Solid dispersions have been employed as a method for improving the dissolution, and hence the bioavailability, and targeting the colon by Class II poorly-water soluble drugs. This project aims to enhance the solubility of the poorly water-soluble drug gefitinib (ZD), which is the first selective epidermal growth factor (EGFR) tyrosine kinase inhibitor that blocks signal pathways implicated in solid tumour growth and metastasis. Furthermore, to target the colon to improve the efficacy and to reduce the adverse effects of ZD by formulation as solid dispersions using spray drying. Methylmethacrylate polymers such as Eudragit S 100 was used for colon targeting, and Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC) were used to enhance the solubility of the drug. A rapid, cost-effective and precise reverse phase HPLC method has been developed to quantify ZD in the formulated solid dispersions. This method was validated using the recommended procedure, and it met the pharmaceutical industry guidelines that are recommended by the ICH and FDA. The developed method of analysis was reproducible, specific, and has demonstrated a isocratic separation mode of ZD. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD_, scanning electron microscope (SEM), and attenuated total reflectance (ATR) were used to investigate the crystalline structure changes of ZD in the dispersion as well as the molecular interaction between the drug and polymer, Dissolution studies (DS) were performed across a range of pH values. Formulations were evaluated by cytotoxicity studies (MTT & Neural red tests) using Caco-2 cell line. A rotating modified cylinder method was used to evaluate the duration of adhesion of HPMC and PVP formulated solid dispersions to excised goat intestine. DSC and XRPD studies confirmed that the spray dried dispersions were amorphous. Infrared spectroscopic experiments revealed the formation of hydrogen bonds between the drug and the two polymers used in the study. Dissolution studies showed a carrier controlled drug release that was achieved with solid dispersion containing a 10% drug loading with 80:20 PVP- Eudragit S 100, and HPMC- Eudragit S 100. The morphological differences between the pure drug, physical mixtures and solid dispersions were evident from the SEM images. The images revealed that the pure drug particles were needle shaped; the particle size was reduced in the solid dispersions that subsequently enhanced the drug dissolution profile. The formulated solid dispersions were subjected to accelerated storage conditions (40 [degrees]C [plus or minus] 2 [degrees] C/75%RH [plus or minus] 5%RH) over the period of 6 months. The presence of strong molecular interactions between drug and polymers and the high glass transition temperature of the resultant solid dispersions ensured they remained amorphous for at least six months under accelerated storage conditions. The mucoadhesion study showed that the HPMC solid dispersion formulations had a higher duration of adhesion than PVP solid dispersion formulation. The placebo formulation containing only the polymers showed no toxic effect on Caco-2 cell line in the cell viability assay. Therefore, it can be safely concluded that the formulated solid dispersions have no initial inhibitory effect compared to the pure drug.

The majority of prostate cancer cases are shown to be androgen-dependant for growth as the blocking of androgen production has shown to reduce the size of prostate metastasis. The biosynthesis of the androgens is catalysed by the cytochrome P450 enzyme 17a-hydroxylase/17,20-lyase (P45017a) by converting the C21 steroids (pregnenolone and progesterone) to the androgens (dehydroepiandrosterone and androstenedione, respectively). Inhibition of P45017a would therefore bring about a decrease in the level of androgen production and furthermore prevent an increase in the stimulation of androgen-dependent prostate cancer cells. The current study was concerned with designing and synthesising compounds which were able to donate a lone pair of electrons to the Fe atom of the haem group with in the active site of the enzyme P45017a. As well as this, we were also interested in being able to mimic the C(3) of the natural substrate by varying the R group. In doing so, we were able to observe the impact of the interactions which take place within the active site. The compounds synthesised are based on the benzyl imidazole and the imidazolphenyl ethanonebackbone, where a small number of the synthesised products are phenyl alkyl imidazole based compounds, in order to consider physiochemical factors like hydrophobicity. Overall, the results of the study showed that the benzyl imidazole-based compounds were comparable to that of the standard ketoconazole (KTZ) in their inhibitory activity against 17,20-lyase and 17a-OHase (KTZ; %inhibition = 75% against 17,20-lyase: %inhibition = 64% against 17a-OHase). The nitro substituted derivatives (270-272) were shown to have improved inhibitory activity when compared to KTZ against 17a-OHase. With respect to the imidazol-phenyl ethananes, all with the exception of the 3-bromo substituted derivative ~88) were shown to possess either equipotent inhibitory activity to that of KTZ (%inhibition = 80% against 17a-OHase: %inhibiton = 82% against 17,20-lyase) or substantially lower activity. Compound 288 was found to possess greater inhibitory activity against the 17a-OHase component (288 %inhibition = 84%). Deliberation of structure-activity relationships determined no obvious correlation between the substitution pattern of the benzyl ring and the inhibitory activity against 17,20-lyase in the benzyl imidazole-based compounds. However, in the activity against 17a-OHase, a general trend towards the para substitution of the benzyl ring was shown to have an impact on the inhibition of the enzyme. In the imidazol-phenyl ethananes, consideration of the inhibitory activity of the halogen derivatives shows that there is an increase in potency with decreasing electronegativity of substituent group. In the inhibitory activity against 17a-OHase, some compounds show a correlation between decreasing electron-withdrawing ability and an increase in percentage inhibition. This would therefore appear to suggest that an ·interaction exists between the substituent and complementary group(s) at the active site of the enzyme - this interaction appears to be weaker within derivatives which possess substituents of high electronegativity. The substitution of the phenyl ring was too shown to influence the inhibitory activity of the compounds, which was rationalised by use of the SHC approach. This was proposed as results clearly indicate that the meta-substituted compounds were found to possess greater inhibitory activity in comparison to the para-substituted compounds.