Crystal Growth Kinetics of a Metastable Polymorph of Tolbutamide in Organic Solvents

The crystal growth of tolbutamide (Form I^L) in different solvents has been investigated by isothermal seeded desupersaturation experiments at different temperatures (268-283 K). Experimental data have been evaluated using empirical power law equations and the mechanistic based models: Burton-Cabrera-Frank (BCF) and birth and spread (B + S). The estimated activation energies and growth exponents suggest surface integration controlled growth as confirmed separately by mass transfer analysis. From the B + S model, the estimated solid-liquid interfacial energies and the mean diffusion distances on the surface range are 1.23-1.90 mJ/m² and 1-16 nm, respectively. The growth rate is strongly dependent on the solvent, decreasing in the order: acetonitrile > ethanol > ethyl acetate > n-propanol > toluene. The crystal growth becomes slower as the overall strength of the solute-solvent binding increases. This influence of the solvent corresponds very well with that found for nucleation of tolbutamide in the same solvents and further supports the hypothesis that desolvation is an important step in crystallization. The similarity in the influence of the solvent on the kinetics of nucleation and growth very strongly supports the hypothesis that the solvent-solute interactions play an important role in the kinetics of formation of crystalline phases.