Solution concentration prediction for pharmaceutical crystallization processes using robust chemometrics and ATR FTIR spectroscopy

In the pharmaceutical industry, a vast number of compounds are produced by solution crystallization, making the design and development of such processes of critical importance. The kinetics of crystal growth and nucleation, the fundamental mechanisms of a solution crystallization process, are strongly dependent on supersaturation (the difference between solution concentration and the saturation concentration). The present study uses attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, coupled with robust chemometric techniques, for the on-line measurement of solution concentration of two pharmaceutical compounds in multicomponent systems in the presence of impurities and over a wide range of temperature. To our best knowledge, this is the first time that ATR FTIR spectroscopy has been applied to a multicomponent pharmaceutical system. The resulting models show high accuracy, in predicting the solution concentration and are applied successfully in measuring the solubility for the cases of cooling and antisolvent crystallization.