Thesis
Nucleation mechanism of crystal formation during antisolvent or cooling induced crystallisation
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- Awarding institution
- University of Strathclyde
- Date of award
- 2010
- Thesis identifier
- T12762
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- This project studied the nucleation mechanism of crystal formation during antisolvent or cooling crystallisation of simple amino acids: D,L-valine and glycine. These amino acids can co-precipitate with proteins to form Protein Coated Microcrystals (PCMCs) in which the crystals create a solid support and the biomacromolecules cover their surface while remaining in a native state. The understanding of the formation mechanism of small microcrystals would help to better control and manage the process which leads to ordered attachment of biomacromolecules on their surfaces. Spectrophotometry, 1H nuclear magnetic resonance (NMR), dynamic light scattering (DLS) and optical microscopy were used to probe the evolution of the system from the transparent solution to a suspension of microcrystals. The nucleation mechanism of antisolvent crystallisation was found to involve formation of a transparent nanoemulsion composied of sub-micron valine-rich liquid nanodroplets with an average size and size distribution depending on supersaturation and the mixing conditions used during sample preparation. The supersaturated solutions prepared by cooling crystallisation, without agitation produced smaller nanodroplets and resulted in formation of only a few large crystals with an extremely slow crystallisation rate compared to samples with identical composition prepared by antisolvent crystallisation. The following nucleation mechanism of amino acids crystals is proposed: dissolution of amino acid into an aqueous/2-propanol mixture at concentration close to saturation results in spontaneous formation of a thermodynamically stable system consisting of amino acid rich liquid nanodroplets dispersed in amino acid solution; above a particular amino acid composition (consistent with the crystal solubility limit) the dispersed nanodroplets become metastable and shear induced coalescence of nanodroplets can provide access to a fast crystallisation pathway (non-classical); in the absence of shear the nanodroplets are colloidally-stable and crystallisation follows a much slower pathway (classical). The spontaneous formation of solute-rich nanodroplets below the crystalline saturation limit as well as formation of metastable solute-rich nanodroplets above this limit provides a paradigm shift which can be potentially used to develop fundamental understanding of nonclassical crystallisation phenomena. It will be crucial for better design and control of crystallisation processes in pharmaceutical applications.
- Resource Type
- Note
- This thesis was previously held under moratorium from 10th May 2011 until 10th May 2013.
- DOI
- Date Created
- 2010
- Former identifier
- 821694
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