Harnessing dicarboxylate-based salts for enhancing the performance of amorphous solid dispersions: The case of olanzapine

Abstract

Previous studies have shown that the use of dicarboxylic acid salts can improve the performance of drug amorphous solid dispersions (ASDs), such as in the case of olanzapine (OLN). However, these studies focused only on the use of limited ASD matrices/carriers, e.g. polyvinyl alcohol, overlooking thus the critical impact of their selection on the drug's physical stability and dissolution performance. This study evaluates the performance of ASDs containing fumarate (FUM) and succinate (SUC) drug salts in comparison to ASDs prepared with the drug base, by utilizing the same model drug (i.e., OLN) and various ASD matrices/carriers. Results revealed that inappropriate matrix/carrier selection, even with the more stable amorphous drug salts, led to physical instability (i.e., drug recrystallization) during long term storage. Specifically, only certain matrices/carriers, such as Soluplus® (SOL) for OLN_SUC, copovidone (PVPVA64) or hydroxypropyl cellulose (HPC-SL) for OLN_FUM, and povidone (PVP) for OLN base, were effective in preventing drug recrystallization after three months of storage. Molecular interactions, supported by differential scanning calorimetry (DSC), attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and molecular dynamics (MD) simulations, demonstrated strong hydrogen bonds between OLN molecules (base and salts) and specific matrices/carriers, contributing to the system's physical stability. Dissolution studies conducted under non-sink conditions further highlighted the importance of matrix/carrier selection for drug supersaturation, with OLN_FUM and OLN_SUC ASDs showing superior performance (higher degree of supersaturation) compared to OLN in its base form. However, all OLN_FUM formulations, as well as OLN_SUC-based ASDs with SOL, showed significant physical instability during solubilization, leading to API's recrystallization in the precipitates collected after dissolution - a pitfall that was not observed in ASD prepared with OLN base and SOL. Hence, the obtained results highlight the necessity of extensive pre-formulation and formulation studies in the preparation of ASDs for various poorly water-soluble drugs (such as OLN) before suggesting dicarboxylate-based drug salts as a one-size-fits-all solution.

Keywords: Amorphous solid dispersions; Dicarboxylic acid salts; Matrix/carriers; Olanzapine; Physical stability; Supersaturation.