The effect of combined use of enteric polymers and precipitation inhibitors on cinnarizine crystallization from the supersaturated state

Abstract

Introduction: poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. Aim: In this work the inhibitory effect on Cinnarizine crystallization in buffer solution (pH=6.8) was evaluated using various polymers including HPMC, Eudragit L100, NaCMC, HPC, PEG and PVP Method: Upon induction of supersaturation in buffer solution using a pH shift method, precipitation was assessed as a function of time. The solid dispersions and physical mixtures containing drug and polymer were prepared and were characterized using dissolution studies. Dissolution analyses were conducted at supersaturated conditions using a pH change method and the area under the concentration-time curve values were calculated for each evaluated composition to provide a quantitative means of comparing the extent of supersaturation. Results: Supersaturation in buffer solution was observed for Cinnarizine following an acidic to neutral pH transition, but proved to be unstable due to fast precipitation. Excipient- mediated stabilizing effects on supersaturation were observed using Eud L100, while HPMC also stabilized supersaturation, but to a lesser extent than observed with Eud L100. Dissolution studies demonstrated the stabilizing effect of on supersaturated levels of Cinnarizine in vitro when physically mixed with Cinnarizine. In contrast, Eud L100 in solid dispersion had no significant effect on Cinnarizine concentration in buffer solution. Because solid dispersion of Eud L100 yields an acid resistance delivery system which would not be able to generate supersaturated levels of Cinnarizine following an acidic to neutral pH transition. Interaction between drug and polymer which was confirmed by FT-IR and DSC was necessary for supersaturation stabilization. Conclusion: From these findings, the addition of Eud L100 in Cinnarizine formulation might be beneficial to enhance the dissolution and bioavailability of cinnarizine