洛韦类抗病毒药物的晶型研究

发布时间：2018-05-12 02:20

本文选题：阿昔洛韦 + 盐酸伐昔洛韦　；参考：《浙江理工大学》2017年硕士论文

【摘要】：药物的多晶型可直接影响原料药和制剂的生产及质量,进而影响药物制剂的生物利用度和临床疗效,故对药物晶型的研究已成药物研究开发过程的重要内容。洛韦类抗病毒药物存在复杂的多晶型现象,目前报道的有6种阿昔洛韦晶型,7种盐酸伐昔洛韦晶型。在临床应用中,洛韦类药物仍然存在一定的质量和疗效不稳定现象,所以更全面地研究洛韦类药物的晶型,寻找优势晶型有利于提高药品质量。本文以洛韦类抗病毒药物——阿昔洛韦和盐酸伐昔洛韦为研究对象,针对不同药物晶型的制备工艺、晶型筛选等问题进行了深入研究。首先优化了阿昔洛韦三分之二水合物的制备工艺,提高了产品的晶型纯度和产率;其次系统地研究了盐酸伐昔洛韦的水合物和无水晶型,确认了各晶型产品的制备工艺条件;最后通过晶型筛选,发现了一种盐酸伐昔洛韦的半水合物新晶型,并研究了该新晶型的稳定性。具体内容如下:(1)采用加入氢氧化钠调节pH值的方式增大了阿昔洛韦在水中的溶解度,过程中阿昔洛韦成盐,再以冰醋酸破盐,优化了阿昔洛韦三分之二水合物的晶型制备工艺;再通过X射线衍射、热分析等技术表征该晶型产品,结果证明上述工艺条件能有效提高晶型纯度并提高纯晶型产率。同时测定了本研究所制备晶型的稳定性,结果表明其在高温、高湿及强光照条件下均具有良好的稳定性。另外,相比于传统工艺,新工艺得到的晶型粒度更大,流动性更好,更加便于制剂加工。(2)通过调控溶剂体系、水含量、投料方式、降温速度和干燥时间等工艺条件,得到四种盐酸伐昔洛韦晶型,分别为I,II,V和VII;再通过X射线衍射、热分析等技术确认产物的晶型归属,并探讨了各晶型结构间的差异,建立了各晶型分析鉴别的方法。(3)采用重结晶法展开新晶型的筛选研究,最终以乙二醇为良溶剂,在异丙醇与三氯甲烷的混合溶媒体系中成功制备出一种盐酸伐昔洛韦的新晶型IX。该晶型的X衍射特征峰对应的2θ为3.5°,6.9°,7.9°,8.5°,9.3°,13°,14.4°,16.3°,20.0°,23.5°,24.5°,27.2°,熔点约为197°C,失重率约为2.42%,经计算为半水合物,即每两个盐酸伐昔洛韦分子与一个水分子构成一个不对称单元。同时了进行新晶型的稳定性实验,结果表明其在高温高湿条件下具有良好的稳定性。另外,表观溶解度实验表明无水晶型的表观溶解度优于水合物,且新晶型的表观溶解度数值最低,说明其在实验条件下是最稳定的晶型。
[Abstract]:The polycrystalline form of drugs can directly affect the production and quality of raw materials and preparations, and then affect the bioavailability and clinical efficacy of drug preparations. Therefore, the study of drug crystal form has become an important content in the process of drug research and development. There are 6 kinds of acyclovir crystal forms and 7 valaciclovir hydrochloric acid crystal forms. In clinical application, there is still instability in the quality and curative effect of lovir drugs, so it is beneficial to improve the quality of drugs to study the crystal form of lovir drugs more comprehensively and to find the dominant crystal form. In this paper, acyclovir and valaciclovir hydrochloride were used as the research objects. Firstly, the preparation process of acyclovir 2/3 hydrate was optimized to improve the crystal purity and yield of the product, secondly, the hydrate and crystal free type of valaciclovir hydrochloride were studied systematically, and the preparation conditions of each crystal product were confirmed. Finally, a new crystal form of valaciclovir hydrochloride hemihydrate was found by screening the crystal form, and the stability of the new crystal form was studied. The specific contents are as follows: (1) the solubility of acyclovir in water was increased by adding sodium hydroxide to adjust pH value. During the process, acyclovir salt was formed, and then the glacial acetic acid was used to break the salt to optimize the preparation process of acyclovir 2/3 hydrate. The product was characterized by X-ray diffraction and thermal analysis. The results show that the above process conditions can effectively improve the purity of crystal form and the yield of pure crystal form. At the same time, the stability of crystal form was determined. The results showed that the stability was good under the conditions of high temperature, high humidity and strong illumination. In addition, compared with the traditional process, the new process has larger grain size, better fluidity and easier preparation processing. The process conditions such as solvent system, water content, feeding mode, cooling rate and drying time are regulated. Four kinds of valciclovir hydrochloric acid crystal forms were obtained, which were Ignia IIV and VII.The crystal forms of the products were confirmed by X-ray diffraction and thermal analysis, and the differences among the crystal structures were discussed. A new crystal form IX of valciclovir hydrochloride was successfully prepared in the mixed solvent system of isopropanol and chloroform with ethylene glycol as a good solvent by recrystallization method. The X ray diffraction characteristic peak of this crystal form is 2 胃 corresponding to 3.5 掳/ 6.9 掳/ 7.9 掳/ 8.5 掳/ 9.3 掳/ 13 掳/ 14.4 掳/ 14.4 掳/ 14.3 掳/ 16.3 掳/ 20. 0 掳/ 20. 0 掳/ 23.5 掳/ 24.5 掳/ 27.2 掳, melting point of about 197 掳C and weight loss rate of 2.42%. The calculated results show that the crystal form an asymmetrical unit between each two valaciclovir hydrochloride molecules and one water molecule by the calculation of the half-hydrate, I. E. faciclovir hydrochloride molecule and one water molecule. At the same time, the stability experiment of the new crystal form is carried out. The results show that it has good stability under the condition of high temperature and high humidity. In addition, the apparent solubility experiment shows that the apparent solubility of the crystal free form is better than that of the hydrate, and the apparent solubility of the new crystal form is the lowest, which indicates that it is the most stable crystal form under the experimental conditions.
【学位授予单位】：浙江理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ460.1

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