Optimizing Particle Size of pH Modifiers Enhances Dissolution of Weakly Basic Drugs

This study aimed to investigate the pH-dependent dissolution of the weakly basic drug carvedilol (BCS Class II) and systematically examine the influence of citric acid concentration and particle size on its release.

A series of dissolution studies was conducted in media simulating the gastrointestinal pH range (1.2-7.8), specifically evaluating the effects of citric acid concentration (3% and 9%) and particle size (fine Dv50 44 μm vs. coarse Dv50 608 μm).

Under acidic conditions (pH 1.2-1.6), carvedilol solubility was high and the effect of citric acid particle size was negligible (<1.3% difference). In the mid-pH range (3.8-6.5), fine citric acid particles rapidly created an acidic microenvironment (pH 3.5±0.2), enhancing carvedilol solubility 2.1-2.8-fold and improving dissolution by 3.1-15.7% compared to coarse particles; increasing the citric acid concentration from 3% to 9% reduced this particle size-dependent variability. At high pH (6.8-7.8), the effect of citric acid weakened, though coarse particles still prolonged acid release.

While citric acid concentration universally enhanced carvedilol dissolution, the effect of its particle size was pH-dependent, being negligible at low pH but pronounced at higher pH, where larger particles sustained drug release more effectively.