Absorptive Dissolution Testing: An Improved Approach to Study the Impact of Residual Crystallinity on the Performance of Amorphous Formulations

Abstract

Amorphous solid dispersions typically improve the oral bioavailability of poorly soluble drugs. However, residual crystallinity is always a concern, in terms of potential impact on the product stability and performance. Consequently, in vitro tools that allow biorelevant assessment of residual crystallinity are of interest. The goal of the present study was to use absorptive dissolution testing to evaluate the impact of different levels of crystallinity in an amorphous formulation on membrane mass transport kinetics and supersaturation-time profiles. Partial crystallinity was induced in commercially available tacrolimus formulations by exposure to moderate temperature and high relative humidity. A hollow fiber membrane was coupled to a dissolution vessel to create an absorptive dissolution testing apparatus, and concentration-time profiles were simultaneously monitored during dissolution (donor compartment) and after absorption across the membrane (receiver compartment). The coupled dissolution-absorption measurements indicated that residual crystallinity impacted the absorption profiles in a manner that depended on the volume of fluid used for the dissolution measurement. A high percentage of residual crystallinity hampered the drug release from the formulation. Higher supersaturation in nonsink dissolution conditions improved mass transfer rates; however, the presence of seed crystals led to rapid desupersaturation. Further systematic studies to delineate the interplay between the rate of absorption and desupersaturation revealed that for a given dissolution rate, the crystallization rate would supersede the absorption rate only at high supersaturations. Thus, seeds have a lower impact on absorption when the overall supersaturation generated is lower. This study underscores the importance of considering competing physical processes when evaluating amorphous formulations. A further consideration highlighted is that different fluid volumes may impact the absorption profile for supersaturating dosage forms. Absorptive dissolution testing appears to be a potentially valuable tool to mechanistically investigate amorphous solid dispersion formulation release and phase behavior under more biorelevant conditions.