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

Abstract

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.

Nuances in the Calculation of Amorphous Solubility Enhancement Ratio

“…In a previously published report, SPIR was raised to 214 C-217 C for 3 min with less than 0.5% degradation. 34 Thus, the degradation during the present DSC measurement was not significant.…”

“…The cooled material was ground in a mortar and passed through a 100 mm sieve in a glove bag at 3% relative humidity (% RH). Amorphous SPIR was prepared by spray drying as described by Kleppe et al 34 The amorphous nature was confirmed by the absence of birefringence under polarized light at 20X magnification, and the presence of a halo with no peaks by powder X-ray diffraction amorphous samples were stored in vials with a dry air headspace at À20 C.…”

“…The solubility of SPIR was extracted from data on dissolution in distilled/de-ionized water at 25 C determined using a flow through dissolution apparatus. 34,41 Briefly, compacts of either amorphous SPIR prepared by spray-drying or Form II as received underwent dissolution in the flow through apparatus. The solubility of SPIR Form II was proportional to the steady-state dissolution flux of drug from the compact.…”

Development of a Continuous Crystallization Process of the Spironolactone Hydrate Form with a Turbidity-Based Level Control Method

“…Based on single-crystal X-ray diffraction and thermogravimetric analysis, SP incorporates 1/3 water into its crystal lattice . This new crystal form and polymorphism of spironolactone are still actively studied − because of its variety, scientific relevance, and the importance as a worldwide-known API. , …”

Solution-Mediated Phase Transformation of Aripiprazole: Negating the Effect of Crystalline Forms on Dissolution and Oral Pharmacokinetics

“…4,5 Phase changes can also occur during dissolution by a solution-mediated transformation of the metastable or unstable form of a compound to a more stable form or hydrates. 6e8 For example, Kleppe et al 8 showed that solution-mediated phase transformation of amorphous spironolactone to a hydrate resulted in decreased dissolution rates, which depended on the dissolution media. Differences in solubility and dissolution rate among polymorphs may have a significant impact on pharmacokinetics.…”