Buccal delivery of saquinavir has the advantage to bypass the gastrointestinal enzymatic degradation and the hepatic first-pass metabolism. Saquinavir has a pH-dependent solubility and is poorly soluble in human saliva at the physiological pH. Decreasing microenvironmental pH (pH M) in saliva may increase saquinavir release from buccal formulations. The present study aimed to investigate the effects of organic acids on the pH M, saquinavir release in vitro and the solid-state form of saquinavir. An UV/Vis imaging method was used to measure pH M. After 5 min of swelling of the buccal films containing malic acid, pH M was reduced from 6.8 to 5.4. The films containing malic acid were more efficient in maintaining low pH M than films containing citric acid and succinic acid. Addition of organic acids in the buccal films resulted in a faster drug release than films without acids due to the reduced pH M. However, the enhancement of saquinavir release was limited by the fast release of organic acids. Addition of malic acid and citric acid suppressed the crystallization of saquinavir during 3 months storage at the elevated temperature (40 °C) and humidity (RH 75%) respectively. These results suggest that pH M modifying film is a potential formulation strategy for buccal delivery of saquinavir.