Improvement of physicochemical parameters of acyclovir using cocrystallization approach

ABSTRACT Acyclovir is an antiviral drug having potent activity against the virus of herpes family and varicella zoster. Unfortunately, drug suffers very poor oral bioavailability (15-30%). The main objective of present study was to develop acyclovir cocrystals with improved solubility which may result in improvement of bioavailability. Hansen solubility approach was used as a tool to predict the cocrystal formation of a drug with selected coformer. Cocrystals of acyclovir with various coformers were screened in order to enhance their water solubility. Cocrystals of the drug were prepared using various methods like solvent evaporation, wet grinding, and antisolvent addition. Formation of cocrystals by solvent evaporation method was found to be better method amongst all. Optimization of cocrystal formation was carried out by employing different solvents as well as the stoichiometric ratio of acyclovir with that of coformer. Synthesis of cocrystals was optimized using water as a solvent system resulted in good agreements. The potential cocrystal formation of acyclovir was characterized by IR, PXRD and DSC techniques. An in-vitro dissolution study was performed to determine the dissolution rate of cocrystals. The results suggest that acyclovir forms cocrystals with tartaric acid and the initial dissolution rate of synthesized cocrystals were considerably faster as compared to pure acyclovir.摘要：阿昔洛韦（acyclovir）是一类对疱疹科病毒及水痘带状疱疹病毒（varicella zoster）具有强效抗病毒活性的药物。然而该药物存在口服生物利用度极低的缺陷，仅为15%~30%。本研究的核心目标是制备阿昔洛韦共晶以提升其溶解度，进而改善药物的生物利用度。研究采用汉森溶解度法（Hansen solubility approach）作为工具，预测药物与选定共晶形成物（coformer）的共晶形成可行性。为提升阿昔洛韦的水溶性，研究人员对阿昔洛韦与多种共晶形成物的共晶体系进行了筛选。通过溶剂蒸发法、湿磨法及反溶剂添加法等多种手段制备了阿昔洛韦共晶，其中溶剂蒸发法被证实为所有方法中效果最优的制备方式。研究通过调节溶剂种类及阿昔洛韦与共晶形成物的化学计量比，对共晶的制备工艺进行了优化，其中以水作为溶剂体系的优化方案取得了良好的实验一致性结果。采用红外光谱（IR）、X射线粉末衍射（PXRD）及差示扫描量热法（DSC）技术对潜在的阿昔洛韦共晶进行了表征。通过体外溶出试验测定了共晶的溶出速率，结果表明：阿昔洛韦可与酒石酸形成共晶，且所合成共晶的初始溶出速率显著快于纯阿昔洛韦。