Li P, Tabibi S E, Yalkowsky S H
The Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson 85721, USA.
J Pharm Sci. 1998 Dec;87(12):1535-7. doi: 10.1021/js9801889.
Both pH control and complexation are widely used as solubilization techniques in drug formulation studies. Although these two techniques are often utilized in combination, few theoretical studies have shown why the combined approach would work better than either one alone. This study constructs a background in which both the pH effect and complexation constants are used to explain the synergism between these techniques. The total solubility is determined by the addition of the concentrations of the four components present in the solution: free un-ionized drug [Du], free ionized drug [Di], un-ionized drug complex [DuL], and ionized drug complex [DiL]. A detailed description of [Di] and [DiL] reveals that the complexation constants and the pH at which the drug may ionize are both critical. The weakly basic drug flavopiridol is used as a test compound to examine the validity of the equation. Although the complexation constant for ionized flavopiridol (Ki = 124 M(-1)) is less than one-third of that of the un-ionized species (Ku = 445 M(-1)), the solubility of the ionized drug complex [DiL] is 6-fold greater than that of the un-ionized drug complex [DuL]. This unexpected result is due to the 25-fold greater solubility of the ionized drug [Di] at pH 4.3 over that of the free un-ionized species [Du] at pH 8.4. The results of this and other complexation studies of several drugs taken from the literature lend the support to the following: If [Di]/[Du] >Ku/Ki, then [DiL] >[DuL].
在药物制剂研究中，pH调节和络合作用作为增溶技术被广泛应用。尽管这两种技术经常联合使用，但很少有理论研究表明联合方法为何比单独使用任何一种方法效果更好。本研究构建了一个背景，其中pH效应和络合常数都被用来解释这些技术之间的协同作用。总溶解度由溶液中存在的四种成分的浓度相加确定：游离未电离药物[Du]、游离电离药物[Di]、未电离药物络合物[DuL]和电离药物络合物[DiL]。对[Di]和[DiL]的详细描述表明，络合常数和药物可能电离时的pH值都至关重要。弱碱性药物黄酮哌啶醇用作测试化合物以检验该方程的有效性。尽管电离黄酮哌啶醇的络合常数（Ki = 124 M(-1)）小于未电离物种（Ku = 445 M(-1)）的三分之一，但电离药物络合物[DiL]的溶解度比未电离药物络合物[DuL]大6倍。这一意外结果是由于在pH 4.3时电离药物[Di]的溶解度比在pH 8.4时游离未电离物种[Du]的溶解度大25倍。从文献中选取的几种药物的这项研究及其他络合研究结果支持以下观点：如果[Di]/[Du] > Ku/Ki，那么[DiL] > [DuL]。
