School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing 210009, China.
Int J Pharm. 2012 Nov 15;438(1-2):327-35. doi: 10.1016/j.ijpharm.2012.09.027. Epub 2012 Sep 16.
Adefovir dipivoxil (AD) is a bis(pivaloyloxymethyl) prodrug of adefovir with chemical stability problem. It undergoes two degradation pathways including hydrolysis and dimerization during storage. Pharmaceutical cocrystallization exhibits a promising approach to enhance aqueous solubility as well as physicochemical stability. In this study we attempted to prepare and investigate the physiochemical properties of AD cocrystals, which were formed with two coformers having different acidity and alkalinity (weakly acidic saccharin (SAC) and weakly basic nicotinamide (NCT)). The presence of different coformer molecules along with AD resulted in altered physicochemical properties. AD-SAC cocrystal showed great improvement in solubility and chemical stability, while AD-NCT did not. Several potential factors giving rise to different solid-state properties were summarized. Different coformers resulted in different cocrystal formation, packing style and hydrogen bond formation. This study could provide the coformer selection strategy based on degradation pathways for some unstable drugs in pharmaceutical cocrystal design.
阿德福韦酯（AD）是阿德福韦的双（特戊酰氧甲基）前药，具有化学稳定性问题。它在储存过程中会经历两种降解途径，包括水解和二聚化。药物共晶化是一种提高水溶解度和物理化学稳定性的有前途的方法。在这项研究中，我们试图制备和研究 AD 共晶的物理化学性质，这些共晶是由具有不同酸度和碱度的两种共晶形成剂（弱酸性糖精（SAC）和弱碱性烟酰胺（NCT））形成的。不同共晶形成剂分子的存在与 AD 一起导致了物理化学性质的改变。AD-SAC 共晶在溶解度和化学稳定性方面有了很大的提高，而 AD-NCT 则没有。总结了导致不同固态性质的几个潜在因素。不同的共晶形成剂导致不同的共晶形成、堆积方式和氢键形成。这项研究可以为一些不稳定药物的药物共晶设计提供基于降解途径的共晶形成剂选择策略。
