WO2019052470A1 - 一种艾尔骨化醇晶型、药物组合物及制备方法和应用 - Google Patents

一种艾尔骨化醇晶型、药物组合物及制备方法和应用 Download PDF

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WO2019052470A1
WO2019052470A1 PCT/CN2018/105239 CN2018105239W WO2019052470A1 WO 2019052470 A1 WO2019052470 A1 WO 2019052470A1 CN 2018105239 W CN2018105239 W CN 2018105239W WO 2019052470 A1 WO2019052470 A1 WO 2019052470A1
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crystal form
alcohol
solvent
alec
alecbolic
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PCT/CN2018/105239
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English (en)
French (fr)
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王猛
王东
王方道
苏奇峰
吴伟锋
匡正霞
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上海彩迩文生化科技有限公司
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Publication of WO2019052470A1 publication Critical patent/WO2019052470A1/zh

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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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

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  • the invention relates to the field of medicines, in particular to an Aleccinol crystal form, a pharmaceutical composition, a preparation method and an application thereof.
  • Al-calcitol (also known as edecalcitol, ED-71) is an active vitamin D3 derivative of Japan's Chugai Pharmaceutical Co., Ltd. for the treatment of osteoporosis.
  • the Japanese Ministry of Health and Welfare was approved for marketing on January 21, 2011. It is a new active vitamin D3 derivative for the treatment of osteoporosis after Alfacalcidol, which can increase bone density and reduce fracture risk more effectively.
  • a 3-year phase III clinical trial of 1054 patients with osteoporosis showed that Alcohol has better efficacy than Alfacalcidol and is safer than Alfacalcidol. Application prospects.
  • the phenomenon of aging in China is serious, and the number of people with osteoporosis is huge. There are about 70 million patients with osteoporosis.
  • the drug polymorph refers to the presence of two or more different crystal forms of the active ingredient (API). About 90% of the currently marketed small molecule drugs are administered in the form of crystals. This is because the crystal form has obvious physical and chemical properties and process advantages over other states, such as amorphous or liquid state. For example, it has excellent physical and chemical stability, can effectively eliminate impurity components, and has excellent processing properties. fluidity. These advantages have a positive impact on the quality of the drug and the process.
  • the raw material of Al's bone alcohol is a white crystalline powder.
  • the patent EP 0 924 199 A1 discloses a crystal form of Alecbolic Alcohol (designated herein as Form I for ease of distinction) and is currently medicinal.
  • the technical problem to be solved by the present invention is to find a more effective Alclavanol medicinal crystal form, and to provide a novel Al's bone alcohol crystal form, a pharmaceutical composition, a preparation method and application.
  • the crystal form provided by the invention has higher bioavailability than the crystal form I, and has good stability and is suitable for storage; the preparation method of the crystal form is simple in operation, low in cost, simple in post-treatment, physical and chemical stability of the target compound. It is higher in processing performance than other crystal forms than other existing crystal forms.
  • the relative intensities of the peaks at a diffraction angle of 2 ⁇ are as follows:
  • the X-ray powder diffraction pattern of the Alecbolic alcohol crystal form is shown in FIG.
  • the differential scanning calorimetry (DSC) of the Alecbolic alcohol crystal form has a maximum absorption peak at 120 ° C to 145 ° C; preferably, a maximum absorption peak at 139.24 ° C; More preferably, the differential scanning calorimetry pattern of the Alecbolic alcohol crystal form is shown in FIG.
  • the melting point of the Alecbolic alcohol crystal form read out from the differential scanning calorimetry pattern is 139.24 °C.
  • the infrared spectrum of the crystal form of the Al-calcified alcohol has infrared absorption characteristic peaks at 3329.34, 1260.13 and 1231.54 cm -1 , especially at 1260.13 cm -1 , which has a distinct characteristic absorption peak.
  • the infrared spectrum of the Alecbolic alcohol crystal form is shown in FIG.
  • the present invention also provides a method for preparing the crystal form of the Alergic Alcohol, which comprises the steps of: mixing Al's bone alcohol solid with solvent A and solvent B, dissolving and crystallization, that is, obtaining;
  • the solvent A is one or more of tetrahydrofuran, methyltetrahydrofuran, methyl ethyl ketone, 4-methyl 2-pentanone and toluene
  • the solvent B is n-hexane and n-heptane. And one or more of n-octane.
  • the solvent A is a good solvent
  • the solvent B is an anti-solvent
  • the volume of the solvent A and the solvent B is preferably (5:1) to (1:5), more preferably (2: 1) ⁇ (1:2).
  • the amount of the solvent A and the solvent B is determined by completely dissolving the solid of the Alcoholic Alcohol to form a clear solution.
  • the temperature of the crystallization is preferably from 10 to 60 ° C, more preferably from 20 to 50 ° C, still more preferably from 30 to 40 ° C.
  • the manner of crystallization is preferably slow crystallization, more preferably natural volatile crystallization.
  • the method for preparing the Alecbolic alcohol crystal form further preferably comprises the steps of dissolving the Alecbolic alcohol solid in a mixed solvent of methyl ethyl ketone and n-heptane, or tetrahydrofuran and positive In the mixed solvent of heptane, it may be naturally volatilized at 30 to 40 ° C.
  • volume of the methyl ethyl ketone and the n-heptane is preferably 1:1, and the volume of the tetrahydrofuran and the n-heptane is preferably 1:1.
  • the present invention also provides the use of the crystallized form of Alcohol in the preparation of a medicament for the treatment and/or prevention of osteoporosis.
  • the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of said crystallized form of Alculenol and a pharmaceutically acceptable carrier.
  • the crystal form II obtained by the present invention is an amorphous type, white sheet-like irregular crystal.
  • XRPD powder X-ray diffraction
  • IR infrared spectroscopy
  • DSC differential scanning calorimetry
  • HPLC means high performance liquid chromatography
  • good solvent means a solvent having a good solubility to a solute
  • antisolvent means a solvent which is miscible with a solvent and does not dissolve a solute
  • the Alecbolic Alcohol crystal form provided by the present invention is determined by XRPD pattern, IR spectrum and DSC pattern.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the present invention is that the crystal form of the Alecbolic alcohol of the present invention is excellent in stability and high in bioavailability, and the preparation method is simple in operation, low in cost, simple in post-treatment, and high in physical and chemical stability of the target compound.
  • the processing performance is also higher than other crystal forms, and these advantages have an important positive impact on the quality and process of the drug.
  • Figure 1 is an X-ray powder diffraction pattern of Alecbolic Alcohol Form II prepared in accordance with the present invention.
  • FIG. 3 is a differential scanning calorimetry (DSC) of Al's bone alcohol Form II prepared in accordance with the present invention.
  • DSC differential scanning calorimetry
  • Figure 5 is an infrared spectrum of the crystallized form II of Alec made in the present invention.
  • Figure 6 is an infrared spectrum of Al's bone alcohol form I which has been disclosed in the prior art.
  • Figure 7 is a blood sample concentration curve of Alecbolic Alcohol Form I.
  • Figure 8 is a blood sample concentration curve of Alecbolic Alcohol Form II.
  • the room temperature was 10 to 30 ° C and the normal pressure was 0.8 to 1.2 atm. Unless otherwise specified in the following examples, all are atmospheric pressure reactions.
  • the starting material in the following examples refers to an Alkali alcohol solid.
  • the synthetic route is fully synthetic, reference BioBioic Medicinal Chemistry Letters, Vol. 7, No. 22, pp. 2871-2874, 1997, the synthetic route is as follows.
  • Oxygen phosphorus 17 and ketone 19 are coupled under the action of lithium hexamethyldisilazide, and then the silicon protecting group is removed by reaction with tetrahydrofuran/tetrabutylammonium fluoride system to obtain edecalcitol, and the crude product is simply purified. To obtain a product with a purity of 98% or more.
  • the preparation of the crystal forms in Examples 1-7 and Comparative Examples 1-2 of the present application was carried out using this as the raw material of Alec's bone alcohol.
  • ethyl acetate is added to the reaction system to carry out extraction washing, and after the organic phase is dried, the obtained viscous solid is directly used as a raw material for the alkali alcohol.
  • the ratio in the following examples refers to the volume ratio.
  • an exploratory test is carried out: after the reaction is completed, the crude ergic alcohol is first purified by using acetonitrile water, replaced with ethanol solvent, and finally replaced by ethyl acetate to be crystallized. Purification, first room temperature crystallization, cooling to -10 degrees, precipitation of crystals, filtration detection, is Form I.
  • the inventors of the present application dissolved 10 mg of the Alkeninol solid obtained in the above Comparative Example 5 in 5 mL of ethyl acetate at the time of the crystal form study, and stirred at room temperature for half an hour without precipitation of solids; and dropwise addition of 15 mL of the reverse polar solvent.
  • the alkane slowly precipitated crystals, cooled to -10 ° C, and detected by filtration, being Form I.
  • the yield was 46%.
  • the Alecbolic Alcohol crystal form provided by the present invention is determined by XRPD pattern, IR spectrum and DSC pattern.
  • Powder X-ray diffraction was performed using a Shimadzu PXRD-6000 X-ray powder diffractometer.
  • the test conditions were: Cu target, K ⁇ light source.
  • the DSC test used a Perkin Elmer DSC Q2000 Differential Scanning Calorimeter.
  • the working conditions were: the reference material was an Al pot (pan Al), the atmosphere was N 2 , the temperature reference was metal indium, and the heating rate was 10 K/min. 45-200 ° C.
  • Figs. 3 and 4 The differential scanning calorimetry patterns of the crystallized form II and crystal form I of the test are shown in Figs. 3 and 4, respectively.
  • Alecbolic Alcohol Form II has a maximum absorption peak at 120 ° C to 145 ° C; especially at 139.24 ° C, it has a maximum absorption peak, and the melting enthalpy is about 119.6 J/g.
  • Alec's bone alcohol Form I has a maximum absorption peak at 140.45 ° C and a melting enthalpy of about 127.6 J/g.
  • test instruments and methods specifically used by IR are as follows: PE Spectrum Two FT-IR type infrared spectrometer, test method: the crystallized form II of the present invention and the crystal form I obtained by the comparative example are compressed by KBr and from The IR spectrum was measured by scanning from 400 to 4000 cm -1 .
  • the infrared spectra of the crystallized form II and crystal form I of the test are shown in Fig. 5 and Fig. 6, respectively.
  • the infrared spectrum of Form II has a bimodal structure at positions 1260.13 and 1231.54 cm -1 , and also has a characteristic peak of 3329.34 cm -1 .
  • the characteristic peak position of the infrared spectrum of Form I is located at a nearly symmetrical peak at 1231.57 cm -1 .
  • HPLC purity was examined by this method in both the examples and comparative examples of the present invention.
  • DSC has the lowest melting point Form II, which is 135.79 ° C, and Form I is 139.20 ° C (patent EP0924199A1 data is 137 ° C), indicating that the crystal lattice energy of Form II is relatively small (relatively easy to change from crystalline state to melting) State), under the same conditions, the crystal is more susceptible to dissolution, and there is an increase in utilization of bioavailability.
  • Dosage (calculated as free base): PO: 5 mg/kg; oral sample collection time: 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, 24 hr, standard curve (8 non-zero) and QC samples (6)
  • the compound concentration in the sample was measured by API-4000/5500 LC-MS/MS.
  • the relevant PK parameters were calculated using WinNonLin software, and the experimental data was reported in Excel.
  • the PK parameters are reported as follows:
  • IV PK AUC(0-t); AUC(0- ⁇ ); MRT(0-t); Vz; CLz; T1/2z; Cmax
  • PO PK AUC(0-t); AUC(0- ⁇ ); MRT(0-t); Vz/F; CLz/F; T1/2z; Tmax; Cmax;
  • Fig. 7 and Fig. 8 are graphs showing the blood sample concentration when the crystal form I and the form II are administered, wherein 101M, 102M, and 103M refer to three parallel samples corresponding to the 1# mouse used in the detection of the crystal form I, respectively.
  • 2# mouse and 3# mouse, 201M, 202M, 203M are another set of parallel samples corresponding to 1# mouse, 2# mouse and 3# mouse used in the detection of Form II.

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Abstract

本发明公开了一种艾尔骨化醇晶型、药物组合物及制备方法和应用。所述的艾尔骨化醇晶型在使用辐射源为Cu-Kα的X-射线粉末衍射图谱中，在衍射角2θ＝5.2°±0.2°、10.4°±0.2°、15.6°±0.2°、20.9°±0.2°和31.5°±0.2°处有特征峰，本发明的艾尔骨化醇晶型的稳定性优异，生物利用度高，且制备方法操作简单、成本低、后处理简单。

Description

一种艾尔骨化醇晶型、药物组合物及制备方法和应用
本申请要求申请日为2017年9月14日的中国专利申请CN201710828964.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及药物领域，具体涉及一种艾尔骨化醇晶型、药物组合物及制备方法和应用。
背景技术
艾尔骨化醇(又名艾地骨化醇，ED-71)是日本中外制药株式会社原研的治疗骨质疏松症的活性维生素D3衍生物，日本厚生省于2011年1月21日批准上市，它是继阿法骨化醇后又一新的用于治疗骨质疏松症的活性维生素D3衍生物，能更有效增加骨密度，降低骨折风险。一项由1054例骨质疏松症患者参加的历时3年的Ⅲ期临床数据显示，艾尔骨化醇疗效优于阿法骨化醇，且安全性与阿法骨化醇相似，具有较好的应用前景。中国老龄化现象严重，骨质疏松人群数量巨大，现有骨质疏松症患者约7000万人。据国际骨质疏松症基金会统计，到2020年，仅我国内地就将有2.86亿人患骨密度过低或骨质疏松症，到2050年这一数字将上升到5.33亿人。艾尔骨化醇作为目前最新的治疗骨质疏松药物，市场前景看好。
药物多晶型是指药物活性成分(API)存在两种及以上不同的晶体形态。目前市售的小分子药物中，有约90％左右的药物是以晶体形态给药。这是由于晶体形态比其它状态，如无定形或液态，具有明显的物理化学性能和工艺处理的优势，例如具有优良的物理和化学稳定性能，能够有效排除杂质成份，以及优良的加工性能，可流动性。这些优点对于药物的质量和工艺过程都会产生积极的影响。
艾尔骨化醇原料是白色结晶性粉末，理论上也存在多晶型，寻找更适合药用的晶体，将有助于改善药效，提高剂型选择性。例如，专利EP0924199A1公开了一种艾尔骨化醇 的晶型(为了便于区分，本申请将其命名为晶型I)，目前已经药用。
发明内容
本发明所要解决的技术问题在于寻求一种效果更优的艾尔骨化醇药用晶型，而提供了一种全新的艾尔骨化醇晶型、药物组合物及制备方法和应用。本发明提供的晶型具有比晶型I更高的生物利用度，且稳定性好，适于存储；晶型的制备方法操作简单、成本低、后处理简单、目标化合物的物理和化学稳定性能高于现有其他晶型，其加工性能也高于其他晶型。
本发明提供了一种艾尔骨化醇晶型，所述的艾尔骨化醇晶型在使用辐射源为Cu-Kα的X-射线粉末衍射图谱中，在衍射角2θ＝5.2°±0.2°、10.4°±0.2°、15.6°±0.2°、20.9°±0.2°和31.5°±0.2°处有特征峰。
其中较佳地，所述的粉末X-射线衍射图谱中，在衍射角2θ＝5.6°±0.2°、26.2°±0.2°和36.9°±0.2°还有次要峰。
其中较佳地，衍射角为2θ时的峰的相对强度如下表所示：
衍射峰序号 2θ角(°) 相对强度(％)
1 5.2±0.2 100
2 5.6±0.2 0.8
3 10.4±0.2 3.3
4 15.6±0.2 3.3
5 20.9±0.2 3.1
6 26.2±0.2 1
7 31.5±0.2 6.5
8 36.9±0.2 0.3
更佳地，所述的艾尔骨化醇晶型的X-射线粉末衍射图谱如图1所示。
本发明中，所述的艾尔骨化醇晶型的差示扫描量热法图谱(DSC)中，在120℃～145℃有最大吸收峰；较佳地，在139.24℃有最大吸收峰；更佳地，所述的艾尔骨化醇晶型的差示扫描量热法图谱如图3所示。
本发明中，从差示扫描量热法图谱中读出所述的艾尔骨化醇晶型的熔点为139.24℃。
本发明中，所述的艾尔骨化醇晶型的红外图谱中，在3329.34、1260.13和1231.54cm -1 处有红外吸收特征峰，特别是在1260.13cm -1处有一个明显的特征吸收峰。较佳地，所述的艾尔骨化醇晶型的红外光谱图如图5所示。
本发明还提供了所述的艾尔骨化醇晶型的制备方法，其包括下述步骤：将艾尔骨化醇固体与溶剂A和溶剂B混合，溶解，析晶，即得；
其中，所述的溶剂A为四氢呋喃、甲基四氢呋喃、甲基乙基酮、4-甲基2-戊酮和甲苯中的一种或多种，所述的溶剂B为正己烷、正庚烷和正辛烷中的一种或多种。
其中，溶剂A为良溶剂，溶剂B为反溶剂，所述的溶剂A与所述的溶剂B的体积比较佳地为(5：1)～(1：5)，更佳地为(2：1)～(1：2)。
其中，所述的溶剂A与所述的溶剂B的用量以艾尔骨化醇固体完全溶解后形成澄清溶液为准。
其中，所述的析晶的温度较佳地为10～60℃，更佳地为20～50℃，进一步更佳地为30～40℃。
其中，所述的析晶的方式较佳地为缓慢析晶，更佳地为自然挥发析晶。
本发明中，所述的艾尔骨化醇晶型的制备方法进一步优选包括下述步骤：将艾尔骨化醇固体溶解在甲基乙基酮与正庚烷的混合溶剂、或四氢呋喃与正庚烷的混合溶剂中，30～40℃下自然挥发析晶即可。
其中，所述的甲基乙基酮与所述的正庚烷的体积比较佳地为1：1，所述的四氢呋喃与所述的正庚烷的体积比较佳地为1：1。
本发明还提供了所述的艾尔骨化醇晶型在制备治疗和/或预防骨质疏松症的药物中的应用。
本发明还提供了一种药物组合物，其包括治疗有效量的所述的艾尔骨化醇晶型和药学可接受的载体。
现有技术(专利EP0924199A1)中已经公开了一种艾尔骨化醇晶型I，本发明所得到的艾尔骨化醇晶型记为晶型II。
本发明制得的晶型II为无水晶型，白色片状无规则晶体。
本发明中：术语“XRPD”是指粉末X-射线衍射；
术语“IR”是指红外光谱法；
术语“DSC”是指差示扫描量热法；
术语“HPLC”是指高效液相色谱法；
术语“良溶剂”是指对溶质具有良好的溶解能力的溶剂，“反溶剂”是指能与溶剂混溶而不能溶解溶质的溶剂。
本发明提供的艾尔骨化醇晶型，通过XRPD图谱、IR图谱和DSC图谱来测定。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的艾尔骨化醇晶型的稳定性优异，生物利用度高，且制备方法操作简单、成本低、后处理简单、目标化合物的物理和化学稳定性能高于现有其他晶型，其加工性能也高于其他晶型，这些优点对于药物的质量和工艺过程有着及其重要的积极影响。
附图说明
图1为本发明制得的艾尔骨化醇晶型II的X-射线粉末衍射图谱。
图2为现有技术中已经公开的艾尔骨化醇晶型I的X-射线粉末衍射图谱。
图3为本发明制得的艾尔骨化醇晶型II的差示扫描量热法图谱(DSC)。
图4为现有技术中已经公开的艾尔骨化醇晶型I的差示扫描量热法图谱(DSC)。
图5为本发明制得的艾尔骨化醇晶型II的红外图谱。
图6为现有技术中已经公开的艾尔骨化醇晶型I的红外图谱。
图7为艾尔骨化醇晶型I的血样浓度曲线。
图8为艾尔骨化醇晶型II的血样浓度曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施 例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述各实施例中，所述的室温为10～30℃，常压为0.8atm～1.2atm。下述实施例中如未特别说明，均为常压反应。
下述实施例中的原料是指艾尔骨化醇固体。其合成路线是全合成的，参考文献Bioorganic Medicinal Chemistry Letters,Vol.7,No.22,pp.2871-2874,1997，合成路线如下。
Figure PCTCN2018105239-appb-000001
氧磷17和酮19在六甲基二硅基胺基锂的作用下偶联，再用四氢呋喃/四丁基氟化铵 体系反应脱除硅保护基，得到艾地骨化醇，粗品简单纯化，得到纯度达到98％以上的产品。以此为艾尔骨化醇原料，进行本申请实施例1-7和对比例1-2中晶型的制备。
或者，上述脱硅反应完成后，向反应体系中加入乙酸乙酯，进行萃取洗涤，有机相干燥后，得到的粘稠状固体直接作为艾尔骨化醇原料。
亦或者，上述脱硅反应完成后，向反应体系中加入乙酸乙酯，进行萃取洗涤，有机相干燥，浓缩去掉大部分溶剂，再补加新的溶剂进行替换，适当浓缩或者挥发后，物料在新的溶剂体系中析出固体。
下述实施例中的比例是指体积比。
实施例1
将20mg原料溶解在4mL四氢呋喃/正庚烷(1:1)混合溶剂中，室温缓慢自然挥发干，得到晶体，为晶型II。收率为100％。
实施例2
将20mg原料溶解在3mL四氢呋喃/正庚烷(2:1)混合溶剂中，40℃缓慢自然挥发干，得到晶体为晶型II。收率为100％。
实施例3
将20mg原料溶解在10mL四氢呋喃/正己烷(1:1)混合溶剂中，30℃缓慢自然挥发干，得到晶体为晶型II。收率为100％。
实施例4
将20mg原料溶解在2mL甲基乙基酮/正庚烷(1:1)混合溶剂中，室温缓慢自然挥发干，得到晶体为晶型II。收率为100％。
实施例5
将20mg原料溶解在10mL甲基乙基酮/正庚烷(1:2)混合溶剂中，室温缓慢自然挥发去除大部分溶剂，残留0.5mL左右溶剂，有晶体析出。用吸管吸掉溶剂，固体干燥，得到晶体为晶型II。收率为81％，HPLC纯度在99％以上。
实施例6
将10mg原料溶解在20mL甲苯/正己烷(1:2)混合溶剂中，30℃缓慢自然挥发干，得 到晶体为晶型II。收率为100％。
实施例7
将10mg原料溶解在10mL 4-甲基2-戊酮/正辛烷(1:2)混合溶剂中，室温缓慢自然挥发干，得到晶体为晶型II。收率为100％。
对比例1
在40℃下将10mg原料溶解在4mL的乙酸乙酯中，缓慢冷却到5℃，搅拌半小时过滤，得到6mg晶型I产品。HPLC纯度99.2％。收率为60％。
对比例2
将10mg原料溶解在四氢呋喃中，40℃减压浓缩蒸干，得到无定形固体。收率为100％。
对比例3
根据EP0184206A2公开的化合物专利中实施例13进行探索性试验，制备纯化方法是：氯仿和正己烷过柱纯化，浓缩蒸干，没有提及产品形态。
本申请的发明人在晶型研究时，氯仿溶解艾尔骨化醇固体，滴加反极性溶剂正己烷，没有得到固体，直接浓缩蒸干，得到无定型固体。
对比例4
在对比例3的基础上，本申请的发明人进一步进行如下探索试验，用二氯甲烷溶解艾尔骨化醇固体，滴加反极性的正己烷，析出固体，得到晶型I。收率为73％。
对比例5
根据专利EP0924199A1公开的固体产品的制备方法实施例2，进行探索性试验：反应完全后，艾尔骨化醇粗品先用乙腈水制备纯化，再乙醇溶剂替换，最后换成乙酸乙酯溶解进行结晶纯化，先室温析晶后降温到-10度，析出晶体，过滤检测，是晶型I。
对比例6
本申请的发明人在晶型研究时，将上述对比例5得到的艾尔骨化醇固体10mg溶解在5mL乙酸乙酯中，室温下搅拌半小时没有析出固体；滴加15mL反极性溶剂正己烷，缓慢析出晶体，降温到-10℃，过滤检测，是晶型I。收率为46％。
本发明提供的艾尔骨化醇晶型，通过XRPD图谱、IR图谱和DSC图谱来测定。
效果实施例1XRPD表征结果
粉末X-射线衍射使用日本岛津PXRD-6000X射线粉末衍射仪，测试条件为：Cu靶，Kα光源
Figure PCTCN2018105239-appb-000002
工作电压40KV，工作电流40mA，步长0.02，扫描速度2°/分钟，扫描角度3°～40.0°。
测试得到的艾尔骨化醇晶型II、晶型I的X-射线粉末衍射图谱分别如图1、图2所示。
其中根据图1，晶型II测试时，衍射角为2θ时的峰的相对强度如下表1所示：
表1晶型II的XRPD表征结果
衍射峰序号 2θ角(°) 相对强度(％)
1 5.2±0.2 100
2 5.6±0.2 0.8
3 10.4±0.2 3.3
4 15.6±0.2 3.3
5 20.9±0.2 3.1
6 26.2±0.2 1
7 31.5±0.2 6.5
8 36.9±0.2 0.3
其中根据图2，所述的艾尔骨化醇晶型I测试时，在使用辐射源为Cu-Kα的X-射线粉末衍射图谱中，在衍射角2θ＝5.2°±0.2°、10.0°±0.2°、11.9°±0.2°、13.8°±0.2°、14.0°±0.2°、14.7°±0.2°、15.0°±0.2°、15.8°±0.2°、17.3°±0.2°、18.0°±0.2°、18.9°±0.2°、20.5°±0.2°、21.0°±0.2°、22.9°±0.2°、24.2°±0.2°和25.1°±0.2°处有特征峰。
效果实施例2 DSC表征结果
DSC测试使用Perkin Elmer DSC Q2000差示扫描量热仪，工作条件为：参比物为Al锅(pan Al)，氛围为N 2，温度基准物为金属铟，升温速率为10K/min，升温范围45-200℃。
结果显示，该艾尔骨化醇晶型II中不含有结晶水。
测试得到的艾尔骨化醇晶型II、晶型I的差示扫描量热法图谱分别如图3、图4所示。 根据图3，艾尔骨化醇晶型II在120℃～145℃有最大吸收峰；尤其在139.24℃有最大吸收峰，熔融焓约为119.6J/g。根据图4，艾尔骨化醇晶型I在140.45℃有最大吸收峰，熔融焓约为127.6J/g。
效果实施例3 IR表征结果
IR具体采用的测试仪器和方法如下：PE Spectrum Two FT-IR型红外光谱仪，测试方法：本发明提供的艾尔骨化醇晶型II和对比例制得的晶型I用KBr压片并从400至4000cm -1扫描测得IR图谱。
测试得到的艾尔骨化醇晶型II、晶型I的红外图谱分别如图5、图6所示。如图5所示，晶型II的红外谱图在位置1260.13和1231.54cm -1处具有双峰结构，另外还有3329.34cm -1也有特征峰。如图6所示，晶型I的红外谱图的特征峰位置位于1231.57cm -1处的一个近乎对称的峰。
效果实施例4 HPLC纯度表征结果
样品HPLC检测方法如下：
高效液相色谱仪:岛津高效液相SPD-10A，检测器LC-10AD；C18色谱柱,250mm×4.6mm(填料5μm粒径)；流动相是乙腈：水＝500:500；等度洗脱；流速：1.0mL/min；柱温：25℃；进样量：20μL，检测波段265nm，此条件下艾尔骨化醇主峰保留时间31分钟左右。
本发明的实施例和对比例中均按此法检测HPLC纯度。
效果实施例5吸湿性、稳定性和生物利用度表征结果
试验表明，实施例1～7获得的艾尔骨化醇晶型II在0～95％相对湿度范围内，晶型II未发生转变，吸湿性变化不大(80％RH，吸水0.22％)，表现为略有引湿性。通过存储条件改变，可以有效控制其引湿性。晶型II在熔融前没有转晶行为，具有良好的稳定性。
由于DSC检测的熔点晶型II最低，为135.79℃，而晶型I是139.20℃(专利 EP0924199A1数据是137℃)，说明晶型II的晶格能相对较小(相对容易由晶体状态转变成熔融状态)，在相同的条件下，该晶体更容易溶蚀，有利用生物利用度的提高。
进一步地，通过SD大鼠口服药代动力学研究，证实，晶型II具有优于晶型I的生物利用度。具体如下：
研究方法：(种属：SD大鼠；雄性；给药方式：PO)
给药剂量(以游离碱计算)：PO：5mg/kg；口服样品采集时间点：15min，30min，1hr，2hr，4hr，8hr，12hr，24hr，制备标准曲线(8个非零点)和QC样品(6个)后用API-4000/5500LC-MS/MS测定样品中化合物浓度。用WinNonLin软件计算相关的PK参数，实验数据用Excel报告。
PK参数报告如下：
IV PK:AUC(0-t)；AUC(0-∞)；MRT(0-t)；Vz；CLz；T1/2z；Cmax
PO PK:AUC(0-t)；AUC(0-∞)；MRT(0-t)；Vz/F；CLz/F；T1/2z；Tmax；Cmax；F；
得到的晶型I、晶型II的血样浓度结果如图7、图8以及下表2所示，其中血样浓度的单位为ng/mL：
表2晶型I、晶型II的血样浓度结果
Figure PCTCN2018105239-appb-000003
图7、图8为使用晶型I与晶型II给药时的血样浓度曲线图，其中的101M、102M、 103M是指3个平行样，分别对应晶型I检测时使用的1#鼠、2#鼠和3#鼠，201M、202M、203M是另外一组平行样，分别对应晶型II检测时使用的1#鼠、2#鼠和3#鼠。
本效果实施例主要关注对PK影响重要的几个参数，例如Tmax，Cmax,AUC。两种晶型的PK数据比较如下表3所示：
表3晶型I、晶型II的PK数据比较
Figure PCTCN2018105239-appb-000004
由上述分析可知，晶型II的达峰时间明显提前，最大血样浓度也提高了15.5％，生物利用度上比晶型I有明显提高。表3中，AUClast使用的是AUC(0→t)来计算的；另外，以AUC(0→t)计算，本申请的晶型II与晶型I的相对生物利用度F值为1.067。

Claims (12)

  1. 一种艾尔骨化醇晶型，其特征在于，所述的艾尔骨化醇晶型在使用辐射源为Cu-Kα的X-射线粉末衍射图谱中，在衍射角2θ＝5.2°±0.2°、10.4°±0.2°、15.6°±0.2°、20.9°±0.2°和31.5°±0.2°处有特征峰。
  2. 如权利要求1所述的艾尔骨化醇晶型，其特征在于，所述的X-射线粉末衍射图谱中，在衍射角2θ＝5.6°±0.2°、26.2°±0.2°和36.9°±0.2°还有次要峰。
  3. 如权利要求2所述的艾尔骨化醇晶型，其特征在于，所述的艾尔骨化醇晶型的X-射线粉末衍射图谱如图1所示。
  4. 如权利要求1所述的艾尔骨化醇晶型，其特征在于，所述的艾尔骨化醇晶型的差示扫描量热法图谱中，在120℃～145℃有最大吸收峰；较佳地，在139.24℃有最大吸收峰。
  5. 如权利要求4所述的艾尔骨化醇晶型，其特征在于，所述的艾尔骨化醇晶型的差示扫描量热法图谱如图3所示。
  6. 如权利要求1所述的艾尔骨化醇晶型，其特征在于，所述的艾尔骨化醇晶型的红外光图谱中，在3329.34、1260.13和1231.54cm -1处有红外吸收特征峰；特别是在1260.13cm -1处有一个明显的特征吸收峰。
  7. 如权利要求6所述的艾尔骨化醇晶型，其特征在于，所述的艾尔骨化醇晶型的红外光谱图如图5所示。
  8. 一种如权利要求1～7任一项所述的艾尔骨化醇晶型的制备方法，其特征在于，其包括下述步骤：将艾尔骨化醇固体与溶剂A和溶剂B混合，溶解，析晶，即得；
    其中，所述的溶剂A为四氢呋喃、甲基四氢呋喃、甲基乙基酮、4-甲基2-戊酮和甲苯中的一种或多种，所述的溶剂B为正己烷、正庚烷和正辛烷中的一种或多种。
  9. 如权利要求8所述的制备方法，其特征在于，所述的溶剂A与所述的溶剂B的体积比为(5：1)～(1：5)，较佳地为(2：1)～(1：2)；
    和/或，所述的析晶的温度为10～60℃，较佳地为20～50℃，更佳地为30～40℃；
    和/或，所述的析晶的方式为缓慢析晶，较佳地为自然挥发析晶。
  10. 如权利要求9所述的制备方法，其特征在于，所述的艾尔骨化醇晶型的制备方法包括下述步骤：将艾尔骨化醇固体溶解在甲基乙基酮与正庚烷的混合溶剂、或四氢呋喃与正庚烷的混合溶剂中，30～40℃下自然挥发析晶即可；
    其中，所述的甲基乙基酮与所述的正庚烷的体积比较佳地为1：1，所述的四氢呋喃与所述的正庚烷的体积比较佳地为1：1。
  11. 一种如权利要求1～7任一项所述的艾尔骨化醇晶型在制备治疗和/或预防骨质疏松症的药物中的应用。
  12. 一种药物组合物，其特征在于，其包括治疗有效量的如权利要求1～7任一项所述的艾尔骨化醇晶型和药学可接受的载体。
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