In recent years the pharmaceutical industry has seen a rise in the number of drug compounds with low aqueous solubility, and consequently poor oral bioavailablility. One potential solution to this problem is to formulate such compounds as solid dispersions, whereby the drug is dispersed in a carrier matrix in the solid state. In this thesis, the hypothesis that a number of drug-drug and drug-polymer intermolecular interactions influence the physical stability and dissolution performance of solid dispersions is considered. The aim is to use correlations between drug molecular structure and solid dispersion performance to develop a platform to rapidly assess whether drug compounds will have favourable properties when formulated as a solid dispersion. Amorphous felodipine/copovidone solid dispersions are used as a model system to develop a suitable testing regime with regards to physical stability and dissolution performance. A laser light scattering technique developed in this work shows that morphological changes in felodipine/copovidone films exposed to water are due to polymer swelling. A combination of dissolution testing methodologies is also used to suggest a mechanism for the dissolution of bulk solid dispersion samples. Contributions of individual functional groups in the felodipine analogues to the physical stability and dissolution performance of their amorphous solid dispersions are assessed. Blocking of the felodipine amine hydrogen-bond-donor with an N-methyl, and the removal of chlorine substituents are both shown to reduce the physical stability of the solid dispersions. Correlations between molecular descriptors and data from the above experiments show that drug compounds are more likely to crystallise from solid dispersions with copovidone if they have a low log P, low relative molecular mass and low polarizability. Such correlations can form the basis of a screening method for the molecular design of analogous drug compounds likely to form high-performance solid dispersions with copovidone.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:546687 |
| Date | January 2011 |
| Creators | Langham, Zoe A. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/12470/ |
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