Direct Measurements of Primary Nucleation Rates of p-Aminobenzoic Acid and Glutamic Acid and Comparison with Predictions from Induction Time Distributions

Abstract

The model-based estimation of primary nucleation rates from the probability distribution of induction time measurements has been used extensively in the literature; however, there has been no experimental validation of this approach via direct measurements of nucleation rates. In this work, we compared the nucleation rates obtained from the probability distribution model against that measured from in situ optical reflectance measurement (ORM) with p-aminobenzoic acid and l-glutamic acid as model compounds. Results reveal that the primary nucleation rates obtained from stochastic models are several orders of magnitude lower than those measured from a direct particle-counting technique. Although differences in fluid dynamics due to agitation and crystallizer geometry may have an effect, this tremendous discrepancy provides strong evidence that primary nucleation rates obtained from induction time measurements are not scalable and should not be used for interpretation of nucleation rates in industrial applications.

A Review of Experimental Methods for Nucleation Rate Determination in Large-Volume Batch and Microfluidic Crystallization

“…Crystal16 2 /Crystalline, colorimeter) 47,48 FBRM 49 (e.g. Lasentec "ParticleTrack" probe) 42,43,48,50 Naked eye 49 Turbidity via in-situ camera 51,52 3D Optical reflectance measurement (ORM) 53 Turbidity probe 54…”

Effect of Crystallization Conditions on the Metastable Zone Width and Nucleation Kinetics of p‐Aminobenzoic Acid in Ethanol

“…Previous studies examined the influence of agitation rate on nucleation of organic compounds in batch cooling crystallization through induction time measurements in small vials agitated by a magnetic stirrer and in laboratory‐scale stirred‐tank crystallizers. Generally, the induction time was found to decrease with higher agitation rate which was attributed to shear‐induced cluster aggregation under turbulent flow conditions .…”

“…In a number of studies, including some of the ones cited above, nucleation kinetics have been determined from the measurements of induction time using the isothermal method or the MSZW applying the polythermal method. Stochastic nucleation models have been extensively employed to extract nucleation rates generally from the measured induction time (see a succinct review in ) whereas methods developed by Nyvlt as well as Kubota and Sangwal have been widely used for the determination of nucleation rates from the MSZW data. In a recent study, Cedeno et al.…”

“…In a recent study, Cedeno et al. demonstrated that stochastic models significantly underpredict the nucleation rates compared with those obtained from the latter approaches , , . They claimed that the nucleation rates predicted by stochastic models may not be scalable and hence are not suitable for the design of industrial crystallizers.…”

“…This investigation focuses on the crystallization characteristics of p ‐aminobenzoic (pABA) acid in ethanol, particularly the effect of cooling and agitation rates on the MSZW and nucleation mechanism and kinetics. Although several groups , , , investigated the effects that cooling rates exert on the onset of nucleation and nucleation kinetics of pABA, these studies were carried out in very small volumes such as in vials and in droplets. The hydrodynamic and mixing conditions in such systems are not representative of large‐scale stirred‐tank crystallizers with a typical industrial configuration.…”