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WO2019042219A1 - 奥扎莫德盐酸盐的晶型及其制备方法 - Google Patents

奥扎莫德盐酸盐的晶型及其制备方法 Download PDF

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WO2019042219A1
WO2019042219A1 PCT/CN2018/102034 CN2018102034W WO2019042219A1 WO 2019042219 A1 WO2019042219 A1 WO 2019042219A1 CN 2018102034 W CN2018102034 W CN 2018102034W WO 2019042219 A1 WO2019042219 A1 WO 2019042219A1
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present
preparation
crystalline form
hydrochloride salt
salt form
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French (fr)
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陈敏华
张炎锋
翟晓婷
鄢楷强
杨朝惠
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmaceutical Suzhou Co Ltd
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Priority to CN201880047898.4A priority Critical patent/CN110944982A/zh
Priority to US16/643,011 priority patent/US11117876B2/en
Priority to EP18851473.1A priority patent/EP3677575A4/en
Publication of WO2019042219A1 publication Critical patent/WO2019042219A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a crystalline form of ozazod hydrochloride and a process for its preparation and use.
  • MS Multiple sclerosis
  • RFMS relapsing
  • PRMS progressive recurrence
  • PPMS primary progression
  • Ozanimod is a novel oral selective sphingosine 1 phosphate receptor (S1P1R) modulator developed by Receptos for the treatment of autoimmune diseases.
  • S1P1R selective sphingosine 1 phosphate receptor
  • Ozamod With very good pharmacokinetic, pharmacodynamic and safety data, it can meet the development strategy and is expected to be the best second-generation S1P1R modulator.
  • the chemical structural formula of the drug is as shown in formula (I), and the compound is in the S configuration.
  • the compound (I) hydrochloride salt is referred to in CN102762100B, and only the preparation method of the R type compound is disclosed in the text, and the preparation method, solid form or crystal form of the S type compound is not disclosed in detail. Therefore, there is a need in the art for a comprehensive system of polymorphic screening of Ozamod to achieve its pharmacological development and release its potential, thereby facilitating the preparation of better formulations of the active pharmaceutical ingredient.
  • the inventors of the present application have unexpectedly discovered the hydrochloride salt form CS2 of the compound (I) provided by the present invention in an attempt to prepare a different crystal form. It has advantages in at least one of stability, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility, fluidity, and processing properties, purification, formulation production, etc., in particular It has good stability, high solubility, good dissolution of the preparation and uniform particle size distribution. It provides a new and better choice for the development of drugs containing Ozamod, which is of great significance.
  • the main object of the present invention is to provide a novel crystalline form of the compound (I) hydrochloride and a process for its preparation and use.
  • the present invention provides the hydrochloride salt form CS2 of the compound (I) (hereinafter referred to as "crystal form CS2").
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ value of 19.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.4° ⁇ 0.2°, 18.8° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or more of diffraction angle 2 ⁇ values of 4.0° ⁇ 0.2°, 15.1° ⁇ 0.2°, and 20.6° ⁇ 0.2°; preferably, The X-ray powder diffraction of the crystal form CS2 has a characteristic peak at a diffraction angle of 2theta of 4.0 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, and 20.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two of the diffraction angle 2 ⁇ value of 13.9° ⁇ 0.2° and 12.7° ⁇ 0.2°; preferably, the crystal form CS2 X-ray powder diffraction has a characteristic peak at a diffraction angle of 2theta of 13.9 ° ⁇ 0.2 ° and 12.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or more of diffraction angle 2 ⁇ values of 13.0° ⁇ 0.2°, 13.3° ⁇ 0.2°, and 11.8° ⁇ 0.2°; preferably, The X-ray powder diffraction of the crystal form CS2 has a characteristic peak at a diffraction angle 2theta of 13.0 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, and 11.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ of 19.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.4° ⁇ 0.2°, 18.8° ⁇ 0.2°, 4.0° ⁇ 0.2°, 15.1° ⁇ 0.2°, 20.6° ⁇ 0.2°, 13.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.3° ⁇ 0.2°, 11.8° ⁇ 0.2°, any 3 or 4 , or 5, or 6, or 7, or 8, or 9, or 10, or 11 or 12 have characteristic peaks.
  • the present invention also provides a method for preparing the crystalline form CS2, the preparation method comprising:
  • the hydrochloride salt of the compound (I) is dissolved in a mixed solvent of an ether and water, and slowly volatilized to obtain a crystal form CS2.
  • the ether is preferably tetrahydrofuran; further, the volume ratio of tetrahydrofuran to water is preferably 19:1.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form CS2 and a pharmaceutically acceptable carrier, diluent or excipient.
  • crystalline form CS2 provided by the present invention in the preparation of a pharmaceutical preparation of a selective sphingosine 1 phosphate receptor modulator.
  • crystalline form CS2 provided by the present invention for the preparation of a pharmaceutical preparation for treating ulcerative colitis.
  • the crystalline form CS2 provided by the present invention is useful in the preparation of a pharmaceutical preparation for treating multiple sclerosis.
  • the crystal form CS2 provided by the invention has the following beneficial effects:
  • the crystal form CS2 provided by the present invention has good physical and chemical stability. Crystalline CS2 is placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity, at least 7 weeks, the crystal form does not change, at 25 ° C / 60% relative humidity, 40 Placed under °C/75% relative humidity, the chemical purity is above 99% for at least 7 weeks, and the purity remains basically unchanged during storage.
  • the crystalline CS2 drug substance has good physical stability under grinding conditions. The grinding and pulverization of the raw material medicine is often required in the processing of the preparation, and the good physical stability under the grinding condition can reduce the risk of crystallinity change and crystal transformation of the raw material medicine during the processing of the preparation.
  • the transformation of the crystal form will lead to changes in the absorption of the drug, affecting the toxic side effects of the drug, especially the concentration change in the toxic target organ, directly affecting the toxic side effects of the drug.
  • the crystalline form CS2 has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and the preparation, and maximally reducing the toxicity of the drug due to the change of the crystal form, and ensuring the therapeutic effect of the drug.
  • the crystalline form CS2 provided by the present invention has a high solubility. Higher solubility is beneficial to increase the speed and extent of absorption of the drug in the human body, so that the drug can exert a better therapeutic effect; in addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug's Side effects and improve the safety of the drug.
  • the crystal form CS2 provided by the present invention has low wettability.
  • the test results show that the wettability weight gain of crystal form CS2 is only 2.34% under 80% relative humidity.
  • Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. At the same time, the hygroscopicity affects the preparation, post-treatment and storage 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 CS2 of the present invention is prepared into a capsule having good in vitro dissolution and dissolution rate.
  • the crystalline form CS2 of the present invention was prepared into capsules, and its dissolution curve was tested in a pH 6.8 phosphate buffer medium containing 0.5% sodium dodecyl sulfate. The test results showed that the dissolution rate of the crystalline form CS2 capsule reached 85 minutes. Above 100%, the capsule having the crystalline form CS2 of the present invention as an active ingredient has good in vitro dissolution rate and dissolution rate.
  • Dissolution and dissolution rates are important prerequisites for drug absorption. Good in vitro dissolution results in higher absorption of the drug, better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug; high dissolution rate allows the drug to reach the highest concentration in plasma quickly after administration. To ensure that the drug works quickly.
  • crystal form CS2 provided by the present invention has the following beneficial effects:
  • the crystalline form CS2 provided by 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.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction pattern characterization Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the X-ray powder diffraction pattern 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.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CS2 of the present invention is pure, 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.
  • Embodiment 1 is an XRPD pattern of a crystalline form CS2 in Embodiment 1.
  • 3 is an XRPD pattern of the crystal form CS2 in the second embodiment.
  • Figure 5 is a DSC diagram of the crystalline form CS2 in the third embodiment.
  • FIG. 6 is a TGA diagram of the crystalline form CS2 in the third embodiment.
  • Figure 7 is an XRPD overlay of the crystal form CS2 before and after placement (from top to bottom, before the crystal form CS2 is placed, placed under 25°C/60% relative humidity for 7 weeks, and placed at 40°C/75% relative humidity for 7 weeks). , XRPD pattern placed at 60 ° C / 75% relative humidity for 7 weeks)
  • Fig. 8 XRPD overlay before and after crystal form CS2 polishing (the above figure shows the XRPD pattern of the crystal form CS2 before polishing, and the figure below shows the XRPD pattern of the crystal form CS2 after grinding)
  • Figure 9 is a DVS diagram of the crystalline CS2
  • Figure 10 is the dissolution profile of crystalline CS2 capsules
  • Figure 11 is a PSD diagram of the crystalline CS2
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • 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 instrument control software is DVS-Intrinsic control software
  • the analysis software is DVS-Intrinsic Analysis software.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • HPLC High performance liquid chromatography
  • the elution gradient is as follows:
  • the particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken 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 ozamod hydrochloride as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the hydrochloride salt of the compound (I) as a raw material is in the form of a solid powder.
  • ozamod hydrochloride used in the following examples can be prepared according to the prior art, for example, according to the method described in the document CN102762100B.
  • the solid obtained in this example was the hydrochloride salt form CS2.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1, and the XRPD pattern thereof is shown in Fig. 1.
  • 1 H NMR is shown in Figure 2.
  • the NMR data are: 1 H NMR (400 MHz, DMSO) ⁇ 9.06 (s, 2H), 8.56 - 8.51 (d, 1H), 8.42 (dd, 1H), 8.16 (d) , 1H), 7.90 (d, 1H), 7.58 (m, 2H), 5.23 (s, 1H), 4.99 (m, 1H), 4.89 (s, 1H), 3.69 (q, 2H), 3.59 - 3.42 ( m, 1H), 3.27 (m, 1H), 3.02 (ddd, 2H), 2.51 (m, 1H), 2.31 - 2.17 (m, 1H), 1.39 (d, 6H).
  • the solid obtained in this example was the hydrochloride salt form CS2.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 2, and the XRPD pattern thereof is shown in Fig. 3.
  • the solid obtained in this example was tested to be CS2.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 3, and the XRPD pattern thereof is shown in Fig. 4.
  • Sample Placement condition Purity after placement Sample 1 25°C/60% relative humidity 99.14% Sample 2 40 ° C / 75% relative humidity 99.07%
  • the results show that the crystalline form CS2 is placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity for seven weeks, the crystal form remains unchanged, at 25 ° C / 60% relative humidity , placed at 40 ° C / 75% relative humidity for at least 7 weeks, the purity is higher than 99%.
  • the above test results show that the crystalline form CS2 has good stability.
  • Simulated 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 effect of the solubility tested in such media is closer to that in the human environment.
  • the crystalline form CS2 provided by the present invention has higher solubility in SGF, FeSSIF, FaSSIF and H 2 O.
  • Form CS2 was placed in a mortar and manually ground for 5 minutes to test the solid XRPD pattern.
  • the XRPD stack before and after the crystal form CS2 is shown in Fig. 8.
  • the preparation process of the prescription is as follows:
  • the capsule was placed in a 35 cc HDPE bottle and sealed.
  • the dissolution was tested in a 900 mL pH 6.8 phosphate buffer containing 0.5% sodium lauryl sulfate using a paddle method (75 rpm) and samples were taken at 5, 10, 15, 20, 30, 45 and 60 minutes.
  • the capsule preparation of Form CS2 was dissolved in a pH 6.8 phosphate buffer medium containing 0.5% sodium dodecyl sulfate for more than 85% in 30 minutes, indicating that The capsules in which the crystalline form CS2 is an active ingredient have a good dissolution rate and a dissolution rate.
  • 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 average particle diameter of the crystalline form CS2 of the present invention is about 64.22 ⁇ m and is normally distributed, and has good uniformity.

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Abstract

本发明涉及奥扎莫德盐酸盐的晶型及其制备方法。本发明提供的奥扎莫德盐酸盐的晶型可用于治疗自身免疫疾病，特别是多发性硬化症和溃疡性结肠炎。本发明提供的奥扎莫德盐酸盐的晶型在溶解度、熔点、稳定性、溶出度、生物有效性以及加工性能、提纯等方面中的至少一方面上存在优势，为含奥扎莫德的药物制剂的制备提供了新的更好的选择，对于药物开发具有重要意义。

Description

奥扎莫德盐酸盐的晶型及其制备方法 技术领域
本发明涉及药物化学领域，具体而言，涉及奥扎莫德盐酸盐的晶型及其制备方法和用途。
背景技术
多发性硬化症(multiple sclerosis，MS)是一种中枢神经系统脱髓鞘疾病，青、中年多见，临床特点是病灶播散广泛，常有缓解复发的神经系统损害症状，其具体发病机制尚未清晰。全球范围内，多发性硬化症影响着大约230万人的生活，其中大部分患者为RFMS(复发型)，占比高达约85％，而PRMS(进展复发型)及PPMS(原发进展型)两种亚型分别占比为5％及10％。尽管全球发病率很低，但多发性硬化症一直是制药市场中最具活力的领域之一，自2010以来已有超过五个新药获批。2011年至2016年间，MS治疗领域市场年均复合增长率为12％。全球范围内，MS治疗药物市场预计2022年市场容量将增长至230亿美元。
奥扎莫德(Ozanimod)是由Receptos公司研发的一种新型口服选择性鞘氨醇1磷酸受体(S1P1R)调节剂，用于自身免疫性疾病的治疗，在临床试验中，奥扎莫德具有非常好的药代动力学、药效及安全性数据，能够满足开发战略，有望成为最好的第二代S1P1R调节剂药物。该药物的化学结构式如式(I)所示，该化合物为S构型。
Figure PCTCN2018102034-appb-000001
CN102762100B中涉及化合物(I)盐酸盐，文本中仅公开了R型化合物的制备方法，而未详细公开S型化合物的制备方法、固体形式或晶型。因此，本领域需要对奥扎莫德进行全面系统的多晶型筛选，从而实现其药物学上的发展并释放其潜能，进而促进该活性药物成分的更好的配方的制备。
本申请的发明人在尝试不同晶型制备方法中，意外发现了本发明提供的化合物(I)的盐酸盐晶型CS2。其在稳定性、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，特别是稳定性好，溶解度高，制剂溶出度较好、粒度分布均一，为含奥扎莫德的药物开发提供了新的更好的选择，具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物(I)盐酸盐的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物(I)的盐酸盐晶型CS2(以下称作“晶型CS2”)。
一方面，使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为19.7°±0.2°，7.8°±0.2°，14.4°±0.2°，18.8°±0.2°处具有特征峰。
进一步地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为4.0°±0.2°，15.1°±0.2°，20.6°±0.2°中的一处或多处有特征峰；优选地，所述晶型CS2的X射线粉末衍射在衍射角2theta为4.0°±0.2°，15.1°±0.2°，20.6°±0.2°处有特征峰。
进一步地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为13.9°±0.2°，12.7°±0.2°中的一处或两处有特征峰；优选地，所述晶型CS2的X射线粉末衍射在衍射角2theta为13.9°±0.2°，12.7°±0.2°处有特征峰。
进一步地，所述晶型CS2的X射线粉末衍射在衍射角2θ值为13.0°±0.2°，13.3°±0.2°，11.8°±0.2°中的一处或多处有特征峰；优选地，所述晶型CS2的X射线粉末衍射在衍射角2theta为13.0°±0.2°，13.3°±0.2°，11.8°±0.2°处有特征峰。
另一方面，所述晶型CS2的X射线粉末衍射在衍射角2θ值为19.7°±0.2°，7.8°±0.2°，14.4°±0.2°，18.8°±0.2°，4.0°±0.2°，15.1°±0.2°，20.6°±0.2°，13.9°±0.2°，12.7°±0.2°，13.0°±0.2°，13.3°±0.2°，11.8°±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处有特征峰。
非限制性地，晶型CS2的X射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明还提供所述晶型CS2的制备方法，所述制备方法包括:
将化合物(I)的盐酸盐溶于醚类与水的混合溶剂中，缓慢挥发制备得到晶型CS2。
进一步的，所述醚类优选四氢呋喃；更进一步的，四氢呋喃与水的体积比优选19:1。
根据本发明的目的，本发明还提供一种药物组合物，所述药用组合物包含有效治疗量的晶型CS2以及药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提供的晶型CS2，在制备选择性鞘氨醇1磷酸受体调节剂的药物制剂中的用途。
进一步地，本发明提供的晶型CS2，在制备治疗溃疡性结肠炎药物制剂中的用途。
更进一步地，本发明提供的晶型CS2，在制备治疗多发性硬化症药物制剂中的用途。
本发明提供的晶型CS2具有以下有益效果：
(1)本发明提供的晶型CS2物理、化学稳定性好。晶型CS2在25℃/60％相对湿度，40℃/75％相对湿度，60℃/75％相对湿度条件下放置，至少7周晶型未发生变化，在25℃/60％相对湿度、40℃/75％相对湿度条件下放置，至少7周化学纯度在99％以上，储存过程中纯度基本保持不变。另外，晶型CS2原料药在研磨条件下具有良好的物理稳定性。制剂加工过程中常需要原料药的研磨粉碎，研磨条件下良好的物理稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
晶型的转变会导致药物的吸收发生变化，影响药物的毒副作用，尤其是在毒性靶器官中的浓度变化，直接影响药物的毒副作用。晶型CS2具有良好的物理化学稳定性，保证原料药 和制剂质量一致可控，最大可能地减少药物由于晶型改变引起的毒性增加，保证药物疗效发挥。
(2)本发明提供的晶型CS2具有较高的溶解度。更高的溶解度有利于提高药物在人体内被吸收的速度和程度，使药物发挥更好的治疗作用；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(3)本发明提供的晶型CS2具有低的引湿性。测试结果表明，晶型CS2在80％相对湿度条件下引湿性增重仅为2.34％。
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。同时，引湿性会影响药物的制备、后处理与储存。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。
(4)本发明晶型CS2制备成胶囊剂具有好的体外溶出度与溶出速率。将本发明的晶型CS2制备成胶囊，测试其在含0.5％十二烷基硫酸钠的pH6.8磷酸盐缓冲液介质中溶出曲线，测试结果表明，晶型CS2胶囊30分钟溶出度达到85％以上，以本发明晶型CS2为活性成分的胶囊具有良好的体外溶出度和溶出速率。
不同的晶型可能导致制剂在体内有不同的溶出速率，直接影响制剂在体内的吸收、分布、排泄、代谢，最终因其生物利用度不同而导致临床药效的差异。溶出度和溶出速率是药物被吸收的重要前提。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；高的溶出速率使得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。
进一步地，本发明提供的晶型CS2还具有以下有益效果：
本发明提供的晶型CS2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。
在本发明的晶型CS2的制备方法中：
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的。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射线粉末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射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，本文所述“XRPD图相同”并非 指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CS2是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
附图说明
图1为实施例1中晶型CS2的XRPD图
图2为实施例1中晶型CS2的 1H NMR图
图3为实施例2中晶型CS2的XRPD图
图4为实施例3中晶型CS2的XRPD图
图5为实施例3中晶型CS2的DSC图
图6为实施例3中晶型CS2的TGA图
图7为晶型CS2放置前后的XRPD叠图(从上至下依次为晶型CS2放置前，25℃/60％相对湿度条件下放置7周，40℃/75％相对湿度条件下放置7周，60℃/75％相对湿度条件下放置7周的XRPD图)
图8晶型CS2研磨前后的XRPD叠图(上图为研磨前的晶型CS2的XRPD图，下图为研磨后的晶型CS2的XRPD图)
图9为晶型CS2的DVS图
图10为晶型CS2胶囊剂的溶出曲线
图11为晶型CS2的PSD图
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
PSD：粒径分布
1H NMR：液态核磁氢谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
               
Figure PCTCN2018102034-appb-000002
1.540598；
Figure PCTCN2018102034-appb-000003
1.544426
                Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
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：
扫描速率：10℃/min
保护气体：氮气
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。仪器控制软件是DVS-Intrinsic control software，分析软件是DVS-Intrinsic Analysis software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明实施例4测试纯度的高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为紫外双波长检测(VWD)，方法参数如下：
色谱柱：Waters XBridge C18,150×4.6mm,5μm
流动相：A:0.1％的三氟乙酸水溶液
        B:0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
Figure PCTCN2018102034-appb-000004
Figure PCTCN2018102034-appb-000005
流速：1.0ml/min
进样量：10μl
检测波长：270nm
柱温：40℃
稀释剂：甲醇:四氢呋喃＝6:4(v/v)
本发明中实施例5测试溶解度的高效液相色谱(HPLC)数据采自于安捷伦1100，所用检测器为二极管阵列检测器(DAD)，方法参数如下：
色谱柱：L005#Waters Xbridge C18,150×4.6mm,5μm
流动相：A:0.1％的三氟乙酸水溶液
        B:0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
时间(min) ％B
0.0 25
10.0 50
12.0 80
15.0 80
15.1 25
20.0 25
流速：1.0ml/min
进样量：5μl
检测波长：270nm
柱温：40℃
稀释剂：甲醇:四氢呋喃＝6:4(v/v)
本发明实施例8测试溶出度的高效液相色谱(HPLC)数据采自于安捷伦1100，所用检测器为紫外检测器(VWD)。本发明所述的测试纯度的HPLC方法参数如下：
1、色谱柱：75 Waters Xbridge C18，150×4.6mm,5μm
2、流动相：A：0.1％的三氟乙酸水溶液
           B：0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
Figure PCTCN2018102034-appb-000006
Figure PCTCN2018102034-appb-000007
3、流速：1.0mL/min
4、进样量：10μL
5、检测波长：270nm
6、柱温：40℃
7、稀释剂：甲醇:四氢呋喃＝6:4(v/v)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：
Figure PCTCN2018102034-appb-000008
*：流速60％为65毫升/秒的60％。
核磁共振氢谱数据( 1H NMR)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。
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。
根据本发明，作为原料的所述奥扎莫德盐酸盐指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述化合物(I)的盐酸盐为固体粉末形式。
以下实施例中所使用的奥扎莫德盐酸盐可根据现有技术制备得到，例如根据CN102762100B文献所记载的方法制备获得。
实施例1晶型CS2的制备方法：
称取20.4mg奥扎莫德盐酸盐，置于20mL的玻璃瓶中，加入约5mL的四氢呋喃与水的混合溶剂(四氢呋喃/水19：1，v/v)溶解，过滤后向溶液中加入约0.2mg的高聚物(高聚物为聚己内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素的混合物，其质量比为1：1：1：1：1)，在室温下缓慢挥发得到白色固体。
经检测，本实施例得到的固体为盐酸盐晶型CS2。本实施例得到的晶型的X射线粉末衍射数据如表1所示，其XRPD图如附图1所示。
表1
2theta d间隔 强度％
3.95 22.34 77.36
5.21 16.97 33.12
7.83 11.29 57.15
11.77 7.52 34.29
12.73 6.95 30.23
13.07 6.78 24.22
13.35 6.63 18.90
13.99 6.33 32.14
14.41 6.15 24.96
15.09 5.87 16.19
16.11 5.50 4.67
16.71 5.30 5.94
18.85 4.71 32.67
19.71 4.51 100.00
20.58 4.32 42.16
21.04 4.22 36.00
21.64 4.11 24.52
22.86 3.89 15.48
23.37 3.81 16.20
23.80 3.74 23.96
24.31 3.66 41.05
25.04 3.56 35.78
25.43 3.50 34.33
26.32 3.39 20.48
27.33 3.26 22.88
27.70 3.22 25.68
28.93 3.09 27.52
30.19 2.96 15.49
31.32 2.86 6.18
32.51 2.75 4.94
35.88 2.50 12.98
37.21 2.42 8.54
1H NMR如附图2所示，核磁数据为： 1H NMR(400MHz,DMSO)δ9.06(s,2H),8.56– 8.51(d,1H),8.42(dd,1H),8.16(d,1H),7.90(d,1H),7.58(m,2H),5.23(s,1H),4.99(m,1H),4.89(s,1H),3.69(q,2H),3.59–3.42(m,1H),3.27(m,1H),3.02(ddd,2H),2.51(m,1H),2.31–2.17(m,1H),1.39(d,6H).
实施例2晶型CS2的制备方法：
称取5.4mg的奥扎莫德盐酸盐，置于5mL的玻璃瓶中，加入约1.5mL的四氢呋喃与水的混合溶剂(四氢呋喃/水19：1，v/v)溶解并过滤，将其置于室温下缓慢挥发得到白色固体。
经检测，本实施例得到的固体为盐酸盐晶型CS2。本实施例得到的晶型的X射线粉末衍射数据如表2所示，其XRPD图如附图3所示。
表2
2theta d间隔 强度％
3.89 22.72 100.00
5.12 17.27 38.84
7.79 11.34 60.88
8.96 9.87 6.40
11.11 7.97 5.05
11.73 7.55 41.68
12.09 7.32 5.53
12.67 6.99 15.28
13.02 6.80 17.75
13.28 6.67 15.43
13.86 6.39 10.79
14.37 6.17 18.37
15.07 5.88 16.56
16.10 5.51 5.85
16.66 5.32 7.38
18.78 4.73 17.03
19.65 4.52 90.59
20.54 4.32 25.95
20.99 4.23 24.32
21.60 4.11 14.84
22.28 3.99 9.94
23.74 3.75 8.79
24.98 3.57 12.45
25.35 3.51 9.61
26.31 3.39 4.41
27.31 3.27 8.23
27.66 3.22 7.99
28.98 3.08 4.61
30.16 2.96 4.39
35.84 2.51 11.40
37.24 2.41 7.50
38.11 2.36 1.95
实施例3晶型CS2的制备方法
称取约100mg的奥扎莫德盐酸盐，置于20mL的玻璃瓶中，加入约20mL的四氢呋喃与水的混合溶剂(四氢呋喃/水19：1，v/v)溶解，过滤后在室温下快速挥发得到白色固体。
经检测，本实施例得到的固体为CS2。本实施例得到的晶型的X射线粉末衍射数据如表3所示，其XRPD图如附图4所示。
表3
2theta d间隔 强度％
3.86 22.92 68.77
5.16 17.12 23.70
7.84 11.28 26.29
11.81 7.49 14.71
12.60 7.02 86.80
12.71 6.96 100.00
13.05 6.79 84.19
13.36 6.63 46.09
13.89 6.38 79.63
14.45 6.13 41.47
15.15 5.85 30.63
16.07 5.51 18.34
17.02 5.21 6.64
18.86 4.71 32.28
19.77 4.49 34.74
20.74 4.28 23.09
22.83 3.90 11.02
24.46 3.64 26.52
25.46 3.50 20.34
26.26 3.39 14.89
27.51 3.24 17.98
27.78 3.21 18.66
29.03 3.08 8.29
30.18 2.96 8.48
31.57 2.83 4.00
该晶型的DSC图如附图5所示，其在加热至235℃附近开始出现吸热峰。
该晶型的TGA图如附图6所示，将其加热至150℃时，具有约4.9％的质量损失。
实施例4晶型CS2的长期与加速稳定性：
取三份晶型CS2样品分别置于25℃/60％相对湿度，40℃/75％相对湿度，60℃/75％相对湿度条件下敞口放置七周，然后取样测其XRPD图。物理稳定性结果如图7所示(从上至下依次为晶型CS2放置前，25℃/60％相对湿度条件下放置7周，40℃/75％相对湿度条件下放置7周，60℃/75％相对湿度条件下放置7周的XRPD图)。晶型CS2在25℃/60％相对湿度条件下放置7周，40℃/75％相对湿度条件下放置7周后测试其纯度，纯度数据见表4。
表4
样品 放置条件 放置后纯度
样品1 25℃/60％相对湿度 99.14％
样品2 40℃/75％相对湿度 99.07％
结果表明，晶型CS2在25℃/60％相对湿度，40℃/75％相对湿度，60℃/75％相对湿度条件下放置七周，晶型保持不变，在25℃/60％相对湿度，40℃/75％相对湿度条件下放置至少7周，纯度高于99％。上述试验结果表明，晶型CS2具有良好的稳定性。
实施例5晶型CS2的动态溶解度：
模拟胃肠道液体例如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。
称取本发明的晶型CS2 20mg分别溶于1.5mL的SGF、1.5mL的FeSSIF、1.5mL的FaSSIF以及1.5mL的水配置成饱和溶液，平衡1小时、4小时和24小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)。其结果如表5所示。
表5
Figure PCTCN2018102034-appb-000009
以上结果表明，本发明提供的晶型CS2在SGF、FeSSIF、FaSSIF和H 2O中均有较高的溶解度。
实施例6晶型CS2的机械稳定性
将晶型CS2置于研钵中，手动研磨5分钟，测试固体XRPD图。晶型CS2研磨前后的XRPD叠图见图8所示。
结果表明，晶型CS2经研磨后，晶型未发生变化，说明本发明的晶型CS2具有良好的机械稳定性。
实施例7晶型CS2的引湿性
取本发明的晶型CS2约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表6所示。盐酸盐晶型CS2的引湿性实验的DVS图如图9所示。
表6
Figure PCTCN2018102034-appb-000010
结果表明，本发明的奥扎莫德盐酸盐晶型CS2在80％湿度下平衡后增重2.34％，引湿性较低。
实施例8晶型CS2的制剂处方及溶出
奥扎莫德盐酸盐晶型CS2胶囊，处方详见表7。
表7
Figure PCTCN2018102034-appb-000011
处方的制备过程如下：
1)根据处方将所有内加组分混合均匀；
2)将混合后物料过35目筛网，然后再次混合均匀；
3)用单冲手动压片机压片(型号：ENERPAC；模具：
Figure PCTCN2018102034-appb-000012
圆；片重：500mg； 压力：5±0.5KN)，将薄片碾碎，过20目筛；
4)称取外加辅料至步骤3)的颗粒中，混合均匀；
5)将终混粉末填充4号胶囊，内容物装量：62.5mg；
6)将胶囊装入35cc HDPE瓶中，封口。
奥扎莫德盐酸盐晶型CS2胶囊溶出度检测：
采用桨法(转速为75rpm)在900mL含0.5％十二烷基硫酸钠的pH6.8磷酸盐缓冲液中测试溶出度，于5,10,15,20,30,45和60分钟取样。
测试结果如表8和附图10所示：
表8
时间(min) 累积溶出度(％)
0 0.00
5 57.32
10 76.17
15 83.47
20 90.02
30 91.28
45 94.14
60 94.51
如表8和附图10中数据所示，晶型CS2的胶囊制剂在含0.5％十二烷基硫酸钠的pH6.8磷酸盐缓冲液介质中30分钟溶出度达到85％以上，表明以本发明晶型CS2为活性成分的胶囊具有很好的溶出度和溶出速率。
实施例9晶型CS2的粒径分布
取10-30mg晶型CS2，然后加入10mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使样品量指示图达到合适位置，开始实验，进行粒径分布的测试，从而得到按照体积计算的平均粒径、粒径分布中(体积分布)占10％所对应的粒径、粒径分布中(体积分布)占50％所对应的粒径。粒径分布中(体积分布)占90％所对应的粒径以及晶型粒度分布图。具体结果见表9，PSD图见图11。
表9
晶型 MV(μm) SD D10(μm) D50(μm) D90(μm)
CS2 64.22 51.36 7.6 44.90 149.4
本发明中所用到的缩写的解释如下：
MV：按照体积计算的平均粒径
D10：表示粒径分布中(体积分布)占10％所对应的粒径
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径
D90：表示粒径分布中(体积分布)占90％所对应的粒径
上述试验结果来看，本发明的晶型CS2的平均粒径在64.22μm左右并呈正态分布，具有良好的均一性。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (9)

  1. 一种奥扎莫德的盐酸盐晶型CS2，其特征在于，其X射线粉末衍射图在2θ值为19.7°±0.2°，7.8°±0.2°，14.4°±0.2°，18.8°±0.2°处具有特征峰。
  2. 根据权利要求1所述的盐酸盐晶型CS2，其特征还在于，其X射线粉末衍射图在2θ值为4.0°±0.2°，15.1°±0.2°，20.6°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的盐酸盐晶型CS2，其特征还在于，其X射线粉末衍射图在2θ值为13.9°±0.2°，12.7°±0.2°中的一处或两处具有特征峰。
  4. 一种奥扎莫德的盐酸盐晶型CS2的制备方法，其特征在于，所述方法包含：将奥扎莫德盐酸盐溶于醚类与水的混合溶剂中，缓慢挥发制备得到。
  5. 根据权利要求4所述的制备方法，其特征在于，所述醚类为四氢呋喃，所述四氢呋喃与水的体积比为19:1。
  6. 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中所述的盐酸盐晶型CS2及药学上可接受的载体、稀释剂或赋形剂。
  7. 权利要求1中所述的盐酸盐晶型CS2在生产用于制备磷酸鞘氨醇1受体调节剂的药物制剂中的用途。
  8. 权利要求1中所述的盐酸盐晶型CS2在生产用于制备治疗溃疡性结肠炎药物制剂中的用途。
  9. 权利要求1中所述的盐酸盐晶型CS2在生产用于制备治疗多发性硬化症药物制剂中的用途。
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