The primary aim of this work was to synthesise and characterise sevelamer hydrochloride (SH), the active pharmaceutical ingredient in Renagel®, an oral drug prescribed to prevent the absorption of dietary phosphate for kidney dialysis patients. SH is a polyallylamine (PAA-HCl) crosslinked with epichlorohydrin (EPI). Initial work involved a systematic and comprehensive study of structural –property relationships using a series of (PAA-HCl) hydrogels (not synthesised in the literature before) in an aqueous reaction. The parameters involved in the reaction, such as concentration EPI, NaOH and polymer were all investigated. Variation of these parameters influenced the hydrogel morphology as shown by swelling ratio, Fourier transform infra red spectroscopy (FTIR), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and solid state nuclear magnetic resonance (SSNMR) studies. The binding characteristics of PAA-HCl hydrogels were comprehensively examined using the Langmuir (LI), Freundlich (FI) and Langmuir – Freundlich isotherms (L-FI) and using affinity distribution spectra (AD). The LI was identified as the most appropriate model in describing the binding behaviour of the hydrogels. L-FI was also found suitable in analysing the hydrogels behaviour, as the hydrogels contained a homogeneous binding site surface, thus L-FI was reduced to the LI when heterogeneity index approached 1. A relationship between the number of binding sites and affinity in different hydrogels was identified and visualised by plotting AD spectra. This was the first report on the use of AD spectra generated from L-FI binding parameters to display the sensitivity of the binding site number and affinity to changes in PAA-HCl hydrogel morphology. A detailed examination into the influence of pH on the performance of SH was carried out. The hydrogel is pH sensitive as shown by the differences in binding capacity and affinity constants obtained at various pHs. The maximum binding capacity, Nt, was found at pH 3 where the hydrogel was fully protonated, and decreased at elevated pHs of 4.5, 7 and 8.5 where the hydrogel was partially protonated. The affinity constant, a, at pH 3 and 8.5 was found to be the lowest, 2.4 ± 0.6 and 1.6 ± 0.1 mol/L, respectively. At pH 4.5 and 7, a increased to 9.1 and 7.0 ± 1.3 mol/L, respectively, due to the availability of the divalent phosphate ion form which binds preferably with SH. The kinetics of phosphate ion binding to SH in vitro and its relationship to physiological conditions was studied in detail. The reaction was found to follow pseudo second order kinetics. The rate constant found depended on the phosphate ion concentration and temperature. Thermodynamic parameters were evaluated with phosphate binding found to be a spontaneous endothermic reaction as shown by ΔG° data, the positive value of �H° and the high value of ΔS°. Consequently, the kinetics of phosphate binding was faster than transit times (hours) through the gastrointestinal tract, thus binding rate did not affect the efficacy of the drug in terms of phosphate binding. The interaction of SH with water was found to be crucial to an understanding of waterbased processes such as tablet manufacturing. The Dynamic Vapour Sorption (DVS) method was successfully applied for the determination of equilibrium sorption isotherms of SH. The study has shown that water vapour sorption behaviour of this polymer is accurately described by the parallel exponential kinetics (PEK) model. The combined DVS, DSC and SSNMR results highlighted the contribution of the physicochemical properties of the APIs and water permeability to tablets processing and the impact on the final tablet properties. The significance of process parameters such as moisture, temperature and compression forces on the mechanical properties of the tablets was also demonstrated.
|Publication status||Unpublished - 2013|
- Polymeric Pharmaceuticals, Tablet Processing