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  • Modeling and Computational Fluid Dynamics-Population BalanceEquation-Micromixing Simulation of Impinging Jet Crystallizers

    Xing Yi Woo,, Reginald B. H. Tan,*,, and Richard D. Braatz*,

    Department of Chemical and Biomolecular Engineering, UniVersity of Illinois at Urbana-Champaign,600 South Mathews AVenue, Urbana, Illinois 61801, Department of Chemical and BiomolecularEngineering, National UniVersity of Singapore, 4 Engineering DriVe 4, Singapore 117576, andCrystallization and Particle Science Group, Institute of Chemical and Engineering Sciences,1 Pesek Road, Jurong Island, Singapore 627833

    ReceiVed January 27, 2008; ReVised Manuscript ReceiVed August 11, 2008

    ABSTRACT: Computational fluid dynamics (CFD), micromixing modeling, and the population balance equation (PBE) are coupledto simulate the crystal size distribution in a confined impinging jet crystallizer. For the antisolvent crystallization of lovastatin inconfined impinging jets, the simulation results show varying degrees of inhomogeneity in the supersaturation and the nucleation andgrowth rates in the impinging jet crystallizer for different jet Reynolds numbers. The shape of the crystal size distribution and itsvariation with jet Reynolds number are consistent with experimental observations of unconfined impinging jets. The crystallizationof L-histidine was also modeled to predict the crystal size distribution of stable and metastable polymorphs obtained from a confinedimpinging jet crystallizer. It is predicted how to adjust the inlet velocity to tailor the crystal size distribution, while the polymorphratio remained relatively constant. The simulation results presented in this manuscript demonstrate the possibility of designing impingingjet crystallizers by modeling and simulation, to provide increased process understanding and reduce the experimental material requiredfor design.

    1. Introduction

    Impinging jet crystallization, developed by Midler et al.1 morethan a decade ago, is recognized as one of the most reliableapproaches to produce small crystals with a narrow sizedistribution. The basic principle in this design is to utilize highintensity micromixing of fluids to achieve a homogeneouscomposition of high supersaturation before the onset of nucle-ation. As highlighted by DAquino,2 this technology is nowbeing used by various pharmaceutical companies in theircommercial drug production.3-5 The direct production of smalluniform crystals of high surface area that meet the bioavailabilityand dissolution requirements can eliminate the need for milling,which can produce dust issues, yield losses, long productiontimes, polymorphic transformation, and amorphization.6-9 Anarrow particle size distribution is especially important forinhalation drugs, in which the specific size range depends onthe region of the human respiratory tract where the drug istargeted.10-12 Continuous crystallization using T-mixers andY-mixers to produce small uniform particles also have beenexperimentally and numerically studied.13-17

    Numerous experimental studies have been carried out to gaina deeper understanding of the impinging jet crystallizationprocess so as to increase efficiency during process developmentand optimization. For the antisolvent crystallization of lovastatin,Mahajan and Kirwan18 measured the dependency of the crystalsize distribution (CSD) on the jet velocity and level ofsupersaturation in the impinging jet crystallizer operated in non-submerged mode. Hacherl et al.19 investigated the effects of jetvelocity on the crystal size distribution and the proportion ofhydrates formed for the reactive crystallization of calciumoxalate. Johnson and Prudhomme20 experimentally investigated

    the dependency of the crystal size distribution on the jet velocityand the inlet concentrations for a confined and submergedimpinging jet crystallizer in which amphiphilic diblock copoly-mers were added to inhibit crystal growth. Recently, Marchisioet al. applied confined impinging jets to reactive precipitation,and reported on the dependence of particle size distribution withjet velocity and inlet reactant concentrations.21

    The mixing in impinging jets has been characterized by anoverall micromixing time by Mahajan and Kirwan18 and Johnsonand Prudhomme22 using competitive reactions. The micromix-ing times, correlated to the jet velocity, the fluid properties, andsome geometrical aspects of the impinging jet crystallizer, canbe used to establish scale-up criteria for impinging jets. Thethree-dimensional turbulent flow field in the impinging jetchamber also can be visualized experimentally (for example,by using laser-induced fluorescence, laser doppler anemometry,or particle image velocimetry) or simulated using computationalfluid dynamics (CFD).23-26 The modeling of mixing andreactions in impinging jets has been widely studied as well.27-31

    The extension of experimental visualization and simulations thatinclude the crystal nucleation and growth would offer a deeperunderstanding of impinging jet crystallization, which could speedup the design of impinging jets and reduce the time required toidentify the operating conditions that produce the desired crystalsize distribution. Consequently, the time required to bring a newdrug to the market could be reduced.

    In this paper, a coupled CFD-micromixing-populationbalance algorithm32 is used to model the crystallization processin an impinging jet crystallizer. The geometry of the confinedimpinging jet is adapted from Johnson and Prudhomme.22 TheCFD simulations of confined impinging jets of similar geometryhave been reported recently by Liu and Fox,30 Marchisio et al.,21

    and Gavi et al.31 Liu and Fox30 and Gavi et al.31 modeled theturbulent macromixing using the k- turbulent model withenhanced wall treatment and the micromixing using the two-environment direct quadrature method of moments (DQMOM)-interaction by exchange with the mean (IEM) model33 with the

    * Corresponding author. (R.D.B.) E-mail: [email protected]; phone: 217-333-5073; fax: 217-333-5052. (R.B.H.T.) E-mail: [email protected]; phone: 65-65166360; fax: 65-67791936.

    University of Illinois at Urbana-Champaign. National University of Singapore. Institute of Chemical and Engineering Sciences.

    CRYSTALGROWTH& DESIGN

    2009VOL. 9, NO. 1

    156164

    10.1021/cg800095z CCC: $40.75 2009 American Chemical SocietyPublished on Web 12/09/2008

  • micromixing parameter as a function of local turbulent Reynoldsnumber. They reported good agreement with the experimentalresults (conversion of the slower reaction in competitive-parallelreactions at the outlet of the confined impinging jets) reportedin Johnson and Prudhomme22 for a wide range of jet Reynoldsnumbers. These studies motivate our use of the turbulent/micromixing model of Liu and Fox30 and Gavi et al.31 to modelthe antisolvent crystallization process in confined impinging jets.

    In the first part, the full crystal size distribution for theantisolvent crystallization of lovastatin in the confined impingingjet crystallizer was simulated by coupling the macromixing andmicromixing models with the solution of the population balanceequation as described by Woo et al.,32 and the effects of jetvelocity are numerically investigated. In the second part, theantisolvent crystallization of two polymorphic forms of L-histidine in the confined impinging jet crystallizer is presented.To the authors knowledge, this is the most thorough simulationstudy on impinging jet crystallizers reported to date.

    2. CFD-Micromixing-Population Balance Model

    The development and implementation of the CFD-micro-mixing-population balance coupled algorithm is presented indetail by Woo et al.,32 which applied the integrated model tosimulate semibatch antisolvent crystallization in a stirred tank.The mathematical details of the models, for application toconfined impinging jet crystallization, are presented in thissection.

    2.1. Macromixing. In this work, the macromixing wasmodeled by the Reynolds-averaged Navier-Stokes (RANS) andtransport equations and the k- turbulence model with enhancedwall treatment34,35 due to the small volume of the mixingchamber and the confinement of the impinging region by thechamber walls, computed using a commercial CFD software(Fluent 6.2.16, Fluent Inc.). The equations are summarizedbelow; the reader is referred to the software documentation forthe nomenclature and more details on the equations.35,36

    continuity equation:Ft

    + (FVb)) 0 (1)

    momentum conservation equation:

    t(FVb)+ (FVbVb))

    - p+ (c)+Fgb (2)

    k- equations: t

    (Fk)+ (FkVb))

    [(+ tk) k]+Gk-F, t(F)+ (FVb)) [(+ t) ]+C1kGk -C2F

    2

    k(3)

    where t ) FCk2/

    scalar transport equation:

    t(Fk)+ (FVbk -F(Dm +

    Dt) k)) Sk (4)

    where Dt ) t/FSct.The choice of the k- turbulence model with enhanced wall

    treatment is based on the analysis presented by Liu and Fox30

    and Gavi et al.31 Besides the good agreement with theexperimental results in Johnson and Prudhomme,22 Gavi et al.31

    showed that the flow field prediction obtained with RANS usingthe k- turbulence model with enhanced wall treatment agreedreasonably well with large eddy simulation (LES) results.

    2.2. Micromixing. Micromixing (mixing at a molecularlevel) was modeled by a three-environment (N ) 3) presumed-probability density function (PDF) micromixing model, whichapproximates the fluctuations of the species concentrations onthe subgrid scale.37 One inlet stream (saturated solution) isrepresented by Environment 1, and the other inlet stream(antisolvent) is represented by Environment 2. Environments 1and 2 transfer matter by engulfment into Environment 3, wherecrystallization occurs in a supersaturated solution.33 The equa-tions, which are coupled with the CFD algorithm,32 are

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