title: A rational approach towards development of amorphous solid dispersions: Experimental and computational techniques.
abstract: 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 <10nm scale. Orthogonal computational and experimental approaches indicate phase mixing of the system components.
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA, 94080, United States.
authors.forename: Paroma
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA, 94080, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lubach
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA, 94080, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hau
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA, 94080, United States. Electronic address: nagapudi.karthik@gene.com.
authors.forename: Karthik
authors.initials: K
authors.lastname: Nagapudi
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D004355:Drug Stability; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations; D011108:Polymers; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose
keywords: Amorphous solid dispersion; Miscibility; Molecular modeling; Polymer; Solid-state NMR; Solubility parameter