The microencapsulation of macrolides with polymers has been reported to retard the release of the drug in oral cavity. However, these methods are unable to control drug release in gastrointestinal tract. The aim of the present study was to investigate the effect of formulation of a new polymeric encapsulation of azithromycin which is suitable for both masking and sustained release usage. Eudragit E100 and polyethylene glycol (PEG) 4000 were chosen as the barrier coatings. The spray drying technique was used to obtain the microcapsules containing azithromycin. To obtain the initial results, the effects of several parameters were evaluated. A 3:2:1 ratio of E100:PEG 4000:azithromycin at pH 6 gave the best coating condition. Thermogravimetric analysis and IR analysis data confirmed the encapsulation of azithromycin inside polymers. The encapsulated drug was released in different rates from the particles by changing the pH (1.7 and 7.4). An analysis of the kinetic release properties indicates that the release of the drug is a combination of swelling and diffusion mechanism. The synergistic cooperation between polymers and drug due to the existence of several hydrogen bonding is supposed to influence the pH-responsive property of the encapsulated drug. Moreover, the use of mixtures of E100 and PEG 4000 appears to offer a good balance between cost and efficiency.