Novel modulation of drug delivery using binary zinc-alginate-pectinate polyspheres for zero-order kinetics over several days: experimental design strategy to elucidate the crosslinking mechanism.

A Box-Behnken design was applied to mathematically establish whether different degrees of crosslinking were induced by Zn2+ and Ca2+ ions in polyspheres composed of alginate and/or pectin, and the model drug ibuprofen. Based on their different crystal structures and coordination numbers, a theoretical model was proposed demonstrating that Zn2+ ions preferentially crosslink alginate and pectin. In addition, the lower coordination number of Zn2+ (4-6) would significantly retard hydration of both polymers, as opposed to Ca2+ (7-9). The responses studied for 28 statistically derived polyspheres included drug encapsulation efficiency, physicomechanical behavior, and in vitro drug release potential. Single-tailed Student's t-tests on data generated for the encapsulation efficiencies, primary facture values, and rupture energies indicated that Zn2+ was statistically superior (p<0.05) in crosslinking alginate and pectin. Further textural analysis revealed a good correlation between the Brinell hardness number and fracture load, while an inverse relationship was found for matrix tensile strength. Viscosity studies demonstrated different in situ crosslinking thresholds for Zn2+. The Durbin-Watson statistic and correlation coefficient revealed that the quadratic regression function was highly accurate in predicting the responses. Using a generalized reduced gradient algorithm on dissolution values obtained after 2 hours (t2h) provided optimized solutions for achieving zero-order release extending from 2 hours to 7 days. Mathematical simulations projected drug release from 25 to 50 days.