Pure but Not Simple: Supersaturation from Excipient-Free, Vapor-Generated, Amorphous Griseofulvin Nanoparticles

Rapid crystallization of an active pharmaceutical ingredient can suppress its observable supersaturation and negate this potential advantage of the amorphous form. Excipients added to formulations can prolong supersaturation, but reduce drug loading and obscure the intrinsic dissolution behavior of the drug in testing. Here, we describe spring-and-parachute dissolution behavior in fasted-state simulated intestinal fluid of an archetypal poorly soluble and strongly crystallizing drug, griseofulvin (GSF), in the form of excipient-free, pure, amorphous nanopowders generated using a novel, single-step, solvent-free technique of organic vapor jet desublimation. Using experiments and modeling, we establish how initial dissolution rate, peak concentration, and area under the concentration-time curve scale with dose, distinguishing between dose regimes in which supersaturation behavior is monotonic and nonmonotonic. The roles of local surface crystallization, particle aggregation, and nonequilibrium crystallization at high supersaturation are elucidated, providing a framework for attaining excipient-free supersaturation and guiding the development of improved dissolution models.