Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518970
Title: Thermodynamic stability and kinetic analysis of pharmaceutical channel hydrate during dehydration process
Author: Khoo, Ji Yi
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Abstract:
This thesis presents a detailed study into the thermodynamic stability and dehydration kinetics of a model pharmaceutical channel hydrate: carbamazepine dihydrate. The model compound of different crystal habits and particle size distributions was prepared via solventmediated crystallisation technique and agitated hydration method. The causal relationship between key drying process parameters (i.e. temperature, pressure, relative humidity and organic solvent partial pressure) and dehydration behaviour of this model compound was established using Dynamic Vapour Sorption instruments. Solid state phase transformation mechanisms under these drying conditions were elucidated through the evolution of crystal structural determined by X-ray Powder Diffraction technique. Dehydration kinetics of carbamazepine dihydrate were found to be markedly influenced by increasing temperature, reducing pressure, low humidity and higher organic solvent partial pressure, providing that the drying environment stays below the critical humidity and partial pressure for the dihydrate and acetone solvate formations. Activation energy determined from the kinetic study allows differentiation between the physically bound water in the bulk and water of crystallisation. Agglomerated dihydrate however possessed a high free water retention capacity when it exceeded a certain particle size distribution. This type of agglomerate exhibited distinct closed structure characteristics, leading to a relatively more stable form of carbamazepine dihydrate, than those without inclusion of unbound water. The agglomeration effect can thus be potentially controlled and exploited to expand the environmental stability envelope of the desired hydrated forms during manufacturing processes. Subtle changes in the drying environment were able to induce polymorphic anhydrates of different stabilities. The solid state phase transformation pathway of carbamazepine dihydrate to the four polymorphic anhydrates and an amorphous form was strongly correlated to types of dehydration mechanism, and specifically to the accessibility of and interaction with surrounding solvent vapours (i.e. hydrogen bonding propensity). Alkanol solvent vapourmediated dehydration process was found to facilitate the formation of the thermodynamically stable anhydrate, without any loss in product crystallinity. Dipolar aprotic solvents however induced the (intermediate) formation of least metastable anhydrate, depending on the local chemical environment of solute-solvent system. In conclusion, the surrounding solvent vapour plays a crucial role in drying strategies for a channel type hydrate, as it provides potential to predict and tailor the polymorphism of the desired forms which could have profound implications on the quality and performance of the final product.
Supervisor: Heng, Jerry Sponsor: HEFCE ; Imperial College
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.518970  DOI: Not available
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