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Title: An examination into the influence and change of solution structure on the polymorphic behaviour of 2, 6-dihydroxybenzoic acid
Author: Adam, Fatmawati Binti
ISNI:       0000 0004 2744 8294
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Polymorphism is a major problem in the manufacturing of many active pharmaceutical ingredient solid crystals. 2,6-dihydroxybenzoic acid solute behaves differently depending on the type of the solvent used i.e., it might act as a H -bond donor or acceptor and result in three different solid forms. This PhD work is mainly to investigate and develop the effect of solvent structure on the 2, 6-dihydroxybenzoic acid polymorph through molecular modelling and experimental study approaches. About 23 types of wet and anhydrous solvents were carried out using the gravimetric method to study the solubility and the effect on the solid form of 2, 6-dihydroxybenzoic acid. The solid forms were characterized using an optical microscope, XRD, DSC and TGA. The existence of water in the solvent used gave a big impact on the formation of the monohydra~e polymorph. In addition, the MSZW studies were run in acetonitrile and ortho-xylene using the turbidity approach to investigate the effect on the nucleation of FII and FI respectively. Besides, the molecular dynamic work has been used to investigate the solution, molten liquid and solid phases. An interesting result from the experiment work concluded that solvents which include the benzene ring structure such 0-, m-, p-xylene and toluene tend to crystallise the unstable FI solid form. The result has led to the hypothesis that solvent structure chemistry plays a significant role in the nucleation of 2,6-dihydroxybenzoic acid polymorphs. It is observed that ortho-xylene solution has provided a wider metastable zone width and higher nucleation order for the FI form compared to acetonitrile solution at different saturation concentration because of its different chemical nature. Meanwhile the novel molecular dynamics simulation approach has successfully recognized the effect of solvent structure towards the solubility and pre-nucleation of FI and FII solid form in toluene and chloroform solvent respectively. The Molecular Dynamic simulations employed the computer program DL _POLY and the result assessed using the radial distribution functions and diffusion coefficient from the simulation trajectory files. The result has found that the stronger intermolecular hydrogen-bonding interactions presence in the chloroform solution system has lead to the FII solid form. Besides, the selection of force field is considered as a crucial task to model the crystallization which depends on the simulated properties to be extracted such as RDF and diffusion.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available