Evolution of supersaturation of amorphous pharmaceuticals: nonlinear rate of supersaturation generation regulated by matrix diffusion.

The importance of rate of supersaturation generation on the kinetic solubility profiles of amorphous systems has recently been shown by us; however, the previous focus was limited to constant rates of supersaturation generation. The objective of the current study is to further examine the effect of nonlinear rate profiles of supersaturation generation in amorphous systems, including (1) instantaneous or infinite rate (i.e., initial degree of supersaturation), (2) first-order rate (e.g., from dissolution of amorphous drug particles), and (3) matrix diffusion regulated rate (e.g., drug release from amorphous solid dispersions (ASDs) based on cross-linked poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels), on the kinetic solubility profiles of a model poorly soluble drug indomethacin (IND) under nonsink dissolution conditions. The previously established mechanistic model taking into consideration both the crystal growth and ripening processes was extended to predict the evolution of supersaturation resulting from nonlinear rates of supersaturation generation. Our results confirm that excessively high initial supersaturation or a rapid supersaturation generation leads to a surge in maximum supersaturation followed by a rapid decrease in drug concentration owing to supersaturation-induced precipitation; however, an exceedingly low degree of supersaturation or a slow rate of supersaturation generation does not sufficiently raise the supersaturation level, which results in a lower but broader maximum kinetic solubility profile. Our experimental data suggest that an optimal area-under-the-curve of the kinetic solubility profiles exists at an intermediate initial supersaturation level for the amorphous systems studied here, which agrees well with the predicted trend. Our model predictions also support our experimental findings that IND ASD in cross-linked PHEMA exhibits a unique kinetic solubility profile because the resulting supersaturation level is governed by a matrix diffusion regulated mechanism opposite to that resulted from a high level of initial supersaturation or a rapid dissolution of amorphous solids. This more gradual drug release from IND-PHEMA ASD leads to a more gradual buildup of a sustained supersaturation even without the presence of any dissolved polymer to inhibit the drug precipitation, which avoids the rapid surge of supersaturation above a critical value as normally associated with high initial degrees of supersaturation or rapid dissolution of amorphous IND solids and thus avoids the onset of fast uncontrolled precipitation. This characteristic feature makes cross-linked insoluble PHEMA an attractive carrier for amorphous pharmaceuticals.