Experimental Estimation of Primary and Secondary Nucleation Kinetics of Antisolvent Crystallization As Measured by Induction Time

Abstract

Methodologies for the estimation of nucleation rate parameters, which are rate constants and orders in antisolvent crystallization, are proposed with the aim of applying to the pharmaceutical industry. Primary and secondary nucleations are clearly distinguished and these rates are defined as power laws of the supersaturation in our antisolvent crystallization model. Primary nucleation rate parameters were experimentally determined using the theoretical equation about the modified induction time in antisolvent crystallization based on the past study reported by KubotaN. Kubota, N. J. Cryst. Growth], in which the induction time is defined as the time when the number density of the crystal reaches a fixed value. It is difficult to estimate the number density at the detection point using an experimental approach. Therefore, a numerical approach was used to determine the number density. The estimated number density at the detection point can determine the secondary nucleation rate parameters. These determined nucleation rate parameters become effective factors for simulating the number mean diameter in antisolvent crystallization and can be applied to the pharmaceutical industry.

Nucleation Kinetics Estimated by Using the Modified Induction Time in Cooling Crystallization and the Applicability to the Combined Process of Antisolvent and Cooling Crystallization

“…nucleation rate parameters e primary nucleation rate parameters were determined using the modi ed induction time (t indm ) in this study. Two types of equations that describe the relationship between the modi ed induction time and the supersaturation for antisolvent crystallization were proposed in a previous study (Kodera et al, 2019b). ese equations were derived based on the original interpretation of the metastable zone width or induction time proposed by Kubota (2010).…”

“…e primary nucleation rate parameters were determined using Eq. (4) and the secondary nucleation and growth rate parameters were determined by parameter optimization as in our previous studies (Kodera et al, 2019a(Kodera et al, , 2019b. e data that were normalized and then used for optimization were the number mean diameter of the produced crystal and the measured solute concentration.…”

“…e seed crystal (with a seed weight to theoretical product weight ratio of 0.024) was added to the ltered solution at 30°C, and the solution was cooled to 10°C at a rate of 1°C/min. 2.2.3 Estimation of the nucleation rate parameters and evaluation of determined kinetic parameters To determine the primary nucleation rate parameters, the modi ed induction time was determined by visually detecting nucleation (Kodera et al, 2019b) with the use of a white LED light on the side wall of the crystallizer for illumination. Paracetamol (approximately 28 g) was dissolved in the IPA/water mixture (approximately 500 g) at 30°C.…”

“…In our study, this number density was estimated by combining experimental results and numerical calculations to properly distinguish between primary and secondary nucleation. We employed a sensitive detection method for primary nucleation, i.e., visual detection; therefore, our estimated number density at the detection point was smaller than that determined by other research groups (Ó'Ciardhá et al, 2011;Kodera et al, 2019b). is method can also be applied to cooling crystallization.…”

“…is could reduce experimental and developmental e orts necessary in the pharmaceutical industry. An antisolvent crystallization model and methods for estimating growth rate parameters and nucleation rate parameters, which include the rate parameters for primary and secondary nucleation, were proposed in our previous studies (Kodera et al, 2019a(Kodera et al, , 2019b. is model and these estimation methods can also be applied to cooling crystallization because the supersaturation in all of the rate equations are expressed in terms of the solute concentration.…”