WO2016180205A1 - 一种阿魏酸右旋冰片酯晶型、其制备方法及应用 - Google Patents

一种阿魏酸右旋冰片酯晶型、其制备方法及应用 Download PDF

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WO2016180205A1
WO2016180205A1 PCT/CN2016/079861 CN2016079861W WO2016180205A1 WO 2016180205 A1 WO2016180205 A1 WO 2016180205A1 CN 2016079861 W CN2016079861 W CN 2016079861W WO 2016180205 A1 WO2016180205 A1 WO 2016180205A1
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crystal form
dextrorotatory
acid ester
degrees
degree
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French (fr)
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李云森
陈子珺
邓世平
刘乾
李勇
冯海梅
高原
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苏州沪云肿瘤研究中心股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the invention belongs to the field of compound crystal forms, and in particular relates to a novel crystal form of dextrorotatory ferric acid ester, a preparation method thereof and application thereof.
  • Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a kind of phenolic acid extracted from plants such as Angelica, Chuanxiong and Awei, which has anti-inflammatory, anti-oxidation, anti-thrombosis and various physiological functions. Active, widely used in health care products, cosmetics, pharmaceuticals, pesticides and food additives.
  • ferulic acid can inhibit platelet aggregation and release, can significantly inhibit experimental thrombosis, regulate immune, clear and inhibit free radical reactions
  • ferulic acid molecules can be used in a variety of ways to the structure of biological macromolecules in vivo The function is protective.
  • ferulic acid has strong hydrophilicity and poor fat solubility, and its metabolism in the body is fast, the brain is less distributed, and it is difficult to pass through the blood-brain barrier, making it widely restricted in the treatment of cerebrovascular diseases.
  • Solid materials exist in a variety of crystal forms or crystal structures, each crystal structure is called a crystal form, and different crystal forms of the same material have different physical properties and chemical stability, such as different solubility characteristics, different melting points. Temperature and different X-ray diffraction peaks.
  • Polymorphic forms of the compounds can be distinguished in the laboratory by X-ray diffraction spectroscopy or by other methods such as infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and melting point analysis.
  • the performance of different crystalline forms of the same active pharmaceutical component can have different effects on the preparation of the pharmaceutical product, for example, solubility, stability, fluidity, handleability and compressibility, as well as the safety and efficacy of the pharmaceutical product are dependent on Polymorphic. Therefore, finding new crystal forms of compounds is also one of the main goals in the field of chemical medicine.
  • the present invention provides a novel crystal form of dextromethorphanate, a preparation method thereof, a pharmaceutical composition comprising the same, and use thereof.
  • the crystal form of ferulic acid dextrorotate provided by the invention has better solubility, bioavailability, stability, easy handling and high efficiency, and has good application prospect in the field of pharmaceutical preparations.
  • the present invention provides a crystal form of dextrorotatory ferric acid ester characterized by having an angle of 2 ⁇ of 10.8° ⁇ 0.2°, 12.4° ⁇ 0.2°, and 14.0° ⁇ 0.2°. 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.4
  • One or more of ° ⁇ 0.2 °, 25.7 ° ⁇ 0.2 °, and 26.4 ° ⁇ 0.2 ° contain characteristic X-ray powder diffraction peaks.
  • the crystal form has a D value of 5.5 at a 2 theta angle of 16.2 ° ⁇ 0.2 ° and a peak intensity is extremely strong.
  • the crystal form has a D value of 6.1 at a 2 theta angle of 14.6 ° ⁇ 0.2 ° and a peak intensity is strong.
  • the crystalline form has an X-ray powder diffraction pattern as shown in Figure 1; the X-ray powder diffraction is performed using Cu-Ka radiation, X-ray powder diffraction.
  • the infrared spectrum and the DSC spectrum of the crystal form are as shown in Figures 2 and 3, respectively.
  • the crystalline form of the dextrorotatory ferroflavonate crystal form has a melting point of 98.5 to 100.0 ° C, which is determined by a DSC method.
  • the present invention provides a method for preparing a crystal form of ferulic acid dextrorotate according to the first aspect, which comprises: adding dextrorotatory ferulic acid ester to a good solvent, stirring until the solution is clarified, Further, an anti-solvent is added, and the crystallized is stirred to obtain a powdery solid, which is the crystal form of the dextrorotatory ferric acid ester.
  • the good solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, acetic acid Ester, butyl acetate, tert-butyl methyl ether, diisopropyl ether and toluene;
  • the anti-solvent is one or more selected from the group consisting of water, n-hexane, cyclohexane, n-heptane and petroleum ether.
  • the present invention provides another method for preparing a crystal form of dextrorotatory ferric ideolate according to the first aspect, which comprises: adding dextrorotatory ferulic acid ester to a good solvent, and heating and stirring. After the solution is clarified, the mixture is cooled and decrystallized to obtain a powdery solid, which is the crystal form of the dextrorotatory ferric acid ester.
  • the good solvent is one or more selected from the group consisting of n-hexane, cyclohexane, n-heptane and petroleum ether.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form of dextroferric acid ferrate as described in the first aspect, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and pharmaceutically acceptable An acceptable carrier or excipient.
  • the present invention provides the crystalline form of dextroferric acid ferrorate according to the first aspect or the pharmaceutical composition according to the fourth aspect, in the preparation of a medicament for treating antithrombotic, hypolipidemic or cerebrovascular diseases Applications;
  • the cerebrovascular disease is stroke.
  • the crystal form of ferulic acid dextrorotate of the invention is easily soluble in water, reduces dissolution time, and reduces product degradation, when applied to antithrombotic, hypolipidemic and therapeutic brain. Stroke is more conducive to drug absorption and drug stability.
  • the crystal form of ferulic acid dextrorotate of the invention has simple preparation process, is easy to dry, and has stable nature in the drying process; the crystal has high purity, and the purification process in the preparation process is obvious, which is favorable for industrial production.
  • the crystalline form of dextrorotatory ferric acid ester obtained by the invention improves the performance characteristics of the borneol ferric acid medicinal product, and provides a basis for further in-depth study of borneol ferulate.
  • Figure 1 is an X-ray powder diffraction pattern of the crystalline form of dextrorotatory ferric acid ester of the present invention.
  • FIG. 2 is an infrared spectrum diagram of the crystalline form of dextrorotatory ferric ideolate of the present invention.
  • Figure 3 is a DSC chart of the crystalline form of dextrorotatory ferric acid ester of the present invention.
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • dextrorotatory ferric acid ester 10 g was added to 90 ml of methanol, stirred and dissolved, 45 ml of purified water was added at room temperature, stirred and crystallized, and filtered to obtain a white powdery solid, weighing 8.8 g, and the powdery solid was the present invention.
  • the form of dextrorotatory dextroyl ester has a melting point of 98.5-100.0 °C.
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • dextromethorphanate 100 g was added to 900 ml of methanol, stirred and dissolved, 450 ml of purified water was added at room temperature, stirred and crystallized, and filtered to obtain a white powdery solid to obtain 88.5 g.
  • the powdery solid was the ferulic acid of the present invention.
  • the crystalline form of dextrorotyl ester has a melting point of 98.5-100.0 °C.
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • dextromethorphanate 10 g was added to 100 ml of absolute ethanol, stirred and dissolved, and 60 ml of purified water was added at room temperature, stirred and crystallized, and filtered to obtain a white powdery solid, weighing 8.5 g, and the powdery solid was the present invention.
  • the crystalline form of dextrorotatory ferulic acid ester has a melting point of 98.5-100.0 °C.
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • dextromethorphanate 100 g was added to 1000 ml of absolute ethanol, stirred and dissolved, 600 ml of purified water was added at room temperature, stirred and crystallized, and filtered to obtain a white powdery solid, weighing 84.6 g, and the powdery solid was the invention.
  • the crystalline form of dextrorotatory ferulic acid ester has a melting point of 98.5-100.0 °C.
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • dextrorotatory ferric acid ester 100 g was added to 1500 ml of petroleum ether, and the mixture was heated to reflux to dissolve. The mixture was cooled and stirred to crystallize, and filtered to obtain a white powdery solid. The weight was 78.0 g, and the powdery solid was the ferulic acid of the present invention.
  • the crystalline form of dextrorotyl ester has a melting point of 98.5-100.0 °C.
  • This embodiment discloses a preparation method of a crystal form of ferulic acid dextrorotyl ester, and the specific steps are as follows:
  • dextrorotatory ferric acid ester 10 g was added to 100 ml of n-hexane, and the mixture was heated to reflux to dissolve, and the mixture was cooled and stirred to crystallize, and filtered to obtain a white powdery solid, weighing 7.8 g, and the powdery solid was the ferulic acid of the present invention.
  • the crystalline form of dextrorotyl ester has a melting point of 98.5-100.0 °C.
  • the inventors performed X-ray diffraction detection on the crystal form of the dextrorotatory ferulic acid ester obtained in Examples 1-8, which was performed using Cu-Ka radiation.
  • X-ray powder diffraction the results are shown in Figure 1;
  • X-ray diffraction is represented by 2 ⁇ , and the XRPD characteristic peaks of the crystal form I are: 10.8 ° ⁇ 0.2 °, 12.4 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.4° ⁇ 0.2° 22.4° ⁇ 0.2°, 25.7° ⁇ 0.2° and 26.4° ⁇ 0.2°.
  • the D value corresponding to the XRPD characteristic peak of the crystal form of the dextrorotatory ferric acid ester and the peak intensity are shown in Table 1; as shown in Table 1, the crystal form I is 16.2 ⁇ 0.2 at the 2 ⁇ angle. The D value is 5.5, and its peak intensity is extremely strong. When the 2 ⁇ angle is 14.6 ⁇ 0.2, the D value is 6.1, and its peak intensity is strong.
  • the inventors also performed infrared detection on the crystal form of the dextrorotatory ferric acid ester obtained in Examples 1-8, and the infrared spectrum of the crystal form of the dextrorotatory ferric acid ester is shown in FIG.
  • the inventors determined the melting points of the crystalline form of the dextrorotatory ferroflavonate obtained in Example 1-8 by the DSC method, and the results are shown in FIG. 3; as shown in FIG. 3, the melting point of the crystal form is 98.5-100.0. °C.
  • the inventors also tested the effect of the crystal form of the ferulic acid dextrorotate obtained in Examples 1-8, and found that the crystal form of the ferulic acid dextrorotate of the present invention is easily soluble in water and reduces the dissolution time. Reduced product degradation, when applied to antithrombotic, hypolipidemic and treatment of stroke, it is more conducive to drug absorption and drug stability.
  • the inventors also conducted an influencing factor test on the crystal form of the ferulic acid dextrorotate ester of the present invention obtained in Examples 1-8.
  • the specific steps are:
  • the crystal form of ferulic acid dextrorotate of the invention has simple preparation process, is easy to dry, and has stable nature in the drying process; the crystal has high purity, and the purification process in the preparation process is obvious, which is favorable for industrial production.
  • the crystalline form of dextrorotatory ferric acid ester obtained by the invention improves the performance characteristics of the borneol ferric acid medicinal product, and provides a basis for further in-depth study of borneol ferulate.

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Abstract

本发明公开了一种阿魏酸右旋冰片酯的新晶型、其制备方法、包含其的药物组合物及其应用。本发明所提供的阿魏酸右旋冰片酯晶型在2θ角为：10.8°±0.2°、12.4°±0.2°、14.0°±0.2°、14.2°±0.2°、14.6°±0.2°、16.2°±0.2°、16.6°±0.2°、17.7°±0.2°、18.6°±0.2°、20.1°±0.2°、21.4°±0.2°、22.4°±0.2°、25.7°±0.2°和26.4°±0.2°中的一处或多处包含特征性X射线粉末衍射峰，其具有更好的溶解性、生物利用度、稳定性、易处理性以及高效能，在药物制剂领域具有良好的应用前景。

Description

一种阿魏酸右旋冰片酯晶型、其制备方法及应用 技术领域
本发明属于化合物晶型领域，具体涉及一种阿魏酸右旋冰片酯的新晶型、其制备方法及应用。
背景技术
阿魏酸(4-羟基-3-甲氧基肉桂酸)，是一种存在当归、川穹、阿魏等植物中提取的酚酸，其具有抗炎、抗氧化、抗血栓和多种生理活性，广泛应用于保健品、化妆品、医药、农药和食品添加剂等领域。
经过研究发现，阿魏酸能够抑制血小板聚集和释放，能够明显抑制实验性血栓形成，调节机体免疫、清楚和抑制自由基反应，阿魏酸分子可以通过多种途径对体内生物大分子的结构和功能起到保护作用。但是阿魏酸分子亲水性强，脂溶性差，且其体内代谢速度快，脑分布少，较难透过血脑屏障发挥作用，使其在治疗脑血管疾病领域应用大受限制。
为了解决阿魏酸的缺陷，研究人员对阿魏酸分子进行修饰制备衍生物以提高分子脂溶性的研究是解决阿魏酸分子缺陷的一个关键，阿魏酸与醇反应成阿魏酸酯是改进其脂溶性和使用效果的最佳方法。传统中药冰片具有开窍醒神的功效，同时对于脑卒中也有不错的疗效，最终研究人员发现阿魏酸冰片酯很好的解决了上述阿魏酸的缺陷。
固体材料以多种晶型或晶体结构存在，每种晶体结构被称作一种晶型，并且同一种材料不同晶型具有不同的物理性能和化学稳定性，例如不同的溶解特性、不同的熔点温度和不同的X射线衍射峰。
化合物的多晶型可以在实验室中通过X射线衍射光谱法或通过其它方法例如红外光谱法、差示扫描量热法、热重分析以及熔点分析来加以区别。特别是在制药领域中， 相同活性药物组分的不同晶型的性能会对药物产品的制备具有不同的影响，例如，溶解性、稳定性、流动性、易处理性和可压性以及药物产品安全性和效能均取决于多晶型。因此，寻找化合物的新晶型也是化学医药领域的主要目标之一。
因此，为了拓宽阿魏酸冰片酯在治疗脑卒中领域中的应用，需要开发阿魏酸冰片酯的新晶型。
发明内容
为解决上述技术问题，本发明提供了一种阿魏酸右旋冰片酯的新晶型、其制备方法、包括其的药物组合物及其应用。本发明所提供的阿魏酸右旋冰片酯晶型具有更好的溶解性、生物利用度、稳定性、易处理性以及高效能，在药物制剂领域具有良好的应用前景。
具体地，第一方面，本发明提供了一种阿魏酸右旋冰片酯晶型，其特征在于，其在2θ角为：10.8°±0.2°、12.4°±0.2°、14.0°±0.2°、14.2°±0.2°、14.6°±0.2°、16.2°±0.2°、16.6°±0.2°、17.7°±0.2°、18.6°±0.2°、20.1°±0.2°、21.4°±0.2°、22.4°±0.2°、25.7°±0.2°和26.4°±0.2°中的一处或多处包含特征性X射线粉末衍射峰。
在一个较佳的实施方案中，所述晶型在2θ角为16.2°±0.2°时D值为5.5，其峰强度为极强。
在一个较佳的实施方案中，所述晶型在2θ角为14.6°±0.2°时D值为6.1，其峰强度为强。
在一个具体实施方案中，所述晶型具有如图1所示的X射线粉末衍射图谱；所述X射线粉末衍射是使用Cu-Ka辐射，
Figure PCTCN2016079861-appb-000001
的X-射线粉末衍射。
优选地，所述晶型的红外光谱图及DSC谱图分别如附图2和3所示。
优选地，所述阿魏酸右旋冰片酯晶型的熔点为98.5～100.0℃，该熔点为通过DSC法测定的。
第二方面，本发明提供了如第一方面所述的阿魏酸右旋冰片酯晶型的制备方法，其包括：将阿魏酸右旋冰片酯加入到良溶剂中，搅拌至溶液澄清，再加入反溶剂，搅拌析晶，获得粉末状固体，即为所述阿魏酸右旋冰片酯晶型。
优选地，所述良溶剂为选自以下物质中的一种或几种：甲醇、乙醇、异丙醇、丙酮、甲基异丁酮、乙腈、四氢呋喃、二氯甲烷、三氯甲烷、乙酸乙酯、乙酸丁酯、叔丁基甲基醚、异丙醚和甲苯；
优选地，所述反溶剂为选自以下物质中的一种或几种：水、正己烷、环己烷、正庚烷和石油醚。
第三方面，本发明提供了如第一方面所述的阿魏酸右旋冰片酯晶型的另一种制备方法，其包括：将阿魏酸右旋冰片酯加入到良溶剂中，升温搅拌至溶液澄清，然后搅拌降温析晶，获得粉末状固体，即为所述阿魏酸右旋冰片酯晶型。
优选地，所述良溶剂为选自以下物质中的一种或几种：正己烷、环己烷、正庚烷和石油醚。
第四方面，本发明提供了一种药物组合物，其包含如第一方面所述的阿魏酸右旋冰片酯晶型或其药学上可接受的盐、溶剂合物或前药，以及药学上可接受的载体或赋形剂。
第五方面，本发明提供了如第一方面所述的阿魏酸右旋冰片酯晶型或如第四方面所述的药物组合物在制备治疗抗血栓、降血脂或脑血管疾病的药物中的应用；
优选地，所述脑血管疾病为脑卒中。
有益效果
相对于现有技术的阿魏酸冰片酯，本发明的阿魏酸右旋冰片酯晶型易溶于水、减少了溶解时间，降低了产品降解，当应用于抗血栓、降血脂和治疗脑卒中时，更有利于药物的吸收和药效稳定。
此外，本发明的阿魏酸右旋冰片酯晶型，其制备操作简单；易于干燥，干燥过程性质稳定；晶体纯度高，制备过程纯化作用明显，利于工业化生产。
最后，本发明获得的阿魏酸右旋冰片酯晶型改善了阿魏酸冰片酯药物产品的性能特征，为阿魏酸冰片酯的进一步深入研究提供了依据。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明的阿魏酸右旋冰片酯晶型的X射线粉末衍射图。
图2为本发明的阿魏酸右旋冰片酯晶型的红外光谱图。
图3为本发明的阿魏酸右旋冰片酯晶型的DSC谱图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将10g阿魏酸右旋冰片酯加入到90ml甲醇中，搅拌溶解，室温下加入45ml纯化水，搅拌析晶，过滤得白色粉末状固体，称重为8.8g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例2
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将100g阿魏酸右旋冰片酯加入到900ml甲醇中，搅拌溶解，室温下加入450ml纯化水，搅拌析晶，过滤得白色粉末状固体，得88.5g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例3
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将10g阿魏酸右旋冰片酯加入到100ml无水乙醇中，搅拌溶解，室温下加入60ml纯化水，搅拌析晶，过滤得白色粉末状固体，称重为8.5g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例4
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将100g阿魏酸右旋冰片酯加入到1000ml无水乙醇中，搅拌溶解，室温下加入600ml纯化水，搅拌析晶，过滤得白色粉末状固体，称重为84.6g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例5
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将10g阿魏酸右旋冰片酯加入到10ml甲基叔丁基醚中，搅拌溶解，室温下加入100ml石油醚，搅拌析晶，过滤得白色粉末状固体，称重为80.4g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例6
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将10g阿魏酸右旋冰片酯加入到150ml石油醚中，升温回流至溶清，降温搅拌析晶，过滤得白色粉末状固体，称重为7.5g，粉末状固体为本发明的阿魏酸右旋冰片酯 晶型，其熔点为98.5-100.0℃。
实施例7
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将100g阿魏酸右旋冰片酯加入到1500ml石油醚中，升温回流至溶清，降温搅拌析晶，过滤得白色粉末状固体，称重为78.0g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例8
本实施例公开了一种阿魏酸右旋冰片酯晶型的制备方法，具体步骤为：
将10g阿魏酸右旋冰片酯加入到100ml正己烷中，升温回流至溶清，降温搅拌析晶，过滤得白色粉末状固体，称重为7.8g，粉末状固体为本发明的阿魏酸右旋冰片酯晶型，其熔点为98.5-100.0℃。
实施例9
发明人对实施例1-8中获得的阿魏酸右旋冰片酯晶型进行了X射线衍射检测，所述X射线粉末衍射是使用Cu-Ka辐射，
Figure PCTCN2016079861-appb-000002
的X-射线粉末衍射，其结果如图1中所示；以2θ表示X-射线衍射，所述晶型I的XRPD特征峰为：10.8°±0.2°、12.4°±0.2°、14.0°±0.2°、14.2°±0.2°、14.6°±0.2°、16.2°±0.2°、16.6°±0.2°、17.7°±0.2°、18.6°±0.2°、20.1°±0.2°、21.4°±0.2°、22.4°±0.2°、25.7°±0.2°和26.4°±0.2°。
根据图1，所述阿魏酸右旋冰片酯晶型的XRPD特征峰对应的D值以及峰的强度如表1中所示；由表1可见，晶型I在2θ角为16.2±0.2时，D值为5.5，其峰强度表现极强；在2θ角为14.6±0.2时，D值为6.1，其峰强度表现强。
表1、晶型的XRPD特征峰
2θ角 D值 强度
10.8±0.2 8.2 弱
12.4±0.2 7.1 弱
14.0±0.2 6.3 中
14.2±0.2 6.2 中
14.6±0.2 6.1 强
16.2±0.2 5.5 极强
16.6±0.2 5.3 中
17.7±0.2 5.0 中
18.6±0.2 4.8 中
20.1±0.2 4.4 中
21.4±0.2 4.1 中
22.4±0.2 4.0 中
25.7±0.2 3.5 中
26.4±0.2 3.4 中
此外，发明人还对实施例1-8中获得的阿魏酸右旋冰片酯晶型进行了红外检测，所述阿魏酸右旋冰片酯晶型的红外光谱图如图2所示。
发明人通过DSC法测定了实施例1-8中获得的阿魏酸右旋冰片酯晶型的熔点，其结果如图3所示；由图3可知，所述晶型的熔点为98.5-100.0℃。
发明人还对实施例1-8中获得的阿魏酸右旋冰片酯晶型进行了效果检测，发现，本发明的阿魏酸右旋冰片酯晶型易溶于水、减少了溶解时间，降低了产品降解，当应用于抗血栓、降血脂和治疗脑卒中时，更有利于药物的吸收和药效稳定。
发明人还对实施例1-8中获得的本发明阿魏酸右旋冰片酯晶型进行了影响因素试 验，具体步骤为：
称取9份本发明阿魏酸右旋冰片酯晶型，每份0.5g，分别取三份放置于高温(60℃)、高湿(25℃、湿度92.5％)、光照(光强4500±500lx)等条件下，于0天、5天、10天取样检测有关物质。影响因素试验结果显示该晶型具有良好的稳定性。其检测结果如下：
Figure PCTCN2016079861-appb-000003
此外，本发明的阿魏酸右旋冰片酯晶型，其制备操作简单；易于干燥，干燥过程性质稳定；晶体纯度高，制备过程纯化作用明显，利于工业化生产。
最后，本发明获得的阿魏酸右旋冰片酯晶型改善了阿魏酸冰片酯药物产品的性能特征，为阿魏酸冰片酯的进一步深入研究提供了依据。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (10)

  1. 一种阿魏酸右旋冰片酯晶型，其特征在于，其在2θ角为：10.8°±0.2°、12.4°±0.2°、14.0°±0.2°、14.2°±0.2°、14.6°±0.2°、16.2°±0.2°、16.6°±0.2°、17.7°±0.2°、18.6°±0.2°、20.1°±0.2°、21.4°±0.2°、22.4°±0.2°、25.7°±0.2°和26.4°±0.2°中的一处或多处包含特征性X射线粉末衍射峰。
  2. 根据权利要求1所述的阿魏酸右旋冰片酯晶型，其特征在于，所述晶型在2θ角为16.2°±0.2°时D值为5.5。
  3. 根据权利要求1所述的阿魏酸右旋冰片酯晶型，其特征在于，所述晶型在2θ角为14.6°±0.2°时D值为6.1。
  4. 根据权利要求1所述的阿魏酸右旋冰片酯晶型，其特征在于，其具有如图1所示的X射线粉末衍射图谱；
    优选地，所述阿魏酸右旋冰片酯晶型的熔点为98.5～100.0℃。
  5. 根据权利要求1-4任一项所述的阿魏酸右旋冰片酯晶型的制备方法，其包括：将阿魏酸右旋冰片酯加入到良溶剂中，搅拌至溶液澄清，再加入反溶剂，搅拌析晶，获得粉末状固体，即为所述阿魏酸右旋冰片酯晶型。
  6. 根据权利要求5所述的制备方法，其特征在于，所述良溶剂为选自以下物质中的一种或几种：甲醇、乙醇、异丙醇、丙酮、甲基异丁酮、乙腈、四氢呋喃、二氯甲烷、三氯甲烷、乙酸乙酯、乙酸丁酯、叔丁基甲基醚、异丙醚和甲苯；
    优选地，所述反溶剂为选自以下物质中的一种或几种：水、正己烷、环己烷、正庚烷和石油醚。
  7. 根据权利要求1-4任一项所述的阿魏酸右旋冰片酯晶型的制备方法，其包括：将阿魏酸右旋冰片酯加入到良溶剂中，升温搅拌至溶液澄清，然后搅拌降温析晶，获得粉末状固体，即为所述阿魏酸右旋冰片酯晶型。
  8. 根据权利要求7所述的制备方法，其特征在于，所述良溶剂为选自以下物质中 的一种或几种：正己烷、环己烷、正庚烷和石油醚。
  9. 一种药物组合物，其包含如权利要求1-4任一项所述的阿魏酸右旋冰片酯晶型或其药学上可接受的盐、溶剂合物或前药，以及药学上可接受的载体或赋形剂。
  10. 如权利要求1-4任一项所述的阿魏酸右旋冰片酯晶型或如权利要求9所述的药物组合物在制备治疗抗血栓、降血脂或脑血管疾病的药物中的应用；
    优选地，所述脑血管疾病为脑卒中。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104856983A (zh) * 2015-05-13 2015-08-26 苏州沪云肿瘤研究中心股份有限公司 阿魏酸冰片酯的合成和应用
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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BOHLMANN, F. ET AL.: "Eudesmane derivatives from verbesina species", PHYTOCHEMISTRY, vol. 19, no. 11, 31 December 1980 (1980-12-31), pages 2391 - 2397, XP055328414 *
LI, LIMEI ET AL.: "Chemical Constituents of Notopterygium incisum", CHINESE JOURNAL OF NATURAL MEDICINES, vol. 5, 20 September 2007 (2007-09-20), pages 351 - 353 *
MA, FENGSHI ET AL.: "The Research Progresses of Ferulic Acid Derivatives and its Bioactivities", PROGRESS IN PHARMACEUTICAL SCIENCES, vol. 32, no. 8, 25 August 2008 (2008-08-25), pages 345 - 350, ISSN: 1001-5094 *
TOYOTA, M. ET AL.: "A comparative study on three chemo-types of the liverwort Conocephalum conicum using volatile constituents", PHYTOCHEMISTRY, vol. 44, no. 7, XP004293038 *

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