Spontaneous Polymorphic Nucleation of D-Mannitol in Aqueous Solution Monitored with Raman Spectroscopy and FBRM

The spontaneous nucleation of D-mannitol polymorphs at different initial concentrations in an aqueous solution was investigated. Two in situ process analytical technology (PAT) tools, Raman spectroscopy and focused beam reflectance measurement (FBRM), were combined to monitor the process, allowing instantaneous detection of polymorphs after nucleation. It was found that the stable beta form of mannitol was favored at low initial concentrations, whereas the metastable alpha form nucleated at high concentrations and the metastable delta polymorph crystallized when the concentration was in the medium level. To help understand this phenomenon, the thermodynamic and kinetic characteristics of different polymorphs were analyzed. The solubility of the two metastable forms was determined by an innovative method with the aid of Raman spectroscopy, whereas the interfacial energy between polymorphs and the bulk solution were obtained from the induction time measurements. Consequently, the critical excess free energy and other critical parameters associated with the nucleation of various polymorphs were calculated. It was concluded that the nucleation of mannitol polymorphs from an aqueous solution depends on both the thermodynamic and kinetic properties, with the importance of each highly dependent on the supersaturation prevailing in the system.