Synthesis of alkyl quaternary amino celluloses and an investigation of their potential as bile acid sequestrants : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Chemistry at Massey University, New Zealand

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Massey University
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One method of treatment for patients with elevated serum cholesterol levels (hypercholesterolemia) is the oral administration of an anion exchange resin to adsorb bile acids in the gastrointestinal tract. The resins used successfully to date have been mainly synthetic ones, whereas anion exchange derivatives of cellulose have not been shown to be effective. Alkyl quaternary amino (QA) cellulose ion exchangers were prepared from hydroxypropylated regenerated cellulose (HP IndionR). Their capacities for cholate anions were measured in the presence of a background of chloride ions at physiological concentration. It was shown that butyl QA cellulose was ineffective at binding cholate anions. However, alkyl QA celluloses with alkyl groups longer than butyl (octyl and dodecyl) bound cholate anions in preference to the chloride ions and greatly improved capacities were obtained. The capacities of the octyl and dodecyl QA celluloses were dependent on the cross-linking present in the HP Indion used. If the cross-linking was greater than the 15% used in HP5 Indion, then the capacity for binding cholate dropped off. A significant increase in substitution level and decrease in swollen volume were obtained by reprocessing the alkyl QA cellulose ion exchangers and this improved their cholate binding capacities. The alkyl QA celluloses were all prepared by first attaching chemically reactive epoxide groups to HP Indion and then reacting those epoxide groups with a tertiary amine (N,N­ dimethyl-N-alkylamine) to form the quaternary amino cellulose. These two steps were repeated for the reprocessed products. The optimum conditions for epoxidation of HP5 Indion were shown to be 48 hours at 4-6°C in 6% sodium hydroxide with excess epichlorohydrin. In the reprocessing step, where this reaction was used a second time, 24 hours was sufficient to reach maximum epoxidation levels. When coupling the N,N- dimethyl-N-alkylamine to the epoxide cellulose it was necessary to use aqueous ethanol as a solvent. The ethanol concentration was dependent on the size of the alkyl group. For N,N-dimethyl-N-dodecylamine a concentration of greater than 60% ethanol was required. For larger amines considerable hydrolysis of the epoxide groups occured during coupling. This was avoided almost completely in the first coupling step by half-neutralising the amine with hydrochloric acid, to lower the pH and buffer the reaction. The optimum coupling time and temperature were shown to be 10 hours at 70°C. As a result of optimising these processing steps the substitution level obtained for dodecyl QA cellulose was increased from 0.83 to 1.14 meq/g at the end of the first stage and from 1.18 to 1.50 meq/g with the reprocessed product. A range of alkyl QA celluloses were prepared using the optimum conditions found for dodecyl QA cellulose. Octyl and dodecyl QA celluloses prepared on HP7 Indion were shown to have higher capacities for cholate than cholestyramine and colestipol {ColestidR) at cholate concentrations less than 6 mmol/L. The dodecyl QA cellulose had superior capacities at all cholate concentrations (0-15 mmol/L) when measured on the basis of the volume of the ion exchanger used. In contrast, cholestyramine and colestipol had higher capacities for deoxycholate anions than either of the cellulose products, except when the residual concentration of deoxycholate was very low {less than 0.5 mmol/L). Cholestyramine and colestipol bound deoxycholate efficiently (97-99%) when the residual concentration was between 5-10 mmol/L, but not cholate (29-48%). However the alkyl QA celluloses bound deoxycholate and cholate with very high efficiency (82-138%). To compare the efficiencies of the ion exchangers at low concentrations a more sensitive test was developed utilising a mixture of conjugated bile salts, similar in composition to that found in the human duodenum. This was equilibrated with samples of each ion exchanger and then analysed by HPLC. Methyl and butyl QA celluloses were the least effective at reducing the concentrations of the bile salts, however they still performed as well as colestipol. The capacity of octyl QA cellulose was much better than the methyl or butyl QA celluloses, indicating the importance of the hydrophobic alkyl chain. Cholestyramine had a similar capacity to the octyl QA cellulose, except that it was not as effective at binding glycocholate. The most effective product was found to be dodecyl QA cellulose, which reduced the concentration of all of the bile salts to lower levels than any other ion exchanger.
Anticholesteremic agents, Congresses, Ion exchange