A study on the mechanism of polymorphic nucleation

A substance capable of crystallizing into different, but chemically identical, crystalline forms is said to exhibit polymorphism. Different polymorphs of the same substance can have different physical properties, such as color, transparency, crystal shape and solubility. Different polymorphs of the same substance might lead to different biological activity due to the possibility of conversion among polymorphic forms affecting the dissolution rate. Thus, polymorphism plays an important role for pharmaceutical products. When multiple polymorphs of the same substance crystallize together out of a solution, the relative productivity of different polymorphs depends on supersaturation, temperature, cooling rate, solvent, agitation, PH, additive, impurity, seeding, etc. Understanding the nucleation and growth mechanisms of polymorphism is crucial to better control of the desired forms during polymorph crystallization. Polymorph nucleation kinetics of L-glutamic acid will be studied in this two-year proposal. Many studies have indicated that L-glutamic acid nucleates as two polymorphs- ? form (prismatic) and ? form (needlelike). However, the exact polymorph nucleation kinetics of L-glutamic acid is still unclear. In the first year, a batch experimental set-up will be designed to study the effects of temperature, supersaturation, stirring rate, impurities and ultrasound on the induction time of the two polymorphs. The polymorphic powder composition will be analyzed at the end of the experiment by both X-ray diffraction (XRD) and Raman spectroscopy. Thus, the relative nucleation rate of each polymorph is determined. In the second year, an in-situ nucleation cell will be designed to study the effects of temperature, supersaturation and impurities on the nucleation kinetics of the two polymorphs. The in-situ monitoring technique using Raman spectroscopy allows to measure nucleation kinetics of the two polymorphs in aqueous solution. Besides, the transformation kinetics between two polymorphs under various conditions will also be investigated. A polymorph nucleation model will be proposed to study the kinetic data obtained by in-situ Raman spectroscopy. This knowledge will help to gain insight into polymorph crystallization.

Project ID:PB10202-1067
External Project ID:NSC101-2221-E182-066-MY2