2021
DOI: 10.1021/acs.oprd.1c00209
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Investigation of Wet Milling and Indirect Ultrasound as Means for Controlling Nucleation in the Continuous Crystallization of an Active Pharmaceutical Ingredient

Abstract: This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on partic… Show more

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Cited by 10 publications
(10 citation statements)
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“…Control over particle size distribution can be achieved by controlling nucleation and growth during crystallization or implementing postcrystallization techniques such as milling, selective dissolution, etc. Nucleation and growth can be controlled through various methods, such as using upstream processes like ultrasound or wet milling , to induce primary nucleation or employing different crystallizers to alter hydrodynamics and mixing conditions. There have been several recent studies on using nonconventional crystallizers to tailor particle size distribution. Another way to control the crystallization rate is by feedback control through two approaches: model-free control and model-based control.…”
Section: Introductionmentioning
confidence: 99%
“…Control over particle size distribution can be achieved by controlling nucleation and growth during crystallization or implementing postcrystallization techniques such as milling, selective dissolution, etc. Nucleation and growth can be controlled through various methods, such as using upstream processes like ultrasound or wet milling , to induce primary nucleation or employing different crystallizers to alter hydrodynamics and mixing conditions. There have been several recent studies on using nonconventional crystallizers to tailor particle size distribution. Another way to control the crystallization rate is by feedback control through two approaches: model-free control and model-based control.…”
Section: Introductionmentioning
confidence: 99%
“…Gassing crystallization hence poses a suitable alternative to the conventional method of seeding for controlling the crystallization process and can principally be operated in inert atmosphere by gassing with an inert gas. One advantage compared to other nucleation methods like sonication , or wet milling is the simple application without extensive additional equipment and less energy input to the system, by introducing the inert gas already present in the system into the solution. Here it should be noted that the choice of inert gas may affect the crystallization process, as studies by Ceyhan et al and Huang et al suggest, explained by the combined effects of dissolved gas on solubility and crystallization kinetics and changing properties of the gas–liquid interface.…”
Section: Introductionmentioning
confidence: 99%
“…Another problematic scenario is a wide MSZW, which makes it hard to control crystallization generating particles out of spec. External intervention such as sonication and milling can be used to induce nucleation . As pointed out in the previous literature, it can be very challenging to achieve desired physicochemical properties for the compounds in practice; the motivation of the current work is to review and summarize relevant strategies useful to meet these challenges.…”
Section: Key Process Parameters To Obtain Large Particle Sizesmentioning
confidence: 99%