Soluble drug release from a non-swelling polymer matrix studied by magnetic resonance and other imaging methods.

Research in the area of controlled drug release is increasingly important in the pharmaceutical industry both from quality of life and commercial perspectives. One form of controlled release is of active components incorporated in solid polymer matrices. Understanding the nature and control of drug release is focal to the effective control and targeting of drugs. This will allow the prediction and modelling of new delivery systems. The aim of this thesis is to determine the principal manufacturing parameters affecting the release of a soluble drug from a non-swelling polymer matrix and so to understand better the dissolution mechanism. The matrix chosen for study is Eudragit and the chosen drug is Diltiazem Hydrochloride. Magnetic Resonance Imaging (MRI) experiments on Eudragit tablets with different levels of compression, drug loading and particle size exposed to water were made in order to observe the ingress of the water into the tablets. Nuclear Magnetic Resonance (NMR) spectroscopy was used to assess the amount of drug released. Stimulated-echo pulsed-field-gradient diffusion measurements of drug and water mobility in Diltiazem Hydrochloride solutions were made so as to estimate the self-diffusion coefficient of drug and water. Additional X-ray Computed Microtomography (muCT) and optical microscopy experiments were used to characterise the tablet microstructure. Experimental evidence shows that there is a rapid capillary uptake (≤ 10mins) of water into the initial pore space of a tablet ahead of the primary dissolution. This porosity is very small, less than 4% for pure compact Eudragit and even less for a drug loaded tablet. There is a slow subsequent dissolution characterised by a sharp diffusion front which separates the invaded and un-invaded regions. The water ingress proceeds linearly with the square root of time, t1/2. It is observed that water ingresses faster into tablets with small drug particle size and higher drug loading. Swelling of the whole tablet at intermediate ding loadings is seen as water ingresses into the system. However, no comparable swelling for either 100% polymer or 100% drug tablets is observed. There is evidence that as water ingresses into the tablet, air voids start to accumulate and ripen within the sample. Theoretical models are developed based on the experimental results in terms of diffusion and solubility parameters and the measured microstructure. In particular, a dimensionless time is introduced to best reflect the competition between dissolution and diffusion. This parameter is defined as the ratio of the time required for water to diffuse across the tablet and the time for the drug to dissolve