Solubilities of Trimethoprim and Sulfamethoxazole at Various pH Values and Crystallization of Trimethoprim from Infusion Fluids

Abstract

Solubilities of sulfamethoxazole (SMX) and trimethoprim (TMP) have been measured in the absence and presence of various concentrations of hydroxypropyl β-cyclodextrin (HPCD) in buffers over a range of pH values. The solubilities of TMP increased linearly in the presence of HPCD at pH values of 7.0, 7.5, 8.9, and 9.9 indicating the formation of 1 to 1 complexes, whose association values increase as pH does and as the ionization of TMP decreases. For SMX at pH 7.0, a 1:1 complex is formed, but at pH 7.5 HPCD has little effect on the solubility of the highly ionized SMX, presumably since only un-ionized molecules can form inclusion complexes with the HPCD. At pH 7.0 when solubilities of TMP and SMX are measured in the same system containing buffer and HPCD, a massive decrease in the solubility of TMP is found, while that of SMX decreases slightly. A slightly soluble complex of TMP/SMX may be formed. When TMP/SMX injection is diluted 1:10 with phosphate buffer (pH 7.8), an immediate massive precipitation which is mostly TMP is observed. The presence of 10% w/v HPCD in the buffer delays and modifies the precipitation of TMP and SMX but does not prevent it. Mixing the injection (1 to 10) with normal saline (pH 9.5) gives a steadily increasing precipitation of TMP with time, but no discernible change in the concentration of SMX. However, in normal saline containing 10% w/v HPCD there is no crystallization of either drug over a 5 day period.