Shah S P, Flanagan D R
Searle Research and Development, Stokie, IL 60077.
J Pharm Sci. 1990 Oct;79(10):889-92. doi: 10.1002/jps.2600791009.
The effect of self-association of the antihistaminic drugs pheniramine, chlorpheniramine, and brompheniramine as their maleate salts on the solubilization of salicylamide and acetaminophen in aqueous solution has been investigated. The total solubility of salicylamide increased nonlinearly at lower antihistamine concentrations (less than 0.4 M), but reached limiting linearity (slope = 0.34 mol/mol of antihistamine) at higher concentrations (up to 0.8 M). Salicylamide solubility increases are approximately 10-fold at high concentrations (0.6-0.8 M) of antihistamine, while acetaminophen solubility increases are about fivefold at similar antihistamine concentrations. The solubilization data were analyzed with a stepwise self-association model. Based on a dimer model, the experimental and theoretical log excess salicylamide solubility profiles were in good agreement (r2 = 0.982) except at the lowest chlorpheniramine maleate concentrations. Such deviation at the lowest concentrations increased when trimer and 11-mer models were utilized. To account for this deviation, a monomer-dimer model based on interaction with both the chlorpheniramine maleate monomer and dimer was proposed. This model was in excellent agreement (r2 = 0.996) with the solubility data.
已研究了抗组胺药非尼拉敏、氯苯那敏和溴苯那敏的马来酸盐自身缔合对水杨酰胺和对乙酰氨基酚在水溶液中增溶作用的影响。在较低抗组胺药浓度（小于0.4 M）时，水杨酰胺的总溶解度呈非线性增加，但在较高浓度（高达0.8 M）时达到极限线性（斜率 = 0.34 mol/mol抗组胺药）。在高浓度（0.6 - 0.8 M）抗组胺药条件下，水杨酰胺的溶解度增加约10倍，而在相似抗组胺药浓度下，对乙酰氨基酚的溶解度增加约5倍。用逐步自缔合模型分析了增溶数据。基于二聚体模型，除了在最低的马来酸氯苯那敏浓度下，实验和理论的过量水杨酰胺溶解度对数曲线吻合良好（r2 = 0.982）。当使用三聚体和11聚体模型时，最低浓度下的这种偏差会增大。为了解释这种偏差，提出了一种基于与马来酸氯苯那敏单体和二聚体相互作用的单体 - 二聚体模型。该模型与溶解度数据吻合极佳（r2 = 0.996）。
