The Role of an Impurity in Ceftriaxone Sodium Preparation for Injection in Determining Compatibility with Calcium-Containing Solutions

Abstract

Ceftriaxone sodium preparation for injection is known to form insoluble microparticles with calcium. The purpose of this study was to evaluate the role of an impurity in the ceftriaxone sodium preparation on this incompatibility. Firstly, using HPLC, two impurities were identified in the ceftriaxone sodium solution. The major impurity (impurity 1) was identified as tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione by LC/MS. Secondly, the role played by this impurity in the incompatibility with calcium was examined. Using seven different ceftriaxone preparations for injection, the effect of adding impurity 1 to mixed solutions of ceftriaxone sodium and calcium chloride on the appearance of insoluble microparticles, was examined using a light obscuration particle counter. Although incompatibility was not completely suppressed by the addition of impurity 1, the number of insoluble microparticles formed with calcium chloride solution was decreased in proportion to the concentration of impurity 1, and the concentration of calcium ion decreased as the concentration of added impurity 1 increased. These results show that impurity 1 plays a concentration-dependent role in incompatibility between ceftriaxone sodium preparation for injection and calcium-containing solutions.

Graphical Abstract