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Adipic Acid Sonocrystallization in Continuous Flow Microchannels

Rossi, D; (2017) Adipic Acid Sonocrystallization in Continuous Flow Microchannels. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Crystallization is widely employed in the manufacture of pharmaceuticals during the intermediate and final stages of purification and separation. The process defines drug chemical purity and physical properties: crystal morphology, size distribution, habit and degree of perfection. Particulate pharmaceuticals are typically manufactured in conventional batch stirred tank crystallizers that are still inadequate with regard to process controllability and reproducibility of the final crystalline product. Variations in crystal characteristics are responsible for a wide range of pharmaceutical formulation problems, related for instance to bioavailability and the chemical and physical stability of drugs in their final dosage forms. This thesis explores the design of a novel crystallization approach which combines in an integrated unit continuous flow, microreactor technology, and ultrasound engineering. By exploiting the various benefits deriving from each technology, the thesis focuses on the experimental characterization of two different nucleation systems: a droplet-based system and a single-phase system. In the former, channel fouling is avoided using a carrier fluid to segment the crystallizing solution in droplets, thus avoiding the contact with the walls. In the latter channel blockage is prevented using larger channel geometries and employing higher flow rates. The flexibility of the developed setup also allows performing stochastic nucleation studies to estimate the nucleation kinetics under silent and sonicated conditions. The experiments reveal that very high nucleation rates, small crystal sizes, narrow size distributions and high crystal yields can be obtained with both setups when the crystallizing solution is exposed to high pressure field as compared to silent condition. It is concluded that transient cavitation of bubbles and its consequences are a significant mechanism for enhancing nucleation of crystals among several proposed in the literature. A preliminary study towards the development and design of a growth stage is finally performed. Flow pulsation is identified as a potential method to enhance radial mixing and narrow residence time distribution therefore achieving optimal conditions for uniform crystal growth. The results suggest that increasing values of Strouhal number as well as amplitude ratio improve axial dispersion. Helically coiled tubes are identified as potential structures to further improve fluid dynamic dispersion.

Type: Thesis (Doctoral)
Title: Adipic Acid Sonocrystallization in Continuous Flow Microchannels
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Sonocrystallization, Adipic acid, Microfluidics, Continuous flow, Ultrasound
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
URI: https://discovery.ucl.ac.uk/id/eprint/1557884
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