Guiding excipient selection for physically stable Amorphous Solid Dispersions: A combined in-vitro in-silico approach

Abstract

Fast screening of amorphous solid dispersions (ASDs) is a need in the pharmaceutical industry. To support this, several emerging technologies have been developed ranging from in-silico prediction to miniaturized high-throughput experimentation. However, a notable challenge lies in the absence of comparative data. In the present work, a combination of a miniaturized screening of ASDs with calculation of activity coefficients using the conductor like screening model for real solvents (COSMO-RS) was proposed.

First, the physical stability of ASDs comprising drugs of different glass forming ability (GFA) each with ten pharmaceutically relevant polymers was evaluated under accelerated stress conditions at two drug:polymer ratios. The miniaturized high-throughput screening method was based on the instability onset time that was monitored by polarized light microscopy (PLM). Furthermore, COSMO-RS was used to assess the interaction strength between the drugs and polymers by calculating activity coefficients, which was combined with estimations of the wet glass transition temperature (T_g), to account for molecular mobility.

The computational calculations showed an overall alignment of 87% with the instability of the ASDs observed experimentally for comparable drug:polymer ratios and humidity conditions. This positive result supports the current understanding of stable ASD formulation where at given ambient conditions, a low molecular mobility as well as the strength of interaction between drug and polymer has a main impact on the physical stability of ASDs. The current results are further encouraging to implement such a combined in-vitro/high-throughput (HTS) and in-silico strategy in early industrial screening of ASDs.

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Materials

Nifedipine was purchased from Thermo Fisher Scientific (Dreieich, Germany). Felodipine was obtained from TCI Europe (Eschborn, Germany) and griseofulvin was purchased from Sigma-Aldrich (Darmstadt, Germany). HPMC AS grades LG, MG and HG were purchased from Shin Etsu AQOAT (Chigasaki, Japan), Eudragit grades E100, L100 and L100 55 were obtained from Evonik (Essen, Germany), Soluplus, PVP K30 and PVP VA 64 were purchased from BASF (Ludwigshafen, Germany) and HPMC E5 was obtained from VWR (Leuven, Belgium).

Egis Zeneli, Hugo Bohets, Frédéric Ngono Mebenga, René Holm, Christophe Tistaert, Martin Kuentz, Guiding excipient selection for physically stable Amorphous Solid Dispersions: A combined in-vitro in-silico approach, European Journal of Pharmaceutical Sciences, 2025, 107152, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107152.