title: 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 beta-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.
authors.affiliation: School of Pharmacy, Curtin University of Technology, Perth, Australia.
authors.forename: C
authors.initials: C
authors.lastname: McDonald
authors.lastname: Faridah
mesh_terms: D002021:Buffers; D003460:Crystallization; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D012995:Solubility; D013420:Sulfamethoxazole / Q000008:administration & dosage / Q000737:chemistry*; D014295:Trimethoprim / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D002021:Buffers; D014295:Trimethoprim; D013420:Sulfamethoxazole