Investigations into the physical and chemical stability of concentrated co-trimoxazole intravenous infusions

Abstract

Objectives: High dose of intravenous sulfamethoxazole and trimethoprim (co-trimoxazole) is often used in immunocompromised patients for the treatment of Pneumocystis jiroveci pneumonia. Current manufacturer's dilution recommendation for intravenous co-trimoxazole (1:25 v/v) requires the administration of 2 L of additional fluid per day causing serious complications including pulmonary oedema. Intravenous administration of concentrated solution of co-trimoxazole may minimise the risk of fluid overload associated side effects. Therefore, the objective of the study was to investigate the physicochemical stability of concentrated intravenous co-trimoxazole solutions.

Methods: Four ampoules of intravenous co-trimoxazole were injected into an infusion bag containing either 480 (1:25 v/v), 380 (1:20 v/v), 280 (1:15 v/v) or 180 (1:10 v/v) mL of glucose 5% solution. Three bags for each dilution (total 12 bags) were prepared and stored at room temperature. An aliquot was withdrawn immediately (at 0 hour) and after 0.5, 1, 2 and 4 hours of storage for high-performance liquid-chromatography (HPLC) analysis, and additional samples were withdrawn every half an hour for microscopic examination. Each sample was analysed for the concentration of trimethoprim and sulfamethoxazole using a stability indicating HPLC method. Samples were assessed for pH, change in colour (visually) and for particle content (microscopically) immediately after preparation and on each time of analysis.

Results: Intravenous co-trimoxazole at 1:25, 1:20, 1:15 and 1:10 v/v retained more than 98% of the initial concentration of trimethoprim and sulfamethoxazole for 4 hours. There was no major change in pH at time zero and at various time points. Microscopically, no particles were detected for at least 4 hours and 2 hours when intravenous co-trimoxazole was diluted at 1:25 or 1:20 and 1:15 v/v, respectively. More than 1200 particles/mL were detected after 2.5 hours of storage when intravenous co-trimoxazole was diluted at 1:15 v/v.

Conclusions: Intravenous co-trimoxazole is stable over a period of 4 hours when diluted with 380 mL of glucose 5% solution (1:20 v/v) and for 2 hours when diluted with 280 mL glucose 5% solution (1:15 v/v).

Keywords: High Performance Liquid Chromatography; Pneumocystis Jiroveci Pneumonia; Stability And Incompatibility; Sulfamethoxazole; Trimethoprim.

Figure 1

HPLC chromatograms of intravenous co-trimoxazole (trimethoprim and sulfamethoxazole) (A), trimethoprim before (B) and after stressing under acidic, basic or oxidative conditions at 50°C for 1 hour (C–E), sulfamethoxazole before (F) and after stressing under acidic, basic or oxidative conditions at 50°C for 1 hour (G–I). Each sample was prepared in triplicate and analysed in duplicate.

Figure 2

Microscopic images (10× magnification) of positive control prepared by mixing 1 mL of glucose 5% with 1 mL of intravenous co-trimoxazole at time 0, 2 and 4 hours (A1, A2 and A3), intravenous co-trimoxazole infusion (1:20 v/v) stored at room temperature for 0, 2 and 4 hours (B1, B2 and B3) and intravenous co-trimoxazole infusion (1:15 v/v) stored at room temperature after 0, 2 and 4 hours (C1, C2 and C3). Each sample was prepared in triplicate and analysed in duplicate.

Figure 3

Photographs of infusion bag A and infusion bag B. Infusion bag A was prepared by mixing 20 mL of intravenous co-trimoxazole with 180 mL of glucose 5% and stored at room temperature for 1.5 hours. Infusion bag B was prepared by mixing 20 mL of intravenous co-trimoxazole with 280 mL of glucose 5% and stored at room temperature for 2.5 hours. Microscopic images (10× magnification) of an aliquot (50 µL) withdrawn from the infusion bag A (C) and infusion bag (B) after being stored at room temperature for 1.5 and 2.5 hours at room temperature (C and D).