Dissolution Profile of Tosufloxacin Tosylate in Biorelevant Bicarbonate Buffer Containing Sodium Chloride: Precipitation of Hemi-hydrochloride Salt at the Particle Surface.

Abstract

Purpose: The purpose of the present study was to investigate the dissolution profile of tosufloxacin tosylate monohydrate (TFLX TS) in biorelevant bicarbonate buffer (BCB). TFLX is a zwitterionic drug (pK_a: 5.8 and 8.7), formulated as tosylate salt to enhance its dissolution.

Methods: The dissolution profiles were measured in BCB or phosphate buffer (PPB) at pH 6.5 with buffer capacity (β) = 0.88 or 4.4 mM/pH, containing NaCl or Na₂SO₄ (I = 0.14 M). The residual particles were analyzed by powder X-ray diffraction. In a separate study, the particle surface of TFLX TS after contact with BCB was observed by scanning electron microscopy and real-time polarized light microscopy. The pH solubility profile of TFLX was measured using HCl and TS solutions.

Results: TFLX TS dissolved less in the NaCl media than in the Na₂SO₄ media. It also dissolved less in PPB than in BCB (at β = 4.4 mM/pH), and less at β = 4.4 mM/pH than at 0.88 mM/pH. The analysis of residual particles indicated that the hemi-hydrochloride salt (TFLX 1/2HCl) precipitated on the particle surface of TFLX TS in the NaCl media. In contrast, the free form of TFLX precipitated in the Na₂SO₄ media. The pH solubility profile matched the hemi-hydrochloride stoichiometry (K_sp = [TFLX∙H⁺][TFLX][Cl^-]).

Conclusion: The dissolution of TFLX TS in the NaCl media was suppressed by the precipitation of TFLX 1/2HCl on the particle surface. This is an important case showing that NaCl can suppress the dissolution profile of a non-HCl drug salt at a neutral pH.