Electrolyte-induced compositional heterogeneity: A novel approach for rate-controlled oral drug delivery

In this work a new approach for in situ interactions between drug and elect rolyte(s) is devised to control the release of highly water soluble drugs f rom oral hydrophilic monolithic systems. The model drug diltiazem hydrochlo ride (water solubility in excess of 50% at 25 degrees C), in conjunction wi th specific electrolytes, was principally employed in the design of swellab le tablet formulations comprised of hydrophilic polymers such as hydroxypro pylmethlcellulose (HPMC) or poly(ethylene oxide) (PEO). Electrolytes such a s sodium bicarbonate or pentasodium tripolyphosphate were used to modulate intragel pH dynamics, swelling kinetics, and gel properties. Through in sit u ionic interactions tan intragel matrix system composed of different chemi cal species that promote competition for water of hydration), a composition ally heterogeneous structure referred to as a "metamorphic scaffold" was es tablished. It is shown that this latter structure results in the inhibition of drug dissolution, induction of a differential swelling rate, and attain ment of "matrix stiffening" and axially provides a uniform gel layer. Prese nce of such phases in matrix structure and its influence on swelling dynami cs enabled control of diltiazem hydrochloride release in a zero-order manne r in different pH environments over a 24-h period. From kinetic analysis us ing the power law expressions [M-t/M-infinity = k(1)t(n), M-t/M-infinity = k(1)t(n) + k(2)t(2n) and Hopfenberg model [M-t/M-infinity = 1 - (1 - k(1)t) (n)]), it became apparent that the dynamics of matrix relaxation and contro lled erosion were major factors involved in the release mechanism, while th e composite rate constant k(1) (in Hopfenberg model) decreased by approxima tely 2-fold in the presence of electrolyte(s). These findings indicated tha t the dynamics of swelling and gel formation in the presence of ionizable s pecies within hydrophilic matrices provide an attractive alternative for ze ro-order drug delivery from a simple monolithic system.