In the present work, new matrix bead formulations based on linear and branched polysaccharides have been developed using an ionic gelation technique, and their potential use as oral drug carriers has been evaluated. Using calcium chloride as a cross-linking agent and sodium diclofenac (SD), as a model drug, acacia gum-calcium alginate matrix beads were formulated.The response surface methodology based on 3 2 factorial design was used as a statistical method to evaluate and optimize the effects of the biopolymers-blend ratio and the concentration of calcium chloride on the particle size (mm), density (g/cm 3 ), drug encapsulation efficiency (%), and the cumulative drug release after 8 hours (R 8h ,%). The optimized beads with the highest drug encapsulation efficiency were examined for a drug-excipients compatibility by powder X-ray diffraction, differential scanning calorimetry, thermo-gravimetric analysis, and Fourier transforminfrared spectroscopy analyses. The swelling and degradation of the matrix beads were found to be influenced by the pH of medium. Higher degrees of swelling were observed in intestinal pH than in stomach pH. Accordingly, the drug release study showed that the amount of SD released from the acacia gum-calcium alginate beads was higher in intestinal pH than in stomach pH. Therefore, the in vitro drug release from the SD-loaded beads appears to follow the controlledrelease (Hixson-Crowell) pattern involving a case-2 transport mechanism operated by swelling and relaxation of the polymeric blend matrix. KEYWORDS acacia gum-calcium alginate, beads, branched polysaccharide, linear polysaccharide, oral drug delivery 1 | INTRODUCTION Polysaccharides represent a class of natural chemical compounds characterized by repetitive structural units with a wide degree of dispersion. 1 A growing interest in these chemical compounds has resulted in the identification of a number of important biochemical and biomedical applications, not only because of their low cost, biocompatibility, biodegradability, high swelling capability, and stability in various pHs but also because of their potential use in controlled drug delivery systems. 1-4 Different forms of natural polysaccharides such as nanostructures, 5,6 films, 7 tablets, 8,9 and hydrogels 10 have been reported in the literature. Recently, attention has been focused on the development of ionic polysaccharide hydrogel beads for use as oral drug carriers. 11 Different ionic polysaccharide beads based on sodium alginate (SA), 12 chitosan, 13 and pectin 14 have been extensively developed and examined for the encapsulation of a wide range of drugs. 15,16 However, major limitations of these ionic beads are the small drug encapsulation capacity due to drug leaching through the pores and the fast degradation in alkaline pH media resulting in burst release of drugs. 17 To overcome the limitations of these ionic polysaccharide beads, the combination of ionic and natural polysaccharides has been proposed. 18,19 Most of the reported results using this approach are based ...