Biorelevant Media Slows the Solution-Mediated Phase Transformation of Amorphous Spironolactone

• Published in: Journal of pharmaceutical sciences 2018-01, Vol.107 (1), p.426-435
• Main Authors: Kleppe, Mary S., Haskell, Roy J., Bogner, Robin H.
• Format: Article
• Language: English
• Subjects: crystal growth; crystallization; dissolution; dissolution rate; hydrate; phase transformation; poorly water-soluable drugs; solubility; supersaturation; surfactants
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.10.041

Solution-mediated phase transformation (SMPT) can reduce the high drug concentration expected from amorphous formulations, eliminating the improvement in drug absorption one hoped to gain from this high energy drug state. The differences in SMPT of a supersaturating system were compared in biorelevant media (fasted state simulated intestinal fluid and fed state simulated intestinal fluid) and United States Pharmacopeia compendial medium, simulated intestinal fluid without pancreatin. Amorphous spironolactone underwent SMPT to the same hydrate of spironolactone in all 3 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 which may lead to greater in vivo oral drug absorption was found in both biorelevant media, compared to compendial (average > 90 vs. 20 min), indicating that the presence of surfactants in biorelevant media delays crystal growth. Surface profiles and polarized light micrographs suggest that (1) a significant increase in surface area due to 3D crystal formation, (2) amorphous areas remaining exposed on the surface, and (3) a lower nucleation rate are potential reasons for an elevated dissolution rate even after SMPT.