Problematic Crystal Growth – A Microfluidic Solution

Stainton, Paul (2019) Problematic Crystal Growth – A Microfluidic Solution. PhD thesis, University of Lincoln.

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Problematic Crystal Growth – A Microfluidic Solution
PhD Thesis
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Abstract

This project aim was to develop a method to increase the likelihood of a crystalline product, in systems
which are often difficult to crystallise. Eight organic acids were chosen for this study, citric, tartaric,
malonic, mandelic, oxalic, glutamic, adipic and salicylic acids. These acids exhibit varied solubility
profiles, from super soluble with citric acid to the insoluble with glutamic acid in ethanol. These acids
are well documented and are often used in food processing as well as medicines. A variety of methods
are used to produce crystals, all of which require the system to be in a state of supersaturation for
crystallisation to proceed. As supersaturation drives nucleation and crystal growth. Many methods of
classical recrystallization in solutions include; varying temperature, allowing the solvent to evaporate, or
causing supersaturation by the addition of an antisolvent.
Herein, the latter method is adopted, and a novel micro channel approach is employed, rather than
adding antisolvent to a batch crystalliser to produce supersaturation. For this project the solution was
mobilised through a narrow channel. A microfluidic reactor in Y-mixer configuration was employed. The
converging angle of the channel was varied, as with the width and flow rates to increase the chances of
laminar flow. Laminar flow allows the input solvent and antisolvent to run parallel in the initial mixing
stage, where subsequent mixing occurs by diffusion at the liquid-liquid interface. This modulation of the
diffusion band leads to a dramatic increase in supersaturation.
In this configuration using micro channels nucleation initiated and subsequent limited growth resulting
in nanoparticles. All size distribution of resulting particles was analysed by NanoSight, this allowed the
mapping of particle size distribution as crystallisation conditions were varied. This rapid onset of
nucleation within micro channel was successful where direct antisolvent addition in batch crystallisers
failed to induce crystallisation.
In first instance all acids were examined, and this was also extended to cocrystals, where more than one
different neutral non-solvent molecules produce a single crystal and salts.
Fours new phases of a polymorphic cocrystal system was synthesised, the coformers being a 2:1 ratio of
isonicotinamide and citric acid. Each structure was synthesised concomitantly, while three of the
systems are true polymorphs, the forth appeared to be a salt form of the same 2:1 coformers, which
also was found to be metastable. The order of stability according to Ficks law of the citric acid cocrystals
were in order of appearance the metastable salt, α, β and γ. However, the energetics were investigated
more fully, and it was found that by the lattice energies, the order is changed to salt, γ, α and β. It is
likely the latter order is accurate and can be explained by an increase in supersaturation at the point γ
appears, which is known to produce a more metastable phase, especially as the growth rate of γ was
much faster than β, once nucleated.

Another new salt malonic acid and nicotinamide (1:1) was compared to the known 1:2 polymorphic
cocrystals forms I and II. The morphology and growth rate of each phase was examined, and the salt was
found to be more stable compared to its stoichiometrically different polymorphic cocrystals.
The new forms were adapted to the microfluidic method where polymorphic and stoichiometric control
was successful. Whereby one form was produced in excess in solution, and after microfluidic reaction,
nucleates a more metastable polymorph. This shows the potential for a polymorphic drug to undergo
similar screening to produce a desirable form required to treat a patient.

Keywords:Microfluidics, solubility, secondary nucleation, crystal growth, cocrystals, nanoparticles
Subjects:B Subjects allied to Medicine > B230 Pharmacy
Divisions:College of Science > School of Pharmacy
ID Code:48495
Deposited On:09 Mar 2022 09:36

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