Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109-1065.
J Pharm Sci. 2018 Jan;107(1):113-120. doi: 10.1016/j.xphs.2017.10.033. Epub 2017 Oct 31.
This work challenges the popular notion that pharmaceutical salts are more soluble than cocrystals. There are cocrystals that are more soluble than salt forms of a drug and vice-versa. It all depends on the interplay between the chemistry of both the solid and solution phases. Aqueous solubility, pH, and supersaturation index (SA = S/S or S/S) of cocrystals and salts of a basic drug, lamotrigine (LTG), were determined, and mathematical models that predict the influence of cocrystal/salt K and K were derived. K and SA followed the order LTG-nicotinamide cocrystal (18) > LTG-HCl salt (12) > LTG-saccharin salt (5) > LTG-methylparaben cocrystal (1) > LTG-phenobarbital cocrystal (0.2). The values in parenthesis represent SA under nonionizing conditions. Cocrystal/salt solubility and thermodynamic stability are determined by pH and will drastically change with a single unit change in pH. pH values ranged from 5.0 (saccharin salt) to 6.4 (methylparaben cocrystal) to 9.0 (phenobarbital cocrystal). Cocrystal/salt pH dependence on pK and pK shows that cocrystals and salts exhibit different behavior. Solubility and pH are as important as supersaturation index in assessing the stability and risks associated with conversions of supersaturating forms.
这项工作挑战了一个普遍的观点，即药物盐比共晶更易溶。有些共晶比药物的盐形式更易溶解，反之亦然。这完全取决于固相与溶液相之间的化学相互作用。测定了一种碱性药物拉莫三嗪（LTG）的共晶和盐的水溶解度、pH 值和过饱和度指数（SA=S/S 或 S/S），并推导出了预测共晶/盐 K 和 K 影响的数学模型。K 和 SA 遵循以下顺序：LTG-烟酰胺共晶（18）>LTG-HCl 盐（12）>LTG-糖精盐（5）>LTG-对羟基苯甲酸甲酯共晶（1）>LTG-苯巴比妥共晶（0.2）。括号中的值表示非电离条件下的 SA。共晶/盐的溶解度和热力学稳定性由 pH 值决定，pH 值的微小变化会导致其发生剧烈变化。pH 值范围从 5.0（糖精盐）到 6.4（对羟基苯甲酸甲酯共晶）到 9.0（苯巴比妥共晶）。共晶/盐对 pK 和 pK 的 pH 值依赖性表明，共晶和盐表现出不同的行为。在评估过饱和形式的稳定性和相关风险时，溶解度和 pH 值与过饱和度指数一样重要。
