Physicochemical stability of piperacillin/tazobactam in syringe and elastomeric device for continuous administration in critical care and at home

Loeuille G.1, Vigneron J. 1,4, D’Huart E. 1,4, Charmillon A. 2, Demore B. 1,3,4
1 Pharmacie, CHRU de Nancy, Allée du Morvan, 54511 Vandœuvre-lès-Nancy, France
2 Equipe transversale d’infectiologie, CHRU de Nancy, Allée du Morvan, 54511 Vandœuvre-lès-Nancy, France
3 Université de Lorraine, EA 4360 APEMAC, Nancy, France.
4 Infostab, Association à but non lucratif, 54180 Heillecourt France

Piperacillin/tazobactam is the combination of a ureidopenicillin and a β-lactamase inhibitor. A time-dependent antibiotic of the β-lactam family, continuous administration improves its efficacy. The recommended dosage is 16/2 g/d for severe infections. Its interest in hospitals is based on its very broad spectrum, being active on both Gram-positive and Gram-positive bacteria. Stability data exist (in syringe and diffuser), however these studies are old with a low level of evidence.
The aim is to investigate the physicochemical stability of piperacillin/tazobactam 125/15.62mg/mL (6/0.75g in 48mL), in polypropylene syringe, stored at 20-25°C for continuous administration in intensive care units and 66.67/8.33mg/mL (16/2g in 240mL) in elastomeric device, stored at 37°C, protected from light for continuous administration at home.

Materials and methods
Three diffusers and 3 syringes were prepared for each condition. At each analysis time, 3 samples of each preparation were analysed with a validated method according to ICH Q2(R1) by high performance liquid chromatography coupled with a diode array detector at 210 nm. Physical stability was assessed by visual and subvisual inspection (turbidimetry by spectrophotometry at 350, 410 and 550 nm and by particle counting). The pH values were measured. Solutions were diluted in 0.9% sodium chloride (0.9% NaCl) or dextrose 5% in water (D5W) and analysed at T0, T8, T24 and T48 hours.

Linearity was validated with an R² of 0.9999 for piperacillin and tazobactam. The coefficients of variation for repeatability and intermediate precision were below 2% for both molecules. The retention time was 2.2 min for tazobactam and 13.5 min for piperacillin. After 48h, tazobactam in syringes and diffusers retained more than 90% of its initial concentration in both solvents. After 48 hours in syringes and 24 hours in diffusers, piperacillin retained more than 90% of its initial concentration in both solvents. No physical or visual instability was detected throughout the study. Spectrophotometric analysis revealed a change in absorbance at 350 nm, the spectral analysis of the degradation product (n°7) could be the cause of this change. The particle count is within specifications. The pH changes by more than one unit in the diffusers diluted with 0.9% NaCl after 24 hours.

In a polypropylene syringe, piperacillin/tazobactam at 125/15.62 mg/mL is stable, diluted in 0.9% NaCl or D5W for 48 hours, stored at room temperature. For a return home, administration in elastomeric device has been validated at 66.67/8.33mg/mL in D5W with stability over 24 hours at 37°C, but not in 0.9% NaCl.

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