Precipitation Inhibition by Small-Molecule Analogues To Sustain Drug Supersaturation
Abstract
High Resolution Image Download MS PowerPoint Slide Maintaining supersaturation during gastric-to-intestinal pH transitions can be essential to maximize the oral exposure of pH-sensitive drugs. This study demonstrates a mechanistically guided strategy to stabilize ciprofloxacin supersaturation using structurally related fluoroquinolone analogues as nucleation inhibitors. Structural similarity screening identified danofloxacin and levofloxacin as promising candidates, and their effects were evaluated using nucleation induction time, dynamic pH-shift dissolution, and 1 H NMR spectroscopy. Danofloxacin produced the most significant extension of nucleation induction time and was superior to classical polymeric precipitation inhibitors (hypromellose and polyvinylpyrrolidone). During pH-shift dissolution, ciprofloxacin alone retained only ∼20% of its initial concentration after 30 min at pH 7.0, whereas danofloxacin and levofloxacin sustained ∼92% and ∼37%, respectively. Correspondingly, AUC 0–240 min increased by 5.44-fold for danofloxacin and 1.65-fold for levofloxacin, with HPMC and PVP providing 2.8-fold and 1.25-fold increases. 1 H NMR revealed concentration-dependent aromatic shielding consistent with ciprofloxacin···analogue heteroassociation, with danofloxacin producing the most substantial and most symmetric perturbations. These data sets support a kinetic mechanism in which isostructural analogues disrupt ciprofloxacin self-association, delay the formation of…
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