Evolution of Supersaturation of Amorphous Pharmaceuticals: The Effect of Rate of Supersaturation Generation

Abstract

The combination of a rapidly dissolving and supersaturating "spring" with a precipitation retarding "parachute" has often been pursued as an effective formulation strategy for amorphous solid dispersions (ASDs) to enhance the rate and extent of oral absorption. However, the interplay between these two rate processes in achieving and maintaining supersaturation remains inadequately understood, and the effect of rate of supersaturation buildup on the overall time evolution of supersaturation during the dissolution of amorphous solids has not been explored. The objective of this study is to investigate the effect of supersaturation generation rate on the resulting kinetic solubility profiles of amorphous pharmaceuticals and to delineate the evolution of supersaturation from a mechanistic viewpoint. Experimental concentration-time curves under varying rates of supersaturation generation and recrystallization for model drugs, indomethacin (IND), naproxen (NAP) and piroxicam (PIR), were generated from infusing dissolved drug (e.g., in ethanol) into the dissolution medium and compared with that predicted from a comprehensive mechanistic model based on the classical nucleation theory taking into account both the particle growth and ripening processes. In the absence of any dissolved polymer to inhibit drug precipitation, both our experimental and predicted results show that the maximum achievable supersaturation (i.e., kinetic solubility) of the amorphous solids increases, the time to reach maximum decreases, and the rate of concentration decline in the de-supersaturation phase increases, with increasing rate of supersaturation generation (i.e., dissolution rate). Our mechanistic model also predicts the existence of an optimal supersaturation rate which maximizes the area under the curve (AUC) of the kinetic solubility concentration-time profile, which agrees well with experimental data. In the presence of a dissolved polymer from ASD dissolution, these observed trends also hold true except the de-supersaturation phase is more extended due to the crystallization inhibition effect. Since the observed kinetic solubility of nonequilibrium amorphous solids depends on the rate of supersaturation generation, our results also highlight the underlying difficulty in determining a reproducible solubility advantage for amorphous solids.

Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations

“…To fully characterize the dissolution profiles of supersaturating formulations under nonsink conditions with a small SI value, Sun and Lee have demonstrated the effects of supersaturation generation rate and initial degree of supersaturation on the overall kinetic solubility profiles (27,28). They investigated these effects via an infusion experiment in which poorly water-soluble drugs (e.g., indomethacin) dissolved in a limited volume of water-miscible organic solvents (e.g., ethanol) were gradually infused into a dissolution medium.…”

“…Considering the fact that the mechanistic model simulation is based exclusively on physical parameters reported in the literature without employing any curve fitting in order to provide mechanistic insights into the resulting kinetic solubility profiles of ASD systems, the discrepancies mentioned above are therefore not surprising and the resulting predicted kinetic solubility profiles can be considered as quite good (please consult Ref. 27, 28 for detailed theoretical simulation of the effects of linear and nonlinear supersaturation generation rates).…”

“…The effect of supersaturation generation rate also has direct implications on the prediction and measurement of solubility advantages of amorphous pharmaceuticals based on the generation of kinetic solubility profiles (27). In previous attempts of estimating the solubility advantages of amorphous solids, there usually exists a large discrepancy between the measured values and those predicted from various estimations of Gibbs free energy difference (32,33).…”

“…Within such a metastable zone, the time evolution of supersaturation is nevertheless a kinetic process in which a system inevitably moves from a nonequilibrium supersaturated state to an equilibrium saturated state by forming a separate solid phase. Since the observed kinetic solubility of non-equilibrium amorphous solids depends on the rate and the degree of supersaturation generation (27,28), available experimental results highlight the underlying difficulty in determining a reproducible kinetic Fig. 8.…”

“…8. It has been hypothesized that the solubility of a supercooled and liquidlike amorphous drug dissolved in an aqueous solution is analogous to that of two miscible liquids: Each component dissolves completely in the other regardless of the proportions in which two liquids are mixed (27). In fact, the molecular arrangement of one-phase solid solution appears to be more similar to that of a liquid solution than that of crystalline and amorphous solid dispersions (see Fig.…”