Diffusion in HPMC Gels. I. Determination of Drug and Water Diffusivity by Pulsed-Field-Gradient Spin-Echo NMR

Purpose. This work describes diffusivity measurements of drug (adinazolam mesylate) and water in a variety of solutions including polymer gels. Methods. Pulsed-field-gradient spin-echo (PFGSE) NMR methods were employed to measure the diffusivity. Results. In binary component solutions, adinazolam diffusivity is generally found to exhibit an exponential dependence on the concentration of the viscosity-inducing agent (VIA), which is glucose, lactose, maltoheptaose, hydroxypropyl methylcellulose (HPMC) or drug itself. An increasing obstruction power to drug diffusion from glucose to HPMC is observed, which can be related to the polymerization degree of the VIA. In contrast, adinazolam diffusivity in HPMC gels shows little dependence upon the polymer viscosity grades examined (K100LV, K4M, and K15M). The temperature dependence of adinazolam diffusivity in dilute VIA solutions reveals that the diffusion barrier for the drug is similar to that for self-diffusion of water. Conclusions. The retarding effect from the VIA for drug diffusion is concluded to be primarily associated with a steric obstruction mechanism. In multicomponent gels with varied concentrations of drug, lactose and HPMC, the drug diffusivity can be approximately described as an exponential function of the summation of the products of the proportionality constant (K_i) and concentration for each VIA component. In contrast, water diffusion behavior shows an universal exponential dependence upon the VIA concentration and small dependence upon the nature of the VIA. The interpretation of the diffusivity data is discussed and compared to two existing diffusion models (Yasuda and Mackie-Meares models).