A link between the ATR-UV/Vis and Raman spectra of zwitterionic solutions and the polymorphic outcome in cooling crystallization

Abstract

Many substances can exist in different crystalline forms called polymorphs that have the same chemical formula but different properties such as solubility, density, melting point, stability or bioavailability. In order to guarantee the purity and quality of the final product it is very important to monitor and control the polymorphic form of the crystals during batch or continuous crystallization. Additionally, understanding the solvent effect and how the equilibrium of the different chemical species in solution influences the nucleation and transformation of different polymorphs is fundamental for better design and control of polymorphic crystallization processes. Zwitterionic compounds represent an important class of active pharmaceutical ingredients; in this study ATR-UV/Vis and Raman spectroscopy are used to investigate the relationship between the amount of zwitterions in the clear solution and the polymorphic outcome of cooling crystallizations, using anthranilic acid (OABA) as the model compound. It is shown that the shift in the UV absorbance and in the Raman signal in clear solution caused by changing the equilibrium of different species of OABA (by modifying the composition of the solvent) can be correlated with the polymorphic outcome of the crystallization. The results provide new insight on the effect of equilibrium of the ionic, zwitterionic and neutral species in solution on the polymorphic outcome of crystallization and demonstrate how UV and Raman spectroscopy can be used to control the polymorphic crystallization of zwitterionic compounds by manipulating the solvent composition.