Population Balance Modeling of Diastereomeric Salt Resolution

Abstract

Diastereomeric salt crystallization is a classical, widely applicable chiral resolution technique, which enables the separation of the enantiomers of both racemate and conglomerate-forming compounds. A resolution method for racemic pregabalin with l-tartaric acid was developed to obtain pure (S)-pregabalin l-tartrate monohydrate crystals with the yield ranging from 43 to 50%. A series of designed resolution experiments were executed at different cooling rates and temperature end points to estimate the crystallization kinetics using population balance modeling. Inline ATR-FTIR measurements of these experiments were used to calculate concentrations in the crystallization phase and to collect solid–liquid equilibrium data by the solubility trace method after product sampling. Since diastereomeric salts are dissociable ionic compounds, solubility product expressions were used in the model to express the relative supersaturation as the driving force of crystallization. As a result, a population balance model with secondary nucleation, growth, and agglomeration mechanisms was identified, and the simulated supersaturation profiles and product size distributions well reproduced the measured data.

Strategies for chiral separation: from racemate to enantiomer

“…In addition, PBMs encompassing simplified crystallization kinetics and objective functions can also be applied to CCR for the prediction of temperature, concentration, or particle size distribution in the system. 218 In short, these integrating advances show a bright future to produce CCR products with higher optical purity, yields and desired size distribution.…”

Preparation and Enantioselective Permeation of Polymer Membranes Containing One-Handed Helical Channels

“…Because the 1:1 mixture of enantiomers (= racemates) is produced in the conventional chemical synthesis, separation (= optical resolution) is needed. Conventional optical resolution methods using optical resolution reagents are not a continuous procedure and need several steps. − The optical resolution method by chiral high performance liquid chromatography is a simple and continuous process, but the amount of racemates that can be separated at once is usually low.…”