The process of pharmaceutical tablet dissolution is a vital stage in the delivery of
active pharmaceutical ingredients (APIs). The constituent components and their
spatial arrangement within the tablet determine the release characteristics of the
API. It is therefore important to understand and characterise the various processes
and component interactions that occur during tablet dissolution. Computational
simulations of tablet dissolution can be used to obtain parametric sensitivities and
optimise formulations so that the desired API release profile is achieved.
This thesis describes the methods behind modelling the behaviour of non-swelling
and swelling tablets, the mathematical validation of the models, parametric studies
and the experiments which were used to obtain parameters and verify the models.
The experimental method used in this work is Fourier Transform Infrared (FTIR)
spectroscopic imaging, which, when using an attenuated total reflection (ATR) accessory
and flow cell, enable chemical and spatial information to be obtained from
the tablet as it dissolves. UV/Visible spectroscopy was also used to obtain drug
release information.
The non-swelling model discretised a tablet over a Cartesian grid and solved the
mass transfer equations (dissolution and diffusion) to obtain drug release profiles.
Two parametric studies were conducted where the particle size distribution and mass
fractions were varied in one, and the API diffusivity, saturated concentration and
mass fraction in the other to see what effect these had on drug release, demonstrating
the importance of the choice of excipient and the impact of particle size on release
variability. For experimental validation, tablets containing different quantities of
polyethylene glycol and nicotinamide were dissolved and imaged, and optimisation
was used to obtain the pure component saturated concentrations. The model was
then tested against a different tablet to demonstrate the predictive capability of the
model.
The swelling model discretised a tablet into small cylindrical particles, whose
size was proportional to the mass of components within them and whose motion
was determined using the Discrete Element Method (DEM). As water diffused into
polymer particles, they could expand, resulting in macroscopic swelling. The DEM
model of a swelling and dissolving tablet was validated against a numerically exact
model of the same tablet and parametric studies were conducted into the effect of
polymer disentanglement threshold, polymer equilibrium water fraction and polymer
dissolution rate. The model was also optimised against a dissolving tablet containing
HPMC to obtain parameters for this excipient.
To conclude, both models were implemented, validated and found to accurately
describe the dissolution kinetics of both swelling and non-swelling tablets.