The Effects of Temperature and Dissolution Media on Crystallization of Amorphous Drugs and Potential Effects on Predicting Bioavailability

Poorly soluble crystalline drug candidates are often made amorphous to increase their solubility with the intent to enhance oral bioavailability, thus improving the likelihood of becoming a commercial drug product. Currently, considerable time, material and effort are expended to determine whether an amorphous approach will provide the required bioavailability improvement. However, often the solubility enhancement of the amorphous form is not fully realized in vivo due to solution-mediated phase transformation (SMPT). This study investigated the effects of key factors, through experimentation and modeling, that affect SMPT and model the potential effects of SMPT on bioavailability. Sparsely parameterized biopharmaceutical models were developed to quickly obtain estimates of the bioavailability from in vitro dissolution data for compounds that precipitate in the gastrointestinal tract. The models highlight the complex effects of drug absorption rate on expected in vivo drug peak concentration and duration in the small intestinal lumen from where orally administered drug is absorbed, depending on whether the peak concentration or the peak duration is assumed to better translate from in vitro to in vivo. Furthermore, a model with limited number of input variables allowed us to quantify variation in bioavailability based on known variations of one or more model input parameters. The differences in SMPT of a supersaturating system were compared in biorelevant media and a medium without surfactants. Amorphous spironolactone underwent SMPT to a channel hydrate in all three media which was confirmed by the decrease in dissolution rates assessed in a flow-through dissolution apparatus, as well as by the appearance of crystals on the amorphous solid surface detected by polarized light microscopy. Longer duration of supersaturation was found in both biorelevant media, compared to the medium without surfactants. The contribution(s) of the molecular mobility of the hydrated amorphous drug and degree of supersaturation to the rate of SMPT of amorphous spironolactone. The degree of supersaturation was not the sole determinant of SMPT. Rather, mobility of the solid at/near the dissolution surface of amorphous material, relative to 37°C (i.e., physiological relevant temperature) is more likely to be govern the extent and time course of dissolution enhancement by amorphous drugs