Impact of Drug-Polymer Interactions on Stability in Simvastatin-Based Amorphous Solid Dispersions

This study aimed to investigate the drug-polymer interactions between simvastatin (SIM) and three polymers [PVP-VA, HPMC-AS, and Soluplus® (SOL)] in amorphous solid dispersions (ASDs) prepared by hot melt extrusion (HME), and to understand the implications on physical stability. ASDs are of significant interest within the pharmaceutical industry for improving drug bioavailability. However, the amorphous nature of a drug in an ASD presents physical stability challenges. Utilizing novel applications of accessible tools such as ATR-FTIR or DSC aid in understanding the mechanisms of stabilization which are critical to the rational design of ASDs. ASDs were prepared using HME and were characterized using mDSC, ATR-FTIR, TGA, PXRD, PLM, and UPLC. Mathematical processing of ATR-FTIR spectra and Pearson coefficient analysis was used to quantitatively determine the degree of intermolecular bonds between SIM and each polymer. Results were verified using experimental and theoretical approaches such as mDSC and Flory-Huggins Theory. Formulations were stored at 50°C/96%RH, and physical stability was monitored using PXRD, PLM, and mDSC. Pearson coefficient analysis of ATR-FTIR data showed that SIM exhibited a higher degree of interactions with PVP-VA and SOL relative to HPMC-AS. Experimental observations and theoretical calculations of SIM miscibility and solubility in the polymers were used as an indicator of intermolecular interactions, and both were consistent with this ranking of drug-polymer interactions. Stability assessments at 50°C/96%RH demonstrated SIM crystallization in all PVP-VA ASDs and in high SIM load HPMC-AS ASDs, while no crystallization was observed in SOL ASDs. This demonstrated that although the degree of interactions between SIM and PVP-VA were the strongest, the extent of interactions between water and PVP-VA may also play a critical role in the ASD physical stabilization. In addition, although SIM/SOL systems were the lowest overall in glass transition temperature and may perhaps have the highest degree of molecular mobility, the interactions between SOL and SIM were sufficient to inhibit crystallization. These findings highlight the utility of applying Pearson coefficient analysis to accessible tools such as ATR-FTIR on the understanding of drug-polymer interactions in ASDs. While drug-polymer interactions are a significant factor in maintaining SIM’s amorphous nature, other mechanisms of physical stabilization need to be considered in the rational design of ASDs.