WO2022262244A1 - 一种阿哌沙班的尿素共晶及其制备方法 - Google Patents

一种阿哌沙班的尿素共晶及其制备方法 Download PDF

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WO2022262244A1
WO2022262244A1 PCT/CN2021/141012 CN2021141012W WO2022262244A1 WO 2022262244 A1 WO2022262244 A1 WO 2022262244A1 CN 2021141012 W CN2021141012 W CN 2021141012W WO 2022262244 A1 WO2022262244 A1 WO 2022262244A1
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urea
formula
cocrystal
apixaban
preparation
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PCT/CN2021/141012
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English (en)
French (fr)
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曾雪遥
谷慧科
黄翠
陈洪
王颖
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成都苑东生物制药股份有限公司
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Priority to CN202180006023.1A priority Critical patent/CN115244046B/zh
Priority to US18/004,276 priority patent/US20240010646A1/en
Publication of WO2022262244A1 publication Critical patent/WO2022262244A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of pharmaceutical crystal forms, and in particular relates to a urea cocrystal form A of apixaban and a preparation method thereof.
  • Apixaban (trade name Eliquis, Eliquis) is a new oral direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer, with a chemical formula of 1-(4-methoxyphenyl)-7 -Oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine- 3-Carboxamide, which acts directly on coagulation factor Xa, is used for the treatment of venous thrombotic diseases including deep venous thrombosis (DVT) and pulmonary embolism (pulmonary embolism, PE).
  • DVDTT deep venous thrombosis
  • PE pulmonary embolism
  • Apixaban is almost insoluble in water, and has the disadvantages of slow dissolution rate, low in vitro dissolution rate, and low bioavailability, thus having certain influence on drug absorption. Therefore, it is particularly important to seek ways to improve the dissolution rate of apixaban and enhance its solubility.
  • patents CN102908324, CN103830199 and CN102770126 provide other new crystal forms of apixaban, but these new crystal forms have long time-consuming, high energy consumption, low production efficiency and finished product yield in industrial production. lower issues.
  • Co-crystal is the formation of active pharmaceutical ingredient (API) molecules and other physiologically acceptable acids, bases, salts, non-ionic compound molecules and other co-crystal formers (CCF) connected by non-covalent bonds such as hydrogen bonds. combined in the same lattice.
  • API active pharmaceutical ingredient
  • CCF co-crystal formers
  • the biggest advantage of drug co-crystal is that it can change various physical and chemical properties of the drug without changing the covalent structure of the drug.
  • the ligands participating in the formation of the co-crystal are different, the direction and degree of changing the physical and chemical properties of the drug are different. , so as to effectively improve the crystallization properties, physicochemical properties and efficacy of the drug itself, and provide more options for the development of solid drug preparations.
  • HEC patent CN106986868 discloses four co-crystals of apixaban/oxalic acid, apixaban/isonicotine, apixaban/3-aminopyridine, and apixaban/urea, but except for urea, the other three None of these excipients are FDA-approved, and have varying degrees of toxicity, and there are many regulatory restrictions on the actual use of drugs.
  • the urea eutectic disclosed therein uses trifluoroethanol as a preparation solvent, which is an unused solvent and has certain toxicity, so it is not suitable for scale-up production, and the toxicity of residual solubility of the obtained product also needs to be considered.
  • the present invention aims to provide a urea co-crystal form A of apixaban and a preparation method thereof, and its material basis is clarified through single crystal diffraction.
  • the obtained urea eutectic has good stability, low toxicity, is beneficial to preparation processing, has better solubility, higher bioavailability, good repeatability of the preparation process, high yield, environmental protection, easy operation, strong plasticity, and can be passed.
  • the adjustment of parameters prepares and obtains products in various particle size ranges.
  • the present invention provides a cocrystal A of apixaban and urea, a compound represented by formula (I), wherein the ratio of apixaban and urea in the cocrystal A is 1:2.
  • the X-ray powder diffraction pattern of cocrystal A is 7.00 ⁇ 0.2°, 10.76 ⁇ 0.2°, 11.60 ⁇ 0.2°, 19.18 ⁇ 0.2°, 20.00 ⁇ 0.2°, 22.94 ⁇ 0.2°, 23.78 ⁇ 0.2° at 2 ⁇ angle ° and 28.08 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of cocrystal A is 7.00 ⁇ 0.2°, 10.76 ⁇ 0.2°, 11.60 ⁇ 0.2°, 12.52 ⁇ 0.2°, 19.18 ⁇ 0.2°, 20.00 ⁇ 0.2°, 22.94 ⁇ 0.2° at 2 ⁇ angle °, 23.78 ⁇ 0.2°, 25.16 ⁇ 0.2° and 28.08 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of cocrystal A is 7.00 ⁇ 0.2°, 10.76 ⁇ 0.2°, 11.60 ⁇ 0.2°, 12.52 ⁇ 0.2°, 13.96 ⁇ 0.2°, 16.72 ⁇ 0.2°, 19.18 ⁇ 0.2° at 2 ⁇ angle
  • cocrystal A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the DSC spectrum of cocrystal A has an endothermic peak at 176 ⁇ 5°C.
  • TGA spectrum of cocrystal A is basically shown in FIG. 3 .
  • the present invention also provides a preparation method of the urea cocrystal A of the compound represented by the above formula (I), comprising the following steps:
  • the first step adding the compound apixaban shown in formula (I) and a certain equivalent of urea to ethanol or a mixed solvent of ethanol and other solvents, after heating up and refluxing to dissolve, cooling down to room temperature for 5-24h of crystallization; other solvents selected from ketones, esters;
  • the second step suction filtration, collecting the obtained solid, and drying to obtain apixaban urea cocrystal A.
  • the molar ratio of apixaban to urea in the first step is 1:4-12, preferably 1:6-10.
  • the mass volume ratio of apixaban to the solvent in the first step is 1:10-1:30 (g/ml).
  • solvents in the first step are selected from acetone, butanone, ethyl acetate, methyl acetate or isopropyl acetate.
  • the present invention further provides a pharmaceutical composition of apixaban urea co-crystal form A, comprising the urea co-crystal form A of the compound represented by formula (I) and pharmaceutically acceptable excipients.
  • the present invention also provides the use of apixaban urea cocrystal form A and the pharmaceutical composition of apixaban urea cocrystal form A in preparing medicines for venous thrombosis-related diseases.
  • the obtained apixaban urea cocrystal form A has higher physical and chemical stability, crystal form stability and pharmaceutical stability, better solubility and higher bioavailability.
  • the preparation process has good repeatability and high yield.
  • the solvents used are all three types of solvents, which are environmentally friendly, easy to operate, easy to recycle, and easy to realize large-scale production.
  • the process has strong plasticity and can be prepared by adjusting parameters. Products in various particle size ranges to meet the different needs of formulations.
  • Figure 1 is an XRD pattern of apixaban urea cocrystal Form A.
  • Figure 2 is a DSC trace of apixaban urea cocrystal Form A.
  • Figure 3 is a TGA trace of apixaban urea cocrystal Form A.
  • Fig. 4 is a 1 H-NMR chart of apixaban urea cocrystal Form A.
  • Fig. 5 is a single crystal analytical molecular structure diagram of apixaban urea co-crystal form A.
  • Figure 6 is a single crystal unit cell diagram of apixaban urea cocrystal Form A.
  • Fig. 7 is a comparison chart of the solubility of apixaban urea cocrystal form A and pharmaceutical crystalline form N-1.
  • Fig. 8 is a graph showing the results of stability investigation of the urea co-crystal form A of apixaban.
  • Figure 9.1 is the mean drug concentration-time curve of female rats of apixaban urea cocrystal form A.
  • Figure 9.2 is the average drug concentration-time curve of apixaban urea cocrystal Form A male rats.
  • Figure 10.1 is a comparison of the dissolution curves of the prepared tablet of urea cocrystal A obtained in Example 1 and the commercially available product in pH 1.0 medium.
  • Figure 10.2 is a comparison of the dissolution curves of the tablet prepared from urea cocrystal A obtained in Example 1 and the commercially available product in pH 4.5 medium.
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) described in this application is collected by METTLER TOLEDO model TGA-2, the heating rate is 10°C/min, the temperature range is 30-300°C, and the nitrogen purging rate during the test is 20mL /min.
  • the LC/MS/MS biological sample analysis described in this application refers to the analysis of biological samples using liquid chromatography-mass spectrometry technology, which has high sensitivity, selectivity and wide applicability to the analysis of mixtures, and can Fast and reliable quantitative or qualitative analysis of trace compounds in complex biological matrices.
  • the involved liquid mass spectrometer is: AB Sciex Triple Quad 4500.
  • Embodiment 1 the preparation of urea eutectic A
  • Embodiment 2 the preparation of urea eutectic A
  • Embodiment 3 the preparation of urea eutectic A
  • Embodiment 4 the preparation of urea eutectic A
  • Embodiment 5 the preparation of urea eutectic A
  • Embodiment 6 the preparation of urea eutectic A
  • Embodiment 7 the preparation of urea eutectic A
  • Example 8 Single crystal cultivation and single crystal diffraction of urea cocrystal A
  • the present inventor directly obtained a single crystal sample with large particle size and regular shape by developing the crystallization process of the acetone/ethanol system, and carried out single crystal diffraction analysis on the single crystal sample, and the obtained single crystal data are shown in Table 1.
  • the single crystal analytical molecular structure diagram is shown in Figure 5, and the single crystal unit cell diagram is shown in Figure 6.
  • Test Example 1 Solubility investigation test of urea eutectic A
  • the pharmaceutical crystal form N-1 was purchased from Srini Pharmaceuticals Pvt Ltd.
  • the urea cocrystal A prepared in Example 1 of the present invention was purchased from Srini Pharmaceuticals Pvt Ltd.
  • the urea cocrystal A prepared in Example 1 and the drug were determined by the external standard method.
  • the equilibrium solubility (saturated solution) of crystal form N-1 the results are shown in Table 2 below:
  • Test Example 2 Stability investigation experiment of urea eutectic A
  • Example 3 In order to investigate the storage stability of the obtained urea eutectic A prepared in Example 1 of the present invention, the obtained sample was investigated under high temperature light for the test of influencing factors, and the sample was set out at 25 ⁇ 2°C-60 ⁇ 5%RH to investigate the long-term stability test and 40°C ⁇ 2°C-75 ⁇ 5%RH to investigate the accelerated stability test, the results are shown in Table 3 below:
  • Test Example 3 In vivo pharmacokinetic test in rats
  • Apixaban medicinal crystal form N-1 provided by Srini Pharmaceuticals Pvt Ltd, off-white solid, batch number Y20071, purity: 99.94%;
  • test drug was prepared into a uniform suspension of 1.25 mg/kg with corn oil, it was orally administered to rats at a volume of 4 mL/kg immediately, and 15 min, 30 min, 1 h, 2 h, 3 h, At 4h, 5h, 6h, 7h, 8h, and 24h, 0.1 mL of blood was collected from the jugular vein, placed in an EDTA-K2 tube, centrifuged at 3000 r/min for 10 min, separated from the plasma, and stored in a -80°C refrigerator.
  • Apixaban pharmaceutical crystal form N-1, urea cocrystal A and HEC urea cocrystal IV were used for animal experiments, that is, the average concentration of API in plasma at different times was measured after a single oral administration to male and female rats (ng mL-1), the average drug concentration-time curves in the plasma of male and female rats after a single oral administration are shown in Figure 9.1 and Figure 9.2, and the main pharmacokinetic parameters are as follows:
  • Test Example 4 Dissolution test of formulations of urea cocrystal A and crystal form N-1
  • Prescription process refer to the tablet prescription provided in Table 3 in the specific implementation of the original patent CN109602713A, adopt the method of dry granulation, and use apixaban urea cocrystal A as raw material to prepare a tablet with a specification of 5 mg of apixaban combination.
  • the urea co-crystal A sample obtained in Example 1 was compressed into tablets through the preparation prescription process, compared with commercially available products, and the dissolution curves in media pH 1.0 and pH 4.5 were investigated. The data are shown in Figures 10.1 and 10.2. It can be seen that The dissolution behavior of the preparation product of the obtained urea cocrystal A is consistent with that of the commercially available product.
  • the apixaban urea cocrystal A provided by the present invention has better solubility, good crystal form and physical and chemical stability, and significantly improved bioavailability , the dissolution effect of each medium can achieve the same advantage as that of commercially available products.

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Abstract

一种阿哌沙班的尿素共晶形式A及其制备方法。该尿素共晶A具有较高的理化稳定性、晶型稳定性及成药稳定性，溶解性更好，生物利用度更高。其制备工艺重复性好，收率高，绿色环保，易于操作，容易实现规模化放大生产，且能够通过参数的调整制备获得各个粒径范围的产品，从而满足制剂的不同需求。

Description

一种阿哌沙班的尿素共晶及其制备方法 技术领域
本发明属于药物晶型领域，具体涉及一种阿哌沙班的尿素共晶形式A及其制备方法。
背景技术
阿哌沙班(商品名Eliquis，艾乐妥)是一种新型口服直接Xa因子抑制剂，由百时美施贵宝和辉瑞公司共同研发，化学式为1-(4-甲氧基苯基)-7-氧代-6-[4-(2-氧代哌啶-1-基)苯基]-4，5，6，7-四氢-1H-吡唑并[3，4-c]吡啶-3-甲酰胺，其直接作用于凝血因子Xa，用于治疗包括深静脉血栓(deep venous thrombosis，DVT)和肺栓塞(pulmonary embolism，PE)在内的静脉血栓疾病。2011年5月，欧盟批准口服Xa因子直接抑制剂阿哌沙班(商品名Eliquis)上市，用于择期髋关节或膝关节置换手术的成年患者，以预防静脉血栓形成(venous thrombembolic events，VTE)。2012年11月20日，欧盟委员会批准艾乐妥(阿哌沙班)用于具有一个或多个风险因素的非瓣膜性房颤(NVAF)成人患者卒中和体循环栓塞的预防。2013年4月12日，正式宣布在中国上市。阿哌沙班结构如下式(I)所示：
Figure PCTCN2021141012-appb-000001
阿哌沙班几乎不溶于水，存在溶解速度慢、体外溶出度低、生物利用度低的缺点，因而对药物的吸收有一定的影响。所以寻求提高阿哌沙班溶出度，增强其溶解性能的方法就显得尤为重要。为解决这一问题，专利CN102908324、CN103830199及CN102770126等提供了阿哌沙班的其他新晶型，但这些新晶型在工业化生产中存在耗时长、能耗消耗大、生产效率低及成品收率较低等问题。
共晶是活性药物成分(API)分子与其他生理上可接受的酸、碱、盐、非离子化合物分子等共晶形成物(Co-crystal Former,CCF)以氢键等非共价键相连而结合在同一晶格中。药物共晶最大的优点在于其可以在不改变药物共价结构的前提下，改变药物的多种理化性质，参与形成共晶的配体不同时，对药物的理化性质的改变方向和程度均不同，从而有效改善药物本身的结晶性能、物化性质及药效，为药物固体制剂的开发提供更多的选择。
东阳光专利CN106986868公开阿哌沙班/草酸，阿哌沙班/异烟碱，阿哌沙班/3-氨基吡啶，阿哌沙班/尿素四种共晶，但其中除了尿素以外，其他三种均非FDA批准辅料，存在有不同程度的毒性，在药品的实际使用上会存在诸多的法规限制。而其中公开的尿素共晶使用三氟乙醇作为制备溶剂，为非常用溶剂，且具有一定的毒性，不宜进行放大生产，所得产品残溶毒性问题也需要考虑。
因此，为了提高阿哌沙班的溶解性，提高其生物利用度，并确保药物产品的质量、安全和效能，本领域仍然需要开发出一种毒性小、稳定性好、结构明确的阿哌沙班共晶形式。
发明内容
本发明旨在提供一种阿哌沙班的尿素共晶形式A及其制备方法，并通过单晶衍射明确了其物质基础。所得的尿素共晶稳定性好，毒性小，利于制剂加工处理，溶解性更好，生物利用度更高，其制备工艺重复性好，收率高，绿色环保，易于操作，可塑性强，能够通过参数的调整制备获得各个粒径范围的产品。
本发明提供了一种式(I)所示化合物阿哌沙班与尿素的共晶A，共晶A中阿哌沙班与尿素的比例为1:2。
Figure PCTCN2021141012-appb-000002
进一步地，共晶A的X-射线粉末衍射图谱在2θ角为7.00±0.2°、10.76±0.2°、11.60±0.2°、19.18±0.2°、20.00±0.2°、22.94±0.2°、23.78±0.2°和28.08±0.2°处有特征峰。
进一步地，共晶A的X-射线粉末衍射图谱在2θ角为7.00±0.2°、10.76±0.2°、11.60±0.2°、12.52±0.2°、19.18±0.2°、20.00±0.2°、22.94±0.2°、23.78±0.2°、25.16±0.2°和28.08±0.2°处有特征峰。
进一步地，共晶A的X-射线粉末衍射图谱在2θ角为7.00±0.2°、10.76±0.2°、11.60±0.2°、12.52±0.2°、13.96±0.2°、16.72±0.2°、19.18±0.2°、20.00±0.2°、21.18±0.2°、22.94±0.2°、23.78±0.2°、25.16±0.2°、26.88±0.2°、28.08±0.2°和30.20±0.2°处有特征峰。
进一步地，共晶A具有基本如图1所示的X射线粉末衍射图。
进一步地，共晶A的DSC图谱在176±5℃处有吸热峰。
进一步地，共晶A的DSC图谱基本如图2所示。
进一步地，共晶A的TGA图谱基本如图3所示。
进一步地，共晶A的核磁图谱基本如图4所示。
本发明还提供了上述式(I)所示化合物的尿素共晶A的制备方法，包括以下步骤：
第一步：将式(I)所示化合物阿哌沙班与一定当量的尿素加入到乙醇或乙醇与其他溶剂的混合溶剂中，升温回流溶解后，降至室温析晶5-24h；其他溶剂选自酮类、酯类；
第二步：抽滤，收集所得固体，干燥，得阿哌沙班尿素共晶A。
进一步地，第一步中阿哌沙班与尿素的摩尔比为1:4-12，优选为1:6-10。
进一步地，第一步中阿哌沙班与溶剂的质量体积比为1:10-1:30(g/ml)。
进一步地，第一步中其他溶剂选自丙酮、丁酮、乙酸乙酯、乙酸甲酯或乙酸异丙酯。
本发明进一步提供阿哌沙班尿素共晶形式A的药物组合物，包括所述的式(I)所示化合物的尿素共晶形式A和药学上可接受的辅料。
本发明还提供阿哌沙班尿素共晶形式A、阿哌沙班尿素共晶形式A的药物组合物在制备静脉栓塞的相关疾病的药物中的用途。
本发明带来的有益效果有：
1.所得阿哌沙班尿素共晶形式A具有较高的理化稳定性、晶型稳定性及成药稳定性，溶解性更好，生物利用度更高。
2.其制备工艺重复性好，收率高，所用溶剂均为三类溶剂，绿色环保，易于操作，便于回收，容易实现规模化放大生产，且该工艺可塑性强，能够通过参数的调整制备获得各个粒径范围的产品，从而满足制剂的不同需求。
附图说明
图1为阿哌沙班尿素共晶形式A的XRD图。
图2为阿哌沙班尿素共晶形式A的DSC图。
图3为阿哌沙班尿素共晶形式A的TGA图。
图4为阿哌沙班尿素共晶形式A的 1H-NMR图。
图5为阿哌沙班尿素共晶形式A的单晶解析分子结构图。
图6为阿哌沙班尿素共晶形式A的单晶晶胞图。
图7为阿哌沙班尿素共晶形式A与药用晶型N-1的溶解度对比图。
图8为阿哌沙班尿素共晶形式A稳定性考察晶型结果图。
图9.1为阿哌沙班尿素共晶形式A雌鼠平均药物浓度-时间曲线。
图9.2为阿哌沙班尿素共晶形式A雄鼠平均药物浓度-时间曲线。
图10.1为实施例1所得尿素共晶A制备片剂与市售品在pH1.0介质中溶出曲线对比。
图10.2为实施例1所得尿素共晶A制备片剂与市售品在pH4.5介质中溶出曲线对比。
具体实施方式
以下结合实施例对本发明作进一步的详细描述，但并非对本发明的限制，凡依照本发明公开内容所作的任何本领域的等同替换，均属于本发明的保护范围。
本申请中所用到的缩写的解释如下：
XRD：X射线粉末衍射
本申请所述的X射线粉末衍射(XRD)的测定是采用辽宁丹东浩元DX-2700B粉末衍射仪进行采集，具体参数如下表：
Figure PCTCN2021141012-appb-000003
DSC：差式扫描量热仪
本申请所述的差式扫描量热(DSC)的测定是采用METTLER TOLEDO型号DSC-1进行采集，升温速率为10℃/min，温度范围为25-250℃，测试过程中的氮气吹扫速率是60mL/min。
TGA：热重分析仪
本申请所述的热重分析(TGA)的测定是采用METTLER TOLEDO型号TGA-2进行采集，升温速率为10℃/min，温度范围为30-300℃，测试过程中的氮气吹扫速率是20mL/min。
LC/MS/MS生物样品分析
本申请所述的LC/MS/MS生物样品分析是指利用液相色谱质谱联用技术进行生物样品分析，该技术对混合物的分析具有较高的灵敏度和选择性及广泛的适用性，能够对复杂生物基 质中微量化合物进行快速可靠的定量或定性分析。本发明中，所涉及的液质联用仪(质谱)为：AB Sciex Triple Quad 4500。
X射线单晶衍射仪
本申请所述的单晶衍射数据的测定是采用理学XtaL AB-PRO单晶X射线衍射仪进行采集，具体参数如下表：
Figure PCTCN2021141012-appb-000004
实施例1：尿素共晶A的制备
称取阿哌沙班2.3g及尿素1.8g(6.0eq)，加入乙酸乙酯:乙醇(4:3)的混合溶剂46.0ml，升温回流溶解，后降至室温搅拌析晶18h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.75g，收率94.8％，纯度99.93％，XRD图谱如图1所示，DSC图谱如图2所示，TGA如图3所示，核磁 1H-NMR图谱如图4所示。特征峰寻峰报表如下表所示：
Figure PCTCN2021141012-appb-000005
Figure PCTCN2021141012-appb-000006
实施例2：尿素共晶A的制备
称取阿哌沙班2.3g及尿素2.4g(8.0eq)，加入乙酸甲酯:乙醇(4:3)的混合溶剂35.0ml，升温回流溶解，后降至室温搅拌析晶16h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.76g，收率95.2％，纯度99.91％，XRD图谱与图1一致。
实施例3：尿素共晶A的制备
称取阿哌沙班2.3g及尿素3.0g(10.0eq)，加入乙酸异丙酯:乙醇(4:3)的混合溶剂58.0ml，升温溶解，后降至室温搅拌析晶24h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.80g，收率96.5％，纯度99.93％，XRD图谱与图1一致。
实施例4：尿素共晶A的制备
称取阿哌沙班2.3g及尿素3.6g(12.0eq)，加入丙酮:乙醇(4:3)的混合溶剂69.0ml，升温回流溶解，后降至室温搅拌析晶18h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.82g，收率97.2％，纯度99.92％，XRD图谱与图1一致。
实施例5：尿素共晶A的制备
称取阿哌沙班2.3g及尿素2.4g(8.0eq)，加入丙酮:乙醇(4:3)的混合溶剂35.0ml，升温回流溶解，后降至室温搅拌析晶5h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.79g，收率96.2％，纯度99.93％，XRD图谱与图1一致。
实施例6：尿素共晶A的制备
称取阿哌沙班2.3g及尿素1.2g(4.0eq)，加入丁酮:乙醇(4:3)的混合溶剂23.0ml，升温回流溶解，后降至室温搅拌析晶18h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.55g，收率87.9％，纯度99.91％，XRD图谱与图1一致。
实施例7：尿素共晶A的制备
称取阿哌沙班2.3g及尿素2.4g(8.0eq)，加入丙酮:乙醇(1:3)的混合溶剂35.0ml，升温回流溶解，后降至室温搅拌析晶18h，收集所得固体，干燥，得到类白色的阿哌沙班尿素共晶A 2.85g，收率98.28％，纯度99.92％，XRD图谱与图1一致。
实施例8：尿素共晶A的单晶培养及单晶衍射
本发明人通过开发丙酮/乙醇体系的结晶工艺，直接获得了大粒径、形状规则的单晶样品，并对该单晶样品进行了单晶衍射分析，所得单晶数据如表1所示，单晶解析分子结构图如图5所示，单晶晶胞图如图6所示。
表1.尿素共晶A单晶数据
Figure PCTCN2021141012-appb-000007
试验例1：尿素共晶A溶解性考察试验
为了考察本发明实施例1制备所得尿素共晶A与药用晶型N-1的溶解性的差异，药用晶型N-1采购自Srini Pharmaceuticals Pvt Ltd。本发明分别在25℃、37℃条件下在pH＝1.0(0.1N)的盐酸、纯水和pH＝6.8的磷酸缓冲溶液中，通过外标法测定实施例1制备的尿素共晶A与药用晶型N-1的平衡溶解度(饱和溶液)，结果如下表2所示：
表2.溶解性试验
Figure PCTCN2021141012-appb-000008
溶解性试验结果表明，尿素共晶A相较于药用晶型N-1，在25℃/37℃，纯水、pH1.0、pH6.8三种介质中，平衡溶解度均具有明显的优势，尿素共晶A在各介质，各温度的溶解度均约为N-1的1.5倍左右，溶解度得到明显改善。
试验例2：尿素共晶A稳定性考察实验
为了考察本发明实施例1制备所得尿素共晶A的储存稳定性，将所得样品于高温光照下考察影响因素试验，并放样25±2℃-60±5％RH考察长期稳定性试验和40℃±2℃-75±5％RH考察加速稳定性试验，结果如下表3所示：
表3.稳定性试验
Figure PCTCN2021141012-appb-000009
Figure PCTCN2021141012-appb-000010
稳定性试验结果表明，尿素共晶A在所考察的条件下，均具有良好的晶型稳定性。
试验例3：大鼠体内药代动力学试验
1、试验目的
考察相同给药剂量下，大鼠单次口服给予阿哌沙班原研药用晶型N-1，尿素共晶A和东阳光尿素共晶IV后，血浆中阿哌沙班浓度水平及其药代动力学特征。
2、材料和方法
2.1、受试药物
阿哌沙班药用晶型N-1，由Srini Pharmaceuticals Pvt Ltd提供，类白色固体，批号Y20071，纯度：99.94％；
阿哌沙班尿素共晶A，由成都苑东生物制药股份有限公司晶型研究部提供，类白色固体，纯度：99.93％；
阿哌沙班东阳光尿素共晶IV，由成都苑东生物制药股份有限公司晶型研究部提供，根据专利CN106986868B实施例5制备，类白色固体，纯度：99.93％；
2.2、试验动物
SD大鼠18只，雌雄性各9只，体重220-240g，由成都恩斯维尔生物科技有限公司代购于湖南斯莱克景达实验动物有限公司，许可证号：SCXK(湘)2019-0004。
2.3、试验方法
受试药物用玉米油配制成1.25mg/kg均匀的混悬液后，立即按4mL/kg的体积口服给予大鼠，并在给药前及给药后15min、30min、1h、2h、3h、4h、5h、6h、7h、8h、24h颈静脉取血0.1mL，置于EDTA-K2管中，3000r/min，离心10min，分离血浆，-80℃冰箱冷冻保存。
2.4、LC/MS/MS生物样品分析：
取50μL血浆与5μL工作液或空白稀释液混匀，加入150μL含内标乙腈沉淀剂，旋涡震荡2min，12000r/min离心10min，取上清2μL与200μL纯水：乙腈(1:1)混匀后，以3μL体积进样分析。
2.5、试验结果：
分别将阿哌沙班药用晶型N-1，尿素共晶A及东阳光尿素共晶IV进行动物实验，即对雌雄性大鼠单次口服给药后测试不同时间血浆中API的平均浓度(ng·mL-1)，绘制得雌雄性大鼠单次口服后血浆中的平均药物浓度-时间曲线如图9.1、图9.2所示，其主要药物动力学参数如下表：
表4.雌鼠单次口服给药后主要药动学参数
参数 晶型N-1 尿素共晶A 东阳光尿素共晶IV
T 1/2(h) 6.83 4.49±0.10 6.55±2.37
T max(h) 5.83±3.75 1.08±0.72 1.00±0.87
C max(ng·mL -1) 2570±999 4653±763 2563±985
AUC last(h·ng·mL -1) 27787±13050 33636±8113 23201±8105
Cl_F_obs(mL/hr/kg) 0.56 0.30±0.08 0.43±0.15
MRT(h) 7.37±1.79 5.55±0.61 6.29±0.87
表5.雄鼠单次口服给药后主要药动学参数
参数 晶型N-1 尿素共晶A 东阳光尿素共晶IV
T 1/2(h) 5.05±1.43 5.53±2.98 5.16±1.14
T max(h) 1.00±0.87 1.00±0.00 1.08±0.88
C max(ng·mL -1) 4093±3253 7970±4475 4193±862
AUC last(h·ng·mL -1) 19764±13974 25567±14447 17052±6085
Cl_F_obs(mL/hr/kg) 0.64±0.32 0.45±0.20 0.58±0.27
MRT(h) 4.78±0.75 4.16±0.41 3.86±0.07
动物实验表明：1.雌鼠：共晶A生物利用度较原研晶型N-1提高21％，较东阳光尿素共晶IV提高44.98％；2.雄鼠：共晶A生物利用度较原研晶型N-1提高29.36％，较东阳光尿素共晶IV提高49.94％。综上所述，可见本发明所得尿素共晶A的生物利用度相较于药用晶型N-1及尿素共晶IV均有明显的提高。
试验例4：尿素共晶A与晶型N-1的制剂溶出试验
处方工艺：参照原研制剂专利CN109602713A具体实施方式中表3提供的片剂处方，采用干法制粒的方法，以阿哌沙班尿素共晶A作为原料，制备获得阿哌沙班5mg规格的片剂组合物。
市售产品：百时美施贵宝公司ELIQUIS，5mg。
将实施例1所得的尿素共晶A样品经过制剂处方工艺压片，与市售产品进行对比，考察介质pH1.0、pH4.5中的溶出曲线，数据如附图10.1、10.2所示，可见所得尿素共晶A的制剂产品溶出行为与市售产品表现一致。
综合上述试验例可以看出，本发明提供的阿哌沙班尿素共晶A相较于药用晶型N-1，具有溶解性能更优，晶型及理化稳定性良好，生物利用度明显提高，各介质溶出效果能与市售产品达到一致的优点。
对于本领域的普通技术人员而言明显的是，在不偏离本申请精神或者范围的情况下，可对本申请化合物及其制备方法进行的多种修饰和变化，因此，本申请的保护范围涵盖了对本申请进行的各种修饰和变化，只要所述修饰或变化处于权利要求和其等同实施方式所涵盖的范围内。
Figure PCTCN2021141012-appb-000011
Figure PCTCN2021141012-appb-000012
Figure PCTCN2021141012-appb-000013
Figure PCTCN2021141012-appb-000014
Figure PCTCN2021141012-appb-000015
Figure PCTCN2021141012-appb-000016
Figure PCTCN2021141012-appb-000017
Figure PCTCN2021141012-appb-000018
Figure PCTCN2021141012-appb-000019
Figure PCTCN2021141012-appb-000020

Claims (15)

  1. 一种式(I)所示化合物的尿素共晶A，其特征在于，共晶A中阿哌沙班与尿素的比例为1:2
    Figure PCTCN2021141012-appb-100001
  2. 根据权利要求1所述的式(I)所示化合物的尿素共晶A，其特征在于，其X-射线粉末衍射图谱在2θ角为7.00±0.2°、10.76±0.2°、11.60±0.2°、19.18±0.2°、20.00±0.2°、22.94±0.2°、23.78±0.2°和28.08±0.2°处有特征峰。
  3. 根据权利要求1所述的式(I)所示化合物的尿素共晶A，其特征在于，所述尿素共晶A的X-射线粉末衍射图谱在2θ角为7.00±0.2°、10.76±0.2°、11.60±0.2°、12.52±0.2°、19.18±0.2°、20.00±0.2°、22.94±0.2°、23.78±0.2°、25.16±0.2°和28.08±0.2°处有特征峰。
  4. 根据权利要求1所述的式(I)所示化合物的尿素共晶A，其特征在于，所述尿素共晶A的X-射线粉末衍射图谱在2θ角为7.00±0.2°、10.76±0.2°、11.60±0.2°、12.52±0.2°、13.96±0.2°、16.72±0.2°、19.18±0.2°、20.00±0.2°、21.18±0.2°、22.94±0.2°、23.78±0.2°、25.16±0.2°、26.88±0.2°、28.08±0.2°和30.20±0.2°处有特征峰。
  5. 根据权利要求1～4所述的式(I)所示化合物的尿素共晶A，其特征在于，所述式(I)所示化合物的尿素共晶A具有基本如图1所示的X射线粉末衍射图。
  6. 根据权利要求1～4所述的式(I)所示化合物的尿素共晶A，其特征在于：其DSC图谱在176±5℃处有吸热峰。
  7. 根据权利要求6所述的式(I)所示化合物的尿素共晶A，其特征在于：其DSC图谱基本如图2所示。
  8. 根据权利要求1～4所述的式(I)所示化合物的尿素共晶A，其特征在于：其TGA图谱基本如图3所示。
  9. 根据权利要求1～4所述的式(I)所示化合物的尿素共晶A，其特征在于，其核磁图谱基本如图4所示。
  10. 一种制备如权利要求1～9所述的式(I)所示化合物的尿素共晶A的制备方法，其特征在于，包括以下步骤：
    第一步：将式(I)所示化合物阿哌沙班与一定当量的尿素加入到乙醇或乙醇与其他溶剂 的混合溶剂中，升温回流溶解后，降至室温析晶5-24h；其他溶剂选自酮类、酯类；
    第二步：抽滤，收集所得固体，干燥，得阿哌沙班尿素共晶A。
  11. 根据权利要求10所述的式(I)所示化合物的尿素共晶A的制备方法，其特征在于，第一步中阿哌沙班与尿素的摩尔比为1:4-12，优选为1:6-10。
  12. 根据权利要求10所述的式(I)所示化合物的尿素共晶A的制备方法，其特征在于，第一步中阿哌沙班与溶剂的质量体积比为1:10-1:30(g/ml)。
  13. 根据权利要求10所述的式(I)所示化合物的尿素共晶A的制备方法，其特征在于，第一步中其他溶剂选自丙酮、丁酮、乙酸乙酯、乙酸甲酯或乙酸异丙酯。
  14. 一种药物组合物，包括权利要求1～9所述的式(I)所示化合物的尿素共晶A和药学上可接受的辅料。
  15. 如权利要求1～9所述的式(I)所示化合物的尿素共晶A在制备抗凝血药物中的用途。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112851666A (zh) * 2019-11-28 2021-05-28 中国医学科学院药物研究所 阿哌沙班与槲皮素共晶物及制备方法和其组合物与用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103830199A (zh) * 2014-03-24 2014-06-04 重庆东得医药科技有限公司 含阿哌沙班的药用制剂及其制备方法
US20160113912A1 (en) * 2013-06-18 2016-04-28 Cadila Healthcare Limited An improved process for the preparation of apixaban and intermediates thereof
CN106986868A (zh) * 2016-01-21 2017-07-28 广东东阳光药业有限公司 包含阿哌沙班的共晶体及其制备方法
CN110862389A (zh) * 2018-08-28 2020-03-06 江苏康缘药业股份有限公司 一种阿哌沙班晶型的制备方法
CN110922403A (zh) * 2019-09-26 2020-03-27 浙江天宇药业股份有限公司 阿哌沙班与羧酸形成的共晶及其制备方法
CN112851666A (zh) * 2019-11-28 2021-05-28 中国医学科学院药物研究所 阿哌沙班与槲皮素共晶物及制备方法和其组合物与用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160113912A1 (en) * 2013-06-18 2016-04-28 Cadila Healthcare Limited An improved process for the preparation of apixaban and intermediates thereof
CN103830199A (zh) * 2014-03-24 2014-06-04 重庆东得医药科技有限公司 含阿哌沙班的药用制剂及其制备方法
CN106986868A (zh) * 2016-01-21 2017-07-28 广东东阳光药业有限公司 包含阿哌沙班的共晶体及其制备方法
CN110862389A (zh) * 2018-08-28 2020-03-06 江苏康缘药业股份有限公司 一种阿哌沙班晶型的制备方法
CN110922403A (zh) * 2019-09-26 2020-03-27 浙江天宇药业股份有限公司 阿哌沙班与羧酸形成的共晶及其制备方法
CN112851666A (zh) * 2019-11-28 2021-05-28 中国医学科学院药物研究所 阿哌沙班与槲皮素共晶物及制备方法和其组合物与用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112851666A (zh) * 2019-11-28 2021-05-28 中国医学科学院药物研究所 阿哌沙班与槲皮素共晶物及制备方法和其组合物与用途
CN112851666B (zh) * 2019-11-28 2023-11-03 中国医学科学院药物研究所 阿哌沙班与槲皮素共晶物及制备方法和其组合物与用途

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