The main aim of present work was to investigate the influence of processing parameters which affect the dissolution rate of highly water soluble drug. Diltiazem HCl was selected as model drug and used to prepare SR formulation. First, proper sustained release tablet formulation was selected by using different amount of HPMC K15 M and Ethyl Cellulose as sustained release polymers. Dissolution test was performed in USP apparatus 2, at 100 rpm in water as dissolution media. Selection of formula was made based on USP criteria for Diltiazem SR. After that seven different parameters: milling time (2/10 min), pre lubrication mixing time (5/10 min), lubrication time (1/5 min), compression speed (10/30 rpm), temperature (25°C/37°C), stirrer rpm (50/100 rpm) and stirrer alignment (50/100 mm) were used at two different levels to select three most critical parameters which affect the dissolution profile of drug. Initial screening was done by using Plackett Burman Design by taking 8 batches. Three selected parameters were again investigated in detail by using Face Centered Central Composite Design with three levels taking Mean Dissolution Time as primary response. The model was then analyzed by ANOVA to check the significance difference. From seven different parameters, speed of stirring, lubrication time and compression speed were found as most critical parameters for Diltiazem HCl. The detail study on three selected most significant parameters has revealed that lubrication time is the most significant parameter for water soluble drug (Diltiazem HCl).