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,x, was obtained by calculating the solubility parameters for GENE-A and HPMC-AS over the temperature range of 25100 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 degrees 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. (C) 2017 Elsevier B.V. All rights reserved.