Mechanisms of water permeation and diffusive API release from stearyl alcohol and glyceryl behenate modified release matrices.

This work aims to develop complimentary analytical tools for lipid formulation selection that offer insights into the mechanisms of in-vitro drug release for solid lipid modified release excipients. Such tools are envisioned to aide and expedite the time consuming process of formulation selection and development. Two pharmaceutically relevant solid lipid excipients are investigated, stearyl alcohol and glyceryl behenate, which are generally known to exhibit faster and slower relative release rates, respectively. Nuclear magnetic resonance spectroscopy and diffusometry are used, along with water uptake and dissolution experiments to help distinguish between two proposed in-vitro release mechanisms for crystalline caffeine from these matrices: 1) rate limiting movement of the wetting front through the particle, and 2) rate limiting diffusive release of the active from the wetted particle. Findings based on water permeation rates, API diffusion coefficients and kinetic modeling suggest that the rate limiting steps for caffeine release from these matrices are different, with stearyl alcohol being co-rate limited by movement of the wetting front and diffusive release of API, whereas glyceryl behenate is more strictly limited by diffusive release of API from the wetted matrix. A Peclet-like number is proposed to describe the different regimes of rate limitation for drug release. NMR spectroscopy and diffusometry are demonstrated to be useful tools for elucidating mechanisms of API release from crystalline drug/lipid mixtures and have significant potential value as screening tools in MR formulation development.

Solvent-Assisted Secondary Drying of Spray-Dried Polymers.

PURPOSE: The purpose of this work is to introduce solvent-assisted secondary drying, a method used to accelerate the residual solvent removal from spray dried materials. Spray-drying is used to manufacture amorphous solid dispersions, which enhance the bioavailability of active pharmaceutical ingredients (APIs) with low aqueous solubility. In the spray-drying process, API and excipients are co-dissolved in a volatile organic solvent, atomized into droplets through a nozzle, and introduced to a drying chamber containing heated nitrogen gas. The product dries rapidly to form a powder, but small amounts of residual solvent (typically, 1 to 10 wt%) remain in the product and must be removed in a secondary-drying process. For some spray-dried materials, secondary drying by traditional techniques can take days and requires balancing stability risks with process time. METHODS: Spray-dried polymers were secondary dried, comparing the results for three state-of-the-art methods that employed a jacketed, agitated-vessel dryer: (1) vacuum-only drying, (2) water-assisted drying, or (3) methanol-assisted drying. Samples of material were pulled at various time points and analyzed by gas chromatography (GC) and Karl Fischer (KF) titration to track the drying process. RESULTS: Model systems were chosen for which secondary drying is slow. For all cases studied, methanol-assisted drying outperformed the vacuum-only and water-assisted drying methods. CONCLUSIONS: The observation that methanol-assisted drying is more effective than the other drying techniques is consistent with the free-volume theory of solvent diffusion in polymers.

Glass Dynamics and Domain Size in a Solvent-Polymer Weak Gel Measured by Multidimensional Magnetic Resonance Relaxometry and Diffusometry.

Nuclear magnetic resonance measurements of rotational and translational molecular dynamics are applied to characterize the nanoscale dynamic heterogeneity of a physically cross-linked solvent-polymer system above and below the glass transition temperature. Measured rotational dynamics identify domains associated with regions of solidlike and liquidlike dynamics. Translational dynamics provide quantitative length and timescales of nanoscale heterogeneity due to polymer network cross-link density. Mean squared displacement measurements of the solvent provide microrheological characterization of the system and indicate glasslike caging dynamics both above and below the glass transition temperature.