Simultaneous Effects of Multiple Factors on Solution-Mediated Phase Transformation: A Case of Spironolactone Forms

In this work, the single-crystal structure of the ethanol solvate of spironolactone was determined for the first time. The thermodynamic stabilities of the ethanol solvate, form II, and the hydrate of spironolactone were determined from the water-ethanol-spironolactone ternary phase diagram. Meanwhile, the solution-mediated phase transformation of spironolactone forms was investigated using in situ Raman and ATR-FTIR spectroscopy. The transformation processes were controlled by nucleation and growth of the stable form and/or dissolution of the metastable form in different situations. Then the simultaneous effects of temperature and solvent composition on phase transformation were investigated in detail. The desired spironolactone form could be obtained by adjusting the temperature and the water content in the solvent mixture. Furthermore, the phase transformation was examined in relation to the intermolecular interactions. It appeared that the conformational flexibility of spironolactone and the hydrogen-bond donor propensity of the solvent played critical roles in the formation of the final forms.