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Title: Solid oral dosage forms of sparingly soluble compounds: enhancement of their release profiles to predict bioavailability of dissolution rate limited drugs
Author: Matthews, Darren W.
Awarding Body: Aston University
Current Institution: Aston University
Date of Award: 2006
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Two drugs, troglitazone and atovaquone, were selected based upon them being poorly soluble in aqueous media and being relatively lipophilic. These drugs were incorporated into solid dispersions, of various drug to polymer ratios, to improve their solubility. Three polymers were chosen to be the carrier in the solid dispersions; two gastric soluble polymers hydroxypropyl methylcellulose, polyvinylpyrrolidone and one enteric polymer, hydroxypropyl methylcellulose phthalate. Dissolution runs, in Fasted State Simulated Intestinal Fluid (FaSSIF), were performed upon the drugs, physical mixtures and the solid dispersions. The results showed that incorporation of the drug into the solid dispersion enhanced the dissolution of both drugs, the enhancement was more pronounced with troglitazone. Increasing the polymer:drug ratio and the polymer used had an effect upon the dissolution of the drugs. Physical characterisation of the dispersions showed that troglitazone was more compatible with the polymers than atovaquone. Examination of the dissolution of troglitazone in various gastric media yielded the information that the selection of dissolution medium is important. Exposure of the troglitazone dispersions to gastric medium prior to dissolution in FaSSIF showed that there are advantages to using an enteric polymer. A computer model was derived in an attempt to predict the in vivo performance of the dispersions. The influence of the carrier upon the dissolution of the drugs from a solid dispersion was investigated. It was shown that the polymers improved the dissolution rate of troglitazone when pre-dissolved. Investigation into the ability of each polymer at preventing the recrystallisation of the drug from a supersaturated solution found that polymers helped slow down the rate of recrystallisation. Two methods were investigated, ultra-violet spectroscopy and micro-viscometry, to analyse the dissolution of the polymers. This showed that the troglitazone dispersions were, to some extent, controlled by the dissolution rate of the polymer, whereas the atovaquone dispersions were less controlled by the polymer dissolution.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacy ; Biological Sciences