Assessing the impact of endogenously derived crystalline drug on the in vivo performance of amorphous formulations.

Crystallization of drug from an amorphous formulation is expected to negatively impact its bioperformance following oral delivery. In evaluating this in vivo, neat crystalline drug is typically mixed with the amorphous formulation. However, this approach may not adequately mimic the effect of drug crystals that form within the amorphous matrix, because crystal properties are highly dependent on the crystallization environment. The aim of this study was to evaluate the in vivo impact of crystals formed in a generic tacrolimus amorphous formulation, relative to noncrystallized formulations and a reference suspension containing neat crystalline drug. Crystallization of tacrolimus was induced in the generic product by exposing it to moderate temperatures and high relative humidity. Controlled levels of crystallinity in the formulations were achieved by mixing maximally crystallized and fresh formulations at the desired ratios. These formulations were then characterized in vitro and used for oral dosing to beagle dogs. Analysis of blood concentrations versus time revealed that formulations containing 50 and 100% crystalline tacrolimus resulted in lower area under the curve (AUC) and maximum concentration (C-max) values as compared to the fresh amorphous formulation. However, the AUC and the C-max values for these formulations were significantly higher than those observed after dosing the pure crystalline tacrolimus suspension. The innovator formulation, Prograf, showed comparable pharmacokinetics before and after exposure to accelerated stability conditions, confirming the robustness of the innovator product to drug crystallization. This study provides insight into the impact of endogenously crystallized material on the oral absorption of a poorly water-soluble compound and highlights the importance of using representative crystalline material when undertaking risk assessment of amorphous formulations.