention;
图4为本发明实施例1.1所得晶体形式II的差式扫描量热(DSC)图谱；Figure 4 is a differential scanning calorimetry (DSC) spectrum of crystal form II obtained in Example 1.1 of the present invention;
图5为显示本发明实施例1.1所得晶体形式II放置前后的稳定性的X射线粉末衍射对比图；Figure 5 is an X-ray powder diffraction comparison chart showing the stability of crystal form II obtained in Example 1.1 of the present invention before and after placement;
图6为显示本发明对比实施例所得晶体形式C放置前后的稳定性的X射线粉末衍射对比图；Figure 6 is an X-ray powder diffraction comparison chart showing the stability of crystal form C obtained in the comparative example of the present invention before and after placement;
图7为显示根据WO2014174066A1的方法制备得到的晶体形式IV放置前后的稳定性的X射线粉末衍射对比图；Figure 7 is an X-ray powder diffraction comparison chart showing the stability of crystal form IV prepared according to the method of WO2014174066A1 before and after placement;
图8为本发明实施例1.1所得晶体形式II的引湿性测试(DVS)图谱；Figure 8 is a hygroscopicity test (DVS) chart of crystal form II obtained in Example 1.1 of the present invention;
图9为本发明实施例1.1所得晶体形式II引湿性测试前后的X射线粉末衍射对比图；Figure 9 is an X-ray powder diffraction comparison chart before and after the hygroscopicity test of the crystal form II obtained in Example 1.1 of the present invention;
图10为本发明实施例1.1所得晶体形式II与现有技术报道晶型的X射线粉末衍射对比图。Figure 10 is a comparison chart of X-ray powder diffraction of the crystal form II obtained in Example 1.1 of the present invention and the crystal form reported in the prior art.
具体实施方式Detailed ways
下面结合具体实施例，进一步阐述本发明。应理解，以下用实施例对本发明的技术方案进行详细说明，将有助于对本发明的技术方案的优点、效果有更进一步的了解，实施例不限定本发明的保护范围，本发明的保护范围由权利要求来决定。The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following detailed description of the technical solution of the present invention using examples will help to further understand the advantages and effects of the technical solution of the present invention. The examples do not limit the protection scope of the present invention. Determined by claims.
下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer.
实施例中所用的原料或试剂除特别说明之外，均市售可得。The raw materials or reagents used in the examples are all commercially available unless otherwise specified.
除非特别指出，所述的试剂不经纯化直接使用。所有溶剂均购自商业化供应商，并且不经处理就可使用。Unless otherwise stated, the reagents were used without purification. All solvents were purchased from commercial suppliers and used without treatment.
XPRD谱图是在Bruker D8 ADVANCE衍射仪上采集得的，所述的 X射线粉末衍射的方法参数如下：The XPRD spectrum was collected on a Bruker D8 ADVANCE diffractometer. The parameters of the X-ray powder diffraction method are as follows:
X射线反射参数：Cu，KαX-ray reflection parameters: Cu, Kα
管电压：40仟伏特(kV)Tube voltage: 40 kilovolts (kV)
管电流：40毫安培(mA)Tube current: 40 milliamps (mA)
狭缝：2#散射狭缝：1°，3#防散射狭缝：1°，4#接收狭缝：0.3mm。Slits: 2# scattering slit: 1°, 3# anti-scattering slit: 1°, 4# receiving slit: 0.3mm.
扫描模式：步进Scan mode: step
步进角度：0.02°Step angle: 0.02°
采样时间：0.2sSampling time: 0.2s
扫描范围：自3.0至40.0°Scanning range: from 3.0 to 40.0°
动态蒸气吸附(DVS)Dynamic Vapor Sorption (DVS)
将大约5～16mg样品称重放入金属容器中，将金属容器置于Intrinsic DVS Advantage仪器中。样品经过两个连续的吸附-解吸循环，每次运行在0％至90％至0％相对湿度(％RH)。一个循环由10个步骤组成，在0～90％RH之间的那些步骤各自相差10％RH。在每一阶段，使用以下平衡标准：历时5分钟的dm/dt<0.002％以及在每一阶段的最小和最大时间分别为10和360分钟。Weigh approximately 5 to 16 mg of sample into a metal container, and place the metal container in the Intrinsic DVS Advantage instrument. The samples were subjected to two consecutive adsorption-desorption cycles, each run at 0% to 90% to 0% relative humidity (%RH). A cycle consists of 10 steps, with those between 0 and 90% RH each differing by 10% RH. In each phase, the following equilibrium criteria were used: dm/dt <0.002% for 5 minutes and minimum and maximum times in each phase of 10 and 360 minutes respectively.
对比实施例Comparative Example
将111mg依洛昔巴特形式IV单水合物(根据WO2014174066A1实施例6的方法制备得到)称重放入10mL试管中，添加磁性搅拌子和2.0mL丙酮：水50：50％v/v混合溶液。观察现象：产生凝胶状物质，其不得不用手动搅拌并剧烈摇晃几分钟。然后将试管关闭并在20～30℃进行磁性搅拌。Weigh 111 mg of eloxibat form IV monohydrate (prepared according to the method of WO2014174066A1 Example 6) into a 10 mL test tube, add a magnetic stirrer and 2.0 mL of acetone:water 50:50% v/v mixed solution. Observations: A gel-like substance is produced, which has to be stirred by hand and shaken vigorously for several minutes. The test tube was then closed and magnetically stirred at 20-30°C.
将试管内容物过滤，倒入结晶碗中，然后将其在60℃真空干燥2小时。将该样品用XRPD分析，其显示，该固体形态为形式C无水物，经比对XRPD谱图与专利CN112375044A(WO2016062848A1)公开的无水晶型C为同一晶型。The contents of the test tube were filtered and poured into a crystallization bowl, which was then vacuum dried at 60°C for 2 hours. The sample was analyzed by XRPD, which showed that the solid form was Form C anhydrate. The XRPD spectrum was compared with the anhydrous Form C disclosed in patent CN112375044A (WO2016062848A1) and was the same crystal form.
实施例1：依洛西巴特晶型IIExample 1: Eloxibate Form II
实施例1.1Example 1.1
取依洛西巴特粗品30mg，加入0.5mL丙酮/正己烷(体积比1：1)， 加热至50～55℃，继续搅拌，边搅拌边降温，降温速率控制在5℃/min的速率，直至降温至25℃，继续搅拌、保温24h。抽滤，滤饼于50～60℃真空干燥16h，取样检测。Take 30 mg of crude eloxibate, add 0.5 mL acetone/n-hexane (volume ratio 1:1), heat to 50~55°C, continue stirring, and cool down while stirring, and the cooling rate is controlled at a rate of 5°C/min until Lower the temperature to 25°C, continue stirring, and keep warm for 24 hours. After suction filtration, the filter cake was vacuum dried at 50-60°C for 16 hours and sampled for testing.
经检测，所得固体产物的X射线粉末衍射谱图如图1所示，所得晶型II的X射线粉末衍射图谱在2θ值3.9±0.2°、7.8±0.2°、9.4±0.2°、11.7±0.2°、16.1±0.2°、17.6±0.2°、18.3±0.2°、19.6±0.2°、20.9±0.2°、22.1±0.2°、25.8±0.2°及以下位置：8.5±0.2°、8.8±0.2°、10.4±0.2°、11.1±0.2°、13.0±0.2°、14.0±0.2°、14.5±0.2°、15.1±0.2°、17.1±0.2°、19.0±0.2°、20.6±0.2°、21.3±0.2°、22.6±0.2°、23.7±0.2°、24.5±0.2°、24.7±0.2°、26.6±0.2°、27.2±0.2°、27.5±0.2°、28.4±0.2°、28.6±0.2°、29.9±0.2°、30.5±0.2°、31.6±0.2°、32.5±0.2°、33.5±0.2°、34.5±0.2°、35.4±0.2°、37.1±0.2°及38.1±0.2°处具有特征峰。After testing, the X-ray powder diffraction pattern of the obtained solid product is shown in Figure 1. The X-ray powder diffraction pattern of the obtained crystal form II has 2θ values of 3.9±0.2°, 7.8±0.2°, 9.4±0.2°, and 11.7±0.2 °, 16.1±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2°, 25.8±0.2° and below: 8.5±0.2°, 8.8±0.2°, 10.4±0.2°, 11.1±0.2°, 13.0±0.2°, 14.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.1±0.2°, 19.0±0.2°, 20.6±0.2°, 21.3±0.2°, 22.6±0.2°, 23.7±0.2°, 24.5±0.2°, 24.7±0.2°, 26.6±0.2°, 27.2±0.2°, 27.5±0.2°, 28.4±0.2°, 28.6±0.2°, 29.9±0.2°, There are characteristic peaks at 30.5±0.2°, 31.6±0.2°, 32.5±0.2°, 33.5±0.2°, 34.5±0.2°, 35.4±0.2°, 37.1±0.2° and 38.1±0.2°.
所得晶型II的TGA图谱如图3所示，TGA数据显示该晶型在0～150℃的加热区间有约1.02％的失重。The TGA spectrum of the obtained crystal form II is shown in Figure 3. The TGA data shows that the crystal form has a weight loss of approximately 1.02% in the heating range of 0 to 150°C.
所得晶型II的DSC图像如图4所示，晶型II在164～200℃存在单一熔化吸热峰。具体地，晶型II具有在169.5±0.5℃处的单一吸收峰。The DSC image of the obtained crystal form II is shown in Figure 4. The crystal form II has a single melting endotherm peak at 164-200°C. Specifically, Form II has a single absorption peak at 169.5±0.5°C.
实施例1.2Example 1.2
取依洛西巴特粗品30mg，加入0.6mL丙酮，50～60℃条件下搅拌，边搅拌边降温，直至降温至25℃，保温24h。真空抽滤，滤饼于40℃真空干燥16h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.6 mL of acetone, and stir at 50 to 60°C. While stirring, cool down until the temperature drops to 25°C, and keep warm for 24 hours. Vacuum filtration, vacuum drying the filter cake at 40°C for 16 hours, sampling and testing, and obtained crystal form II.
经检测，所得固体产物的X射线粉末衍射谱图XRPD图如图2所示。所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。After detection, the X-ray powder diffraction spectrum XRPD pattern of the obtained solid product is shown in Figure 2. The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.3Example 1.3
取依洛西巴特粗品30mg，加入0.5mL丙酮/正己烷(体积比1：3)，55～60℃条件下搅拌，边搅拌边降温，直至降温至25℃，保温24h。真空抽滤，滤饼于60℃真空干燥12h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.5 mL of acetone/n-hexane (volume ratio 1:3), stir at 55-60°C, and cool while stirring until the temperature drops to 25°C, and keep warm for 24 hours. Vacuum filtration, vacuum drying the filter cake at 60°C for 12 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.4Example 1.4
取依洛西巴特粗品30mg，加入0.6mL丙酮/正己烷(体积比1：5)，20～30℃条件下搅拌，得到混悬液，边搅拌边降温，直至降温至5℃，保温48h。真空抽滤，滤饼于30℃真空干燥16h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.6 mL of acetone/n-hexane (volume ratio 1:5), and stir at 20 to 30°C to obtain a suspension. Cool while stirring until the temperature drops to 5°C, and keep it warm for 48 hours. Vacuum filtration, vacuum drying the filter cake at 30°C for 16 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.5Example 1.5
取依洛西巴特粗品30mg，加入0.5mL丙酮/正己烷(体积比1：9)，50～55℃条件下搅拌，边搅拌边降温，直至降温至25℃，保温24h。真空抽滤，滤饼于30℃鼓风干燥16h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.5 mL of acetone/n-hexane (volume ratio 1:9), stir at 50-55°C, cool down while stirring, until the temperature drops to 25°C, and keep warm for 24 hours. Vacuum filtration, air drying the filter cake at 30°C for 16 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.6Example 1.6
取依洛西巴特粗品30mg，加入0.5mL丙酮/正庚烷(体积比1：3)，50～55℃条件下搅拌，边搅拌边降温，直至降温至25℃，保温24h。真空抽滤，滤饼于30℃鼓风干燥12h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.5 mL of acetone/n-heptane (volume ratio 1:3), stir at 50 to 55°C, and cool while stirring until the temperature drops to 25°C, and keep warm for 24 hours. Vacuum filtration, air drying the filter cake at 30°C for 12 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.7Example 1.7
取依洛西巴特粗品30mg，加入0.5mL丙酮/正己烷(体积比1：7)，20～30℃条件下搅拌，得到混悬液，边搅拌边降温，直至降温至5℃，保温48h。真空抽滤，滤饼于30℃真空干燥16h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.5 mL of acetone/n-hexane (volume ratio 1:7), and stir at 20 to 30°C to obtain a suspension. Cool while stirring until the temperature drops to 5°C, and keep it warm for 48 hours. Vacuum filtration, vacuum drying the filter cake at 30°C for 16 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.8Example 1.8
取依洛西巴特粗品30mg，加入3mL丙酮/正己烷(体积比1：15)，50～55℃条件下搅拌，边搅拌边降温，直至降温至25℃，保温24h。真空抽滤，滤饼于30℃鼓风干燥16h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 3 mL of acetone/n-hexane (volume ratio 1:15), stir at 50-55°C, cool down while stirring, until the temperature drops to 25°C, and keep warm for 24 hours. Vacuum filtration, air drying the filter cake at 30°C for 16 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例1.9Example 1.9
取依洛西巴特粗品30mg，加入0.15mL丙酮/正己烷(体积比2：1)，50～55℃条件下搅拌，边搅拌边降温，直至降温至25℃，保温24h。真空抽滤，滤饼于30℃鼓风干燥16h，取样检测，得晶型II。Take 30 mg of crude eloxibate, add 0.15 mL of acetone/n-hexane (volume ratio 2:1), stir at 50 to 55°C, and cool down while stirring until the temperature drops to 25°C, and keep warm for 24 hours. Vacuum filtration, air drying the filter cake at 30°C for 16 hours, sampling and testing, and obtained crystal form II.
所制得晶体的使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1.1相同。The X-ray powder diffraction pattern measured using Cu-Kα rays of the prepared crystals is the same as that of Example 1.1.
实施例2Example 2
稳定性实验stability test
由实施例1.1获得的化合物目标晶型II、根据WO2014174066A的方法制备得到的晶型IV、对比实施例获得的晶型C于不同温度、不同湿度环境下放置3天或一周，取样品测定XRPD对比晶型，测HPLC对比化学纯度，见下表1所示：The target crystal form II of the compound obtained in Example 1.1, the crystal form IV prepared according to the method of WO2014174066A, and the crystal form C obtained in the comparative example were placed under different temperatures and different humidity environments for 3 days or one week, and samples were taken for XRPD comparison. Crystal form, chemical purity measured by HPLC, as shown in Table 1 below:
表1Table 1
Figure PCTCN2022124083-appb-000002
Figure PCTCN2022124083-appb-000002
结果显示，由表1数据可知，本发明的依洛西巴特的晶体形式II和根据WO2014174066A1的方法制备得到的晶型IV具有相似的稳定性。The results show that, as can be seen from the data in Table 1, the crystal form II of eloxibate of the present invention and the crystal form IV prepared according to the method of WO2014174066A1 have similar stability.
如图5和图7所示，本发明所得晶体形式II和根据 WO2014174066A1的方法制备得到的晶型IV存放于表1所示的五种不同湿度和温度条件(25℃/60％RH、40℃/75％RH、25℃/92.5％RH、室温环境(28℃/66％RH)或25℃/10％RH)一周，其X射线粉末衍射图谱无明显变化，说明所述晶型在上述环境下能保存至少一周。As shown in Figures 5 and 7, the crystal form II obtained by the present invention and the crystal form IV prepared according to the method of WO2014174066A1 were stored in five different humidity and temperature conditions shown in Table 1 (25°C/60%RH, 40°C /75%RH, 25℃/92.5%RH, room temperature environment (28℃/66%RH) or 25℃/10%RH) for one week, there is no obvious change in the X-ray powder diffraction pattern, indicating that the crystalline form is in the above environment. Can be kept for at least a week.
如图6所示，晶体形式C在表1所示的五种不同湿度和温度条件(25℃/60％RH、40℃/75％RH、25℃/92.5％RH、室温环境(28℃/66％RH))下保存三天已经发生晶型改变，转晶为CN112375044A中公布的晶型E。As shown in Figure 6, the crystalline Form C exhibits a high degree of stability under five different humidity and temperature conditions shown in Table 1 (25°C/60%RH, 40°C/75%RH, 25°C/92.5%RH, room temperature environment (28°C/ The crystal form has changed after being stored under 66% RH) for three days, and crystallized into the crystal form E published in CN112375044A.
晶型II和晶型IV在高温、高湿条件下仍然具有良好的稳定性，特别是依洛西巴特的晶体形式II在40℃/75％RH和25℃/92.5％RH条件下都表现出特别突出的稳定性，依洛西巴特的晶体形式II的纯度均无变化。Crystalline form II and crystalline form IV still have good stability under high temperature and high humidity conditions. In particular, crystalline form II of eloxibate shows excellent stability under both 40℃/75%RH and 25℃/92.5%RH conditions. Of particular note is the stability, with no change in the purity of crystalline Form II of eloxibate.
实施例3Example 3
引湿性实验Hygroscopicity test
取实施例1.1制备的晶体形式II约15mg，在0-90-0％RH程序中进行吸附解吸附水测试，采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表2所示：Take about 15 mg of the crystal form II prepared in Example 1.1, perform an adsorption and desorption water test in a 0-90-0% RH program, and use a dynamic moisture adsorption (DVS) instrument to test its hygroscopicity. The experimental results are shown in Table 2:
表2Table 2
Figure PCTCN2022124083-appb-000003
Figure PCTCN2022124083-appb-000003
晶型II的引湿性实验的DVS图如图8所示，样品测试前后的XRPD对比图如图9所示。The DVS chart of the hygroscopicity test of Form II is shown in Figure 8, and the XRPD comparison chart before and after the sample test is shown in Figure 9.
结果表明，本申请的晶体形式II在90％湿度下平衡后增重约1.14％，属于略有引湿性。说明本申请的晶型形式II在不同湿度条件下均能保持稳定，具有良好的低引湿性。The results show that the crystal form II of the present application has a weight gain of about 1.14% after equilibrium at 90% humidity, and is slightly hygroscopic. It shows that the crystal form II of the present application can remain stable under different humidity conditions and has good low hygroscopicity.
专利CN112375044A(WO2016062848A1)公开了无水晶型C和晶型E的DVS，晶型C在30～70％RH会转晶水合物E，在90％湿度下吸水大约5％，在实际生产或者制剂过程中要严格控制水分及环境湿 度。Patent CN112375044A (WO2016062848A1) discloses DVS without crystalline form C and crystalline form E. Crystalline form C will transform into crystalline hydrate E at 30-70% RH and absorb about 5% water at 90% humidity. In the actual production or preparation process Water and environmental humidity must be strictly controlled.
专利WO2014174066A1公开了单水合物晶型IV的DVS，晶型IV在0％RH与10％RH之间吸收约2.45％水，在90％湿度下吸水超过3％，在实际生产或者制剂过程中也要控制水分及环境湿度，防止转晶。Patent WO2014174066A1 discloses the DVS of monohydrate crystal form IV. Crystal form IV absorbs about 2.45% water between 0% RH and 10% RH, and absorbs more than 3% water at 90% humidity. In the actual production or preparation process, the Moisture and environmental humidity must be controlled to prevent crystallization.
即，本申请的晶型II相较于专利CN112375044A(WO2016062848A1)公开的无水晶型C和WO2014174066A1公开的单水合物晶型IV具有良好的低吸湿性。在药品生产与存放过程中，无需严格的湿度控制即可保持稳定。对药品制备工艺以及存储条件要求低。That is, the crystal form II of the present application has good low hygroscopicity compared to the anhydrous form C disclosed in patent CN112375044A (WO2016062848A1) and the monohydrate crystal form IV disclosed in WO2014174066A1. During pharmaceutical production and storage, strict humidity control is not required to remain stable. It has low requirements on drug preparation process and storage conditions.
实施例4Example 4
在室温条件(约35℃)下，将对比实施例制备的晶型C、实施例1.1制备的晶型II与根据WO2014174066A1的方法制备得到的晶型IV的样品分别加入到pH 6.8的磷酸缓冲溶液(模拟人工小肠液)中，分别在2小时、6小时和24小时后采用高效液相色谱(HPLC)测定溶液中依洛西巴特的含量。实验结果如表3所示：At room temperature (about 35°C), samples of the crystal form C prepared in the comparative example, the crystal form II prepared in Example 1.1, and the crystal form IV prepared according to the method of WO2014174066A1 were added to a phosphate buffer solution of pH 6.8. (Simulated artificial small intestinal fluid), high-performance liquid chromatography (HPLC) was used to determine the content of eloxibate in the solution after 2 hours, 6 hours and 24 hours. The experimental results are shown in Table 3:
表3动态溶解度对比研究Table 3 Comparative study of dynamic solubility
Figure PCTCN2022124083-appb-000004
Figure PCTCN2022124083-appb-000004
结果表明，本申请的新晶型II与根据WO2014174066A1的方法得到的晶型IV相比，在pH 6.8磷酸缓冲溶液中具有显著更高的溶解度和溶解速率。The results show that the new crystal form II of the present application has significantly higher solubility and dissolution rate in a pH 6.8 phosphate buffer solution than the crystal form IV obtained according to the method of WO2014174066A1.
工业上的可利用性Industrial availability
本发明提供一种依洛西巴特的晶体形式II及其制备方法，该晶体形式理化性质稳定，可满足药用低吸湿要求，且制备方法操作简便，可实现产业化生产。The invention provides a crystal form II of eloxibate and a preparation method thereof. The crystal form has stable physical and chemical properties and can meet the requirements of low hygroscopicity for medicinal purposes. The preparation method is easy to operate and can realize industrial production.

Claims (13)

  1. 一种依洛西巴特晶体形式II，其特征在于：其X射线粉末衍射图谱在2θ值9.4±0.2°及7.8±0.2°处具有特征峰且具有一个或多个以下特征峰：3.9±0.2°、11.7±0.2°、16.1±0.2°、17.6±0.2°、18.3±0.2°、19.6±0.2°、20.9±0.2°、22.1±0.2°及25.8±0.2°。A crystal form II of eloxibate, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 9.4±0.2° and 7.8±0.2° and has one or more of the following characteristic peaks: 3.9±0.2° , 11.7±0.2°, 16.1±0.2°, 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2° and 25.8±0.2°.
  2. 根据权利要求1所述依洛西巴特晶体形式II，其特征在于：其X射线粉末衍射图谱在2θ值3.9±0.2°、8.8±0.2°、19.6±0.2°处具有特征峰。The eloxibate crystal form II according to claim 1 is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 3.9±0.2°, 8.8±0.2°, and 19.6±0.2°.
  3. 根据权利要求1所述依洛西巴特晶体形式II，其特征在于：其X射线粉末衍射图谱在2θ值3.9±0.2°、7.8±0.2°、9.4±0.2°、11.7±0.2°、16.1±0.2°、17.6±0.2°、18.3±0.2°、19.6±0.2°、20.9±0.2°、22.1±0.2°及25.8±0.2°处具有特征峰且具有一个或多个以下特征峰：8.5±0.2°、8.8±0.2°、10.4±0.2°、11.1±0.2°、13.0±0.2°、14.0±0.2°、14.5±0.2°、15.1±0.2°、17.1±0.2°、19.0±0.2°、20.6±0.2°、21.3±0.2°、22.6±0.2°、23.7±0.2°、24.5±0.2°、24.7±0.2°、26.6±0.2°、27.2±0.2°、27.5±0.2°、28.4±0.2°、28.6±0.2°、29.9±0.2°、30.5±0.2°、31.6±0.2°、32.5±0.2°、33.5±0.2°、34.5±0.2°、35.4±0.2°、37.1±0.2°及38.1±0.2°。The eloxibate crystal form II according to claim 1, characterized in that its X-ray powder diffraction pattern has 2θ values of 3.9±0.2°, 7.8±0.2°, 9.4±0.2°, 11.7±0.2°, and 16.1±0.2 There are characteristic peaks at 17.6±0.2°, 18.3±0.2°, 19.6±0.2°, 20.9±0.2°, 22.1±0.2° and 25.8±0.2° and one or more of the following characteristic peaks: 8.5±0.2°, 8.8±0.2°, 10.4±0.2°, 11.1±0.2°, 13.0±0.2°, 14.0±0.2°, 14.5±0.2°, 15.1±0.2°, 17.1±0.2°, 19.0±0.2°, 20.6±0.2°, 21.3±0.2°, 22.6±0.2°, 23.7±0.2°, 24.5±0.2°, 24.7±0.2°, 26.6±0.2°, 27.2±0.2°, 27.5±0.2°, 28.4±0.2°, 28.6±0.2°, 29.9±0.2°, 30.5±0.2°, 31.6±0.2°, 32.5±0.2°, 33.5±0.2°, 34.5±0.2°, 35.4±0.2°, 37.1±0.2° and 38.1±0.2°.
  4. 根据权利要求1所述依洛西巴特晶体形式II，其特征在于：其X射线粉末衍射图谱与图1或图2一致。The eloxibate crystal form II according to claim 1, characterized in that its X-ray powder diffraction pattern is consistent with Figure 1 or Figure 2.
  5. 根据权利要求1所述的依洛西巴特晶体形式II，其特征在于：晶体形式II的DSC图谱包括在169.5±0.5℃处的吸收峰。The eloxibate crystal form II according to claim 1, wherein the DSC spectrum of the crystal form II includes an absorption peak at 169.5±0.5°C.
  6. 根据权利要求1所述的依洛西巴特晶体形式II，其特征在于：晶体形式II的TGA图谱包括0～150℃之前有不超过2％的失重，优选不超过1.2％的失重。The crystal form II of eloxibate according to claim 1, characterized in that the TGA spectrum of the crystal form II includes a weight loss of no more than 2% before 0-150°C, preferably no more than 1.2%.
  7. 一种如权利要求1～6之一所述的依洛西巴特晶体形式II的制备方法，包括以下方法：A method for preparing eloxibate crystal form II as claimed in one of claims 1 to 6, including the following methods:
    方法一：method one:
    a)将原料依洛昔巴特溶于酮类或酮类与液态烷烃的混合溶剂中；a) Dissolve the raw material eloxibate in ketones or a mixed solvent of ketones and liquid alkanes;
    b)搅拌并降温至晶体析出，滤集析出结晶、干燥得到晶体形式II；b) Stir and cool down until crystals precipitate, filter and collect the precipitated crystals, and dry to obtain crystal form II;
    方法二：Method Two:
    1)在10～40℃下，将原料依洛昔巴特于酮类或酮类与液态烷烃的混合溶剂中得到混悬液；1) Dissolve the raw material eloxibat in ketones or a mixed solvent of ketones and liquid alkanes at 10 to 40°C to obtain a suspension;
    2)搅拌并降温至0～8℃，继续搅拌12小时以上，优选24～48小时至晶体完全析出，滤集析出结晶、干燥得到晶体形式II。2) Stir and lower the temperature to 0-8°C, continue stirring for more than 12 hours, preferably 24-48 hours until the crystals are completely precipitated, filter the precipitated crystals, and dry to obtain crystal form II.
  8. 根据权利要求7所述的制备方法，其特征在于：所述方法一或方法二中原料依洛昔巴特是无定形依洛昔巴特或依洛昔巴特的另一晶体形式，优选依洛昔巴特单水合物晶体形式IV。The preparation method according to claim 7, characterized in that: the raw material eloxibat in the method one or two is amorphous eloxibat or another crystal form of eloxibat, preferably eloxibat Monohydrate crystal form IV.
  9. 根据权利要求7或8所述的制备方法，其特征在于：所述方法一或方法二中依洛昔巴特与酮类或酮类与液态烷烃的混合溶剂的质量体积比(g：mL)为1：5～100，优选为1：15～30。The preparation method according to claim 7 or 8, characterized in that: in the method one or two, the mass volume ratio (g: mL) of the mixed solvent of eloxibat and ketones or ketones and liquid alkanes is 1:5-100, preferably 1:15-30.
  10. 根据权利要求7或8所述的制备方法，其特征在于：所述方法一或方法二中酮类为丙酮；液态烷烃为戊烷、正己烷或正庚烷中的至少一种，进一步优选为正己烷或正庚烷中的至少一种。The preparation method according to claim 7 or 8, characterized in that: in the method one or two, the ketone is acetone; the liquid alkane is at least one of pentane, n-hexane or n-heptane, and further preferably At least one of n-hexane or n-heptane.
  11. 根据权利要求7或8所述的制备方法，其特征在于：所述方法一或方法二中所述酮类与液态烷烃的体积比优选2：1～1：15；优选酮类为丙酮，液态烷烃为正己烷或正庚烷。The preparation method according to claim 7 or 8, characterized in that: the volume ratio of ketones to liquid alkanes in method one or method two is preferably 2:1 to 1:15; preferably the ketone is acetone, and the liquid Alkanes are n-hexane or n-heptane.
  12. 根据权利要求7或8所述的制备方法，其特征在于：方法一的步骤a)将原料依洛昔巴特溶于酮类或酮类与液态烷烃的混合溶剂中，采用升温溶解，优选升温至50～60℃。The preparation method according to claim 7 or 8, characterized in that: in step a) of method one, the raw material eloxibat is dissolved in ketones or a mixed solvent of ketones and liquid alkanes, and the temperature is raised to dissolve, preferably to 50～60℃.
  13. 一种药物组合物，包含如权利要求1～4之一中所述的依洛西巴特晶体形式II和药学可接受的辅料。A pharmaceutical composition comprising eloxibate crystal form II as described in one of claims 1 to 4 and pharmaceutically acceptable excipients.
PCT/CN2022/124083 2022-08-02 2022-10-09 Crystal form ii of elobixibat and preparation method therefor WO2024027013A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1481373A (en) * 2000-12-21 2004-03-10 1,5-benzothiazepines compounds and its use as antilipemic agent
CN105143194A (en) * 2013-04-26 2015-12-09 依洛比克斯公司 Crystal modifications of elobixibat
CN107001301A (en) * 2014-10-24 2017-08-01 埃洛比克斯股份公司 According to the crystal form of Lip river former times Bart
CN111836804A (en) * 2018-03-09 2020-10-27 埃洛比克斯股份公司 Process for the preparation of eloxibat
EP4029860A1 (en) * 2019-09-09 2022-07-20 Elobix Ab Method for producing a 1,5-benzothiazepin compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1481373A (en) * 2000-12-21 2004-03-10 1,5-benzothiazepines compounds and its use as antilipemic agent
CN105143194A (en) * 2013-04-26 2015-12-09 依洛比克斯公司 Crystal modifications of elobixibat
CN107001301A (en) * 2014-10-24 2017-08-01 埃洛比克斯股份公司 According to the crystal form of Lip river former times Bart
CN111836804A (en) * 2018-03-09 2020-10-27 埃洛比克斯股份公司 Process for the preparation of eloxibat
EP4029860A1 (en) * 2019-09-09 2022-07-20 Elobix Ab Method for producing a 1,5-benzothiazepin compound

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