Process Modeling of the Polymorphic Transformation of l-Glutamic Acid

Abstract

A simulation model for the solvent-mediated transformation from the metastable R-form to the stable β-form of L-glutamic acid (L-Glu) was developed using the concept of the population balance. The solvent-mediated transformation process is a combination of the dissolution of the R-form and the nucleation and subsequent growth of the β-form. The model parameters for the dissolution of the R-form and the nucleation and growth of the β-form were determined with the aid of experimental data (overall crystal size distribution, polymorphic fraction in solid phase, solute concentration) of 1-L scale batch transformation experiments carried out at several temperatures. The growth rate of the β-form is the rate-limiting step in the transformation. The growth rate constant of the β-form showed an increase with temperature, which is the cause for the experimentally observed transformation rate increase with temperature. The simulation results in detailed information on for example the crystal size distribution change of each form, which is very difficult to measure experimentally. The expected gradual decrease in the peak height of the R-form CSD and the increase in the peak height and the size of the β-form CSD was obtained from the simulation as the transformation proceeded. An adequate combination of experiments and simulations helps to understand and predict crystallization behavior and to optimize polymorphic crystallization processes.

Formation and ageing of L‐glutamic acid spherulites

“…The faster ageing at higher temperature is analogous to the transformation of the metastable α-polymorph to the stable β-form of L-glutamic. [13,19] attribute the fact that the transformation of the α-polymorph occurs faster at higher temperature to a larger growth rate constant in this case. An explanation along the same lines seems to be plausible for the ageing of L-glutamic acid spherulites.…”

Crystallization from solutions containing multiple conformers: A new modeling approach for solubility and supersaturation

“…As opposite to heating ramps routinely used since the pioneering work of Carless and Foster (1966) to improve crystal properties via temperature cycling or to achieve solvent-mediated polymorph transitions (e.g., Ono et al (2004) and Bakar et al (2009)), the procedure presented herein employs a single heating to induce and achieve crystallization.…”

In situ monitoring of the solution‐mediated polymorphic transformation of glycine: characterization of the polymorphs and observation of the transformation rate using Raman spectroscopy and microscopy

“…Starbuck et al 11 performed in situ Raman spectroscopy to determine the polymorphic transformation rate of MK-A (a multipolymorphic compound) and establish process boundaries for process optimization. Ono et al 12,13 and Schöll et al 7 have described the use of in situ Raman spectroscopy together with a population balance model to estimate the polymorphic transformation of a model compound, L-glutamic acid. Hu et al 14 monitored online the crystallization and polymorphic transformation of an enantiotropic polymorphic system, flufenamic acid.…”