A rational approach towards development of amorphous solid dispersions: Experimental and computational techniques

The purpose of this study was to determine the drug-polymer miscibility of GENE-A, a Genentech molecule, and hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), a polymer, using computational and experimental approaches. The Flory-Huggins interaction parameter,χ, was obtained by calculating the solubility parameters for GENE-A and HPMC-AS over the temperature range of 25-100 °C to obtain the free energy of mixing at different drug loadings (0-100%) using the Materials Studio modeling and simulation platform (thermodynamic approach). Solid-state nuclear magnetic spectroscopy (ssNMR) was used to measure the proton relaxation times for both drug and polymer at different drug loadings (up to 60%) at RT (kinetic approach). Thermodynamically, the drug and polymer were predicted to show favorable mixing as indicated by a negative Gibbs free energy of mixing from 25 to 100 °C. ssNMR showed near identical relaxation times for both drug and polymer in the solid dispersion at RT and 40 °C for a period up to 6 months showing phase mixing between the API and polymer on <10 nm scale. Orthogonal computational and experimental approaches indicate phase mixing of the system components.

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