title: Application of modeling to scale-up dissolution in pharmaceutical manufacturing.
abstract: Liquid mixing scale-up in pharmaceutical industry has often been based on empirical approach in spite of tremendous understanding of liquid mixing scale-up in engineering fields. In this work, we attempt to provide a model-based approach to scale-up dissolution process from a 2 l lab-scale vessel to a 4,000 l scale vessel used in manufacturing. Propylparaben was used as a model compound to verify the model predictions for operating conditions at commercial scale that would result in similar dissolution profile as observed in lab scale. Geometric similarity was maintained between both of the scales to ensure similar mixing characteristics. We utilized computational fluid dynamics (CFD) to ensure that the operating conditions at laboratory and commercial scale will result in similar power per unit volume (P/V). Utilizing this simple scale-up criterion of similar P/V across different scales, results obtained indicate fairly good reproducibility of the dissolution profiles between the two scales. Utilization of concepts of design of experiments enabled summarizing scale-up results in statistically meaningful parameters, for example -90% dissolution in lab scale at a given time under certain operating conditions will result in 75-88% at commercial scale with 95% confidence interval when P/V is maintained constant across the two scales. In this work, we have successfully demonstrated that scale-up of solid dissolution can be done using a systematic process of lab-scale experiments followed by simple CFD modeling to predict commercial-scale experimental conditions.
authors.affiliation: Pfizer Global Research and Development, Pfizer Inc, 558 Eastern Point Rd, Groton, Connecticut, 06340 USA. venkat.koganti@pfizer.com
authors.forename: Venkat
authors.initials: V
authors.lastname: Koganti
authors.forename: Fred
authors.initials: F
authors.lastname: Carroll
authors.forename: Richard
authors.initials: R
authors.lastname: Ferraina
authors.forename: Rick
authors.initials: R
authors.lastname: Falk
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Waghmare
authors.forename: Mark
authors.initials: M
authors.lastname: Berry
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Norris
authors.forename: Robert
authors.initials: R
authors.lastname: Leasure
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gaudio
mesh_terms: D019411:Clinical Laboratory Techniques; D003198:Computer Simulation; D004339:Drug Compounding / Q000379:methods*; D004345:Drug Industry; D005079:Excipients / Q000737:chemistry*; D057446:Hydrodynamics; D010226:Parabens / Q000737:chemistry*; D012995:Solubility
chemical_list: D005079:Excipients; D010226:Parabens; C006068:propylparaben