The practical resolution of racemic compounds into pure enantiomeric components is a very important process research activity in the pharmaceutical industry today. One commonly used technique for such resolution (separation) is the diastereomeric formation route where the racemic compound reacts with a chiral acid or base to form a mixture of two diastereomers that by definition have different physical properties (i.e. solubilities, and pharmacological activities) and thus can be separated through traditional crystallization techniques. The capability of on-line monitoring of the optical purity of the crystals during diastereomeric crystallization will help to develop a robust crystallization procedure.    The first objective of the presentation is to examine an alternative on-line measurement to replace slurry density used in a Partial Least Square Regression (PLS) model to predict solid composition of one of the two diastereomers[1].  The second objective is to present a PLS model that quantifies the concentration of both diastereomers in liquid phase. 

Our recent research[2] showed that Raman spectroscopy is capable of differentiating diastereomers in a crystallization slurry, and the estimation model accuracy increases provided the changing process parameters of temperature and slurry density are included in the model.  However, slurry density is not easily measured on-line without a sampling loop.  It is essential to find an alternative on-line measurement from which to infer slurry density.  The choice for the alternative online measurement is ATR-FTIR and FBRM.  ATR-FTIR is often used to study how solute concentration changes in solution phase over time during crystallization.  It serves as an indirect measure of the solid phase dynamic.  One the other hand, FBRM is a particle size counter and it gives a more direct measure of slurry density in measuring the total number of crystals.  Different combinations of two or all of the measurements are incorporated into a new PLS estimation model and quantify the solid composition of the diastereomers.

The second objective is achieved by building a calibration model using ATR-FTIR to quantify both the total solute concentration and percent composition of the diastereomer in the solution phase.  The PLS models will be a prelude to understand and model the thermodynamics and kinetics of crystallization process of interest.