Elucidation of the mechanism of precipitate formation on mixing nafamostat mesylate solution with dialysate.

This study clarifies the reagent preparation and administration conditions that lead to precipitation when nafamostat mesylate salt (NM) solution is mixed with dialysate. The objective is to elucidate the mechanism of precipitation. It was observed that the Carbostar^® dialysate forms a precipitate immediately after mixing with the NM solution, whereas Kindaly^® and Subpac^® dialysates form a precipitate after approximately 30 min. This variance is attributed to the pH adjusters used: citric acid for Carbostar^®, acetic acid for Kindaly^®, and hydrochloric acid for Subpac^®. As trivalent negative ions, citrate ions promote faster precipitation compared to acetic acid and hydrochloric acid, which are monovalent ions. Nafamostat acetate and nafamostat chloride salts are soluble, while nafamostat citrate is poorly soluble, leading to differences in precipitation timing. The bicarbonate ion's pK_a value is 6.1, meaning precipitation does not occur if the pH is lowered below 6.1 using acetic acid or hydrogen chloride as pH adjusters. The solubility product of nafamostat bicarbonate is 8.1 × 10^-7 (mol/L)³, making precipitation inevitable under dialysis conditions ([nafamostat²⁺] = 5 mg/mL (9.2 mM), [HCO₃^-] = 35 mM). The primary precipitate component is nafamostat bicarbonate salt. Although NM is initially water-soluble, it undergoes chemical transformation into a poorly soluble salt through ion exchange from mesylate ions to bicarbonate ions within the dialysate, resulting in precipitation. Based on these findings, we propose conditions to avoid precipitation.