Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
in-ADME Research, 1732 First Avenue #102, New York, NY 10128, USA.
Int J Pharm. 2024 Sep 30;663:124548. doi: 10.1016/j.ijpharm.2024.124548. Epub 2024 Aug 2.
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 (pK 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.
提高药物溶解度是开发药物产品的主要挑战。早期的研究表明，通过与不会与药物形成盐的弱酸相互作用，可以大大提高弱碱性药物的水溶解度，并且如此产生的高浓度溶液在干燥时会转化为无定形固体。该技术称为酸碱超增溶（ABS）。本研究探讨了 ABS 原理是否也可应用于弱酸性药物。以氟比洛芬（pK4.09；游离酸溶解度 0.011mg/mL）为模型弱酸性药物，以三羟甲基氨基甲烷、赖氨酸、葡甲胺和 NaOH 为碱，研究哪种碱会导致 ABS。当存在 NaOH 和三羟甲基氨基甲烷时，氟比洛芬转化为水溶解度为 11-19mg/mL 的盐，而与赖氨酸和葡甲胺一起则溶解度增加至>399mg/mL 和>358mg/mL，从而产生超增溶。然而，赖氨酸盐随着时间的推移会发生结晶，在达到最大溶解度后溶解度会有所下降。相比之下，葡甲胺盐的超增溶得以维持，并且没有观察到葡甲胺盐的结晶。干燥后，氟比洛芬-葡甲胺溶液产生无定形物质，在水介质中迅速溶解并产生高药物浓度。因此，ABS 原理也适用于取决于弱碱使用情况的酸性药物。
