Control of Polymorphism in Crystallization of Amino Acid

Abstract

AbstractThe crystallization mechanism and the controlling factors in the crystallization of amino acid polymorphs were investigated. It was demonstrated that the effect of supersaturation (Ostwald's step rule) was not observed for systems of either L‐Glutamic acid (α, β) or L‐Histidine (A, B). The intensive effect of temperature was shown in the crystallization of L‐Glutamic acid (L‐Glu) polymorphs, however, no temperature effect was observed in the case of L‐Histidine (L‐Hist)polymorphs. It was suggested that such a difference could be related to the difference of the molecular conformation between the polymorphs, and the contribution of the conformers in the solutions to the nucleation process of L‐Glu polymorphs. The growth of both L‐Glu polymorphs (α and β) appeared to be due to the nuclei‐above‐nuclei mechanism. With these results, temperature and supersaturation appeared to be the basic important controlling factors (the primary factors) of polymorphism. Solvents and additives (the secondary factors) also have an influence on polymorphism. The influence of ethanol compositions on the crystallization of L‐His polymorphs (A and B) was observed, and demonstrated that the solvent effect is very kinetic, i.e. the nucleation and growth rate of the A form are suppressed with an increase in the ethanol composition. The effects of L‐Phenylalanine as an additive on the crystallization and transformation rates were shown in batch crystallization. The effect of L‐phenylalanine on the growth rate and morphology of L‐Glu polymorphs was also examined using the single crystal method in a flow system. The relationship between the additive concentration and the growth rate of each polymorph was expressed by the proposed equation. The importance of the kinetics of the crystallization for control of the polymorphic crystallization was demonstrated. The supersaturation needed for control of the selective crystallization of the polymorph was also calculated. From these results the controlling factors for the crystallization of polymorphs have been classified in order to clarify their complex interrelationship.