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

Abstract

In this work a new approach for in situ interactions between drug and electrolyte(s) is devised to control the release of highly water soluble drugs from oral hydrophilic monolithic systems. The model drug diltiazem hydrochloride (water solubility in excess of 50% at 25 °C), in conjunction with specific electrolytes, was principally employed in the design of swellable tablet formulations comprised of hydrophilic polymers such as hydroxypropylmethlcellulose (HPMC) or poly(ethylene oxide) (PEO). Electrolytes such as sodium bicarbonate or pentasodium tripolyphosphate were used to modulate intragel pH dynamics, swelling kinetics, and gel properties. Through in situ ionic interactions (an intragel matrix system composed of different chemical species that promote competition for water of hydration), a compo-sitionally heterogeneous structure referred to as a ‘metamorphic scaffold’ was established. It is shown that this latter structure results in the inhibition of drug dissolution, induction of a differential swelling rate, and attainment of ‘matrix stiffening’ and axially provides a uniform gel layer. Presence of such phases in matrix structure and its influence on swelling dynamics enabled control of diltiazem hydrochloride release in a zero-order manner in different pH environments over a 24-h period. From kinetic analysis using the power law expressions [Mt/M∞ = k1tn, Mt/M∞ = k1tn ± k2t2n] and Hopfenberg model [Mt/M∞ = 1 − (1 − k1t)n], it became apparent that the dynamics of matrix relaxation and controlled erosion were major factors involved in the release mechanism, while the composite rate constant k1 (in Hopfenberg model) decreased by approximately 2-fold in the presence of electrolyte(s). These findings indicated that the dynamics of swelling and gel formation in the presence of ionizable species within hydrophilic matrices provide an attractive alternative for zero-order drug delivery from a simple monolithic system.