WO2016169288A1 - 一种无定形态曲札茋苷及其制备方法 - Google Patents

一种无定形态曲札茋苷及其制备方法 Download PDF

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WO2016169288A1
WO2016169288A1 PCT/CN2015/098356 CN2015098356W WO2016169288A1 WO 2016169288 A1 WO2016169288 A1 WO 2016169288A1 CN 2015098356 W CN2015098356 W CN 2015098356W WO 2016169288 A1 WO2016169288 A1 WO 2016169288A1
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amorphous
present
morphocyanin
solvent
preparation
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French (fr)
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龚云麒
李莹
方芳
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昆药集团股份有限公司
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Priority to EP15889768.6A priority Critical patent/EP3287466B1/en
Publication of WO2016169288A1 publication Critical patent/WO2016169288A1/zh

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

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  • the present invention relates to the field of medicinal chemistry, and in particular to an amorphous form of sapporoside, a process for the preparation thereof and a pharmaceutical composition containing the same.
  • Quciside is the main active ingredient extracted from traditional Vietnamese medicine Lhasa rhubarb. Studies have shown that Quci's glycosides can significantly reduce the damage caused by ischemia-reperfusion after heart and brain infarction, and have anti-oxidation, anti-inflammatory and blood vessel improvement. Endothelial dysfunction and other pharmacological activities, can be seen as a prospect for the development of drugs for the treatment of cardiovascular and cerebrovascular diseases. In the previous study, the applicant discovered a new crystal form of saponin, and applied for a patent “a crystal of sapporoside and its preparation method and application”, patent No. ZL2011110166486.2.
  • polymorphic state of solid drugs is an important part of the study of the presence of drugs.
  • polymorphism generally exists.
  • the same drug of different crystal forms differs in appearance, solubility, melting point, dissolution and bioavailability, and may even be significantly different, thus affecting drug stability, bioavailability and efficacy. Since these different crystalline substances affect the physical and chemical properties and biological activities of the drug, the existence state of the drug crystal form should be considered in the research of the raw materials and formulation of the drug.
  • Amorphous is a form of polymorphism in a substance and a special crystalline state.
  • the literature (Konno T., Chem. Pharm. Bul l., 1990; 38; 2003-2007) reports that the amorphous form-amorphous form of many drugs exhibits solubility characteristics compared to the crystalline form, and Some situations show different patterns of bioavailability. For some treatments, a certain bioavailability model may be more advantageous than the other.
  • amorphous state of solid drugs is not a single form.
  • the amorphous shape of a solid drug like a crystalline substance
  • the state can also exist in different forms. This phenomenon is called the amorphous polymorphism of solid matter, also known as polyamorphous.
  • a solid substance can obtain two or more amorphous states with completely different physical, thermodynamic, and kinetic properties due to differences in preparation methods or storage methods. For example, amorphous felodipine prepared at different cooling rates is detected by differential scanning calorimetry (DSC) under constant temperature conditions, and the endothermic position is different.
  • DSC differential scanning calorimetry
  • amorphous polymorphic substances may be related to compound configuration or conformation, chemical composition, chemical substances. Intermolecular forces are related to three factors. Amorphous polymorphism adds more opportunities for drug research, but it also increases the difficulty of studying the dominant drug crystal form, and poses new challenges to the preparation process and control technology of various amorphous substances.
  • the object of the present invention is to study, discover and provide a new amorphous form of scutellarin by a method of crystallography, and a preparation method and application thereof.
  • the amorphous morphocyanin of the present invention has a better solubility than the prior art sapporoside crystal.
  • the present invention studies, discovers, and provides novel amorphous morphocyanin by crystallographic methods having an X-ray powder diffraction pattern substantially as shown in FIG.
  • the present invention also employs differential scanning calorimetry (DSC) to study and characterize new amorphous morphocyanin.
  • DSC differential scanning calorimetry
  • the substantially pure new amorphous morphocyanin provided by the present invention has a differential scanning calorimetry curve as shown in FIG. 2, which has the following characteristics: its differential scanning calorimetry curve is at about 212.4 ° C. There is an endothermic peak.
  • the method for preparing the amorphous morphocyanin according to the present invention is that the saponin is dissolved in an alcohol solvent of C 1-4 , and the solvent is removed to obtain an amorphous morphocyanin.
  • the C 1-4 alcohol solvent may be a linear alcohol such as methanol, ethanol, propanol or n-butanol; or a branched alcohol such as isopropanol, isobutanol or tert-butanol.
  • the C 1-4 alcohol solvent in the method for preparing the amorphous morphocyanin of the present invention is one or more of methanol, ethanol, isopropanol and n-butanol. mixture.
  • the C 1-4 alcohol solvent is methanol.
  • the C 1-4 alcohol solvent is ethanol.
  • the method for preparing amorphic scutagin of the present invention wherein the concentration of the sapporoside in the alcohol solvent of C 1-4 in which the sapporoside is dissolved is 0.1 g/mL. ⁇ 0.5g/mL.
  • the concentration of the sapporoside is 0.1 g/mL.
  • the concentration of the sapporoside is 0.2 g/mL.
  • the solvent for removal of the amorphous form of sapporoside in the method of the present invention is specifically a solvent for recovery under reduced pressure.
  • the reduced pressure recovery solvent is specifically a rotary evaporation solvent at a vacuum of from -0.06 to -0.08.
  • the evaporation temperature varies from 50 ° C to 90 ° C in some embodiments.
  • the saponin may be obtained by any method.
  • the preparation of the amorphous morphocyanin in the preparation Use in medicines for treating cardiovascular and cerebrovascular diseases.
  • a pharmaceutical preparation comprising the amorphous form of the saponin of the present invention and one or more pharmaceutically acceptable excipients.
  • amorphous morphocyanin of the present invention can directly or indirectly add to various pharmaceutically acceptable excipients, such as filling, required for preparing different dosage forms.
  • excipients such as filling, required for preparing different dosage forms.
  • Agents, disintegrators, lubricants, binders and the like are prepared in a conventional pharmaceutical preparation method for a preparation suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration.
  • the usual preparation may be, for example, a tablet, a capsule, an injection, an oral solution, a granule, a pill, a powder, a pill, a lozenge, a suppository, a cream, an ointment, a skin gel, a suspension or the like.
  • the filler may be selected, for example, from starch, lactose, sucrose, glucose, mannitol, and silicic acid;
  • the disintegrant may be, for example, selected from the group consisting of agar, calcium carbonate, potato starch, or tapioca starch, Alginic acid, certain silicates and sodium carbonate, low-substituted hydroxypropyl cellulose;
  • the lubricant may, for example, be selected from the group consisting of talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate
  • the binder may be selected from the group consisting of carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia.
  • the dosage and method of use of the pharmaceutical preparation depends on a number of factors, including the age, weight, sex, natural health status, nutritional status of the user, the activity intensity of the compound, the time of use, Metabolic rate, severity of the disease, and subjective judgment of the physician. Those skilled in the art will vary depending on the nature and severity of the disease, the route of administration, and the age and weight of the patient.
  • the dosage can be varied between 1-500 mg/day. Change, one or more doses.
  • a pharmaceutical composition comprising the amorphous form of sapporoside of the present invention and other drugs for treating cardiovascular and cerebrovascular diseases.
  • the present invention provides a novel amorphous form of saponin.
  • the amorphous form of the present invention has good properties in terms of stability and solubility.
  • the method for preparing the amorphous morphocyanin of the invention is simple in operation, and the yield of the amorphous morphocyanin is high, and is suitable for laboratory development and industrial production, and is widely used.
  • the amorphous morphocyanin product prepared by the method of the invention has stable quality and good solubility, and can be directly used for preparation research and production and for preparing medicine for treating cardiovascular and cerebrovascular diseases.
  • Figure 1 shows an X-ray powder diffraction pattern of the raw material sapporoside, wherein the ordinate indicates the diffraction intensity expressed in counts per second (cps), and the abscissa indicates the diffraction angle 2 ⁇ expressed in degrees;
  • Figure 2 is a view showing an X-ray powder diffraction pattern of the amorphous morphocyanin prepared in Example 1 of the present invention, wherein the ordinate indicates the diffraction intensity expressed in counts per second (cps), and the abscissa indicates the degree in degrees. Diffraction angle 2 ⁇ ;
  • Figure 3 is a differential scanning calorimetry (DSC) graph of the raw material sapporoside, wherein the ordinate is the heat flow rate in units of calories per second; the abscissa is temperature in units of ° C;
  • Figure 4 is a differential scanning calorimetry (DSC) graph showing the amorphous morphocyanin prepared in Example 1 of the present invention, wherein the ordinate is the heat flow rate in units of calories per second; the abscissa is temperature The unit is °C.
  • the saponin contained in the examples is provided by Kunming Pharmaceutical Group Co., Ltd., the calibration purity is 99.5 wt%, and the batch number is 20120402.
  • the X-ray powder diffraction spectrum was measured under the following experimental conditions: D/MAX-2200 diffractometer, temperature control chamber; voltage 40 kV, current 40 mA; fixed angle of divergence slit: 0.9570°; measurement method: continuous from 4.5° Up to 50°, increasing by 0.033°; measuring time/step: 19.7 s; measuring temperature: 25 °C.
  • the differential scanning calorimetry (DSC) curve was determined under the following experimental conditions: instrument: DSC 204 (Germany) differential scanning calorimeter; sample weight was 8.17 mg; heating rate: 2 ° C / min; highest temperature 250 ° C; nitrogen flow rate: 20 mL / min.
  • the raw material sapporoside (hereinafter referred to as the raw material sample) was subjected to an X-ray diffraction test, and the results are shown in Fig. 1.
  • Sample 1 was taken for X-ray powder diffraction test and the results are shown in Fig. 2. It was shown that the sample 1 was in an amorphous state and had a different X-ray diffraction pattern from the raw material sapporoside.
  • Samples 2-4 were subjected to X-ray powder diffraction tests, and the results were similar to those of FIG.
  • Sample 1 was taken for DSC detection and the results are shown in Figure 4.
  • the results of Figure 4 show that Sample 1 has a differential scanning calorimetry curve with an endothermic peak at about 212.4 °C, indicating that the amorphous sapporoside provided by the present invention has a different DSC result than the starting material.
  • the solubility of the amorphous morphocyanin sample prepared in Examples 1-4 of the present invention was above 14.4 mg/mL, and the solubility in the 0.9% sodium chloride aqueous solution was 14.1 mg/ Above mL, the solubility of the raw material sample sapporoside in water is 4.81 mg/mL, and the solubility in 0.9% sodium chloride aqueous solution is 4.67 mg/mL, indicating that the solubility of the amorphous morphocyanin in the present invention is obvious.
  • Acetonitrile is chromatographic grade, and HPLC water is re-distilled distilled water.
  • the content of the amorphous morphocyanin prepared in Examples 1-4 of the present invention was 98.4% or more.

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Abstract

本发明涉及药物化学领域，公开了新的无定形态曲札茋苷及其制备方法和含有它的药物组合物。本发明所述无定形态曲札茋苷在稳定性和溶解度方面具有良好的性能。本发明所述制备所述无定形态曲札茋苷的方法操作简单，无定形态曲札茋苷收率高，既适合实验室开发也适合工业化生产，应用广泛。本发明所述方法制备的无定形态曲札茋苷产品质量稳定、溶解度好，可直接用于制备治疗心脑血管疾病的药物。

Description

一种无定形态曲札茋苷及其制备方法 技术领域
本发明涉及药物化学领域，具体涉及无定形态曲札茋苷及其制备方法和含有它的药物组合物。
背景技术
曲札茋苷是从传统藏药拉萨大黄中提取的主要活性成分，研究表明曲札茋苷能显著减轻心脑梗塞后的缺血再灌注造成的损伤，且具有抗氧化、抗炎、改善血管内皮功能障碍等多做药理活性，可见曲札茋苷有作为治疗心脑血管疾病等药物开发的前景。在前期研究中申请人发现了曲札茋苷的新晶型，并申请了专利“一种曲札茋苷晶体及其制备方法与应用”，专利号ZL2011110166486.2。
固体药物多晶型状态是研究药物存在状态的重要内容，对于多数化学药物，一般都存在多晶型现象。通常，不同晶型的同一药物在外观、溶解度、熔点、溶出度和生物有效性等方面有差别，甚至可能会有显著的不同，因而，会影响药物的稳定性、生物利用度及疗效等。由于这些不同的晶型物质影响着药物的理化性质和生物活性，所以在研究药物的原料、制剂配方等方面，均应考虑药物晶型的存在状态。
无定形态(amorphous)是物质存在多晶型现象中的一种形式，也是一种特殊的晶型状态。文献(Konno T.，Chem.Pharm.Bul l.，1990；38；2003-2007)中报道了与结晶形式相比，许多药物中的非晶性形式-无定形态显示出溶解特性，并在某些情况显示出不同的生物利用模式。对于某些治疗证，某种生物利用模式可能比另一种更有利。
而研究表明(药学学报，2009,44(5):443-448)，固体药物的无定型状态并非单一的形式。同晶态物质那样，固体药物的无定形状 态也可以存在不同的形式，这种现象被称之为固体物质无定形态的多态性，又称为无定形多态(polyamorphous)。广义的讲，由于制备方法或储存方式的不同，一种固体物质可以得到物理学、热力学以及动力学性质完全不同的两种或两种以上的无定形状态的物质。例如：用不同的冷却速度制备的无定形态非洛地平，在恒温条件下用差示扫描量热仪(DSC)检测，吸热位置就有所不同。吕扬与杜冠华(《晶型药物》，人民卫生出版社，2009年10月)指出，形成无定形态多态的物质的原因可能与化合物构型或构相、化学物质的组成成分、化学物质分子间作用力三种因素相关。无定形多态为药物研究增加了更多选择的机会，但也增加了研究优势药物晶型的难度，对各种无定形态物质的制备工艺与控制技术提出了新的挑战。
发明内容
有鉴于此，本发明目的是通过晶体学的方法，研究、发现并提供新的无定形态曲札茋苷及其制备方法与应用。与现有技术中的曲札茋苷晶体相比，本发明所述无定形态曲札茋苷具有较好的溶解度。
本发明通过晶体学的方法，研究、发现并提供了新的无定形态曲札茋苷，其具有基本上如图1所示的X-射线粉末衍射图。
本发明还采用差示扫描量热法(DSC)来研究和表征了新的无定形态曲札茋苷。本发明提供的基本上纯净的新的无定形态曲札茋苷，其差示扫描量热分析曲线如图2所示，其具有如下特性：其差示扫描量热分析曲线在约212.4℃处有吸热峰。
实验结果表明，本发明所述无定形态曲札茋苷具有良好的溶解度。
根据本发明的一个方面，提供了所述无定形态曲札茋苷的制备方法。
本发明所述制备无定形态曲札茋苷的方法为曲札茋苷用C1-4的醇溶剂溶解，去除溶剂得到无定形态曲札茋苷。
其中，所述C1-4的醇溶剂可以为直链醇，如甲醇、乙醇、丙醇、正丁醇；也可以为支链醇，如异丙醇、异丁醇、叔丁醇。
在一些实施方案中，本发明所述制备无定形态曲札茋苷的方法中所述C1-4的醇溶剂为甲醇、乙醇、异丙醇、正丁醇中的一种或多种的混合物。
在一些具体实施例中，所述C1-4的醇溶剂为甲醇。
在一些具体实施例中，所述C1-4的醇溶剂为乙醇。
在一些实施方案中，本发明所述制备无定形态曲札茋苷的方法中所述溶解有曲札茋苷的C1-4的醇溶剂中的曲札茋苷的浓度为0.1g/mL～0.5g/mL。
在一些具体实施例中，所述曲札茋苷的浓度为0.1g/mL。
在一些具体实施例中，所述曲札茋苷的浓度为0.2g/mL。
在一些实施方案中，本发明所述制备无定形态曲札茋苷的方法中所述去除溶剂具体为减压回收溶剂。
在一些优选实施方案中，所述减压回收溶剂具体为在-0.06～-0.08的真空度下旋转蒸发溶剂。
依据溶剂沸点不同蒸发温度不同，在一些实施方案中，所述减压回收溶剂的温度为50℃～90℃。
在本发明制备所述无定形态曲札茋苷的方法中，所述曲札茋苷可使用通过任意方法获得的曲札茋苷。
根据本发明的另一方面，还提供了所述无定形态曲札茋苷在制备 治疗心脑血管疾病的药物中的用途。
根据本发明的又一个方面，还提供了一种药物制剂，所述药物制剂包含本发明所述的无定形态曲札茋苷和一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，本领域技术人员可将本发明所述的无定形态曲札茋苷直接或间接加入制备不同剂型时所需的药学上可接受的各种常用辅料，如填充剂、崩解剂、润滑剂、粘合剂等，以常规药物制剂方法，制成适合于口服、胃肠外(静脉内或皮下)或鼻部给药的常用制剂。
所述常用制剂例如可以是片剂、胶囊剂、注射液、口服液、颗粒剂、丸剂、散剂、滴丸剂、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶、混悬液等。
在本发明的一个实施方案中，所述填充剂例如可以选自淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；所述崩解剂例如可以选自琼脂、碳酸钙、土豆淀粉或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠、低取代羟丙基纤维素；所述润滑剂例如可以选自滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂硫酸钠；所述粘合剂可以选自羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯酮、蔗糖和阿拉伯胶。
在本发明的另一个实施方案中，所述药物制剂的使用剂量和使用方法取决于诸多因素，包括使用者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、使用时间、代谢速率、病程严重程度以及诊治医师的主观判断。本领域的技术人员根据疾病的性质和严重程度、给药途径和患者的年龄和体重而改变。
在一些优选的实施方案中，所述剂量可以在1-500mg/天之间改 变，分一次或多次给药。
根据本发明的再一个方面，还提供了一种药物组合物，所述药物组合物包含本发明所述的无定形态曲札茋苷和其它治疗心脑血管疾病的药物。
本发明的技术方案具有至少下述优势之一：
本发明提供了一种新的无定形态曲札茋苷。本发明所述无定形态曲札茋苷稳定性和溶解度方面具有良好的性能。本发明所述制备所述无定形态曲札茋苷的方法操作简单，无定形态曲札茋苷收率高，既适合实验室开发也适合工业化生产，应用广泛。本发明所述方法制备的无定形态曲札茋苷产品质量稳定，溶解度好，可直接用于制剂研究和生产以及用于制备治疗心脑血管疾病的药物。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示出了原料曲札茋苷的X-射线粉末衍射图，其中纵坐标表示用计数/秒(cps)表示的衍射强度，横坐标表示用度表示的衍射角2θ；
图2示出了本发明实施例1制得的无定形态曲札茋苷的X-射线粉末衍射图，其中纵坐标表示用计数/秒(cps)表示的衍射强度，横坐标表示用度表示的衍射角2θ；
图3示出了原料曲札茋苷的差示扫描量热法(DSC)曲线图，其中纵坐标为热流率，单位为卡/秒；横坐标为温度，单位为℃；
图4示出了本发明实施例1制得的无定形态曲札茋苷的差示扫描量热法(DSC)曲线图，其中纵坐标为热流率，单位为卡/秒；横坐标为温度，单位为℃。
具体实施方式
下面将结合本发明实施例，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做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。
其中，如无特殊说明实施例中所涉及的曲札茋苷为昆明制药集团股份有限公司提供，标定纯度为99.5wt％，批号为20120402。
所述X射线粉末衍射光谱在下列实验条件下测定：D/MAX-2200型衍射仪、温控室；电压40kV，电流40mA；发散狭缝的固定角：0.9570°；测定方式：从4.5°连续至50°，按0.033°递增；测定时间/步骤：19.7s；测定温度：25℃。
所述差示扫描量热法(DSC)曲线图在下列实验条件下测定：仪器：DSC 204(德国)差示扫描量热仪；样品重量为8.17mg；升温速率：2℃/min；最高温250℃；氮气流速：20mL/min。
实施例1
取5g曲札茋苷溶解于50mL乙醇中，搅拌10分钟，使曲札茋苷完全溶解，过滤，滤液-0.06～-0.08的真空度下旋转蒸发乙醇至干，得到样品1。
实施例2
取5g曲札茋苷溶解于25mL乙醇中，搅拌10分钟，使曲札茋苷完全溶解，过滤，滤液-0.06～-0.08的真空度下旋转蒸发乙醇至干，得到样品2。
实施例3
取5g曲札茋苷溶解于50mL甲醇中，搅拌10分钟，使曲札茋苷完全溶解，过滤，滤液-0.06～-0.08的真空度下旋转蒸发甲醇至干，得到样品3。
实施例4
取5g曲札茋苷溶解于25mL甲醇中，搅拌10分钟，使曲札茋苷完全溶解，过滤，滤液-0.06～-0.08的真空度下旋转蒸发甲醇至干，得到样品4。
实验一：X射线粉末衍射检测
对原料曲札茋苷(以下简称原料样品)进行X射线衍射测试，结果如图1所示。
取样品1进行X射线粉末衍射测试，结果如图2所示。表明样品1为无定形态，与原料曲札茋苷具有不同的X射线衍射图谱。
对样品2-4进行X射线粉末衍射测试，结果与图2相似。
实验二：差示扫描量热检测
对原料样品进行DSC检测，结果如图3所示。
取样品1进行DSC检测，结果如图4所示。图4的结果显示样品1其差示扫描量热分析曲线在约212.4℃处有吸热峰，表明本发明提供的无定形曲札茋苷与原料曲札茋苷具有不同的DSC结果。
对样品2-4进行差示扫描量热检测，结果与图4相似。
实验三：溶解度实验：
取上述实施例1-4制备的样品和原料样品适量，在室温条件下分别加水、0.9wt％的氯化钠水溶液各10mL，分别振摇30分钟，使其溶解至饱和状态，取上述溶液，HPLC法测量溶液中曲札茋苷含量，结果见表1。
表1、曲札茋苷溶解度实验比较结果(mg/mL)
样品编号 水 0.9％氯化钠水溶液
样品1 14.87 14.36
样品2 14.64 14.19
样品3 15.22 14.86
样品4 14.45 14.31
原料样品 4.81 4.67
由表1结果可见，本发明实施例1-4制备的无定形态曲札茋苷样品在水中的溶解度均在14.4mg/mL以上，在0.9％氯化钠水溶液中的溶解度均在14.1mg/mL以上，而原料样品曲札茋苷在水中的溶解度为4.81mg/mL，在0.9％氯化钠水溶液中的溶解度为4.67mg/mL，表明本发明所述无定形态曲札茋苷溶解度明显好于原料样品曲札茋 苷。
实验四：纯度检测
仪器与试药试剂：Agi lent1100高效液相色谱仪。
色谱柱：Luna C18 150×4.6mm。
乙腈为色谱级、HPLC用水为重蒸蒸馏水。
对照品：原料样品；
检测品：样品1、样品2、样品3、样品4。
色谱条件与系统适用性试验：用十八烷基硅烷键合硅胶为填充剂；以乙腈-水)(15∶85)为流动相；检测波长为319nm。理论板数按曲札茋苷计算应不低于3000。
测定：取本品约10mg，精密称定，置50mL量瓶中，加甲醇溶解并稀释至刻度，摇匀，精密量取20μL注入液相色谱仪，记录色谱图；另取曲札茋苷对照品约10mg，同法测定，按外标法以峰面积计算，即得。结果见表2。
表2、纯度检测结果
样品批号 样品1 样品2 样品3 样品4
含量(wt％) 99.3 98.9 99.1 98.8
由表2结果可见，本发明实施例1-4制备的无定形态曲札茋苷样品含量在98.4％以上。

Claims (10)

  1. 一种无定形态曲札茋苷，其具有基本上如图1所示的X-射线粉末衍射图。
  2. 根据权利要求1所述的无定形态曲札茋苷，其差示扫描量热分析曲线在约212.4℃处有吸热峰。
  3. 一种制备权利要求1所述的无定形态曲札茋苷的方法，将曲札茋苷用C1-4的醇溶剂溶解，去除溶剂得到无定形态曲札茋苷。
  4. 根据权利要求3所述的方法，所述C1-4的醇溶剂为甲醇、乙醇、异丙醇、正丁醇中的一种或更多种的混合物。
  5. 根据权利要求3或4所述的方法，其中溶解有曲札茋苷的C1-4的醇溶剂中曲札茋苷的浓度为0.1g/mL～0.5g/mL。
  6. 根据权利要求3-4任意一项所述的方法，所述去除溶剂具体为减压回收溶剂。
  7. 根据权利要求6所述的方法，所述减压回收溶剂具体为在-0.06～-0.08的真空度下旋转蒸发溶剂。
  8. 权利要求1所述无定形态曲札茋苷在制备治疗心脑血管疾病的药物中的用途。
  9. 一种药物制剂，包含权利要求1所述的无定形态曲札茋苷和一种或多种药学上可接受辅料。
  10. 一种药物组合物，包含权利要求1所述的无定形态曲札茋苷和其它治疗心脑血管疾病的药物。
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