RESUMEN
Allopurinol delivery problems were attributed to the low water and lipid solubilities of the drug. A promising approach to improve the physicochemical properties of allopurinol, is the chemical transformation of the drug into reversible derivatives [prodrugs] which are converted to the parent compound by virtue of enzymatic or chemical lability within the body system. In the present study, derivatives of allopurinol with ibuprofen were tried. By adjusting the synthesis conditions, the derivatives were linked to the O-atom or the N[1]-atom of allopurinol. The stability of the derivatives and the hydrolysis kinetics in aqueous buffers and in human plasma were studied. The effects of buffer concentration, ionic strength and temperature on the hydrolysis race were determined. Water and lipid solubilities were measured. The results indicated that O-ibuprofenyl allopurinol was more stable, more water-soluble than N-ibuprofenyloxymethyl allopurinol, but the lipophilicites of both were comparable. Compared to allopurinol, O-ibuprofenyl allopurinol had more water - solubility and lipophilicity. Buffer concentration and ionic strength had no effect on the rate of hydrolysis of both derivatives. From the results obtained, it is apparent that 0-ibuprofenyl allopurinol satisfies the prodrug requirements in being stable enough in aqueous buffers and susceptible for enzymatic cleavage. In addition, the attaching moiety is non-toxic and is usually given as a supplement therapy with allopurinoi. In fact, this new derivative had improved the solubility of allopurinol, at the same time it had masked the carboxyl group of ibuprofen, thus reducing its gastric irritation upon oral administration.