Design and modeling of Pharmaceutical polymorphic crystallization processes

Abstract

This research project focuses on the crystallization of polymorphic compounds. With increasing structural complexity of high value-added products, multiple polymorphs are more frequently encountered in the pharmaceutical industry; it is pertinent to establish controlled crystallization for the intended polymorph with its expected physical properties. The goal of this work is to design, control, and model polymorphic crystallization using recent advances in sensor technologies including Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy, laser backscattering, and video microscopy. A systematic methodology using concentration feedback control is presented for the selective crystallization of the metastable form of L-glutamic acid, a monotropic dimorph system, and L-phenylalanine, an enantiotropic pseudo-dimorph system. For the latter, a semi-automated procedure for measuring the solubility of both enantiotropes is developed based on the various in situ measurements. Additionally, a process model for the crystallization of L-phenylalanine is developed with kinetics estimated for the anhydrate and monohydrate forms using in situ ATR-FTIR spectroscopy and laser backscattering.