Crystallization Kinetics of Ampicillin Using Online Monitoring Tools and Robust Parameter Estimation

Abstract

Crystallization kinetics of ampicillin were estimated from induction-times and seeded and unseeded experiments. The concentration of ampicillin in solution was monitored by polarimetry and refractometry, while crystals were analyzed by focused beam refractive measurements and light microscopy. Variations of solute concentration with time, along with measured induction times were used to estimate parameters in kinetic expressions for primary nucleation, secondary nucleation, and crystal growth rate. Experimental data were obtained in runs involving different rates of change of pH, mass of seed crystals, and initial supersaturation. These data were used in parameter-estimation routines consisting of a stochastic minimization to localize a set of parameters spanning all the experiments, followed by a deterministic minimization to refine the parameters. The result was a set of parameters that fit a range of conditions of seeded and unseeded crystallizations and gave good estimates of desupersaturation rates.