WO2017020869A1 - 2-[(2r)-2-甲基-2-吡咯烷基]-1h-苯并咪唑-7-甲酰胺的晶型b及其制备方法和应用 - Google Patents

2-[(2r)-2-甲基-2-吡咯烷基]-1h-苯并咪唑-7-甲酰胺的晶型b及其制备方法和应用 Download PDF

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WO2017020869A1
WO2017020869A1 PCT/CN2016/093770 CN2016093770W WO2017020869A1 WO 2017020869 A1 WO2017020869 A1 WO 2017020869A1 CN 2016093770 W CN2016093770 W CN 2016093770W WO 2017020869 A1 WO2017020869 A1 WO 2017020869A1
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crystal form
abt
crystal
ray powder
powder diffraction
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French (fr)
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陈敏华
张炎锋
刘凯
张晓宇
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苏州晶云药物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 crystalline form B of 2-[(2R)-2-methyl-2-pyrrolidinyl]-1H-benzimidazole-7-carboxamide and a process for the preparation thereof.
  • ABT-888 veliparib
  • Abbott A new high-selection PARP inhibitor developed by Abbvie. In vitro and in vivo experiments have shown that ABT-888 has a significant inhibitory effect on PARP activity and has achieved remarkable effects in the treatment of metastatic breast cancer, colon cancer, metastatic melanoma and brain tumors.
  • ABT-888 combined with whole brain radiotherapy for the treatment of metastatic brain tumor has entered the stage I clinical stage, and for the treatment of metastatic breast cancer, colon cancer and metastatic melanoma also entered the phase II clinical stage, combined with temozolomide
  • the study of breast cancer treatment is about to enter phase III clinical trials.
  • the powder diffraction pattern of Form 1 has respective 2 ⁇ values of about 9.9°, 11.0° and 11.8° and one or more additional peaks having respective 2 ⁇ values of about 14.6°, 15.2°, 18.2°, 19.6°. , 20.3°, 21.3°, 21.3°, 22.5°, 22.8°, 24.7 °, 28.5 ° and 29.1 °, the melting point of Form 1 was 188.6 ⁇ 0.8 ° C.
  • the powder diffraction pattern of Form 2 has 2 ⁇ values of 13.4°, 17.1°, 21.6°, 21.9°, 24.1°, 24.7°, 26.9°, 27.3°, 27.8°, 30.3°, 32.4°, and 34.2° and is not lower than 11.5.
  • the solubility of crystal form 1 is relatively good, but crystal form 1 needs to be reacted with a base by an acid or diacid salt of ABT-888, and mixed with one or more solvents by a deprotonation reaction.
  • the solid, semi-solid, wax or oil form of ABT-888 is obtained by crystallization or recrystallization.
  • the preparation process is complicated and the operation requirements are also high.
  • Form 2 is relatively simple to prepare, it can be obtained by completely dissolving ABT-888 in methanol, then concentrating at 35 ° C, and drying to constant weight, but its solubility is poor.
  • the inventor of the present application unexpectedly discovered a new crystal form of ABT-888 during the research process, and the crystal form has good stability and solubility higher than the existing crystal form, which is of great significance for improving the drug effect and reducing the drug loading amount. Subsequent development of the drug provides more and better options. Moreover, the preparation of the crystal form is simple.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a new crystal form of ABT-888 which is not only highly soluble, stable, and simple to prepare, and is named as Form B.
  • the present invention adopts the following technical solutions:
  • a crystal form B of ABT-888 having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a characteristic peak at a 2theta value of 9.4 ° ⁇ 0.2 °, 17.3 ° ⁇ 0.2 °, 22.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form B also has diffraction peaks at one or more of the 2theta values of 18.8 ° ⁇ 0.2 °, 24.7 ° ⁇ 0.2 °, and 29.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a characteristic peak at a value of 9.4 ° ⁇ 0.1 °, 17.3 ° ⁇ 0.1 °, 22.8 ° ⁇ 0.1 °, at 18.8 ° ⁇ 0.1°, 24.7° ⁇ 0.1°, and 29.0° ⁇ 0.1° have diffraction peaks.
  • the X-ray powder diffraction pattern thereof has a diffraction peak at one or more of the 2theta values of 15.2 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, and 25.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a characteristic peak at a value of 9.4 ° ⁇ 0.1 °, 17.3 ° ⁇ 0.1 °, 22.8 ° ⁇ 0.1 °, at 18.8 ° ⁇ 0.1°, 24.7° ⁇ 0.1°, 29.0° ⁇ 0.1°, 15.2° ⁇ 0.1°, 19.1° ⁇ 0.1°, 25.8° ⁇ 0.1° have diffraction peaks.
  • the X-ray powder diffraction pattern of Form B is as shown in FIG. Further, a total of 16 diffraction peaks were shown in the X-ray diffraction pattern, and the positions of the diffraction peaks and the relative peak intensities are shown in Table 2, in which the peak position was changed within 0.2°.
  • 28 diffraction peaks are shown in the X-ray powder diffraction pattern of Form B, the positions of these diffraction peaks and the peak intensities are shown in Table 3, wherein the peak position is varied within 0.2°.
  • the crystal form exhibits an endothermic peak in a spectrum measured by differential scanning calorimetry, showing that the melting point onset temperature of Form B is 182 ⁇ 2 °C.
  • Form B is obtained by naturally volatilizing a solution of methanol in which ABT-888 is dissolved at room temperature.
  • the temperature at room temperature is usually in the range of 20 to 30 ° C, preferably 20 to 25 ° C.
  • the concentration of ABT-888 in the methanol solution in which ABT-888 is dissolved is 5 to 30 mg/ml, and further may be 14 to 21 mg/ml.
  • the invention also provides a preparation method of crystal form B of ABT-888, which is characterized in that ABT-888 free base is dissolved in methanol and naturally volatilized at room temperature to obtain crystal form B.
  • the weight-to-volume ratio of ABT-888 free base to methanol is 5 to 30 mg/ml, preferably 14 to 21 mg/ml.
  • the ABT-888 free base refers to the solid, semi-solid, wax or oil form of the compound of formula (I).
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used in the present invention refers to a biological response or drug that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent that is reacted.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or exhibiting a disease or condition of the disease, disorder or disorder; and (3) Ameliorating the disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a condition or symptom of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual
  • inhibiting the disease for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • the novel Form B of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially other crystal forms of less than 10% by weight, more preferably less than 5% by weight of other crystal forms, more preferably less than 1% by weight of other crystal forms. type.
  • Polymorphic forms of the drug can be obtained by methods including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, solvent loss, rapid volatilization, rapid temperature drop, slow temperature drop, vapor diffusion, and sublimation. Sometimes, different methods may also achieve the same crystallization. Polymorphs can be detected, discovered, and classified by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), optical microscopy, hygroscopicity, and the like.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • optical microscopy hygroscopicity, and the like.
  • the therapeutically acceptable amount of ABT-888 Form B depends on the recipient of the treatment, the condition and severity of the treatment, the composition comprising the same, the time of administration, the route of administration, the course of treatment, its efficacy, its clearance rate and Whether to give another drug at the same time.
  • the amount of ABT-888 Form B used to prepare a composition for administration to a patient in a single or divided dose per day is from about 0.03 mg/kg to about 200 mg/kg body weight.
  • Single dose compositions comprise a combination of these amounts or submultiples thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of Form B of ABT-888 of the present invention and at least one pharmaceutically acceptable excipient.
  • the excipients include, but are not limited to, for example, encapsulating materials and additives such as absorption enhancers, antioxidants, binders, buffers, coatings, colorants, diluents, disintegrants, emulsifiers, bulking agents, Fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof, and the like.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release;
  • dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agents, patches; dosage forms suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • the crystalline form of the present invention has unexpectedly low hygroscopicity and stability in water or aqueous ethanol solution, it is especially suitable for preparation into tablets, suspensions, capsules, disintegrating tablets, immediate release, and slow release. Release and controlled release tablets; further preferred are tablets, suspensions and capsules.
  • the invention also relates to the use of a crystalline form B comprising ABT-888 as described above for the preparation of a pharmaceutical preparation for the treatment of metastatic breast cancer, colon cancer, metastatic melanoma and brain tumors.
  • the present invention has the following advantages compared with the prior art:
  • the invention provides a new crystal form of ABT-888, which can be obtained by a relatively simple method and has a larger solubility than the previously reported crystal form 1; compared with the previously reported crystal form 2,
  • the solubility of the crystal form is significantly improved, and no heating is required for preparation, and the operation is simpler and the cost is lower.
  • the crystal form B provided by the invention also has good stability, and can well avoid drug storage and crystal transformation during development, thereby avoiding bioavailability and drug effect change.
  • Example 1 is an XRPD pattern of Form B prepared in Example 1;
  • the present invention will be further described in detail below with reference to specific embodiments, but the invention is not limited to the following examples. Conditions not specified in the examples are routine experimental conditions.
  • the free base of the starting compound of the formula I used in the present invention is commercially available as a white powdery solid which has a purity of 97.65% as determined by high performance liquid chromatography.
  • a certain mass of the free base of the compound of formula I is dissolved in a volume of the solvent in Table 1, and volatilized under the set conditions to obtain a solid, which is labeled as comparative sample 1, 2, 3, 4, 5, 6, and 7, respectively. 8,9.
  • X-ray powder diffraction patterns were acquired on a Panalytical Empyrean X-ray powder diffractometer with CuKa radiation. The sample was evenly spread on a single crystal silicon sample pan and subjected to XRPD testing using the parameters described below:
  • Scan range: from 3.0 to 40.0 degrees.
  • the XRPD pattern of sample 1 is shown in Figure 1.
  • a total of 16 peaks are shown.
  • Table 2. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, 2theta value
  • the diffraction peaks at 9.38°, 17.30°, and 22.84° are characteristic peaks.
  • the diffraction peaks at 2theta values of 18.86°, 24.74°, and 29.05° are important peaks.
  • the 2theta values are the second most important peaks at 15.22°, 19.06°, and 25.77°.
  • sample 1 10 mg was taken for dynamic moisture adsorption (DVS) testing.
  • the dynamic moisture adsorption (DVS) pattern was acquired on an Intrinsic dynamic moisture adsorber manufactured by SMS (Surface Measurement Systems Ltd.) with the following parameters:
  • Relative humidity range 0%RH-95%RH
  • the crystal form B (sample 1) of the present invention and the crystal form 1 sample of CN101821270A were respectively made into a saturated solution by SGF (simulated gastric juice), FaSSIF (simulated fasting intestinal juice) and pure water, after 1 hour, 4 hours later.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography after 24 hours.
  • the experimental results are shown in Table 3.
  • the crystal form B of the present invention has a much higher solubility than the crystal form I after 4 hours and 24 hours.
  • the reason why the solid form of the free base is used as a raw material in the above examples is that the solid free base is more readily available, and not only the raw material of this form can be used. According to the inventors' experiments, the acquisition of the final crystal form is closely related to the conditions of preparation, regardless of the form of the starting material.

Abstract

提供了2-[(2R)-2-甲基-2-吡咯烷基]-1H-苯并咪唑-7-甲酰胺(ABT-888)的晶型B及其制备方法和应用，晶型B在25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为9.40°±0.20°、17.30°±0.20°、22.80°±0.2°处具有特征峰。晶型B的制备方法是将ABT-888游离碱溶解于甲醇中，室温下自然挥发即得晶型B。晶型B与现有的晶型相比具有更高的溶解度且制备工艺更简单，同时其稳定性好，对于提高治疗转移性乳腺癌、结肠癌、转移性黑色素瘤和脑肿瘤效果和减小载药量有重要意义。

Description

2-[(2R)-2-甲基-2-吡咯烷基]-1H-苯并咪唑-7-甲酰胺的晶型B及其制备方法和应用 技术领域
本发明涉及2-[(2R)-2-甲基-2-吡咯烷基]-1H-苯并咪唑-7-甲酰胺的晶型B及其制备方法。
背景技术
2-[(2R)-2-甲基-2-吡咯烷基]-1H-苯并咪唑-7-甲酰胺(式I所示化合物)，又名ABT-888(veliparib)，是由雅培(Abbvie)公司研发的一种新型高选择PARP抑制剂。体内外实验表明ABT-888具有显著的抑制PARP活性的作用，在治疗转移性乳腺癌、结肠癌、转移性黑色素瘤和脑肿瘤方面已取得显著的效果。目前ABT-888与全脑放疗联合应用治疗转移性脑瘤已经进入I期临床阶段，而用于治疗转移性乳腺癌、结肠癌和转移性黑色素瘤也进入II期临床阶段，与替莫唑胺联合应用于治疗乳腺癌的研究即将进入III期临床。
Figure PCTCN2016093770-appb-000001
目前仅CN101821270A和CN101821269B报道了ABT-888的二种晶形即晶形1、晶形2和获得该二种晶形的方法。根据该专利的报道，晶形1的粉末衍射图具有各2θ值约为9.9°、11.0°和11.8°和一个或不止一个附加峰具有各2θ值约为14.6°、15.2°、18.2°、19.6°、20.3°、21.3°、21.3°、22.5°、22.8°、 24.7°、28.5°和29.1°，晶形1的熔点为188.6±0.8℃。晶形2的粉末衍射图具有13.4°、17.1°、21.6°、21.9°、24.1°、24.7°、26.9°、27.3°、27.8°、30.3°、32.4°和34.2°的2θ值且没有低于11.5°的峰。这二种晶形中，晶形1的溶解性相对较好，但是晶形1需要通过ABT-888的酸式或二酸式盐与碱反应，由脱质子反应使与一种或不止一种溶剂混合的ABT-888的固体、半固体、蜡或油形式结晶或再结晶得到，制备过程比较复杂，对于操作的要求也较高。而晶形2虽然制备相对简单，通过将ABT-888完全溶解在甲醇中，然后在35℃浓缩，干燥至恒重即可得，但是其溶解性能较差。
本申请发明人在研究过程中意外发现ABT-888的新晶型，该晶型稳定性好，溶解度比现有的晶型高，对于提高药效，减小载药量具有重大意义，也为药物的后续开发提供更多更好的选择。而且该晶型的制备简单。
发明内容
本发明所要解决的技术问题是克服现有技术的不足提供一种不仅溶解度高、稳定性好且制备简单的ABT-888新晶型，命名为晶型B。
为解决以上技术问题，本发明采取如下技术方案：
一种ABT-888的晶型B，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为9.4°±0.2°、17.3°±0.2°、22.8°±0.2°处具有特征峰。
进一步地，晶型B的X射线粉末衍射图还在2theta值为18.8°±0.2°、24.7°±0.2°、29.0°±0.2°中的一处或多处具有衍射峰。
优选地，晶型B，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为9.4°±0.1°、17.3°±0.1°、22.8°±0.1°处具有特征峰，在18.8°±0.1°、24.7°±0.1°、29.0°±0.1°具有衍射峰。
进一步地，其X射线粉末衍射图还在2theta值为15.2°±0.2°、19.1°±0.2°、25.8°±0.2°中的一处或多处具有衍射峰。
优选地，晶型B，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为9.4°±0.1°、17.3°±0.1°、22.8°±0.1°处具有特征峰，在18.8°±0.1°、24.7°±0.1°、29.0°±0.1°、15.2°±0.1°、19.1°±0.1°、25.8°±0.1°具有衍射峰。
根据本发明的一个具体且优选方面，晶型B的X射线粉末衍射图如图1所示。进一步地，该X射线衍射图中显示了共16个衍射峰，这些衍射峰的位置以及相对峰强度如表2所示，其中，峰位置在0.2°内变化。
根据又一具体方面，晶型B的X射线粉末衍射图中显示了28个衍射峰，这些衍射峰的位置以及峰强度如表3所示，其中，峰位置在0.2°内变化。
优选地，所述晶型以差示扫描量热法测定的图谱中显示有一个吸热峰，显示晶型B的熔点起始温度为182±2℃。
优选地，晶型B通过将溶解有ABT-888的甲醇溶液于室温下自然挥发得到。根据本发明，室温的温度范围通常为20～30℃，优选20～25℃。优选地，溶解有ABT-888的甲醇溶液中ABT-888的浓度为5～30mg/ml，进一步可以为14～21mg/ml。
本发明同时还提供一种ABT-888的晶型B的制备方法，其是将ABT-888游离碱溶解于甲醇中，室温下自然挥发，即得晶型B。
进一步地，ABT-888游离碱与甲醇的重量体积比为5～30mg/ml，优选为14～21mg/ml。
所述ABT-888游离碱是指式(I)化合物的固体、半固体、蜡或油形式。
Figure PCTCN2016093770-appb-000002
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
本发明中所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本发明中所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
在一些实施方案中，本发明的新晶型B是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于 20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
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。
药物的多晶型可通过包括但不限于如下的方法获得：熔融重结晶、熔融冷却、溶剂重结晶、失溶剂、快速挥发、快速降温、慢速降温、蒸汽扩散和升华。有时，不同的方法也可能获得相同的结晶。多晶型可以通过X射线粉末衍射(XRPD)、差示扫描量热分析(DSC)、热重分析(TGA)、光学显微镜技术、吸湿性等来检测、发现和归类。
ABT-888晶型B治疗上可接受的量取决于治疗接受者、治疗的疾病及其严重度、包含它们的组合物、给药时间、给药途径、治疗疗程、其功效、其清除率和是否同时给予另一种药物。用于制备以单剂量或分剂量每天给予患者的组合物的ABT-888晶型B的量为约0.03mg/kg至约200mg/kg体重。单剂量组合物包含这些量或其约数的组合。
本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明ABT-888的晶型B以及至少一种药学上可接受的赋形剂。所述赋形剂包括但不限于例如包囊材料和添加剂如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、膨胀剂、填充剂、调味剂、保湿剂、润滑剂、香料、防腐剂、推进剂、释放剂、灭菌剂、甜味剂、助溶剂、湿润剂、其混合物等。
上述药物组合物可制成一定的剂型，通过适合的途径给药。例如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。优选地，由于本发明的晶型具有出人意料的低吸湿性和在水中或乙醇水溶液中的稳定性，因此，尤其适合制备成片剂、混悬剂、胶囊剂、崩解片、即释、缓释和控释片剂；进一步优选为片剂、混悬剂和胶囊剂。
本发明同时还涉及一种含有如上所述的ABT-888的晶型B在制备治疗转移性乳腺癌、结肠癌、转移性黑色素瘤和脑肿瘤药物制剂中的用途。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供了ABT-888的新晶型，与已有报道的晶形1相比，该晶型能够通过比较简单的方法获得，且溶解度有较大提高；与已有报道的晶形2相比，该晶型的溶解度有显著提高，且制备时无需加热，操作更简单，成本更低。此外，本发明提供的晶型B还具有良好的稳定性，能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变。
附图说明
图1为实施例1所制备的晶型B的XRPD图；
图2为实施例1所制备的晶型B的DSC图；
图3为实施例1所制备的晶型B的DVS图；
图4为对比例9所制备对比样品9的XRPD图。
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。实施例中未注明的条件为常规实验条件。本发明使用的起始原料式I化合物的游离碱是通过市售的方式购买得到，为白色粉末状固体，经高效液相色谱分析法测定其纯度为97.65％。
实施例1
将21.8mg的式I化合物游离碱溶解于1.5mL甲醇中，室温下(25±1℃)挥发，得到固体晶体，标记为样品1。
实施例2
将20.7mg的式I化合物游离碱溶解于1.0mL甲醇中，室温下(25±1℃)挥发，得到固体晶体，标记为样品2。
对比例1-9
将一定质量的式I化合物游离碱溶解于一定体积的表1中的溶剂中，在设定条件下挥发，得到固体，分别标记为对比样品1、2、3、4、5、6、7、8、9。
表1
Figure PCTCN2016093770-appb-000003
Figure PCTCN2016093770-appb-000004
样品1～2及对比样品1～9的表征
1、对全部样品进行了粉末X射线衍射分析(XRPD)；还对样品1进行了差示扫描量热分析(DSC)，其中：
X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集，CuKα辐射。将样品均匀平铺在单晶硅样品盘上，用下面描述的参数进行XRPD测试：
X射线反射参数：Cu，Kα
Kα1
Figure PCTCN2016093770-appb-000005
：1.540598；Kα2
Figure PCTCN2016093770-appb-000006
：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。
XRPD测试表明，样品1～2均为晶体，命名为晶型B。
样品1的XRPD图如图1所示，其中共显示了16个峰，具体衍射数据参见表2，综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为9.38°、17.30°、22.84°处的衍射峰为特征峰。2theta值为18.86°、24.74°、29.05°处的衍射峰为重要的峰。2theta值为15.22°、19.06°、25.77°处的衍射峰为次重要的峰。
表2
2theta d间隔 强度％
5.07 17.42 0.20
7.34 12.04 1.43
9.38 9.42 100.00
13.51 6.55 0.68
15.22 5.82 1.51
17.30 5.13 7.52
18.86 4.71 3.52
19.06 4.66 2.23
21.91 4.06 1.51
22.84 3.89 14.58
24.74 3.60 2.34
25.77 3.46 0.19
29.05 3.07 1.57
31.85 2.81 0.30
36.73 2.45 0.32
37.53 2.40 0.16
样品2的XRPD图中共显示了28个峰，具体衍射数据参见表3。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为 9.38°、17.30°、22.84°处的衍射峰为特征峰。2theta值为18.84°、24.74°、29.05°处的衍射峰为重要的峰。2theta值为15.19°、19.06°、25.85°处的衍射峰为次重要的峰。
表3
2theta d间隔 强度％
7.34 12.04 2.35
9.38 9.42 100.00
13.51 6.55 1.31
15.19 5.83 2.15
15.56 5.69 1.71
17.30 5.12 12.05
18.84 4.71 6.08
19.06 4.66 4.33
20.31 4.37 0.65
21.89 4.06 3.51
22.69 3.92 21.38
22.84 3.89 54.48
24.35 3.66 2.89
24.74 3.60 11.34
25.85 3.45 1.58
26.21 3.40 1.69
26.91 3.31 0.65
28.10 3.18 0.67
28.46 3.14 0.86
29.05 3.07 11.12
29.13 3.07 7.64
29.82 2.99 0.50
30.77 2.90 0.74
32.10 2.79 1.43
33.99 2.64 0.35
36.71 2.45 1.30
37.49 2.40 0.89
38.32 2.35 0.45
对比样品1的XRPD图中共显示了36个峰，具体衍射数据参见表4。
表4
2theta d间隔 强度％
10.82 8.17 9.04
11.02 8.03 13.49
11.80 7.50 92.51
14.53 6.09 34.17
15.19 5.83 27.59
15.36 5.77 7.39
15.99 5.54 100.00
18.09 4.91 11.73
19.51 4.55 28.57
20.22 4.39 5.84
21.15 4.20 24.29
21.53 4.13 14.77
22.12 4.02 7.24
22.35 3.98 17.29
22.77 3.91 7.31
22.95 3.88 9.65
23.70 3.75 5.01
24.24 3.67 13.40
24.60 3.62 8.38
24.86 3.58 6.38
25.23 3.53 5.26
26.09 3.42 2.84
26.87 3.32 12.15
27.09 3.29 19.65
28.30 3.15 23.67
28.97 3.08 11.48
29.14 3.06 21.31
29.72 3.01 9.42
31.25 2.86 14.55
34.09 2.63 1.43
34.46 2.60 5.54
35.18 2.55 1.73
35.84 2.51 1.70
36.65 2.45 2.04
37.54 2.40 5.45
38.61 2.33 1.97
对比样品2的XRPD图中共显示了17个峰，具体衍射数据参见表5。
表5
2theta d间隔 强度％
13.32 6.64 100.00
16.95 5.23 38.79
18.10 4.90 2.36
20.68 4.30 24.76
21.53 4.13 18.89
21.71 4.09 10.38
23.93 3.72 10.12
24.67 3.61 29.47
26.84 3.32 11.59
27.60 3.23 3.52
30.11 2.97 4.43
31.80 2.81 2.95
32.38 2.76 14.10
34.09 2.63 5.88
36.16 2.48 3.62
36.77 2.44 1.06
38.28 2.35 1.29
对比样品3的XRPD图中共显示了16个峰，具体衍射数据参见表6。
表6
2theta d间隔 强度％
13.33 6.64 100.00
16.95 5.23 35.41
18.08 4.91 1.16
20.67 4.30 5.57
21.54 4.13 13.13
21.71 4.09 10.44
23.99 3.71 7.45
24.68 3.61 17.76
26.84 3.32 12.96
27.59 3.23 4.18
30.13 2.97 6.87
32.37 2.77 3.88
34.09 2.63 2.05
36.19 2.48 0.79
36.79 2.44 0.80
38.29 2.35 0.61
对比样品4的XRPD图中共显示了19个峰，具体衍射数据参见表7。
表7
2theta d间隔 强度％
13.33 6.64 100.00
16.95 5.23 49.06
18.09 4.90 3.59
20.67 4.30 5.15
21.54 4.13 18.93
21.71 4.09 27.02
23.98 3.71 13.14
24.68 3.61 20.06
26.84 3.32 15.65
27.05 3.30 5.91
27.60 3.23 7.79
30.13 2.97 7.99
31.71 2.82 1.88
32.03 2.79 1.79
32.39 2.76 5.76
34.10 2.63 3.58
36.17 2.48 1.47
36.80 2.44 1.31
38.25 2.35 1.09
对比样品5的XRPD图中共显示了15个峰，具体衍射数据参见表8。
表8
2theta d间隔 强度％
13.33 6.64 100.00
16.95 5.23 28.72
20.67 4.30 6.32
21.54 4.13 15.45
21.71 4.09 10.59
23.98 3.71 13.84
24.67 3.61 19.69
26.84 3.32 12.48
27.60 3.23 4.13
30.12 2.97 5.09
32.38 2.76 8.97
34.09 2.63 3.05
36.18 2.48 2.63
36.79 2.44 1.19
38.26 2.35 2.01
对比样品6的XRPD图中共显示了15个峰，具体衍射数据参见表9。
表9
2theta d间隔 强度％
13.33 6.64 100.00
16.95 5.23 31.77
20.67 4.30 6.70
21.54 4.13 16.45
21.72 4.09 17.18
23.99 3.71 11.43
24.67 3.61 20.09
26.84 3.32 14.47
27.61 3.23 7.33
30.13 2.97 6.13
31.82 2.81 1.16
32.38 2.76 5.69
34.10 2.63 4.12
36.17 2.48 2.47
38.28 2.35 1.26
对比样品7的XRPD图中共显示了17个峰，具体衍射数据参见表10。
表10
2theta d间隔 强度％
13.33 6.64 100.00
16.95 5.23 32.81
18.09 4.90 1.66
20.67 4.30 11.00
21.54 4.13 20.72
21.72 4.09 17.22
23.96 3.71 13.26
24.68 3.61 25.79
26.84 3.32 17.40
27.60 3.23 5.21
30.12 2.97 7.97
31.79 2.82 2.84
32.37 2.77 8.39
34.09 2.63 3.87
36.18 2.48 2.87
36.79 2.44 1.58
38.30 2.35 1.55
对比样品8的XRPD图中共显示了17个峰，具体衍射数据参见表11。
表11
2theta d间隔 强度％
13.35 6.63 100.00
16.95 5.23 8.91
18.09 4.90 0.30
20.67 4.30 0.97
21.70 4.10 6.08
23.97 3.71 13.04
24.68 3.61 9.36
26.85 3.32 31.80
27.61 3.23 2.91
30.14 2.96 12.64
31.77 2.82 0.49
32.39 2.76 3.70
34.08 2.63 1.05
36.20 2.48 0.24
36.71 2.45 0.90
38.28 2.35 0.36
38.63 2.33 0.48
对比样品9的XRPD图如图4所示，结果显示对比样品9是无定形。差示扫描量热分析(DSC)图在TA Q200上采集，方法参数如下：
样品盘：铝盘，压盖
温度范围：25-200℃
扫描速率：10℃/min
保护气体：氮气。
参见DSC图，其中显示实施例1所制备的晶型B在183.02℃处显示吸热峰，熔点起始温度为：181.91℃。
2、对样品1进行引湿性试验
取10mg样品1进行动态水分吸附(DVS)测试。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，方法参数如下：
温度：25℃
载气，流速：N2，200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
样品1的动态水分吸附(DVS)图如图3所示。
本发明晶型B与CN101821270A中晶形1的溶解度对比试验
将本发明晶型B(样品1)与CN101821270A中晶形1样品分别用SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)和纯水配制成饱和溶液，在1个小时后，4个小时后和24个小时后通过高效液相色谱分析法测定饱和溶液中样品的含量。实验结果如表3所示。
表3
Figure PCTCN2016093770-appb-000007
通过上述对比结果可以看出，在SGF，FaSSIF和纯水中放置1小时后，4小时后和24小时后本发明的晶型B与专利晶形I相比，溶解度有较大提高。
值得说明的是，以上实施例中采用固体形式的游离碱作为原料的原因是这种固体的游离碱更容易购买得到，而非只能使用该形式的原料。根据发明人的试验，最终晶型的获得与制备的条件密切相关，而和原料的形式无关。
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 (10)

  1. 一种ABT-888的晶型B，其特征在于：其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为9.4°±0.2°、17.3°±0.2°、22.8°±0.2°处具有特征峰。
  2. 根据权利要求1所述的ABT-888的晶型B，其特征在于：其X射线粉末衍射图还在2theta值为18.8°±0.2°、24.7°±0.2°、29.0°±0.2°中的一处或多处具有衍射峰。
  3. 根据权利要求2所述的ABT-888的晶型B，其特征在于：其X射线粉末衍射图还在2theta值为18.8°±0.2°、24.7°±0.2°、29.0°±0.2°处具有衍射峰。
  4. 根据权利要求1或2所述的ABT-888的晶型B，其特征在于：其X射线粉末衍射图还在2theta值为15.2°±0.2°、19.1°±0.2°、25.8°±0.2°中的一处或多处具有衍射峰。
  5. 根据权利要求4所述的ABT-888的晶型B，其特征在于：其X射线粉末衍射图还在2theta值为15.2°±0.2°、19.1°±0.2°、25.8°±0.2°处具有衍射峰。
  6. 根据权利要求1所述的ABT-888的晶型B，其特征在于：所述晶型B通过将溶解有ABT-888的甲醇溶液于室温下自然挥发得到。
  7. 一种ABT-888的晶型B的制备方法，其特征在于：将ABT-888游离碱溶解于甲醇中，室温下自然挥发，即得所述晶型B。
  8. 根据权利要求7所述的ABT-888的晶型B的制备方法，其特征在于：在温度20～25℃下自然挥发。
  9. 一种含有如权利要求1至6中任一项权利要求所述的ABT-888的晶型B的药用组合物。
  10. 如权利要求1至6中任一项权利要求所述的ABT-888的晶型B在制备治疗转移性乳腺癌、结肠癌、转移性黑色素瘤和脑肿瘤药物制剂中的用途。
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CN106995436A (zh) * 2016-01-25 2017-08-01 重庆医药工业研究院有限责任公司 一种维利帕尼晶型a及其制备方法
US20190092756A1 (en) * 2016-03-09 2019-03-28 Crystal Pharmatech Co., Ltd. Crystalline form a of 2-[(2r)-2-methyl-2-pyrrolidyl]-1h-benzimidazole-7-carboxamide dihydrochloride and preparation method thereof

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