Publications (6)2.26 Total impact
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ABSTRACT: One of the most important problems that can arise in the development of a pharmaceutical crystallization process is the control of polymorphism, in which there exist different crystal forms for the same chemical compound. Different polymorphs can have very different properties, such as bioavailability, which motivates the design of controlled processes to ensure consistent production of the desired polymorph to produce reliable therapeutic benefits upon delivery. The optimal batch control of the polymorphic transformation of L-glutamic acid from the metastable α-form to the stable β-form is studied, with the goal of optimizing batch productivity, while providing robustness to variations in the physicochemical parameters that can occur in practice due to variations in contaminant profiles in the feedstocks. A nonlinear state feedback controller designed to follow an optimal setpoint trajectory defined in the crystallization phase diagram simultaneously provided high-batch productivity and robustness, in contrast to optimal temperature control strategies that were either nonrobust or resulted in long-batch times. The results motivate the incorporation of the proposed approach into the design of operating procedures for polymorphic batch crystallizations. © 2007 American Institute of Chemical Engineers AIChE J, 2007AIChE Journal 08/2007; 53(10):2643 - 2650. · 2.26 Impact Factor
Article: Adaptive concentration control of cooling and antisolvent crystallization with laser backscattering measurement[show abstract] [hide abstract]
ABSTRACT: This article is Restricted Access. It was published in the journal, Crystal Growth and Design [© American Chemical Society] and is available from: http://pubs.acs.org/doi/abs/10.1021/cg800131r The paper presents a thorough simulation and experimental evaluation of the concentration control approach for batch and semibatch crystallization. The sensitivity of concentration feedback control is assessed in the case of various disturbances that result in excessive nucleation events. The enhanced robustness of the concentration control is demonstrated against the widely used direct operation approach, which directly implements the temperature or anti-solvent addition rate versus time. Two adaptive supersaturation control approaches are proposed that employ measurement of the number of particle counts per unit time provided by in-situ laser backscattering, to detect the onset of nucleation and adapt the operating curve accordingly, further enhancing the robustness of the approach. Simulation and experimental results indicate that adaptive concentration control is robust to variations in the nucleation, growth, or dissolution rates due to scale-up or other changes in the process conditions. Restricted access
Article: Simulation of mixing effects in antisolvent crystallization using a coupled CFD-PDF-PBE approach[show abstract] [hide abstract]
ABSTRACT: Antisolvent crystallization is widely used in the production of pharmaceuticals. Although it has been observed experimentally that the crystal size distribution is strongly influenced by the imperfect mixing of the antisolvent with the solution, these effects have not been adequately quantified. In this work, a turbulent computational fluid dynamics (CFD) code was coupled with a multienvironment probability density function (PDF) model, which captures the micromixing in the subgrid scale, and the population balance equation, which models the evolution of the crystal size distribution. The population balance equation (PBE) was discretized along the internal coordinate using a high-resolution central scheme. The presence of solids was addressed by treating the suspension as a pseudo-homogeneous phase with a spatial variation in the effective viscosity. This coupled CFD-PDF-PBE algorithm was applied to an antisolvent crystallization process in an agitated semibatch vessel, where the rising liquid level was modeled by a dynamic mesh. The effects of agitation speed, addition mode, and scale-up on the local primary nucleation and size-dependent growth and dissolution rates, as well as the crystal size distribution, were numerically investigated.
Article: Precise tailoring of the crystal size distribution by controlled growth and continuous seeding from impinging jet crystallizers[show abstract] [hide abstract]
ABSTRACT: The desired bioavailability and the method of drug administration and delivery can require stringent control on the crystal size distribution. Optimal control strategies are proposed to manufacture crystals with a targeted size distribution by combining controlled seeding by impinging jet crystallization with a batch crystallizer operating at a controlled constant growth rate. The same strategies apply if the impinging jet crystallization is replaced by any process equipment that can continuously provide crystal seeds, typically through the application of high supersaturation, to the batch crystallizer. Limitations to the achievable crystal size distributions and sensitivity to process operations are analyzed. Simulation results indicate that one of the strategies has promise for manufacturing pharmaceutical crystals of a desired size distribution.
Article: Determination of the kinetic parameters for the crystallization of paracetamol from water using metastable zone width experiments[show abstract] [hide abstract]
ABSTRACT: A new approach for the estimation of kinetic parameters of crystallization from data obtained during the determination of metastable zone width is presented. The method is based on a simplified dynamic model of the system, which combines the population balance and mass balance, as well as information provided by concentration and particle size distribution measurements using ATR-FTIR spectroscopy and laser backscat-tering to determine simultaneously the nucleation and growth parameters from the experimental data. The application of the proposed approach is illustrated for the cooling crystallization of paracetamol from water. The technique is compared to existing approaches for the determination of nucleation parameters from metastable zone width experiments and is used to corroborate the assumptions used in the classical approaches. The key conclusion is that the assumptions made in the existing approaches, which simplifies the parameters' estimation procedure, can result in substantial error in the nucleation kinetics.
Article: Modeling and Computational Fluid Dynamics− Population Balance Equation− Micromixing Simulation of Impinging Jet Crystallizers[show abstract] [hide abstract]
ABSTRACT: Computational fluid dynamics (CFD), micromixing modeling, and the population balance equation (PBE) are coupled to simulate the crystal size distribution in a confined impinging jet crystallizer. For the antisolvent crystallization of lovastatin in confined impinging jets, the simulation results show varying degrees of inhomogeneity in the supersaturation and the nucleation and growth rates in the impinging jet crystallizer for different jet Reynolds numbers. The shape of the crystal size distribution and its variation with jet Reynolds number are consistent with experimental observations of unconfined impinging jets. The crystallization of L-histidine was also modeled to predict the crystal size distribution of stable and metastable polymorphs obtained from a confined impinging jet crystallizer. It is predicted how to adjust the inlet velocity to tailor the crystal size distribution, while the polymorph ratio remained relatively constant. The simulation results presented in this manuscript demonstrate the possibility of designing impinging jet crystallizers by modeling and simulation, to provide increased process understanding and reduce the experimental material required for design.