A Study On Concomitant Crystallization And Phase Transformation Mechanism Of Spironolactone

The formation of polymorph is a very common phenomenon in the pharmaceutical industry.Different polymorphs may exhibit different physical and chemical properties,which lead to dramatic discrepancies in bioavailability.Studies on the polymorph can provide the theoretical basis for obtaining the desired form,meanwhile,it can also provide much crystallization information,such as structures,nucleation and growth mechanism.Spironolactone is widely used as a diuretic and it may crystalize in two polymorphs and several solvates.In this work,spironolactone was chosed as the research object,and its desolvation process,concomitant crystallization,and phase transformation behaviors were systematically studied.Different spironolactone crystals(form I,form II,ethanol solvate and hydrate)were prepared and characterized by XRD,PLM,DSC,and TGA.The crystal structure of ethanol solvate was elucidated for the first time,and the molar ratio of spironolactone to ethanol in the ethanol solvate was 4 /1.The desolvation routes upon heating effecting of ethanol solvate and hydrate were studied by HSM and VT-XRD.Concomitant crystallization of spironolactone form II and its ethanol solvate was investigated in ethanol by means of process analytical techniques.The effects of temperature and supersaturation on nucleation were analysised in detail.Based on the data of solubility and induction time,the reason of concomitant crystallization of spironolactone was discussed from the aspects of cryatllization thermodynamics and kinetics.The thermodynamic stability of ethanol solvate,form II and hydrate of spironolactone was determined by the ternary phase diagrams of water-ethanol-spironolactone.The solution-mediated phase transformation of spironolactone forms was investigated using process analytical techniques.The transformation processes were controlled by nucleation-growth of the stable form,and/or dissolution of the metastable form at different situations.Then the simultaneous effects of temperature and solvent composition on phase transformation were investigated in detail.Furthermore,the crystal structure of spironolactone and the solvent properties played a critical role in the formation of the final forms.