Formulating poorly water soluble, weakly basic drugs with consistent exposure is often a challenge due to pH-dependent solubility. When the oral formulation is exposed to different pH ranges in the gastrointestinal (GI) tract, drug precipitation, or incomplete dissolution may occur resulting in decreased drug absorption and higher intra- and inter-patient pharmacokinetic (PK) variabilities. In the present study, a series of enhanced formulations containing organic acids and/or surfactants were developed and compared with conventional formulations with respect to their in vitro dissolution performance. The formulation containing 5% citric acid and 1% sodium lauryl sulfate (SLS) showed much less variations in dissolution performance at different pH conditions than a conventional formulation. The combination of citric acid and SLS demonstrated a synergistic effect as compared to use of citric acid alone or in combination with PEG4000 as a precipitation inhibitor. When compared with a conventional formulation and a spray-dried amorphous solid dispersion (ASD) formulation in a dog PK study, the enhanced formulation demonstrated the least AUC and Cmax variability between the two gastric pH-controlled groups. In conclusion, an enhanced formulation using a combination of organic acid and surfactant is recommended for weakly basic drug compounds to minimize drug PK variabilities in clinical studies.
Keywords: Gastric pH; acidifiers; enhanced formulation; pharmacokinetic variability; precipitation inhibitors; surfactants.