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

Abstract

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.