WO2020258660A1 - 盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物 - Google Patents

盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物 Download PDF

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WO2020258660A1
WO2020258660A1 PCT/CN2019/117679 CN2019117679W WO2020258660A1 WO 2020258660 A1 WO2020258660 A1 WO 2020258660A1 CN 2019117679 W CN2019117679 W CN 2019117679W WO 2020258660 A1 WO2020258660 A1 WO 2020258660A1
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crystal form
hydrochloride
hydrate
hydrochloride hydrate
pharmaceutical composition
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PCT/CN2019/117679
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English (en)
French (fr)
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李亚玲
吴燕子
王彪
栗栖凤
夏雪林
刘爱玲
李守军
付春香
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天津瑞普生物技术股份有限公司
瑞普（天津）生物药业有限公司
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Priority to EP19935712.0A priority Critical patent/EP3929178A4/en
Publication of WO2020258660A1 publication Critical patent/WO2020258660A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • 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
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
    • C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
    • C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline

Definitions

  • This application belongs to the technical field of veterinary medicine and chemical engineering crystallization, and specifically relates to a crystal form ofappelmulin hydrochloride hydrate, a preparation method thereof, and a pharmaceutical composition containing the crystal form.
  • Valnemulin hydrochloride the English name is Valnemulin Hydrochloride, the molecular formula is C 31 H 52 N 2 O 5 S ⁇ HCl, the molecular weight is 601.29, it is a white powder, irritating, and its structural formula is as follows:
  • Vonimulin hydrochloride is a new generation of pleuromutilin (pleuromutilin) semi-synthetic antibiotics. It belongs to diterpenes and is an animal-specific antibiotic. It is mainly used to prevent and treat mycoplasma and Gram-positive in pigs, cattle, sheep and poultry. Bacterial infection. It is mainly concentrated in the lungs and is an ideal medicine for the treatment of various pulmonary diseases caused by mycoplasma. Vonemulin interacts with the 50S subunit on the ribosome of the pathogenic microorganism, thereby inhibiting the synthesis of the pathogenic microorganism's protein and leading to its death. Since districtmulin hydrochloride crystals are difficult to be prepared by ordinary crystallization methods, the dormitorin hydrochloride drugs currently produced and sold at home and abroad are all in an amorphous state.
  • Chinese patent CN108892629A proposes a method for preparing vornimulin hydrochloride methyl tert-butyl ether solvate, and an ansolvate is prepared from the solvate, but the bulk density of the ansolvate is only 0.305g/ml, which is stacked with the amorphous substance. There is no improvement in density, and it is not stated whether the obtained ansolvate is crystal. Therefore, there is still a need in the art to obtain saddlemulin hydrochloride crystals with high purity, high bulk density and good palatability suitable for pharmaceutical preparation.
  • Patent CN104876841B reports a cooling-ultrasonic crystallization method for preparing remindmulin hydrochloride, which obtains a crystalline compound of professionmulin hydrochloride. Its characteristic peaks are 2 ⁇ at 8.5 ⁇ 0.1, 10.6 ⁇ 0.1, 10.9 ⁇ 0.1, 11.2 ⁇ 0.1, 12.1 ⁇ 0.1, 12.6 ⁇ 0.1, 15.0 ⁇ 0.1, 17.8 ⁇ 0.1, 18.4 ⁇ 0.1, 19.3 ⁇ 0.1, 20.2 ⁇ 0.1, 20.8 ⁇ 0.1, 25.8 ⁇ 0.1, 27.7 ⁇ 0.1, 28.4 ⁇ 0.1, 29 ⁇ 0.1 display.
  • the crystallization process in the invention is not easy to industrialize, and although the crystalline compound has a certain improvement in moisture absorption, the problem of moisture absorption still exists.
  • the application provides a crystal form ofappelmulin hydrochloride hydrate, a preparation method thereof, and a pharmaceutical composition containing the crystal form.
  • the obtained hydrate crystal form has a large bulk density, no hygroscopicity, and good thermal stability.
  • the hydrate crystal form and the pharmaceutical composition containing the crystal form are widely used in pharmaceutical preparations, and can be used to prepare dosage forms such as soluble powders, sustained-release granules, injections, oral liquids, injections, etc., with broad clinical application prospects.
  • the first aspect of the application provides a crystalline form of professionmulin hydrochloride hydrate.
  • the crystalline form uses CuKa rays as a characteristic to perform X-ray powder determination.
  • the characteristic peaks in the spectrum 2 ⁇ diffraction angles are 9.2 ⁇ 0.2°, 9.5 ⁇ 0.2°, 10.3 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.3 ⁇ 0.2°, 12.8 ⁇ 0.2°, 15.1 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.2 ⁇ 0.2°.
  • the crystalline form of Vonimulin hydrochloride hydrate was determined by X-ray powder with CuKa rays as the characteristic, and the 2 ⁇ diffraction angles of the characteristic peaks in the spectrum also included 4.4 ⁇ 0.2°, 12.6 ⁇ 0.2°, 14.4 ⁇ 0.2°, 14.6 One or more of ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.7 ⁇ 0.2°, 25.8 ⁇ 0.2°, 28.7 ⁇ 0.2°.
  • FIG. 1 The X-ray powder diffraction pattern of the crystalline form of Vonimulin hydrochloride hydrate is shown in FIG. 1.
  • the crystalline form of regularlymulin hydrochloride hydrate has an endothermic peak in the DSC spectrum at 120 ⁇ 5°C.
  • the moisture content (mass content) of the vornimulin hydrochloride hydrate crystal form is 0.01%-8%.
  • the moisture content (mass content) of the crystalline form of regularlymulin hydrochloride hydrate is 0.1%-7%.
  • the second aspect of the application provides a preparation method oflotmulin hydrochloride hydrate crystal form, which specifically includes the following steps:
  • Filter cake A is vacuum dried at 20-40°C to obtain filter cake B;
  • step (3) The filter cake A obtained in step (3) is stirred and balanced in a poor solvent for 6-20 hours, filtered, and vacuum dried at 20-60°C to obtain hydrate crystals; or, the filter cake B obtained in step (4) is heated to 65 Humidification treatment is carried out under -95% humidity for 12-48 hours to obtain hydrate crystals.
  • the organic solvent is selected from one or more of esters, ketones, alcohols, furans or acetonitrile solvents.
  • the organic solvent is selected from one or more of ethyl acetate, acetone, isopropanol, n-butanol, tert-butanol, methanol, ethanol, tetrahydrofuran or acetonitrile.
  • the poor solvent is selected from one or more of alkane solvents, aromatic hydrocarbons, ether solvents or water.
  • the poor solvent is selected from one or more of n-hexane, cyclohexane, n-heptane, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, toluene or water.
  • the weight-volume ratio of the Vonemulin hydrochloride bulk drug to (organic solvent/purified water) is 1:1-1:10; the weight-volume ratio of the Vonemulin hydrochloride bulk drug to the poor solvent is 1:1: 2-1:15.
  • the volume ratio of the organic solvent to the purified water is 2:4-3:2.
  • the third aspect of the present application provides a pharmaceutical composition containing the crystalline form ofappelmulin hydrochloride hydrate of the present application.
  • the pharmaceutical composition is a mixture containing the crystalline form ofministermulin hydrochloride hydrate and other crystalline forms ofministermulin hydrochloride.
  • the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers and/or excipients.
  • the fourth aspect of the application provides the application of the vornimulin hydrochloride hydrate crystal form or the pharmaceutical composition of the application in the preparation of pharmaceutical preparations.
  • the pharmaceutical preparations can be prepared including but not limited to tablets, soluble powders, injections, oral liquids, sustained-release granules, other granules, freeze-dried powders, injections, solid dispersions, pellets, suspensions and other dosage forms.
  • This application uses a conventional crystallization reactor for crystallization, with simple operating steps and preparation processes, stable and easy-to-repeat preparation processes, high yields, easy industrial production, and significant practicability.
  • the vornimulin hydrochloride hydrate crystal form has a large bulk density, no hygroscopicity, strong fluidity, good stability, and no pungent odor.
  • the crystalline form ofappelmulin hydrochloride hydrate and its pharmaceutical composition can be used in the preparation of various pharmaceutical preparations, such as soluble powder, sustained-release granules, injections and other dosage forms, with broad clinical application prospects.
  • Fig. 1 is an X-ray diffraction pattern of the crystalline form of Vonimulin hydrochloride hydrate described in Example 1 of the present application;
  • Fig. 3 is a DSC chart of the crystalline form of Vonimulin hydrochloride hydrate described in Example 1 of the present application;
  • FIG. 4 is an IR comparison spectrum of the departmentmulin hydrochloride hydrate crystal and amorphous raw materials described in Example 1 of the present application;
  • Fig. 5 is an HPLC chart of the crystalline form of Vonimulin hydrochloride hydrate described in Example 1 of the present application;
  • Fig. 6 is a scanning electron micrograph of the crystalline form of Vonimulin hydrochloride hydrate prepared in this application;
  • Figure 7 is the DSC spectrum of amorphous Vonimulin hydrochloride raw material
  • Figure 8 is the XRD pattern of the amorphous Vonimulin hydrochloride raw material
  • Figure 9 is an HPLC chart of amorphous Vonimulin hydrochloride raw material
  • Figure 10 is the XRD pattern of the patent CN104876841B crystal form.
  • Vonemulin hydrochloride raw material used in the examples was purchased from Hubei Longxiang Pharmaceutical.
  • X-ray powder diffraction (XRD) instrument Japan Rigaku D/Max-2500 type: radiation source: copper target scanning at room temperature: scanning range 2.0 ⁇ 50.0°, step length: 0.02°, scanning rate: 8°/min .
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis (TGA) instrument Switzerland METTLER TOLEDO TGA1 type, within the range of 30 ⁇ 180 °C, heating rate: 5 °C / min, nitrogen protection.
  • High performance liquid chromatography (HPLC) testing purity conditions use octadecylsilane bonded silica as filler (150mm ⁇ 4.6mm, 3 ⁇ m); mobile phase A is phosphate buffer (pH 2.5); mobile phase B is phosphoric acid Salt buffer (pH 2.5)-acetonitrile (25:75); flow rate is 1.5ml per minute; column temperature is 50°C; detection wavelength is 200nm. Perform linear gradient elution according to the following table:
  • the DSC chart has a characteristic peak at 119.5°C; the melting point of the hydrate product is 119.5°C, which is 50°C higher than the amorphous solvent removal temperature.
  • the TGA chart shows a weight loss of 6.4%.
  • the hydrate product has no pungent odor, non-hygroscopicity, large bulk density and enhanced stability.
  • the DSC chart has a characteristic peak at 120.1°C; the melting point of the hydrate product is 119.1°C, which is 50°C higher than the amorphous solvent removal temperature. Compared with the original amorphous product, the hydrate product has no pungent odor and no hygroscopicity.
  • the DSC chart has a characteristic peak at 123.9°C; the melting point of the hydrate product is 122.7°C, which is nearly 50°C higher than the amorphous solvent removal temperature.
  • the hydrate product has no pungent odor and no hygroscopicity.
  • the DSC chart has a characteristic peak at 119.3°C; the melting point of the hydrate product is 119.3°C, which is 50°C higher than the amorphous solvent removal temperature. Compared with the original amorphous product, the hydrate product has no pungent odor and no hygroscopicity.
  • the DSC chart has a characteristic peak at 122.2°C; the melting point of the hydrate product is 121.4°C, which is 50°C higher than the amorphous solvent removal temperature. Compared with the original amorphous product, the hydrate product has no pungent odor and no hygroscopicity.
  • the DSC chart has a characteristic peak at 124.4°C; the melting point of the hydrate product is 123.4°C, which is 50°C higher than the amorphous solvent removal temperature. Compared with the original amorphous product, the hydrate product has no pungent odor and no hygroscopicity.
  • the DSC chart has a characteristic peak at 124.9°C; the melting point of the hydrate product is 124.4°C, which is 50°C higher than the amorphous solvent removal temperature. Compared with the original amorphous product, the hydrate product has no pungent odor and no hygroscopicity.
  • Example 1 of CN104876841B the patented crystal form was obtained.
  • the hydrate has a better bulk density and no hygroscopicity, so it can be better applied to formulations.

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Abstract

本申请涉及盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物。具体而言，本申请涉及盐酸沃尼妙林水合物晶型，该晶型在X射线粉末衍射图谱中的特征峰2θ在9.2±0.2°、9.5±0.2°、10.3±0.2°、11.8±0.2°、12.3±0.2°、12.8±0.2°、15.1±0.2°、17.5±0.2°、18.2±0.2°处显示。该盐酸沃尼妙林水合物晶型堆密度大，无引湿性，稳定性好。本申请还提供了一种制备上述盐酸沃尼妙林水合物晶型的方法和含有该晶型的药物组合物，该组合物可用于多种制剂的制备，如可溶性粉、口服液、缓释颗粒、注射液等剂型，临床使用前景广阔。

Description

盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物 技术领域
本申请属于兽药及化学工程结晶技术领域，具体涉及盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物。
背景技术
盐酸沃尼妙林，英文名称为Valnemulin Hydrochloride，分子式为C 31H 52N 2O 5S·HCl，分子量为601.29，其为白色粉末，有刺激性，其结构式如下：
Figure PCTCN2019117679-appb-000001
盐酸沃尼妙林是新一代截短侧耳素(pleuromutilin)类半合成抗生素，属二萜烯类，是动物专用抗生素，主要用于防治猪、牛、羊及家禽的支原体病和革兰氏阳性菌感染。其主要浓集于肺部，是治疗各种霉形体引起的肺部疾病的理想药物。沃尼妙林通过与病原微生物核糖体上的50S亚基相互作用，从而抑制了病原微生物蛋白质的合成，导致其死亡。由于盐酸沃尼妙林晶体很难由普通的结晶方法制备得到，因此，目前国内外生产和销售的盐酸沃尼妙林药物均为无定型态。
对于固体药物，不同的固体形式会对其稳定性、溶解度、溶出速率、堆密度、流动性等物理化学性质产生重要影响，从而造成其在使用过程中产生不同的药效和生物利用度。因此，对固体药物产品，开发其不同固体形态更有利于根据药物制剂特点选择合适的晶型。对盐酸沃尼妙林产品而言，其无定型态产品与晶体态产品相比存在稳定性差、易吸湿、外观差、流动性差、不易存储等问题。同时，在制剂过程中，无定型盐酸沃尼妙林产品水溶液不稳定，实验表明在75℃下制粒会有11.6％的损失。因此，急需开发一种稳定的盐酸沃尼妙林晶体产品来满足兽药市场需求。但是通过文献检索发现，大多数文献是关于盐酸沃尼妙林产品的合成以及制剂方面的报道，而且得到的产品均为无定型。晶体态盐酸沃尼妙林及其制备方法的报道非常少。
中国专利CN108892629A提出一种盐酸沃尼妙林甲基叔丁基醚溶剂化物的制备方法，并由溶剂化物制备得到无溶剂化物，但无溶剂化物的堆密度仅为0.305g/ml，与无定形物堆密度相比并无改善，且所得到的无溶剂化物是否为晶体也未说明。因此本领域仍需要获得适合于药物制备的纯度高、堆密度大、适口性好的盐酸沃尼妙林晶体。
专利CN104876841B报道了一种冷却-超声结晶制备盐酸沃尼妙林的方法，得到的是一种盐酸沃尼妙林结晶性化合物。其特征峰为2θ在8.5±0.1、10.6±0.1、10.9±0.1、11.2±0.1、12.1±0.1、12.6±0.1、15.0±0.1、17.8±0.1、18.4±0.1、19.3±0.1、20.2±0.1、20.8±0.1、25.8±0.1、27.7±0.1、28.4±0.1、29±0.1显示。但该发明中的结晶工艺不易工业化，并且结晶化合物虽在引湿性上得到了一定改善，但其引湿的问题仍然存在。
因此，本领域更需要获得一种不含有机溶剂、纯度高、无引湿性的稳定性更好的盐酸沃尼妙林晶体来应对市场需求。同时，本领域期望进一步拓宽制剂选取的原料库，设计出具有改良特性的药物新剂型，使得药物在口服、注射等制剂剂型上的应用将更加广泛。
发明内容
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
本申请提供一种盐酸沃尼妙林水合物晶型及其制备方法与含有该晶型的药物组合物，所得到的水合物晶型堆密度大，无引湿性，热稳定性好。该水合物晶型及含有该晶型的药物组合物在药物制剂方面应用广泛，可用于制备可溶性粉、缓释颗粒、注射液、口服液、针剂等剂型，临床使用前景广阔。
通过以下技术方案来实现本申请的目的：
本申请的第一方面提供了一种盐酸沃尼妙林水合物晶型，所述晶型用CuKa射线作为特征进行X射线粉末测定，其特征峰在图谱2θ衍射角为9.2±0.2°、9.5±0.2°、10.3±0.2°、11.8±0.2°、12.3±0.2°、12.8±0.2°、15.1±0.2°、17.5±0.2°、18.2±0.2°处显示。
所述盐酸沃尼妙林水合物晶型用CuKa射线作为特征进行X射线粉末测定，其特征峰在图谱中的2θ衍射角还包括4.4±0.2°、12.6±0.2°、14.4±0.2°、14.6±0.2°、16.5±0.2°、17.9±0.2°、18.7±0.2°、25.8±0.2°、28.7±0.2°中的一个或多个。
所述盐酸沃尼妙林水合物晶型具有的X-射线粉末衍射图如图1所示。
所述盐酸沃尼妙林水合物晶型在DSC图谱120±5℃有吸热峰。
所述盐酸沃尼妙林水合物晶型的水分含量(质量含量)为0.01％-8％。
优选地，所述盐酸沃尼妙林水合物晶型的水分含量(质量含量)为0.1％-7％。
本申请的第二方面提供了一种盐酸沃尼妙林水合物晶型的制备方法，具体包括以下步骤：
(1)将盐酸沃尼妙林在有机溶剂/纯化水的混合液中于20-60℃进行热溶解；
(2)保温搅拌0.5-1h，-5-15℃降温，从混合液中析出结晶；
(3)过滤得滤饼A；
(4)将滤饼A在20-40℃真空干燥得滤饼B；
(5)将步骤(3)中所得滤饼A在不良溶剂中进行搅拌平衡6-20h，过滤，20-60℃真空干燥得到水合物晶体；或，将步骤(4)所得滤饼B于65-95％湿度下进行加湿处理12-48h，得到水合物晶体。
所述有机溶剂选自酯类、酮类、醇类、呋喃类或乙腈溶剂中的一种或多种。
优选地，所述有机溶剂选自乙酸乙酯、丙酮、异丙醇、正丁醇、叔丁醇、甲醇、乙醇、四氢呋喃或乙腈中的一种或多种。
所述不良溶剂选自烷烃溶剂、芳香烃类、醚类溶剂或水的一种或多种。
优选地，所述不良溶剂选自正己烷、环己烷、正庚烷、乙醚、二甲基醚、二异丙基醚、甲基叔丁基醚、甲苯或水中的一种或多种。
所述的盐酸沃尼妙林原料药与(有机溶剂/纯化水)的重量体积比为1:1-1:10；所述盐酸沃尼妙林原料药与不良溶剂的重量体积比为1:2-1:15。
所述的有机溶剂与纯化水的体积比为2:4-3:2。
本申请的第三方面提供了一种含有本申请盐酸沃尼妙林水合物晶型的药物组合物。
所述药物组合物是含有所述盐酸沃尼妙林水合物晶型与其他盐酸沃尼妙林晶型的混合物。
或，所述药物组合物还含有一种或一种以上药学上可接受的载体和/或赋形剂。
本申请的第四方面提供了本申请盐酸沃尼妙林水合物晶型或药物组合物在制备药物制剂中的应用。
所述药物制剂可制备包括但不限于片剂、可溶性粉、注射液、口服液、缓释颗粒、其他颗粒剂、冻干粉、针剂、固体分散体、微丸、混悬剂等剂型。
本申请的有益效果为：
(1)本申请采用常规结晶反应釜进行结晶，操作步骤及制备过程简单、制备工艺稳定易 重复、收率高，易于工业化生产，具有显著的实用性。
(2)该盐酸沃尼妙林水合物晶型堆密度大，无引湿性，流动性强、稳定性好、无刺激性气味。
(3)该盐酸沃尼妙林水合物晶型及其药物组合物可用于多种药物制剂的制备，如可溶性粉、缓释颗粒、针剂等剂型，临床使用前景广阔。
在阅读并理解了附图和详细描述后，可以明白其他方面。
附图说明
下面为了更清楚地说明本申请实施例或相关技术中的技术方案，将对实施例中所需要使用的附图作简单地介绍。
图1是本申请实施例1所述的盐酸沃尼妙林水合物晶型的X-射线衍射图谱；
图2是本申请实施例1所述的盐酸沃尼妙林水合物晶型的TGA图谱；
图3是本申请实施例1所述的盐酸沃尼妙林水合物晶型的DSC图谱；
图4是本申请实施例1所述的盐酸沃尼妙林水合物晶体与无定形原料的IR对比图谱；
图5是本申请实施例1所述的盐酸沃尼妙林水合物晶型的HPLC图谱；
图6是本申请制备的盐酸沃尼妙林水合物晶型的扫描电镜图谱；
图7是无定形的盐酸沃尼妙林原料的DSC图谱；
图8是无定形的盐酸沃尼妙林原料的XRD图谱；
图9是无定形的盐酸沃尼妙林原料的HPLC图谱；
图10是专利CN104876841B晶型的XRD图谱。
具体实施方式
为了进一步了解本申请，下面结合实施例对本申请优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本申请的特征和优点，而不是对本申请权利要求的限制。
原料和通用测试方法：
实施例中所用的盐酸沃尼妙林原料药由湖北龙翔药业购得。
X-射线粉末衍射(XRD)仪器：日本Rigaku D/Max-2500型：辐射源：铜靶在室温条件下扫描：扫描范围2.0～50.0°，步长：0.02°，扫描速率：8°/min。
差示扫描量热法分析(DSC)仪器：瑞士梅特勒-托利多DSC1型，30～180℃范围，加 热速率：5℃/min，氮气保护。
热重分析(TGA)仪器：瑞士梅特勒-托利多TGA1型，30～180℃范围内，加热速率：5℃/min，氮气保护。
高效液相色谱(HPLC)检测纯度条件：用十八烷基硅烷键合硅胶为填充剂(150mm×4.6mm，3μm)；流动相A为磷酸盐缓冲液(pH 2.5)；流动相B为磷酸盐缓冲液(pH 2.5)-乙腈(25:75)；流速为每分钟1.5ml；柱温为50℃；检测波长为200nm。按下表进行线性梯度洗脱：
时间(分钟) 流动相A(％) 流动相B(％)
0 95 5
2 55 45
4.5 50 50
5.5 35 65
6.85 35 65
10 0 100
13 0 100
14 95 5
20 95 5
实施例1
取盐酸沃尼妙林原料药10g，加入甲醇30ml，再加入纯化水20ml，升温至40℃溶解，保温搅拌1小时，再缓慢降温至5℃，搅拌析晶4h，过滤；滤饼溶于100ml正己烷中搅拌6h，过滤；滤饼于30℃真空干燥得盐酸沃尼妙林水合物9.5g，收率为95％，归一化纯度为99.63％，水含量为6.9％。
实施例2
取盐酸沃尼妙林原料药10g，加入乙酸乙酯40ml，再加入纯化水50ml，升温至60℃溶解，保温搅拌1小时，再缓慢降温至10℃，搅拌析晶8h，过滤；滤饼溶于150ml正庚烷中搅拌8h，过滤；滤饼于40℃真空干燥得盐酸沃尼妙林水合物9.2g，重量收率为92％，纯度为98.8％，水含量6.5％。
实施例3
取盐酸沃尼妙林原料药10g，加入乙醇50ml，再加入纯化水35ml，升温至55℃溶解，保温搅拌1小时，再缓慢降温至-5℃，搅拌析晶10h，过滤；滤饼于35℃真空干燥12h后置于 饱和的硝酸钾水溶液(92.5％RH)上方，放置16h后得到盐酸沃尼妙林2.5水合物晶型，水分含量6.8％；
在温度为40℃，干燥20h至恒重得到盐酸沃尼妙林1.5水合物的晶型，水分含量4.6％；
继续在温度为60℃干燥20h至恒重得8.9g盐酸沃尼妙林1.25水合物晶型，收率89％，HPLC纯度98.9％，水分含量3.7％。
实施例4
取盐酸沃尼妙林原料药10g，加入叔丁醇35ml，再加入纯化水35ml，升温至56℃溶解，保温搅拌1小时，再缓慢降温至8℃，搅拌析晶9h，过滤；滤饼置于80ml甲基叔丁基醚中搅拌20h，过滤；滤饼于38℃真空干燥得盐酸沃尼妙林水合物9.8g，收率为98％，纯度为99.2％，水含量为6.5％。
实施例5
取盐酸沃尼妙林原料药10g，加入丙酮40ml，再加入纯化水32ml，升温至45℃溶解，保温搅拌0.5小时，再缓慢降温至0℃，搅拌析晶11h，过滤；滤饼置于70ml二异丙基醚中搅拌17h，过滤；滤饼于40℃真空干燥得盐酸沃尼妙林水合物9.5g，收率为95％，纯度为99.4％，水含量为6.4％。
实施例6
取盐酸沃尼妙林原料药10g，加入乙醇30ml，正丁醇5ml，再加入纯化水35ml，升温至52℃溶解，保温搅拌0.5小时，再缓慢降温至12℃，搅拌析晶8h，过滤；滤饼于30℃真空干燥12h后置于饱和的氯化钠水溶液(75％RH)上方，放置32h后得到盐酸沃尼妙林2.5水合物晶型，水分含量6.8％；
在温度为45℃干燥20h至恒重得到盐酸沃尼妙林1.5水合物的晶型，水分含量4.5％；
继续在温度为70℃干燥12h至恒重得8.84g盐酸沃尼妙林一水合物晶型，收率88.4％，HPLC纯度99.2％，水分含量2.9％。
实施例7
取盐酸沃尼妙林原料药10g，加入乙腈40ml，再加入纯化水44ml，升温至50℃溶解，保温搅拌0.5小时，再缓慢降温至-2℃，搅拌析晶12h，过滤；滤饼置于20ml纯化水中搅拌19h， 过滤；滤饼于40℃真空干燥得盐酸沃尼妙林水合物9.5g，收率为92％，纯度为99.5％，水含量为6.7％。
结论：
实施例1中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.2°、9.5°、10.3°、11.8°、12.3°、12.6°、12.8°、14.4°、14.6°、15.1°、16.5°、17.5°、17.9°、18.2°、25.8°、28.7°处有特征峰。DSC图在119.5℃处有特征峰；水合物产品熔点为119.5℃，比无定形脱溶剂温度提高了50℃。TGA图显示失重为6.4％。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性、堆密度大，稳定性增强。
实施例2中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.1°、9.5°、10.2°、11.7°、12.2°、12.7°、12.9°、14.3°、14.5°、15.2°、16.4°、17.4°、17.8°、18.2°、25.8°、28.8°处有特征峰。DSC图在120.1℃处有特征峰；水合物产品熔点为119.1℃，比无定形脱溶剂温度提高了50℃。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性。
实施例3中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.2°、9.4°、10.3°、11.7°、12.3°、12.5°、12.7°、14.3°、14.6°、15.3°、16.5°、17.6°、17.8°、18.1°、25.7°、28.6°处有特征峰。DSC图在123.9℃处有特征峰；水合物产品熔点为122.7℃，比无定形脱溶剂温度提高了近50℃。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性。
实施例4中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.3°、9.5°、10.4°、11.7°、12.3°、12.6°、12.7°、14.4°、14.5°、15.3°、16.6°、17.6°、17.9°、18.1°、25.6°、28.7°处有特征峰。DSC图在119.3℃处有特征峰；水合物产品熔点为119.3℃，比无定形脱溶剂温度提高了50℃。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性。
实施例5中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.2°、9.4°、10.4°、11.6°、12.2°、12.4°、12.6°、14.3°、14.5°、15.2°、16.6°、17.5°、17.7°、18.0°、25.7°、28.7°处有特征峰。DSC图在122.2℃处有特征峰；水合物产品熔点为121.4℃，比无定形脱溶剂温度提高了50℃。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性。
实施例6中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.3°、9.5°、10.4°、11.8°、12.3°、12.7°、14.5°、14.6°、15.1°、16.6°、17.7°、18.0°、18.3°、25.9°、28.9°处有特征峰。DSC图在124.4℃处有特征峰；水合物产品熔点为123.4℃，比无定形脱溶剂温度提高了50℃。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性。
实施例7中盐酸沃尼妙林水合物晶型的X-射线粉末衍射图谱在衍射角2θ＝9.2°、9.5°、10.4°、11.7°、12.2°、12.4°、12.7°、14.4°、14.6°、15.0°、16.6°、17.6°、18.0°、18.3°、25.8°、28.7°处有特征峰。DSC图在124.9℃处有特征峰；水合物产品熔点为124.4℃，比无定形脱溶剂温度提高了50℃。与原来无定型产品相比，该水合物产品没有刺激性气味、无引湿性。
对比例
按照CN104876841B实施例1描述的结晶方法结晶得到专利晶型，得到的晶型X-射线衍射图谱在衍射角2θ＝8.4、10.4、10.8、11.1、12.0、12.4、14.8、17.6、18.2、19.2、20.1、20.7、25.7、27.5、28.4、29.0处有特征峰。
实施例8 水合物晶型的成药性研究
通过对盐酸沃尼妙林无定形物(放置前含量为97.50％，白色固体)、CN104876841B晶型物(对比例晶型)及本申请实施例1的盐酸沃尼妙林水合物晶型(放置前含量为99.25％，白色固体)进行引湿性实验、影响因素试验研究，考察了温度(25℃、40℃、60℃)、湿度(75％RH、90％RH)以及复合条件60℃+75％RH对晶型的影响，结果如下表：
表1 盐酸沃尼妙林水合物与无定形物、对比例晶型稳定性比较研究
Figure PCTCN2019117679-appb-000002
Figure PCTCN2019117679-appb-000003
从表1可知，水合物晶型稳定，含量没有发生变化，而无定形物吸湿严重，高温下含量下降非常严重，并且变色。专利CN104876841B晶型略有吸湿性，高温高湿下略有变色。
对水合物晶型与无定形物及专利CN104876841B晶型进行堆密度、溶解度等方面进行对比研究，如下表：
表2 盐酸沃尼妙林水合物晶型与无定形物及对比例晶型理化性质对比
API 堆密度 引湿性 溶解度
盐酸沃尼妙林无定形物 0.338g/ml 8.86％ 1g/9ml水
对比例晶型 0.636g/ml 1.015％ 1g/49ml水
盐酸沃尼妙林水合物晶型(实施例1) 0.596g/ml 0％ 1g/28.9ml水
从表2可知，水合物堆密度增大近一倍，刺激性也随之减小。在API生产、包装上比无定形物更方便、易操作。进一步的给后期制剂工艺操作也带来方便。溶解度虽然较无定形态有所下降，但完全能够满足临床用药需求。与CN104876841B晶型对比结果显示，盐酸沃尼妙林水合物晶型在引湿性及溶解度方面均明显优于CN104876841B晶型。
综上所述，本申请所得的盐酸沃尼妙林水合物晶型，含量、外观及晶型等均无明显变化，稳定性良好。与无定形物及专利CN104876841B晶型相比，水合物有更好的堆密度，且无吸湿性，可以更好的应用到制剂中。
本申请提出的一种盐酸沃尼妙林水合物晶型及其制备方法已通过实施例进行了描述，应当理解，这些描述只是为进一步说明本申请的特征和优点，而不是对本申请权利要求的限制。

Claims (12)

  1. 一种盐酸沃尼妙林水合物晶型，在所述水合物晶型的用CuKa射线测量得到的X射线粉末衍射图中，特征峰2θ在9.2±0.2°、9.5±0.2°、10.3±0.2°、11.8±0.2°、12.3±0.2°、12.8±0.2°、15.1±0.2°、17.5±0.2°和18.2±0.2°处有特征峰。
  2. 根据权利要求1所述的盐酸沃尼妙林水合物晶型，其中，在所述水合物晶型的用CuKa射线测量得到的X射线粉末衍射图中，特征峰还包括2θ为4.4±0.2°、12.6±0.2°、14.4±0.2°、14.6±0.2°、16.5±0.2°、17.9±0.2°、18.7±0.2°、25.8±0.2°、28.7±0.2°中的一个或多个。
  3. 根据权利要求1或2所述的盐酸沃尼妙林水合物晶型，其中，所述水合物晶型的DSC图在120±5℃处有吸热峰。
  4. 根据权利要求1或2所述的盐酸沃尼妙林水合物晶型，其中，所述水合物晶型的水分含量为0.01％-8％。
  5. 根据权利要求4所述的盐酸沃尼妙林水合物晶型，其中，所述水合物晶型的水分含量为0.1％-7％。
  6. 根据权利要求1-5中任一项所述的盐酸沃尼妙林水合物晶型的制备方法，其包括以下步骤：
    (1)将盐酸沃尼妙林在有机溶剂/纯化水的混合液中于20-60℃进行热溶解；
    (2)保温搅拌0.5-1h，-5-15℃降温，从混合液中析出结晶；
    (3)过滤得滤饼A；
    (4)将滤饼A在20-40℃真空干燥，得滤饼B；
    (5)将步骤(3)所得滤饼A在不良溶剂中进行搅拌平衡6-20h，过滤，20-60℃真空干燥得到水合物晶体；或，将步骤(4)所得滤饼B于65-95％湿度下进行加湿处理12-48h，得到水合物晶体。
  7. 根据权利要求6所述的制备方法，其中，所述有机溶剂选自酯类、酮类、醇类、呋喃类、乙腈溶剂中的一种或多种；所述的不良溶剂选自烷烃溶剂、芳香烃类、醚类溶剂或水中的一种或多种。
  8. 根据权利要求7所述的制备方法，其中，所述有机溶剂选自乙酸乙酯、丙酮、异丙醇、正丁醇、叔丁醇、甲醇、乙醇、四氢呋喃或乙腈中的一种或多种；所述不良溶剂选自正己烷、环己烷、正庚烷、乙醚、二甲基醚、二异丙基醚、甲基叔丁基醚、甲苯或水中的一种或多种。
  9. 根据权利要求6所述的制备方法，其中，所述盐酸沃尼妙林原料药与有机溶剂/纯化水混合液的重量体积比为1:1-1:10；所述的有机溶剂与纯化水的体积比为2:4-3:2；所述盐酸沃尼 妙林原料药与不良溶剂的重量体积比为1:2-1:15。
  10. 一种药物组合物，所述药物组合物中含有如权利要求1-5中任意一项所述的盐酸沃尼妙林水合物晶型。
  11. 根据权利要求10所述的药物组合物，其中，所述药物组合物是所述盐酸沃尼妙林水合物晶型与其他盐酸沃尼妙林晶型的混合物；
    或，所述药物组合物还含有一种或一种以上药学上可接受的载体和/或赋形剂。
  12. 权利要求1-5中任意一项所述的盐酸沃尼妙林水合物晶型或权利要求10-11中任意一项所述的药物组合物在制备药物制剂中的应用。
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