Purpose: The purpose of this study was to prepare pH-sensitive pellets using an extrusion-spheronization pelletization (ESP) technique. Method: Polyacrylamide-grafted-guar gum (pAAm-g-GG) was prepared by taking three different ratios of guar gum to acrylamide (1 : 2, 1 : 3.5 and 1 : 5). Amide groups of these grafted copolymers were converted into carboxylic functional groups. Fourier transform infrared (FT-IR) spectroscopy, Differential Scanning Calorimetry (DSC) and ¹H-NMR spectroscopy were used to characterize the grafted copolymers. Pellets were prepared by pAAm-g-GG (1.0–4.5%) and microcrystalline cellulose incorporating an anti-diabetic drug viz., glimepiride. Here, variables were studied and pellets were characterized for average size, surface morphology, friability, bulk density and flow properties. In vitro drug release was carried out in simulated gastric and intestinal conditions. Result: The in vitro drug release profile indicated an increase in drug release retardation with increasing pAAm-g-GG concentration. The formulated pellets were stable with respect to their physicochemical characters and drug content over a period of 60 days at different temperatures and relative humidity. Conclusion: It has been concluded that the prepared pellets demonstrate the potential use of MCC and pAAm-g-GG for the development of pH sensitive colon specific controlled drug delivery systems of glimepiride for diabetic therapy.