Impact of phosphate buffer strength and unbuffered water on ionizable drug powder dissolution

We are unaware of prior reports of the dependence of drug powder dissolution on buffer strength. The objective was to assess the effect of 5, 10, 50, and 100 mM sodium phosphate concentration on in vitro particle dissolution of ionizable drugs. Three weakly acidic drugs (naproxen, piroxicam, and phenytoin) and one weakly basic drug (dipyridamole) were studied at different pH conditions. Dissolution was conducted using USP Apparatus II with a mini-paddle at 37 °C in 100 mL media. Overall, the effect on dissolution profile was modest, with the largest effect generally being between 5 mM phosphate and zero phosphate (i.e., unbuffered water). Hence, a secondary objective was to predict the dissolution of the four ionizable drugs into unbuffered water, as well as for ibuprofen, ketoprofen, indomethacin, haloperidol, and meloxicam. Predictions anticipated slower ionizable drug dissolution into unbuffered water. Overall, dissolution predictions into buffer were better using the transient pH film model that accounts for the changing solid-liquid interfacial pH during dissolution, than for the conventional z-factor film model.