Abstract : In situ gelling Raft forming system (GRFS), a novel sol-gel system of calcium carbonate (CC) was developed with the aim to prolong the gastric residence time and thereby the bioavailability. A simple lattice mixture design was adopted to study the effect of formulation composition (% HPMC K100 M and % Xanthan gum), on buoyancy lag times, percent of CC released at 1hr and 6hr. The mathematical models generated by analysis of variance (ANOVA) indicated that the levels of HPMC K100 M and Xanthan gum were found to significantly affect all the three responses. The optimized formulation developed by numerical optimization technique was found to display short buoyancy lag time (10.90 ± 0.56 sec), minimum burst release (20.74 ± 1.08%) in 1h and controlled yet near complete release (87.25±1.81%) in 6h. The experimental data for the optimized formulations was in agreement with that predicted by the mathematical models proving the validity of the models generated. In vivo radiographic studies in rabbits indicated that optimized batch displayed a mean gastric retention time of 5.64 ± 0.43 h that was significantly higher (P < 0.05) compared to the marketed suspension that exhibited a mean gastric retention time of less than one hour. The studies proved that the GRFS gastroretentive systems can be a promising platform to improve bioavailability of nutrients having absorption window in upper gastrointestinal tract.