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

Abstract

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/(m 3 min), and the interfacial surface free energy at high and low supersaturation system is 1.74 and 0.576 mJ/m 2 , 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.

Influence of amino acid additives on solution behaviour of L-alanine

“…All the other parameters are identical as in equation 1. Most in the previous literature focus on the comparison between the ideal solubility and non-ideal solubility data which provide useful information in determination of the strength interaction between solute and solvent molecules 12,13 . In addition, the change in Gibbs free energy change, ΔG approach can be used to describe the behaviour and ideality of solutions.…”

“…Approximately 5 ml of solution was filtered from the plastic syringe through 0.20 µm syringe filter and transferred to empty vial. The vial containing solution was weighed and dried in the oven at temperature 40 °C 12 . Finally, the vial containing the solute was weighed and the dissolved amount of L-alanine in vial was subtracted with the initial weight of vial.…”

“…In Figure 4, the van't Hoff solubility plot for the binary system was found to be significantly higher than the ideal solubility plot. The negative deviation of this behaviour indicates that there are interactions between hydrophilic side chains (-COO -and -NH 3 + ) of the Lalanine and water molecules which are defined as hydrogen bond interactions 12,13 . In addition, there are interactions between water molecules and the hydrophobic (-CH 3 ) side chain of L-alanine and this interaction is known as hydrophobic interactions 15,16 .…”

“…The endothermic process involved during the dissolution process in the binary system can be divided into two stages; a) the energies required to break the solute-solute intermolecular bond (in crystal) to form an isolated solute (L-alanine), b) the energies required for breaking the solvent (water) hydrogen bond to create a cavity which is large enough for an isolated solute being accommodated in the cavity of water. The formation of hydrogen bond between L-alanine molecules and water molecules results in an exothermic reaction 12,16 . Nevertheless, the overall endothermic reaction shown by the result in Table 1 might indicate that the endothermic reaction during the dissolution process outweigh the exothermic process from the hydrogen bond formation 12,16 .…”

“…The formation of hydrogen bond between L-alanine molecules and water molecules results in an exothermic reaction 12,16 . Nevertheless, the overall endothermic reaction shown by the result in Table 1 might indicate that the endothermic reaction during the dissolution process outweigh the exothermic process from the hydrogen bond formation 12,16 . The same phenomenon were also reported by previous authors 22,23 dealing with the thermodynamic behaviour of dissolution of non-polar amino acids in water solvent.…”