Determinants of zero-order release kinetics from acetaminophen-layered Suglet® pellets, Wurster-coated with plasticized Aquacoat® ECD (ethyl cellulose dispersion)

Abstract

The potential for zero-order drug-release was evaluated for ethyl cellulose (EC) coated, acetaminophen-layered sugar pellets (Suglets®) of mesh size 18/20 (850-1000 μm). To determine optimal plasticizer/pore-former concentrations for EC films, solvent-cast Aquacoat® ECD (ethyl cellulose dispersion) films were prepared with 0-50% w/w ratios of two triethyl citrate (TEC) or triacetin (TA). Characterization studies showed that films with excipient concentrations ≥20% were homogenous, mechanically strong at room temperature (Young's modulus of 25-35 MPa), and have a glass transition (T_g) in the range of 20-45 °C. Based on these results, a working range of 20-50% weight concentrations was selected for drug release studies. Suglets® were layered with acetaminophen (APAP) using Wurster Glatt GPCG-3 to yield roughly 10% w/w coating (controls). The Controls were coated using the same Wurster process with Aquacoat® ECD containing 20-50% w/w of TEC or TA. Samples were removed periodically at 3-11% weight gain, to evaluate impact of weight gain, and consequently film-formation, on drug release. Dissolution was monitored over a period of 12 h in a media consisting of simulated gastric fluid (first two hours), followed by simulated intestinal fluid. The controls showed near 100% release within the first 30 min, indicating the value of EC-coating to achieve controlled release. Dissolution release profiles showed that TEC is more effective than TA as a plasticizer and pore-former, as linear profiles were apparent at lower concentrations and % weight gain. For a quantitative evaluation of these results, linear regression was fitted to all cumulative release profiles, and R-squared values examined as a function of excipient concentration and % weight gain. The corresponding response surface plots and the second order regression were shown to aid in optimization. The design space for zero-order release was represented as contour plots between excipient concentration and % weight gain.

Keywords: Contour plots; Dissolution testing; Ethyl cellulose; Response surface; Thermal analysis; Triacetin; Triethyl Citrate (TEC); Wurster coating; Zero-order release.