Stella V J, Martodihardjo S, Terada K, Rao V M
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, 66047, USA.
J Pharm Sci. 1998 Oct;87(10):1235-41. doi: 10.1021/js980008v.
Physicochemical properties of neutral N-acyloxyalkyl derivatives of phenytoin in aqueous, organic solvents and simulated intestinal fluid were evaluated. Based on the hypothesis that these low melting prodrugs may have improved physical properties such as solubility and dissolution rate in gastrointestinal fluid, an enhanced bioavailability of these prodrugs may be observed relative to phenytoin. Melting points, aqueous solubilities, and octanol-water (Poct) and cylcohexane-water (Pcyc) partition coefficients of phenytoin and its prodrugs were determined. A simulated intestinal bile salts-lecithin mixture (SIBLM) was also prepared to possibly mimic the intestinal fluid content. Solubility and dissolution rates of phenytoin and its prodrugs were conducted in aqueous buffer and SIBLM. Apparent micelle-water partition coefficients (Kapp) were calculated by using the aqueous and SIBLM equilibrium solubility data. These properties were qualitatively or quantitatively correlated to the alkyl chain length of the prodrugs. The melting points and aqueous solubilities of all the prodrugs were lower than that of the parent compound, phenytoin. The apparent micelle-water partition coefficient increased with an increase in chain length but unlike the octanol-water and cyclohexane-water partition coefficients the relationship was complex. There was a disproportionate increase in the interaction between the micelle and the prodrug with the prodrugs with alkyl groups larger than four carbons. In SIBLM, the solubilities and dissolution rates were increased to a greater extent for the prodrugs than that for phenytoin. The implications are that the bioavailability of phenytoin from these prodrugs may be comparable to or higher than that of phenytoin despite having lower aqueous solubilities, especially after a meal inducing bile flow.
对苯妥英的中性N-酰氧基烷基衍生物在水性溶剂、有机溶剂和模拟肠液中的物理化学性质进行了评估。基于这些低熔点前药可能具有改善的物理性质（如在胃肠液中的溶解度和溶解速率）这一假设，相对于苯妥英，可能会观察到这些前药的生物利用度有所提高。测定了苯妥英及其前药的熔点、水溶性、正辛醇-水（Poct）和环己烷-水（Pcyc）分配系数。还制备了模拟肠胆汁盐-卵磷脂混合物（SIBLM）以模拟肠液成分。在水性缓冲液和SIBLM中测定了苯妥英及其前药的溶解度和溶解速率。通过使用水性和SIBLM平衡溶解度数据计算表观胶束-水分配系数（Kapp）。这些性质与前药的烷基链长度存在定性或定量的相关性。所有前药的熔点和水溶性均低于母体化合物苯妥英。表观胶束-水分配系数随链长增加而增加，但与正辛醇-水和环己烷-水分配系数不同，其关系较为复杂。对于烷基大于四个碳的前药，胶束与前药之间的相互作用增加不成比例。在SIBLM中，前药的溶解度和溶解速率比苯妥英提高的程度更大。这意味着尽管这些前药的水溶性较低，但尤其是在进食诱导胆汁流动后，它们的生物利用度可能与苯妥英相当或更高。
