Investigation of Wet Milling and Indirect Ultrasound as Means for Controlling Nucleation in the Continuous Crystallization of an Active Pharmaceutical Ingredient

Yang, Yihui; Ahmed, Bilal; Mitchell, Christopher; Quon, Justin L.; Siddique, Humera; Houson, Ian; Florence, Alastair J.; Papageorgiou, Charles D.

doi:10.1021/acs.oprd.1c00209

Cited by 2 publications

(2 citation statements)

References 49 publications

(67 reference statements)

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“…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%

Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements

Liu

2022

Org. Process Res. Dev.

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Obtaining a particle size within the specifications for a pharmaceutical compound in an industrial crystallization can be a challenging task. The events affecting the final particle size of the product include nucleation, growth, breakage, and agglomeration, which are often convoluted. Secondary nucleation may significantly influence the particle size distribution. The strategies and techniques relevant to obtaining an in-spec particle size in crystallization are summarized and discussed from a perspective of process parameters. The effect of cooling profiles, seeding strategies, as well as mixing by agitation are reviewed, and an efficient and controlled crystallization process may be achieved using an optimized combination of these conditions. Multiple characterization methods for particle size and distribution are compared, and the discrepancies associated with the measurements are addressed.

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Section: Key Process Parameters To Obtain Large Particle Sizesmentioning

confidence: 99%

Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements

Liu

2022

Org. Process Res. Dev.

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“…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%

Inert Gassing Crystallization for Improved Product Separation of Oleo-Chemicals toward an Efficient Circular Economy

Seifert

Simons

Gutsch

et al. 2022

Org. Process Res. Dev.

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Selective product crystallization for separation and recycling of homogeneous catalysts represents one novel promising method to develop sustainable chemical processes. This specific application holds two main challenges: (1) In the crystallization and subsequent filtration and washing process, isolation of a pure crystalline product is required to obtain the maximum quantity of catalyst in the filtrate for recycling, and (2) the entire process must be operated in an inert atmosphere to maintain the catalytic activity of oxygen-sensitive species. Key to the isolation of a pure product is precise control of the crystallization process, which is realized in this work by gassing-induced nucleation using inert argon. Assuming that the nucleation step is crucial for the control of particle properties of the crystalline product and the related efficiency of downstream separation by filtration and washing, we systematically investigated the effect of controlled nucleation by gassing on these quantities using the oleo-chemical model system, 1,12-dimethyl dodecanedioate/methanol. The experimental results verify that by gassing with argon, the nucleation step can be initiated at lower supersaturation compared to uncontrolled cooling crystallization with spontaneous nucleation despite the comparably small metastable zone width of the investigated model system in the range of 1–3 K. It is further demonstrated that consequently less nuclei are formed that grow to larger product crystals, which can be more efficiently separated from the mother liquor in the filtration and washing step, reducing the mother liquor leaching to the isolated product to nearly 100 ppm. Finally, it is verified that gassing crystallization with argon offers a considerable benefit for the isolation of a pure crystalline product while maintaining inert operating conditions required for recycling of oxygen-sensitive catalysts.

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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

Cited by 2 publications

References 49 publications

Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements

Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements

Inert Gassing Crystallization for Improved Product Separation of Oleo-Chemicals toward an Efficient Circular Economy

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