Investigation of a Palbociclib and Naringin Co-Amorphous System to Ameliorate Anticancer Potential: Insights on <i>In Silico Modeling,</i> Physicochemical Characterization, <i>Ex Vivo</i> Permeation, and <i>In Vitro</i> Efficacy

Palbociclib (PCB), categorized as a BCS class II drug, is characterized by low aqueous solubility. The drug's limited aqueous solubility and poor dissolution rate pose significant challenges, potentially affecting its absorption and overall therapeutic efficacy. Co-amorphous (CAM) systems have been extensively investigated as a potential solution to overcome the issue of poor water solubility in numerous active pharmaceutical ingredients. This research study hypothesized that the coamorphization process involving the compounds PCB and naringin (NG) would lead to an increase in the aqueous solubility of PCB. Additionally, it was proposed that this process would also enhance the anticancer impact of PCB since NG is recognized for its pharmacological impact on breast cancer cells. <i>In silico</i> studies, it was revealed that PCB could interact with NG via hydrogen bonding. Furthermore, the prepared CAM (PCB-NG-CAM) system using PCB and NG was characterized by PXRD, DSC, FTIR, Raman spectroscopy, solid-state ¹³C nuclear magnetic resonance, and SEM. PCB-NG-CAM exhibited a significant increase in solubility, dissolution rate, and intestinal permeation compared to crystalline PCB. Furthermore, PCB-NG-CAM exhibited excellent physical stability at 40 °C/75% RH for up to 3 months. In addition, PCB-NG-CAM showed superior <i>in vitro</i> efficacy on MDA-MB-231 triple-negative breast cancer cell lines. PCB-NG-CAM resulted in a 2.24 times higher apoptosis rate and a 1.6 times greater ROS production than free PCB. Additionally, the inhibitory effect on cell migration and alterations in MMP was more pronounced in cells treated with PCB-NG-CAM. Therefore, this study indicated that PCB-NG-CAM has the potential to significantly improve the oral administration, solubility, and therapeutic efficacy of PCB.