本文選題：阿昔洛韋 + 鹽酸伐昔洛韋　； 參考：《浙江理工大學(xué)》2017年碩士論文

【摘要】：藥物的多晶型可直接影響原料藥和制劑的生產(chǎn)及質(zhì)量,進而影響藥物制劑的生物利用度和臨床療效,故對藥物晶型的研究已成藥物研究開發(fā)過程的重要內(nèi)容。洛韋類抗病毒藥物存在復(fù)雜的多晶型現(xiàn)象,目前報道的有6種阿昔洛韋晶型,7種鹽酸伐昔洛韋晶型。在臨床應(yīng)用中,洛韋類藥物仍然存在一定的質(zhì)量和療效不穩(wěn)定現(xiàn)象,所以更全面地研究洛韋類藥物的晶型,尋找優(yōu)勢晶型有利于提高藥品質(zhì)量。本文以洛韋類抗病毒藥物——阿昔洛韋和鹽酸伐昔洛韋為研究對象,針對不同藥物晶型的制備工藝、晶型篩選等問題進行了深入研究。首先優(yōu)化了阿昔洛韋三分之二水合物的制備工藝,提高了產(chǎn)品的晶型純度和產(chǎn)率;其次系統(tǒng)地研究了鹽酸伐昔洛韋的水合物和無水晶型,確認(rèn)了各晶型產(chǎn)品的制備工藝條件;最后通過晶型篩選,發(fā)現(xiàn)了一種鹽酸伐昔洛韋的半水合物新晶型,并研究了該新晶型的穩(wěn)定性。具體內(nèi)容如下:(1)采用加入氫氧化鈉調(diào)節(jié)pH值的方式增大了阿昔洛韋在水中的溶解度,過程中阿昔洛韋成鹽,再以冰醋酸破鹽,優(yōu)化了阿昔洛韋三分之二水合物的晶型制備工藝;再通過X射線衍射、熱分析等技術(shù)表征該晶型產(chǎn)品,結(jié)果證明上述工藝條件能有效提高晶型純度并提高純晶型產(chǎn)率。同時測定了本研究所制備晶型的穩(wěn)定性,結(jié)果表明其在高溫、高濕及強光照條件下均具有良好的穩(wěn)定性。另外,相比于傳統(tǒng)工藝,新工藝得到的晶型粒度更大,流動性更好,更加便于制劑加工。(2)通過調(diào)控溶劑體系、水含量、投料方式、降溫速度和干燥時間等工藝條件,得到四種鹽酸伐昔洛韋晶型,分別為I,II,V和VII;再通過X射線衍射、熱分析等技術(shù)確認(rèn)產(chǎn)物的晶型歸屬,并探討了各晶型結(jié)構(gòu)間的差異,建立了各晶型分析鑒別的方法。(3)采用重結(jié)晶法展開新晶型的篩選研究,最終以乙二醇為良溶劑,在異丙醇與三氯甲烷的混合溶媒體系中成功制備出一種鹽酸伐昔洛韋的新晶型IX。該晶型的X衍射特征峰對應(yīng)的2θ為3.5°,6.9°,7.9°,8.5°,9.3°,13°,14.4°,16.3°,20.0°,23.5°,24.5°,27.2°,熔點約為197°C,失重率約為2.42%,經(jīng)計算為半水合物,即每兩個鹽酸伐昔洛韋分子與一個水分子構(gòu)成一個不對稱單元。同時了進行新晶型的穩(wěn)定性實驗,結(jié)果表明其在高溫高濕條件下具有良好的穩(wěn)定性。另外,表觀溶解度實驗表明無水晶型的表觀溶解度優(yōu)于水合物,且新晶型的表觀溶解度數(shù)值最低,說明其在實驗條件下是最穩(wěn)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 擄/ 6.9 擄/ 7.9 擄/ 8.5 擄/ 9.3 擄/ 13 擄/ 14.4 擄/ 14.4 擄/ 14.3 擄/ 16.3 擄/ 20. 0 擄/ 20. 0 擄/ 23.5 擄/ 24.5 擄/ 27.2 擄, melting point of about 197 擄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.
【學(xué)位授予單位】：浙江理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：TQ460.1

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