WO2021004209A1 - 一种二氢吡啶钙拮抗剂共晶体及其制备方法和应用 - Google Patents

一种二氢吡啶钙拮抗剂共晶体及其制备方法和应用 Download PDF

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WO2021004209A1
WO2021004209A1 PCT/CN2020/094643 CN2020094643W WO2021004209A1 WO 2021004209 A1 WO2021004209 A1 WO 2021004209A1 CN 2020094643 W CN2020094643 W CN 2020094643W WO 2021004209 A1 WO2021004209 A1 WO 2021004209A1
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crystal
antagonist
dihydropyridine
levoamlodipine
eutectic
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PCT/CN2020/094643
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English (en)
French (fr)
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凌云
周亚明
邓名莉
杨永泰
刘小锋
贾瑜
朱嘉星
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复旦大学
珠海复旦创新研究院
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Priority to JP2021546042A priority Critical patent/JP2022508791A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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

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  • the invention relates to the technical field of crystal form drugs, in particular to a co-crystal of calcium dihydropyridine antagonist and a preparation method and application thereof.
  • Crystalline drugs include polymorphs, hydrates, solvates and salts of drug molecules.
  • the different crystal forms of the drugs have significant differences in their physical and chemical properties, which will directly affect their dissolution and absorption efficiency under physiological conditions, thereby affecting the bioavailability and clinical efficacy of the drugs.
  • L-Amlodipine As a fourth-generation dihydropyridine calcium antagonist antihypertensive drug for the treatment of hypertension, L-Amlodipine is trusted by many doctors and patients due to its high curative effect and small side effects. It is a commonly used drug for the treatment of hypertension. L-Amlodipine is a free base compound that needs to crystallize into salt. At present, the main salt-forming drugs of L-Amlodipine on the domestic market are L-Amlodipine Besylate and L-Amlodipine Maleate (the structural formula is shown below).
  • levoamlodipine besylate has good curative effect and few side effects, it is deeply trusted by patients, but the eutectic form of levoamlodipine besylate, especially the hydrated eutectic form, is not stable.
  • the developed L-Amlodipine Maleate has a slight improvement in the stability of the eutectic crystal form, but studies have shown that the efficacy of L-Amlodipine Maleate is not ideal. Therefore, focusing on the free base of L-Amlodipine, developing new eutectic crystal forms and exploring and improving the above problems are one of the important contents of the research and development of new dihydropyridine calcium antagonists.
  • the purpose of the present invention is to provide a calcium dihydropyridine antagonist co-crystal and its preparation method and application in order to solve the above problems.
  • a co-crystal of dihydropyridine calcium antagonist the molecular formula of the co-crystal is: (C 20 H 25 ClN 2 O 5 ) ⁇ (C 6 H 5 COOH) ⁇ (Y) n , where Y is water molecule, ethanol Either of molecules or isopropanol molecules, 0 ⁇ n ⁇ 3, C 20 H 25 ClN 2 O 5 is levoamlodipine, and C 6 H 5 COOH is benzoic acid.
  • n is limited by the type of solvent in the salt-forming reaction, temperature conditions, and subsequent product drying conditions, so that it can be realized within a certain range, and this change does not affect the eutectic crystal form.
  • unit cell value and the chiral Flack value in parentheses are limited by the solvent molecule and number, and the numerical error generated by the test instrument and analysis method.
  • the absorption correction uses the SADABS program.
  • the crystal system and unit cell values of the eutectic crystal form of the calcium dihydropyridine antagonist provided by the present invention can be calculated as described above, and The number of X-ray powder diffraction peaks that does not mean that the eutectic crystal form is limited to the number listed in the table.
  • the co-crystal form of the calcium dihydropyridine antagonist is the aforementioned co-crystal form of levoamlodipine benzoate, and the preparation method of the co-crystal form of levoamlodipine benzoate includes the following steps:
  • reaction liquid is stirred and heated to the target temperature for a certain period of time, then left to stand for cooling and crystallize, filtered and separated to obtain.
  • the preparation method provided by the present invention is a classic free base salt-forming crystallization method, that is, the free base solution is prepared first, then the salt-forming reagent is added, and it is prepared by crystallization.
  • L-Amlodipine used here is an average of commercially available chemical raw materials. If used in pharmaceuticals, APIs that meet GMP requirements should be used. Optimally, L-Amlodipine crystallized in P2 1 2 1 2 1 Dipine free base is used as a raw material.
  • the solvent used here is any commercially available chemical raw material of isopropanol, ethanol, and water. If it is used for pharmaceuticals, it is best to use a corresponding solvent that meets the requirements of pharmaceuticals.
  • the ratio of the free base of levoamlodipine to the solvent can be determined according to production needs, with the purpose of completely dissolving the free base of levoamlodipine.
  • the molar ratio of the levoamlodipine free base to the solvent is 1:50-200.
  • the salt-forming reagent refers to benzoic acid, and the amount of benzoic acid added is for the purpose of satisfying the complete salt formation of the free base of L-Amlodipine.
  • the molar ratio of the levoamlodipine free base to the benzoic acid is 1:1 to 2.
  • step (2) the specific method of adding benzoic acid can be determined according to the needs of production. It can be added in the form of a solid powder or a solution prepared with benzoic acid. Preferably, the benzoic acid is prepared as Add a solution with a concentration of 0.5-2M.
  • the temperature of the reaction solution raised to the target temperature refers to a temperature range of 50 to 120°C, preferably 80 to 100°C, and the heat preservation for a certain time means that the time is not less than 2 hours, Less than this value, it is difficult to form a crystal phase or the economic benefit of yield is too low, preferably, 5-24 hours.
  • the heat preservation process can be determined according to the conditions of the equipment in the specific production.
  • a constant temperature heating device can be used to keep it sealed, or it can be a heating reflux device.
  • a sealed reaction instrument is used for heat preservation.
  • the preparation step (3) of the levoamlodipine co-crystal product also includes standing and cooling, and the cooling temperature is generally lower than the temperature of the holding reaction.
  • the temperature drops to 5-25°C to crystallize.
  • the step (3) further includes filtration, mother liquor washing (original crystalline solution), and drying at room temperature.
  • the filtration can adopt any suitable method, preferably, in the step (3), the filtration is filtration under reduced pressure.
  • the eutectic crystal form of the calcium dihydropyridine antagonist prepared by the above method is colorless and transparent crystals of needle or rod shape in appearance.
  • the present invention improves the solubility and stability of the existing levoamlodipine co-crystal crystal form, and is potentially beneficial to the improvement of the stability of antihypertensive tablets and the improvement of bioavailability in large-scale production of tablets.
  • the present invention provides a eutectic crystal form of calcium dihydropyridine antagonist, crystallized in the triclinic system, crystals of the P1 chiral space group, with clear crystal form, main crystallographic parameters and exact atoms The spatial position, the value is different from any clinical or commercial dihydropyridine calcium antagonist co-crystal form.
  • the eutectic crystal form of a calcium dihydropyridine antagonist provided by the present invention is specifically the crystal of levoamlodipine benzoate, which is different from the clinical or commercial levoamlodipine besylate and levoamlodipine maleate. Amlodipine.
  • the method for preparing a eutectic crystal form of calcium dihydropyridine antagonist provided by the present invention has a wide source of raw materials, simple operation, regular crystal crystal form, uniform particle size, and clear X-ray powder diffraction data. , Suitable for large-scale promotion and application.
  • the eutectic crystal form of a dihydropyridine calcium antagonist of the present invention with the above-mentioned characteristic parameters improves the solubility and stability of the existing levoamlodipine salt, and is beneficial to the stability of levoamlodipine tablets Enhancement of sex and improvement of bioavailability.
  • Fig. 1 is a schematic diagram of a crystal structure of a specific embodiment of a co-crystal of dihydropyridine calcium antagonist provided by the present invention.
  • Fig. 2 is a schematic diagram of the molecular packing structure of a specific embodiment of the calcium dihydropyridine antagonist co-crystal crystal provided by the present invention.
  • Fig. 3 is an X-ray powder diffraction spectrum of a specific embodiment of the calcium dihydropyridine antagonist co-crystal crystal provided by the present invention.
  • Figure 4 is a thermal analysis spectrum of a specific example of the co-crystal form of calcium dihydropyridine antagonist provided by the present invention.
  • the present invention successfully prepared the crystal product on the basis of a large number of drug crystallization research experiments, and provided clear crystallographic parameters. Space conformation of the functional group.
  • FIG. 1 is a schematic diagram of the crystal structure
  • Figure 2 is a schematic diagram of the molecular stacking structure.
  • the preparation method is the same as in Example 1, and the specific process parameters are shown in Table 1.
  • Example 1 Take the eutectic crystal of levoamlodipine benzoate prepared in Example 1 as an example, select crystals whose quality and size meet the requirements of the testing instrument, and use the Apex Duo X-ray single crystal diffractometer of German Bruker Company to test the parameters.
  • the test temperature is 296K
  • Mo-K ⁇ radiation Diffraction data is collected in ⁇ scan mode and Lp correction is performed.
  • the absorption correction uses the SADABS program.
  • the structure is analyzed by the direct method, and all non-hydrogen atoms are found by the difference Fourier method. All hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the least square method is used to modify the structure. All the parsing process is completed using SHELXTL package.
  • the crystal test can be tested on any X-ray single crystal diffraction instrument, not limited to the Apex Duo model of Bruker, Germany, and the light source is not limited to the Mo target.
  • the crystallographic data obtained from the test does not depend on the analytical method.
  • Example 1 Take the polycrystalline product of levoamlodipine benzoate in Example 1 and test it with the German Bruker Advance D8 X-ray polycrystalline diffractometer.
  • the test parameters are all default standard settings, and the tablet is tested at room temperature.
  • the sample to be tested needs to be processed by tableting, grinding, 300 mesh sieving, and regranulation.
  • Copper target K ⁇ 1 radiation The irradiation wavelength, the scanning angle is from 1 to 50°, and the sample spectrum of the test is shown in Figure 3.
  • the samples of the polycrystalline products of Examples 2-8 have similar X-ray powder polycrystalline diffraction spectra.
  • the present invention adopts the free base eutectic salt formation method to prepare levamlodipine benzoate, which is different from the commercial clinically used levamlodipine besylate and levamlodipine maleate.
  • the new eutectic crystal form of hydropyridine calcium antagonists has clear crystallographic related parameters, unit cell size, and spatial configuration and arrangement of the eutectic structure.
  • the raw materials of the eutectic crystal form of the calcium dihydropyridine antagonist provided by the present invention are widely and easily available, the preparation method is simple and easy to implement, the obtained crystal crystal form is regular, the particle size is uniform, and can meet the requirements of X-ray diffraction testing , The related quality is easy to control and suitable for large-scale promotion and application.

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

本发明涉及一种二氢吡啶钙拮抗剂共晶体及其制备方法和应用，共晶体分子式为(C20H25ClN2O5)·(C6H5COOH)·(Y)n，其中，Y为水分子、乙醇分子或异丙醇分子中的任一种，0≤n≤3，共晶体结晶于三斜晶系，P1手性空间群，晶胞大小：α=7.4~7.8Å, b=7.5~8.1Å, c=25.3~26.2Å, α＝97.1~97.5°，β＝92.2~92.6°，γ＝111.5~112.1°，v=1408~1428Å3.本发明改善现有左旋氨氯地平共晶体晶型的溶解性及稳定性，潜在地，在大规模生产片剂中有利于降压药片剂稳定性的提升及生物利用度的改善。

Description

一种二氢吡啶钙拮抗剂共晶体及其制备方法和应用 技术领域
本发明涉及晶型药物技术领域，具体涉及一种二氢吡啶钙拮抗剂共晶体及其制备方法和应用。
背景技术
晶型药物由于稳定性、重现性、生物利用度及操作性等方面的优势，在成药中被优先选用。晶型药物包括药物分子的多晶型、水合物、溶剂化物和盐类等种类。药物的晶型不同，其理化性质差异显著，会直接影响其在生理条件下的溶出及吸收效率，进而影响药物的生物利用度和临床疗效等。
左旋氨氯地平作为治疗高血压的第四代二氢吡啶类钙离子拮抗剂降压药，由于疗效高、副作用小，深受广大医生患者的信赖，是治疗高血压常用药物。左旋氨氯地平是一种游离碱化合物，需成盐结晶。目前，国内市售的左旋氨氯地平成盐药物主要是苯磺酸左旋氨氯地平和马来酸左旋氨氯地平(结构式如下所示)。
Figure PCTCN2020094643-appb-000001
苯磺酸左旋氨氯，虽疗效好，副作用少，深受患者的信赖，但苯磺酸左旋氨氯地平的共晶晶型，尤其是水合共晶晶型，稳定性并不理想。将苯磺酸替换为马来酸，开发的马来酸左旋氨氯地平，虽然共晶晶型稳定性略有改善，但是研究表明马来酸左旋氨氯地平的疗效并不理想。因此，围绕着左旋氨氯地平游离碱，开发新共晶晶型，探索改善上述问题，是二氢吡啶类钙拮抗剂新药研发的重要内容之一。
发明内容
本发明的目的就是为了解决上述问题而提供一种二氢吡啶钙拮 抗剂共晶体及其制备方法和应用。
本发明的目的通过以下技术方案实现：
一种二氢吡啶钙拮抗剂共晶体，该共晶体的分子式为：(C 20H 25ClN 2O 5)·(C 6H 5COOH)·(Y) n，其中，Y为水分子、乙醇分子或异丙醇分子中的任一种，0≤n≤3，C 20H 25ClN 2O 5是左旋氨氯地平，C 6H 5COOH是苯甲酸。
需要说明的是，n的具体数值受限于成盐反应中溶剂的类型、温度条件，以及后续的产物干燥条件而具有一定范围内的可变现，这种变化不影响共晶晶型。
所述的共晶体结晶于三斜晶系，P1手性空间群，晶胞大小：
Figure PCTCN2020094643-appb-000002
Figure PCTCN2020094643-appb-000003
α＝97.1～97.5°，β＝92.2～92.6°，γ＝111.5～112.1°，
Figure PCTCN2020094643-appb-000004
需要说明的是，单胞数值、手性的Flack值的括号内数值为受限于溶剂分子及个数，测试仪器及分析方法产生的数值误差。
上述晶体学测量参数通过X-射线单晶衍射测试方法获得，基本过程如下：
选取满足测试所需的尺寸大小的晶体，并将该晶体“铆”于玻璃丝顶端，固定于测试仪器上。X-射线晶体数据在德国布鲁克Apex Duo型号仪器上收集，用MoKα辐射
Figure PCTCN2020094643-appb-000005
以ω扫描方式收集衍射数据并进行Lp校正。
吸收校正采用SADABS程序。
用直接法解析结构，用差值傅立叶法找出全部非氢原子，所有碳及氮上的氢原子采用理论加氢得到，结晶水分子的氢原子直接从差值傅立叶图中找出，采用最小二乘法对结构修正。
所有解析过程采用SHELXTL程序包完成。
所述二氢吡啶钙拮抗剂的共晶晶型的特征X-射线粉末衍射数据与所用X-射线波长无关的面间距
Figure PCTCN2020094643-appb-000006
再现的主要衍射数据如下：
Figure PCTCN2020094643-appb-000007
需要说明的是，基于所给出的数值，结合布拉格相关理论公式，可计算出如前所述的本发明提供的二氢吡啶钙拮抗剂的共晶晶型的晶系、单胞数值，并不表示该共晶晶型的X-射线粉末衍射峰的个数仅限于表中所列的个数。
所述二氢吡啶钙拮抗剂的共晶晶型是上述的苯甲酸左旋氨氯地平共晶晶型，所述苯甲酸左旋氨氯地平共晶晶型的制备方法包括以下步骤：
(1)将左旋氨氯地平游离碱完全溶解在溶剂中获得反应液；
(2)室温搅拌条件下，向反应液中加入一定量的成盐试剂，获得成盐反应溶液；
(3)反应液搅拌升温至目标温度保温一定时间，然后静置冷却析晶，过滤分离，即得。
本发明所提供的制备方法是经典的游离碱成盐结晶的方法，即：首先制备游离碱溶液，然后加入成盐试剂，经结晶制备而得。
需要说明的是，这里使用的左旋氨氯地平均为市售化工原料，如 果用于制药，则使用满足GMP要求的原料药，最优的，使用结晶于P2 12 12 1的左旋氨氯地平游离碱作为原料。这里使用的溶剂是异丙醇、乙醇、水中的任意一种市售化工原料，如果是用于制药，则最好使用满足制药要求的相应溶剂。
在步骤(1)中，所述的左旋氨氯地平游离碱与所述的溶剂的比例可以根据生产需要确定，以将左旋氨氯地平游离碱完全溶解为目的，较佳地，在所述步骤(1)中，所述左旋氨氯地平游离碱与所述溶剂的摩尔比是1:50～200。
在步骤(2)中，所述的成盐试剂是指苯甲酸，所述的加入的苯甲酸的量以满足左旋氨氯地平游离碱完全成盐为目的，较佳地，在所述步骤(2)中，所述的左旋氨氯地平游离碱与所述的苯甲酸的摩尔比是1:1～2。
在步骤(2)中，所述加入苯甲酸的具体加入方式可以根据生产的需要确定，可以是固体粉末形式加入，也可以是配置苯甲酸的溶液形式加入，较佳地，将苯甲酸配置成浓度是0.5～2M的溶液加入。
在步骤(3)中，所述的反应液升温至目标温是指在50～120℃温度范围内，较佳地，80～100℃，所述的保温一定时间是指时间不小于2小时，小于此数值，难以形成晶相或产率的经济效益过低，较佳地，5～24小时。
在步骤(3)中，所述的保温过程可根据具体生产中仪器设备条件确定，可采用恒温加热装置使其密闭保温，也可以是加热回流装置，较佳地，采用密闭反应仪器保温。
在所述的左旋氨氯地平共晶体产物的制备步骤(3)中，还包括静置冷却，冷却温度一般比保温反应温度低即可，较佳地，在所述步骤(3)中，将温度降至5-25℃结晶。
为了取得晶体产物，较佳地，在所述步骤(3)中还包括过滤、母液洗涤(原结晶溶液)，室温干燥。
所述过滤可以采用任何合适的方法，较佳地，在所述步骤(3) 中，所述过滤是减压过滤。
通过上述方法制备的所述一种二氢吡啶钙拮抗剂的共晶晶型，在外观上是针状或棒状的无色透明晶体。
本发明改善现有左旋氨氯地平共晶体晶型的溶解性及稳定性，潜在地，在大规模生产片剂中有利于降压药片剂稳定性的提升及生物利用度的改善，其具有不同于苯磺酸左旋氨氯地平和马来酸左旋氨氯地平的分子结构式，具有明确的晶型和原子空间位置，明确的晶体学主要参数，潜在地，适用于规模化生产中的质量控制。
本发明的有益效果，或与现有技术相比的主要优点是：
(1)本发明提供的一种二氢吡啶钙拮抗剂的共晶晶型，结晶于三斜晶系，P1手性空间群的晶体，具有明确的晶型、晶体学主要参数及确切的原子空间位置，数值不同于任何一种临床或市售的二氢吡啶类钙拮抗剂的共晶晶型。
(2)本发明提供的一种二氢吡啶钙拮抗剂的共晶晶型具体是苯甲酸左旋氨氯地平的晶体，不同于临床或市售的苯磺酸左旋氨氯地平、马来酸左旋氨氯地平。
(3)本发明提供的一种二氢吡啶钙拮抗剂的共晶晶型的制备方法，原料来源广、操作简单、晶体晶型规则，粒径尺寸均匀，有明确的X-射线粉末衍射数据，适于大规模推广应用。
(4)具有上述特征参数的本发明的一种二氢吡啶钙拮抗剂的共晶晶型，改善了现有左旋氨氯地平盐的溶解性及稳定性，有利于左旋氨氯地平片剂稳定性的提升及生物利用度的改善。
附图说明
图1是本发明提供的二氢吡啶钙拮抗剂共晶晶体的一具体实施例的晶体结构示意图。
图2是本发明提供的二氢吡啶钙拮抗剂共晶晶体的一具体实施例的分子堆积结构示意图。
图3是本发明的提供的二氢吡啶钙拮抗剂共晶晶体的一具体实 施例的X-射线粉末衍射谱图。
图4是本发明的提供的二氢吡啶钙拮抗剂共晶晶型的一具体实施例的热分析谱图。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。
为了明确本发明提供的一种二氢吡啶钙拮抗剂共晶晶型，本发明在大量的药物结晶研究实验基础上成功制备了该晶体产物，提供了明确的晶体学参数，左旋氨氯地平分子中官能团的空间构象。为了能够更清楚地理解本发明的技术内容，特举以下实施例详细说明。
实施例1
苯甲酸左旋氨氯地平晶体的制备
1)称取左旋氨氯地平游离碱2.04克，将其加入到4.5mL的水溶液中，室温搅拌至全溶解；
2)室温配置浓度是1M的苯甲酸水溶液，在室温搅拌条件下，将5mL苯甲酸的水溶液于30秒钟内逐滴滴加到1)的溶液中；
3)将上述成盐反应溶液转移到反应釜中，升高反应液的温度至50℃，保温5小时，然后静置冷却至5℃，得到大量针状或棒状无色透明、形貌均一的晶体产物；
4)将所得的晶体产物减压过滤，原结晶溶液洗涤，5℃的水溶剂洗涤，即得，图1为晶体结构示意图，图2为分子堆积结构示意图。
实施例2-8
制备方法同实施例1，其具体的工艺参数见表1。
表1 实施例2-8工艺参数
Figure PCTCN2020094643-appb-000008
Figure PCTCN2020094643-appb-000009
实施例9
X-射线单晶衍射测试
以实施例1制备的苯甲酸左旋氨氯地平共晶晶体为例，挑选晶体质量和大小满足测试仪器要求的晶体，采用德国布鲁克公司Apex Duo型号的X-射线单晶衍射仪进行测试，测试参数按照仪器制定的策略进行。测试温度为296K，用Mo-Kα辐射
Figure PCTCN2020094643-appb-000010
以ω扫描方式收集衍射数据并进行Lp校正。吸收校正采用SADABS程序。用直接法解析结构，用差值傅立叶法找出全部非氢原子，所有碳及氮上的氢原子采用理论加氢得到，采用最小二乘法对结构修正。所有解析过程采用SHELXTL程序包完成。
上述测量中，晶体测试可以在任何一台X-射线单晶衍射仪器上 测试，不限于德国布鲁克公司Apex Duo型号，光源不限于Mo靶。测试所得的晶体学数据不依赖于解析方法。
测试及解析所得晶体学数据如表2所示。
表2 晶体学数据
Figure PCTCN2020094643-appb-000011
实施例10
X-射线粉末多晶衍射测试
取实施例1中的苯甲酸左旋氨氯地平多晶产物，采用德国布鲁克Advance D8 X-射线多晶衍射仪对其进行测试，测试参数均为默认标准设置，室温压片测试。为了保证测试效果具有较好的重现性，避免颗粒晶面取向差异导致的强度差异，待测样品，需经压片，研磨，300目筛分，及再造粒工序处理。铜靶Kα1辐射
Figure PCTCN2020094643-appb-000012
辐照波长，扫描角度从1～50°，测试的示例谱图如图3所示，实施例2-8的多晶产物的样品具有类似的X-射线粉末多晶衍射谱图。
实施例11
苯甲酸左旋氨氯地平晶体的热重稳定性
取实施例1制备工艺生产的苯甲酸左旋氨氯地平多晶，经过再造粒工艺处理后，开展热稳定性能研究。采用TAQ600分析仪进行(TG-DSC)测试，测试条件：N 2气氛，温度范围25-500℃，升温速率10℃/min。结果显示化合物受热分解的温度在150℃以上，表明本发明提供的晶型具有较高的热稳定性，热分析谱图如图4所示，
实施例2-8的样品具有类似的热稳定性。
实施例12
苯甲酸左旋氨氯地平晶体的溶解度测试
溶解度测试按照药物溶解度测试表征流程。具体而言，精确称取200毫克的过筛样品，经造粒后，置于玻璃瓶中，分散于温度为37℃，pH为7.4的PBS缓冲溶液中，然后密闭，放置于温度为37℃的摇床上，将转速设置为100rpm。在t＝5小时取出瓶子，采用200nm滤膜将固体与滤液分离，滤液中的含量采用238nm波长的紫外-可见分析方法分析含量。样品平行测量3次，测量得到其溶解度为0.134±0.014mg/mL，表明本发明提供的晶型相对于苯磺酸左旋氨氯地平溶解度有所提高。实施例1-8的样品具有类似的溶解度。
综上所述，本发明采用游离碱共晶成盐方法制备的苯甲酸左旋氨氯地平不同于市售临床使用的苯磺酸左旋氨氯地平和马来酸左旋氨氯地平，是一种二氢吡啶类钙拮抗剂的新共晶晶型，具有明确的晶体学相关参数，单胞大小，及共晶结构的空间构型及排列。本发明提供的这种二氢吡啶钙拮抗剂共晶晶型原料广泛易得，制备方法简单易行，所制得的晶体晶型规则，粒径尺寸均匀，能够满足X-射线衍射测试的要求，相关质量易于控制，适于大规模推广应用。
本领域的技术人员应理解，上述描述及附图中所示的本发明的实施例只作为举例而并不限制本发明。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施 例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (10)

  1. 一种二氢吡啶钙拮抗剂共晶体，其特征在于，该共晶体的分子式为：(C 20H 25ClN 2O 5)·(C 6H 5COOH)·(Y) n，其中，Y为水分子、乙醇分子或异丙醇分子中的任一种，0≤n≤3，C 20H 25ClN 2O 5是左旋氨氯地平，C 6H 5COOH是苯甲酸。
  2. 根据权利要求1所述的一种二氢吡啶钙拮抗剂共晶体，其特征在于，所述的共晶体结晶于三斜晶系，P1手性空间群，晶胞大小：
    Figure PCTCN2020094643-appb-100001
    α＝97.1～97.5°，β＝92.2～92.6°，γ＝111.5～112.1°，
    Figure PCTCN2020094643-appb-100002
  3. 根据权利要求2所述的一种二氢吡啶钙拮抗剂共晶体，其特征在于，所述的共晶体的特征X-射线粉末衍射数据与所用X-射线波长无关的面间距
    Figure PCTCN2020094643-appb-100003
    再现的主要衍射数据是：
    Figure PCTCN2020094643-appb-100004
  4. 如权利要求1所述的一种二氢吡啶钙拮抗剂共晶体的制备方法，其特征在于，将左旋氨氯地平游离碱完全溶解在溶剂中获得反应液；室温搅拌条件下，向反应液中加入成盐试剂，获得成盐反应溶液； 反应溶液搅拌升温至目标温度保温一定时间，然后静置冷却析晶，过滤分离，即得。
  5. 根据权利要求4所述的一种二氢吡啶钙拮抗剂共晶体的制备方法，其特征在于，所述溶剂为异丙醇、乙醇或水中的任意一种，所述左旋氨氯地平游离碱与所述溶剂的摩尔比是1:50～200。
  6. 根据权利要求4所述的一种二氢吡啶钙拮抗剂共晶体的制备方法，其特征在于，所述成盐试剂为苯甲酸，所述左旋氨氯地平与所述苯甲酸的摩尔量比值是1：1～2。
  7. 根据权利要求4所述的一种二氢吡啶钙拮抗剂共晶体的制备方法，其特征在于，所述目标温度为50～120℃，保温时间为2～24小时。
  8. 根据权利要求4所述的一种二氢吡啶钙拮抗剂共晶体的制备方法，其特征在于，所述静置冷却析晶是将温度降至5-25℃结晶。
  9. 根据权利要求4所述的一种二氢吡啶钙拮抗剂共晶体的制备方法，其特征在于，制备得到的共晶体为外观是针状或棒状的无色透明晶体。
  10. 如权利要求1所述的一种二氢吡啶钙拮抗剂共晶体在制备治疗高血压药物中的应用。
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