The purpose of present research work was to fabricate patient friendly, immediate release oral film of ondansetron hydrochloride using hydrophilic excipients. The film was prepared by solvent casting method. Hydroxyethyl cellulose, polyvinyl alcohol and polyvinylpyrrolidone k30 along with different plasticizers (peg 400 and pg) were scrutinized for film formulation. The auxiliary excipients used were sodium saccharin and sodium lauryl sulphate. The final selection was done with hydroxyethyl cellulose as a film former and peg 400 as a plasticizer for the film. The drug loaded films of hydroxyethyl cellulose were evaluated for thickness, uniformity in drug content, folding endurance, disintegration time, in-vitro drug release studies, tensile strength and drug-excipient compatibility studies. Taste masking was done by novel sandwich technology (placing the ondansetron hydrochloride film between two listerine pocket pack films). This approach can be used as platform technology for other formulations also. Optimization of film was done by 32 factorial design taking amount of hydroxyethyl cellulose and sodium lauryl sulphate as independent variables, while disintegration time (dt), % cumulative drug release and folding endurance as response variables. Polynomial equations were derived. The validity of equations was checked by preparing check point batches. Response surface plots were constructed using design expert software. This exercise facilitates bio batch selection. Better predictive ability was achieved, when artificial neural network (ann) was used in place of regression analysis. Batch of3 containing hydroxyethyl cellulose showed disintegration time of 16 sec and 94.35 % drug release in 8 minutes.