Chronotherapeutic delivery of hydroxypropylmethylcellulose based mini-tablets: An in vitro–in vivo correlation

Abstract

The purpose of the study was to develop and internally validate a nonlinear in vitro–in vivo correlation model for a chronotherapeutically programmed HPMC based propranolol HCl (PHCl) mini-tablet. A simple and sensitive HPLC method was developed for the determination of PHCl content in rabbit plasma. The influence of tri-sodium citrate (TSC) on release behaviour was investigated through in vitro dissolution and in vivo absorption. Linear and nonlinear (quadratic, cubic, sigmoid functions) deconvolution based in vitro–in vivo correlation (IVIVC) models were developed using in vitro dissolution data and bioavailability profile. Prediction errors were investigated for Cmax and AUC in the light of US FDA guidelines for average percent prediction error. Release rate indicated that TSC was directly proportional to its concentration in the formulation. In vitro optimized formulation showed nearly 4.5h lag time and 5.24±1.74% drug releases in initial 4.5h following rapid release 97.11±1.87% in 6h. The deconvolution based IVIVC model appeared to be curvilinear for all three pulsatile formulations. Among various functions investigated the model using cubic function showed a better correlation (r>0.99) and satisfies the US FDA guidelines for average percent prediction error of less than 10%.