An Examination of the Solution Chemistry, Nucleation Kinetics, Crystal Morphology, and Polymorphic Behavior of Aqueous phase Batch Crystallized l-Isoleucine at the 250 mL Scale Size: Published as part of a special issue of selected papers presented at the 8th International Workshop on the Crystal Growth of Organic Materials (CGOM8), Maastricht, Netherlands, September 15−17, 2008

An examination of the aqueous solution solubility and batch crystallization kinetics of l-isoleucine at the 250 mL scale size under a poly- and isothermal process condition is presented. Solubility data determined are consistent with the existence of two l-isoleucine polymorphic forms, in which both forms have different solubility and they are enantiotropically related. These polymorphs (A and B) can be recovered at different cooling rates of cooling crystallization. Crystal characterization using optical microscopy, differential scanning calorimetry, X-ray powder diffraction, and Fourier transform IR microscopy confirm this polymorphic behavior. Polythermal crystallization kinetic studies revealed the crystallization temperature increases with cooling rate and solute concentration, which results in a decrease of the metastable zone width (MSZW) with a decreasing cooling/heating rate. The study also revealed that cooling rates affect the polymorph formation, where at cooling rates of 0.25−0.75 °C/min, form B is formed, while a more stable polymorph A can be recovered at a cooling rate of 0.10 °C/min. Isothermal studies showed that the range of nucleation rate is between 1.79 × 10−5 and 7.53 × 10−4 kg/(m3 min), and the interfacial surface free energy at high and low supersaturation system is 1.74 and 0.576 mJ/m2, respectively. For a high supersaturation system, the critical cluster radius r* is between 5−17 Å, associated with between 3−121 molecules (N*), and for a low supersaturation system, r* is between 3 and 14 Å and N* is between 1 and 64. For a pH range of 5.1−6.3 and a temperature range between 10 and 80 °C, zwitterion species of l-isoleucine has remained as a dominating species in both solubility and crystallization studies. Thermodynamics properties generated from solubility data were also presented and discussed.