title: Molecular Dynamics Simulation of Amorphous Hydroxypropylmethylcellulose and Its Mixtures With Felodipine and Water.
abstract: Understanding drug-polymer molecular interactions, their miscibility, supersaturation potential, and the effects of water uptake may be invaluable for selecting amorphous polymer dispersions that can maximize the oral bioavailability of poorly water-soluble drugs. Molecular dynamics simulations were performed using a model for hydroxypropylmethylcellulose (HPMC) resembling the substitution patterns found experimentally. HPMC at low and high water contents (0.9%-23.0% wt/wt) and mixtures with a hydrophobic drug, felodipine (FEL), were constructed. Tgvalues and densities after ∼30 ns aging at 298 K were close to published results. Except for hydrogen bonds (HBs) between the 5-O- and a 3-OH group in a neighboring repeat unit, HPMC oxygen atoms have a low HB probability (p < 0.1) perhaps due to shielding by surrounding substituents. Water molecules tend to be isolated at low water content while clusters were prevalent at ≥10.7% water. The Flory-Huggins FEL-HPMC interaction parameter (-0.20 ± 0.07) predicts complete miscibility at all HPMC compositions, in agreement with experiments. However, HBs between the FEL-N-H and HPMC favoring miscibility are disrupted with increasing water. Apparent diffusion coefficients versus water content were generated for water and FEL and a theory for the non-Einsteinian nature of water diffusion is proposed.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Tian-Xiang
authors.initials: TX
authors.lastname: Xiang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536. Electronic address: bande2@email.uky.edu.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anderson
mesh_terms: D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism; D015736:Felodipine / Q000737:chemistry* / Q000378:metabolism; D065347:Hypromellose Derivatives / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D014867:Water; D065347:Hypromellose Derivatives; D015736:Felodipine
keywords: amorphous; diffusion; drug-excipient interaction; free energy of interaction; glass transition; mobility; molecular dynamics; polymers; solid dispersion; water in solids