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.