The release ofpapaverine, a weakly basic drug, is pH dependent. To allow drug release throughout the changing pH milieu ofthe gastrointestinal tract, weak acid modifiers are often added to modify the microenvironmental pH. A technique to measure the microenvironmental pH by confocal microscopy (CLSMpH) has been optimised to allow accurate measurement in coated pellets. A central composite design was used to investigate the effect of formulation factors on drug release and CLSMpH• Acid modifiers and fillers of varying solubility were also investigated. The solubility and proportion ofthe acid used has a significant effect on drug release. A more soluble acid provides a shorter acidic microenvironment, conversely a greater extent ofdrug release was seen during this time. It is the solubility of the acid and not just the acidity that affects papaverine release. A more soluble excipient may produce a greater internal porosity. Alternately the soluble excipient may increase the internal osmotic pressure. Finally, soluble excipients may partition into the coat and produce pores upon dissolution, however an overlap of mechanisms may occur. The CLSMpH method has provided an insight into the release mechanism from pellets. It would appear an acid less soluble than the drug would be useful to supply a prolonged acidic microenvironment, providing a more soluble excipient is used to allow drug release. Finally, the CLSMpH method has been applied to hydrophilic matrix tablets. Using this technique spatial and temporal measures ofpH can be made. An acidic pH gradient was observed across tablets formulated with acidic excipients. Conversely, the gel layer pH was principally basic in tablets formulated without them. The use of the CLSMpH technique and similar fluorescence techniques could be useful in elucidating the release mechanisms in hydrophilic matrix tablets and as an aid to formulation.