A new insight on the potentiometric log P determination of therapeutically important opioids and fluoroquinolones

Lipophilicity is a crucial physicochemical property that affects ADME behavior, toxicity, and adverse effects of drugs. It can be quantified in terms of partition coefficients, determined typically in octanol-water dual systems. Reliable determination of partition coefficients and their logarithms (log P) is therefore essential in pharmaceutical research and drug design. Traditional methods such as the shake-flask procedure, chromatographic techniques, or potentiometric titration with a special-purpose device are either time-consuming or require expensive instrumentation. In this study, we demonstrate that potentiometric titration performed with a simple and affordable titrator offers a practical and efficient alternative for evaluating lipophilicity. The partitioning behavior of opioids and fluoroquinolones was assessed by determining their apparent protonation macro- and microconstants in aqueous/organic biphasic systems. Titrations were conducted under controlled aqueous-organic phase ratios, with optimized equilibration times to ensure accurate electrode response. Species-specific log p values were then calculated for amphoteric compounds based on the shifts in the apparent protonation constants in the presence of the organic solvent in different phase ratios using established equations. Our findings show that log p values derived from potentiometric measurements using species-specific microconstants in calculations are highly reproducible and internally consistent, and give more reliable results than using macroconstants, which was the only method in the literature until this point. This work highlights that accurate lipophilicity assessment does not require costly or specialized equipment; instead, a standard, low-cost potentiometric setup can also provide accurate, reliable, and robust lipophilicity data under circumstances of moderate cost.