Raloxifene HCl – Naringin co-amorphous system: Preparation, characterization and pharmacokinetic studies

Abstract

Approximately 90 % of NCEs in development and 40 % of recently approved drugs are poorly water-soluble. To improve solubility and stability, co-amorphous systems (CAMs) are used, involving the amorphization of an API with a co-former through interactions like hydrogen bonding. This study explores the co-amorphization of Raloxifene HCl (RLX) and Naringin (NRG). RLX, a BCS class II drug, has limited oral bioavailability of only 2 % due to its poor solubility (0.5 μg/mL) and extensive pre-systemic metabolism. Additionally, it interacts with CYP3A4 and P-glycoprotein (P-gp). NRG, a compound found in citrus fruits, inhibits both CYP3A4 and P-gp. Therefore, utilizing NRG to prepare RLX CAMs could result in a compound with improved solubility and enhanced bioavailability. CAMs were prepared using the solvent evaporation technique, followed by solid-state characterization at the molecular level. Solubility, drug release, and both ex vivo and in vitro studies were conducted. CAMs showed a 3.5-fold solubility increase and a 10-fold increase in ex-vivo permeation compared to RLX. In vivo studies showed an 8.1-fold improvement in Cmax and a 2.8-fold increase in AUC, indicating significantly enhanced bioavailability. These results suggest that co-amorphization could be a viable platform technology for improving API properties at the molecular level.