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In present work an attempt has been made to improve to the therapeutic efficacy, systemic absorption of drug and patient compliance by developing extended release matrix tablet formulations of diltiazem HCl (DIL) and verapamil HCL (VER). DIL and VER matrix tablet formulations were prepared by direct compression by using various combination of HPMC K15M CR and Eudragit RSPO polymer. A full factorial design was applied to systematically optimize drug release profile. For optimization study and data analysis software OPTI STAT was developed. The optimized formulations shows regression value for Higuchi kinetics indicated the diffusion dependence for drug release. Stability trials up to three months displayed excellent reproducibility. In vivo studies were carried out on the optimized batches and CF using new developed HPLC and LC-MS/MS methods A good correlation between the dissolution profiles and bioavailability indicated a linear relationship between in vitro in vivo data.