Thesis
Study and characterisation of fasted state simulated intestinal fluid reflective of in vivo gastrointestinal variablility
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2025
- Thesis identifier
- T17309
- Person Identifier (Local)
- 202170927
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Adequate drug solubility in the gastrointestinal tract is essential for systemic therapy of orally administered medications. In order to measure the solubility of poorly soluble drugs in vitro, simulated intestinal fluid (SIF) is often used in place of human intestinal fluid (HIF). A suite of fasted state SIF, based on variability observed in a range of fasted state HIF samples was designed and used to study the relationship between the solubility of eight poorly soluble biopharmaceutics classification system class II drugs and the particle size of the colloidal structures formed by the drugs in the fluid. The drugs of interest included three acidic drugs (naproxen, indomethacin and phenytoin), three neutral drugs (felodipine, fenofibrate, griseofulvin) and two basic drugs (carvedilol and tadalafil). The overall aim of this research is to work towards a better understanding of the colloidal structures formed in SIF. Solubility was measured using high performance liquid chromatography and results indicated that the solubility was typically greater in the acidic drugs than in the neutrals or bases and that the solubility tended to increase with increasing media point (pH × [TAC]). Particle size was determined using both dynamic light scattering and nanoparticle tracking analysis. Dynamic light scattering data confirmed the polydispersity of size distribution within the samples analysed. Typically, as the concentration of amphiphiles (total amphiphile concentration ([TAC])) is increased, the particle size of the structures measured decreases. A comparison with the solubility data revealed that the general trend indicated that while solubility is to some extent affected by pH and [TAC] or (pH × [TAC]), the relationship between solubility and particle size is linked with [TAC]. Small angle X-ray scattering (SAXS) analysis was carried out at the Diamond Light Source national facility, using the laboratory SAXS (labSAXS) beamline on drug and drug free SIF samples and the data was processed at the University of Strathclyde. Unfortunately, there was no significant scattering measured in the sample fluids which is thought to be a result of samples that are too weakly scattering to be detected by a labSAXS instrument. The data obtained serves as excellent preliminary data for a future beamtime application using a synchrotron beamline. The final work explores a model, using simple mathematics, to estimate the number of drug molecules per colloid or mixed micelle structure in a series of SIF. The experimental data, collected in earlier chapters, was applied in both this calculation and a calculation to estimate the solubility enhancement provided in the SIF media. Analysis of the data and results indicates that there is a direct relationship between particle size of the colloidal structures and the number of estimated drug molecules per structure. As expected, as the particle size decreases, as does the estimated number of drug molecules per micelle. The larger structures can accommodate a greater number of drug molecules per micelle. Solubility enhancement was also calculated, with the acidic drugs, naproxen and indomethacin proving to be most solubility enhanced in the suite of simulated intestinal fluid.
- Advisor / supervisor
- Batchelor, Hannah
- Resource Type
- DOI
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PDF of Thesis T17309 | 2025-06-03 | Public | Download |