Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

Abstract

Continuous crystallization in tubular crystallizers is of particular interest to the pharmaceutical industry to accurately control average particle size, particle size distribution, and (polymorphic) shape. However, these types of crystallizers require fast nucleation, and thus, short induction times at the beginning of the flow process, which is challenging for larger and complex organic molecules. High shear and/or the presence of bubbles were identified to influence the nucleation behavior. This work investigates the effects of both high-shear mixing and ultrasound on the anti-solvent crystallization of paracetamol in acetone-water. Both devices generate intense amounts of shear and gas bubbles. Generally, the results show that increasing input power decreases the induction time significantly for both the rotor-stator mixer and ultrasound probe. However, the induction time is almost independent of the supersaturation for the ultrasound probe, while the induction time significantly increases with decreasing supersaturation for the rotor-stator mixer. In contrast, the particle size distribution for the rotor-stator mixer is independent of the supersaturation, while increasing supersaturation decreases the particle size for the ultrasound probe.

Determination of the Nucleation and Growth Kinetics for Aqueous L-glycine Solutions from the Turbidity Induction Time Data

“…The average growth rates and the corresponding standard deviations (SD) obtained from the photomicroscopic growth experiments are listed in Table 5. Figure 8 displays the growth rate data for various supersaturation from 303.15 K to 323.15 K. The growth rate obtained here is consistent with that reported by Han et al [23] for aqueous α-form L-glycine solutions at S = 1.35 and T = 303.15 K. Substituting Equation (11) into Equation (4) for g = 2 yields:…”

“…The induction time is defined as the elapsed time between the creation of the supersaturation and the appearance of detectable nuclei at a constant temperature. Although the induction time can be detected by visual observation of the crystal's appearance [7,11], turbidity measurements have been commonly adopted in recent years to determine the induction time by detecting the change in the intensity of transmitted light in solution at the onset of nucleation [12][13][14][15][16][17]. Traditionally, determination of the interfacial energy from the induction time data is often simplified by assuming t i −1 ∝ J [1,[4][5][6][7][8][9][10].…”

Enhanced crystallisation kinetics of edible lipids through the action of a bifurcated streamer

“…4 are consistent with the results discussed in the previous solid fat content section, where the presence of HIU, at all acoustic powers studied, alter the crystallisation process and lead to the formation of a more densely packed crystalline network. This is consistent with observations seen previously within different lipid media and provides evidence for a secondary nucleation effect that occurs as a consequence of enhanced crystal contact and shear 22,41,42 in the presence of HIU.…”

Nucleation kinetics for primary, secondary and ultrasound-induced paracetamol crystallization

“…The effect of US on the induction time or nucleation kinetics has also been extensively studied. In both batch 5,[12][13][14] and continuous crystallizers 15,16 sonication has been shown to increase the nucleation rate compared to silent crystallization.…”