药物溶解度的改善是开发药物产品的主要挑战。先前已证明,弱碱性药物的水溶性可以通过与不会与药物形成盐的弱酸相互作用而大大增加,并且由此产生的高度浓缩的溶液在干燥时转化为无定形固体。该技术被称为酸碱超溶解(ABS)。当前的研究探索了ABS原理是否也可以应用于弱酸性药物。以氟比洛芬(pKa4.09;游离酸溶解度0.011mg/mL)为模型弱酸性药物和氨丁三醇,赖氨酸,葡甲胺,和NaOH作为碱,研究了哪种基础会导致ABS。在NaOH和氨丁三醇的存在下,氟比洛芬转化为水溶性为11-19mg/mL的盐,赖氨酸的溶解度增加到>399mg/mL,葡甲胺的溶解度增加到>358mg/mL,产生超溶解。然而,随着时间的推移,观察到赖氨酸盐的结晶,随后与赖氨酸达到最大溶解度后溶解度有所下降。相比之下,用葡甲胺维持超溶解,并且没有观察到葡甲胺盐的结晶。干燥后,氟比洛芬-葡甲胺溶液产生的无定形物质在水性介质中迅速溶解并产生高药物浓度。因此,ABS原理也适用于酸性药物,具体取决于所用的弱碱。
Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pKa 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine,
lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11-19 mg/mL, the solubility increased to > 399 mg/mL with
lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of
lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with
lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.