NMR of HPMCAS/acetone mixtures to characterize concentration and temperature dependent molecular dynamics and inform SDD droplet drying models
Williamson, Nathan Hu.
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Hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based spray-dried dispersions (SDDs) have been shown to offer significant bioavailability enhancement for drugs with low aqueous solubility. However, the impact of macroscale process conditions on microscale droplet drying and the impact of droplet drying history on SDD physical stability, dissolution performance and particle properties are not well understood. Mass transfer to the droplet surface is diffusion limited, and quantifying the mutual diffusivity over the solvent content and wet-bulb temperatures experienced during drying is crucial to modeling droplet drying. This research used nuclear magnetic resonance (NMR) to probe the concentration and temperature dependence of molecular scale interactions within binary systems of HPMCAS polymer and acetone. This data can be incorporated into SDD droplet drying models. Following the generalized droplet drying model of Handscomb and Kraft , a specific SDD modeling procedure was developed. A preliminary form was coded in MATLAB using the finite difference method to approximate the drying time-dependent solvent concentration profiles over the changing droplet radius based on the governing equation for mass conservation. Mixtures of HPMCAS with acetone and wet placebo SDD were tested using high-field NMR. Pulsed gradient stimulated echo (PGSTE) NMR experiments resolved self-diffusion of solvent and polymer. Solvent concentration dependence of the mutual diffusivity was related to a free-volume fit of the acetone self-diffusivity. Multidimensional T 1-T 2 correlation and T 2-T 2 exchange experiments separated proton populations based on correlations of spin-lattice T 1 to spin-spin T 2 relaxation times and discerned time-dependent mixing between T 2 populations. T 1 and T 2 relaxation times depend on the mediation of dipolar coupling by rotational motions; therefore these experiments indicate molecular rotational mobility. Temperature dependence of self-diffusivity and T 1-T 2 correlation measured within a rubbery as well as a glassy HPMCAS/acetone sample indicated that these measurements can determine the thermodynamic phase of polymer-solvent systems. Progression of the SDD droplet drying model and the fundamental aspect of the research on polyelectrolyte and polymer dynamics expanded the current knowledge of polymer glass transition behavior, network formation, and aging. This research demonstrates the potential use of NMR to characterize and quantify mobility and mass transfer of polymers and other pharmaceutically-relevant materials.