Prediction of Agglomerate Type during Scale-Up of a Batch Crystallization Using Computational Fluid Dynamics Models

Abstract

The impact of hydrodynamics on agglomeration during the crystallization of an active pharmaceutical ingredient (API) was investigated. The type of agglomerate formed was experimentally observed to correlate with agitation level at the laboratory and kilo-lab scales. It was hypothesized that differences in agglomerate type were related to differences in the collision rate of primary crystals, caused by differences in the local degree of agitation (e.g., the local values of fluid turbulence dissipation rate, ε). Spatial distributions of ε were determined from computational fluid dynamics (CFD) models at process scales ranging from laboratory (200 mL) to commercial scale (875 L). Higher values of ε were calculated for conditions shown to result in the formation of rounded, compact agglomerates, while at the lower values of ε, looser agglomerates of flakelike particles were observed. Predictions for pilot-plant-and commercial-scale crystallization operating conditions were made using local ε values as the scaling parameter.

Aggregation of growing crystals in suspension: I. Mumtaz revisited

“…Mumtaz's work has found applications in industrial crystallisation (Braun et al, 2004;Brunsteiner et al, 2005;Chen et al, 2004;Chen et al, 2003;Chew et al, 2004;Falk et al, 2011;Hollander et al, 2003;Ilievski, 2001;Ilievski and Livk, 2006;Kramer and Jansens, 2003;Li et al, 2001;Livk and Ilievski, 2007;Rielly and Marquis, 2001;Wang et al, 2006;Yokota et al, 1999;Zauner and Jones, 2000), precipitation (Lakshminarayanan and Valiyaveettil, 2003;Lewis and Mangere, 2011;Lindenberg et al, 2008;Lawler, 2008, 2010;Wagterveld et al, 2012;Wan et al, 2011), nanoprecipitation (Jia et al, 2008;Pujol et al, 2004;Schwarzer and Peukert, 2005;Schwarzer et al, 2006), population balance modelling (Balakin et al, 2012;Briesen, 2006;Briesen, 2007;Derksen, 2002;Hollander et al, 2001a;Hollander et al, 2002;Hollander et al, 2001b;Mersmann et al, 2002;Reinhold and Briesen, 2012;Sgraja et al, 2010) and colloid science (Gruy, 2012;Kind, 2002).…”

Validation of Novel Lattice Boltzmann Large Eddy Simulations (LB LES) for Equipment Characterization in Biopharma

“…Thereby, its applicability is shown to address issues in up-and downstream development as well as for the production of biopharmaceuticals. Typical topics are risk mitigation during transfer, troubleshooting and reduction in lab experiments [5,6]. In line with the digitalization trend in the biopharmaceutical industry, other modeling approaches for upstream and downstream processing have also recently gained recognition [4,[7][8][9].…”

A Review of Computational Fluid Dynamics (CFD) Simulations of Mixing in the Pharmaceutical Industry

“…CFD simulations have become a valuable tool for process design, optimization, and scale-up [1]. In the pharmaceutical industry, stirred-tank reactors are used due to efficient mixing and the possibility of simple scale-up and appropriate mixing in agitated vessels directly relates to the quality of the product for both drug substance, specifically cell culturing and protein purification, and drug product manufacturing [2].…”

“…The presented CFD modeling papers include simulations made in collaboration with or supported by Roche [3], Sanofi [2], Sandoz [4], Krka d.d. [5], Pfizer Inc. [1,6], LEO Pharma A/S [7,8], Astra Zeneca Pharmaceutical Development R&D [9], GlaxoSmithKline [10,11] and one performed with the support of an industrial consortium including BASF, ICI, Malvern Instruments, AstraZeneca, GlaxoSmithKline and Pfizer [12].…”