Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.703522
Title: Novel experimental techniques for biopharmaceutical analysis
Author: Zhou, Zhou
ISNI:       0000 0004 6062 0789
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
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Abstract:
Drug solubility and dissolution are important attributes controlling the bioavailability (BA) of oral dosage forms and can be determined in vivo, however it is expensive and can generate ethical issues. In vitro tests have been introduced utilising simulated gastrointestinal (GI) fluids, capturing the GI composition and conditions. However, individual variation and food-induced changes of the GI environment affecting drug BA have been recognised and in-depth knowledge is required to understand their effects on drug absorption. A fractional factorial design of experiment (DoE) and a 4-component mixture design (4MD) were used to investigate drug equilibrium solubility in media presenting in different levels of pH, concentration of amphiphiles, buffer, salt and pancreatin. Poorly soluble acidic, basic and neutral drugs with various physiochemical properties were tested. Solubility results correlate well with literature values, indicating they explored the solubility variation in the biorelevant space. Except pancreatin, all factors showed significant impacts on drug solubility. The descending order of average effect magnitude is pH, amphiphiles, buffer and salt, some of which also displayed remarkable drug specific interactions. Changing amphiphile ratios in 4MD further indicated that solubilisation is not a simple accumulative solubilisation of individual amphiphiles, but interactions between amphiphile-amphiphile and drug-amphiphiles. Powder dissolution using various biorelevant media indicates intrinsic dissolution rates (IDR) are positively correlated with equilibrium solubility and the diffusion coefficient of drugs in different ionisation states and interactions with amphiphiles. The above studies illustrate the convoluted nature of the GI fluids and provide a visualisation of how solubility/dissolution map varies within the ranges of GI fluid parameters. Statistical approaches can systematically detect critical factors affecting drug solubility and dissolution, and the output can potentially be applied in physiologically based pharmacokinetic (PBPK) model to achieve better in vivo-in vitro correlation (IVIVC).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.703522  DOI: Not available
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