Nucleation Behavior in a Transformation of the Amorphous State to the Crystalline State during Antisolvent Crystallization

The liquid-mediated phase transformation of an amorphous form to a crystalline heptahydrate form of guanosine 5′-monophosphate was studied in antisolvent crystallization using methanol–water mixtures as solvents. Three steps were monitored: the formation of the amorphous form, dissolution of the amorphous form, and growth of the heptahydrate crystals using in situ Raman spectroscopy, focused beam reflectance measurement (FBRM), and particle vision measurement (PVM) and off-line methods like viscosity, thermal gravimetric analysis (TGA), and powder X-ray diffraction (PXRD). Effects of the antisolvent fraction, initial concentration, and addition rate of the antisolvent on the transformation process were discussed. Solid forms, solute concentration, particle size, counts, induction time, metastable zone width, solution viscosity, and amorphous slurry viscosity were all measured for 18 experiment runs. The induction time of the crystalline hydrate increased with the supersaturation but decreased with the increasing viscosity of the amorphous slurry. Both are not as expected. The induction time correlates nicely in the opposite direction with the viscosity of the amorphous slurry concentration. The amorphous slurry viscosity is about 20 times higher than the solution viscosity. Viscosity of the amorphous slurry was discovered to be a crucial factor influencing the transition of the amorphous slurry to the crystalline form in the pre-exponential component of the classical nucleation rate equation. The metastable zone boundaries of the amorphous and heptahydrate crystalline forms were shown in a plot of the solute concentration versus the mass fraction of methanol in the mixed solvent. The amorphous and heptahydrate crystalline forms can be selectively produced under all the conditions of this study. The pre-exponential factor of the nucleation rate equation factor is crucial in comprehending the transformation from an amorphous to a crystalline state.