Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
Department of Gastroenterology, General Hospital of Northern Theater Command (Formerly General Hospital of Shenyang Military Area), Shenyang, 110840, China.
AAPS J. 2024 Jul 15;26(4):83. doi: 10.1208/s12248-024-00949-z.
Salts of weakly basic drugs can partially dissociate in formulations, to give basic drugs and counter acids. The aim of the present study was to clarify the effect of physicochemical properties on the basic drug-acid-polymer interactions and salt-polymer miscibility, and to explain the influence mechanism at the molecular level. Six maleate salts with different physicochemical properties were selected and PVA was used as the film forming material. The relationship between the physicochemical properties and the miscibility was presented with multiple linear regression analysis. The existence state of salts in formulations were determined by XRD and Raman imaging. The stability of salts was characterized by NMR and XPS. The intermolecular interactions were investigated by FTIR and NMR. The results showed that the salt-PVA miscibility was related to polar surface area of salts and T of free bases, which represented hydrogen bond interaction and solubility potential. The basic drug-acid-PVA intermolecular interactions determined the existence state and bonding pattern of the three molecules. Meanwhile, the decrease of the stability after formulation increased the number of free bases in orodispersible films, which in turn affected the miscibility with PVA. The study provided references for the rational design of PVA based orodispersible films.
弱碱性药物的盐在制剂中可以部分解离,生成碱性药物和反离子酸。本研究旨在阐明物理化学性质对碱性药物-酸-聚合物相互作用和盐-聚合物混溶性的影响,并从分子水平上解释其影响机制。选择了 6 种具有不同物理化学性质的马来酸盐,以 PVA 为成膜材料。用多元线性回归分析了物理化学性质与混溶性的关系。用 XRD 和 Raman 成像确定了制剂中盐的存在状态。用 NMR 和 XPS 研究了盐的稳定性。用 FTIR 和 NMR 研究了分子间相互作用。结果表明,盐-PVA 的混溶性与盐的极表面积和游离碱的 T 有关,这代表氢键相互作用和溶解度潜力。碱性药物-酸-PVA 分子间相互作用决定了三种分子的存在状态和键合模式。同时,制剂后稳定性的降低增加了口腔分散片中外游离碱的数量,从而影响了与 PVA 的混溶性。该研究为基于 PVA 的口腔分散片的合理设计提供了参考。