Combining Morphological Population Balances with Face-Specific Growth Kinetics Data to Model and Predict the Crystallization Processes for Ibuprofen

Abstract

A route map for modelling pharmaceutical manufacturing processes utilising morphological population balance (MPB) is presented in terms of understanding and controlling of particle shape and size for optimising the efficiency of both the manufacturing process and final properties of the formulated drugs. This is applied to batch cooling crystallisation of the pharmaceutical compound, ibuprofen, from supersaturated ethanolic solutions in which the MPB is combined the known crystal morphology and associated face-specific growth kinetics (Nguyen et al., CrystEngComm, 2014, 16, 4568-4586) to predict the temporal evolution of the shape and size distributions of all crystals. The MPB simulations capture the temporal evolution of the size and shape of ibuprofen crystals and their distributions at each time instance during the crystallisation processes. The volume equivalent spherical diameter and crystal size distribution converted from MPB simulation are validated against the experimentally studies on the 1 litre scale size (Rashid et al., Chem Eng Res & Des, 2012, 90, 158-161), confirming the promise of this approach as a powerful simulation, optimisation and control tool for the digital design of precision pharmaceutical processes and products with the desirable properties, with potential applications in crystallisation design for personalised medicines.

Measured Growth Rates of Ibuprofen: Comparing Single Crystal and Bulk Suspensions Data

“…Clearly, further work on other crystallizing systems through measurements carried out over a wider range of supersaturations and process scale sizes are needed to establish the generic significance of this kind of approach as well as to answer the question regarding the use of this science of scale methodology within routine process R&D, e.g., through its integration with population balance modeling (see the example 43). It is hoped that the work presented here will stimulate additional interest and through this perhaps provoke further work to this overall aim.…”

Digital Design of Batch Cooling Crystallization Processes: Computational Fluid Dynamics Methodology for Modeling Free-Surface Hydrodynamics in Agitated Crystallizers

“…The overall workflow needed for the crystallization process design is summarized in Figure , which highlights the modeling strategy comprising three stages with increasing complexity, which will deliver information on the final product crystal properties such as particle size and/or shape distributions: CFD for crystallizer’s hydrodynamics fully coupled CFD-1D PBM for the prediction of CSD morphological PBM , solved within well-mixed zones established via CFD using a multi-zonal process modeling approach for the prediction of crystal size and shape distributions. …”

“…morphological PBM , solved within well-mixed zones established via CFD using a multi-zonal process modeling approach for the prediction of crystal size and shape distributions.…”

Unusual Crystal Growth Kinetics of (RS)‐Ibuprofen from Ethanolic Solutions

“…It is also one of a minority of active pharmaceutical ingredients still marketed in a racemate form, although the ( S )‐enantiomorph has been shown to be more biologically active than the ( R )‐enantiomorph. Surprisingly, considering the significance of this molecule in the pharmaceutical industry, there are a limited number of papers on the solubility , growth shape , and particularly the solution crystallization of the species .…”