(217fs) NMR Analysis of the Concentration Dependence of HPMCAS Polymer Dynamics to Inform Drying Models for Spray Dried Dispersions

Hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based spray-dried dispersions (SDDs) have been shown to offer significant bioavailability enhancement for drugs with low aqueous solubility [Friesen, Shanker et al. 2008].  However, the impact of macro-scale process conditions on micro-scale droplet drying and the impact of droplet drying history on SDD physical stability, dissolution performance and particle properties are not well understood.  A significant fraction of solvent drying occurs under internal, diffusion-limited mass transfer.   Quantifying the dynamics of the diffusion-dominated mass transport regime is critical to modeling droplet drying.  In this work, nuclear magnetic resonance (NMR) was used to probe molecular scale interactions, including spectrally resolved diffusion, for a multi-component system containing HPMCAS, acetone, and model active pharmaceutical ingredient (API).  Samples of constant composition from 5-90 % wt. polymer as well as samples undergoing a quasi-steady state acetone evaporative driving force were analyzed towards developing a droplet drying model that accurately captures the dynamics of diffusion-dominated drying.

Diffusion of solvent and polymer were measured using a spectrally resolved pulsed gradient stimulated spin echo (PGSE) NMR method [Callaghan 1991].  Multidimensional diffusion D spin-spin transverse relaxation time T₂ correlation experiments D-T₂ were run to determine correlations between translational and rotational molecular dynamics [Callaghan, Arns et al. 2007].  Spin-spin T₂ magnetic relaxation provides information on the state or phase of the polymer with liquid behavior having long T₂ times due to rotational mobility motionally averaging out dipolar coupling of proton ¹H interactions and solid behavior generating short T₂times due to strong dipolar coupling.  These non-spectrally resolved correlations provide new insight into the liquid solution to gel network and semi-solid glass or crystalline state transition in the polymer solvent system. 

These experiments provided standards to correlate T₂ and diffusion measured by NMR to polymer concentration for use in steady-state drying experiments.  A steady state drying device was built so that a stable fluid height as well as a quasi-steady state concentration profile of the drying HPMCAS-acetone solution could be maintained within the NMR magnet.  To measure the micro-scale dynamics of the drying process, spatially resolved NMR images (MRI) encoded for diffusion and T₂ were used to monitor polymer concentration while simultaneously quantifying the molecular dynamics during drying.