Determining the solubilities for benzoate, nicotinate, hydrochloride, and malonate salts of bedaquiline
Determining the solubilities for benzoate, nicotinate, hydrochloride, and malonate salts of bedaquiline
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DOI：
10.1016/j.ijpharm.2022.122229
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发表时间：
2022-09-29
影响因子：
5.8
通讯作者：
Clase, Kari L.
中科院分区：
文献类型：
--
作者：
Okezue, Mercy A.;Byrn, Stephen J.;Clase, Kari L.
测定化合物的溶解度对于预测其口服生物利用度、用于溶解的介质和制造过程中用于清洁的溶剂非常重要。对新合成的贝达喹啉的苯甲酸盐、盐酸盐、烟酸盐和丙二酸盐的溶解度进行了分析，并指出了它们在实验中溶解度差异的可能原因。采用摇瓶法测定贝达喹啉游离碱及各盐在水、0.01 N HCl、pH 6.8缓冲液中的实验溶解度。在理想和非理想情况下，用方程确定了盐的摩尔溶解度和摩尔分数。此外，还用图形预测了晶格和活度系数对盐的整体水溶性的相对贡献。新盐为盐酸[0.6437 mg/mL]、丙二酸盐[0.0268 mg/mL]、烟酸盐[0.0024 mg/mL]、苯甲酸盐[0.0004 mg/mL]，在游离碱上的溶解度有所提高。一般溶解度方程[GSE]可以很好地预测苯甲酸盐和丙二酸盐的溶解度，但理想溶解度方程不能很好地估计它们的实验值。根据理想溶解度估计，所有盐的晶格贡献为丙二酸盐b>烟酸盐b>盐酸b>苯甲酸盐。而通过活度系数的测定，贝达喹啉盐的疏水性顺序为：苯甲酸酯b>烟酸酯b>丙二酸酯b>盐酸。贝达喹啉的盐类由于其结晶性和疏水性提供了额外的溶解度。
Determining the solubility of a compound is important for predicting its oral bioavailability, the medium to be used for dissolution, and solvents for cleaning during manufacturing. The solubilities of the newly synthesized benzoate, hydrochloride, nicotinate, and malonate salts of bedaquiline were elucidated, and the plausible rea-sons for the differences observed in their experimental aqueous solubilities were highlighted.The shake flask method was used to determine the experimental solubilities of the bedaquiline free base and all the salts in water, 0.01 N HCl, and pH 6.8 buffer. The molar and mole fraction solubility estimates of the salts were determined using equations for ideal and non-ideal situations. Furthermore, the relative contribution of the lattice and activity coefficient to the overall aqueous solubility of the salts were predicted graphically.The new salts ranked hydrochloride [0.6437 mg/mL] > malonate [0.0268 mg/ml] > nicotinate [0.0024 mg/ mL] > benzoate [0.0004 mg/mL], showed improved aqueous solubility over the free base. The general solubility equation [GSE], fairly predicted the solubilities for the benzoate and malonate salts, but the ideal solubility equations provided poor estimates of their experimental values. Based on the ideal solubility estimates, the crystal lattice contributions of all salts were malonate > nicotinate > HCl > benzoate. However, using the ac-tivity coefficient values, the order of hydrophobicity of the bedaquiline salts was: benzoate > nicotinate > malonate > HCl.The salts forms of bedaquiline offered additional solubility as a function of their crystallinity and hydrophobicity.