Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition
Abstract
:1. Introduction
2. Results
2.1. Physical Stability
2.2. Chemical Stability
3. Discussion
4. Materials and Methods
4.1. General Procedures
4.2. Composition of PN Emulsions and CT Solutions
4.3. Simulation of Y-Site Administration
4.4. Sample Collection, Storage, and Analysis
4.5. Stability Assessment
- The presence of macroscopic precipitates, changes in color, and phase separation were assessed according to the European Pharmacopeia [35]. Visual inspection was conducted against a black-and-white contrast background by two pharmacists. Visual inspection was also performed with PN emulsions, without the drug.
- Microscopy was assessed using a LEICA DM2500 LED microscope (Leica Microsistemas S.L.U. L’Hospitalet de Llobregat, Spain) by two observers at t = 0 h and t = 24 h. Ten µL of the mixture were assessed at 400× magnification (10× ocular lens and 40× objective lens). Admixtures with CT as a bolus and as continuous infusion concentrations were used as negative control solutions. We also assessed PN with no drug. PN with final unstable calcium and phosphate concentrations was used as a positive control. Each combination of drug and PN was prepared in triplicate.
- pH measurement was made using potentiometry (senIONTM+ PH 1, Hach, Spain) at room temperature.
- Osmolality was measured at room temperature (Osmo1, Advanced Instruments, Tecil, Spain).
- The particle size of the lipid emulsion was measured at 25 °C using dynamic light scattering (Zetasizer NanoZS90, Malvern Instruments Ltd., Malvern, UK) 6 h after the simulation. Samples for DLS were prepared by diluting the solutions into PBS at a final concentration of approximately 30 μg/mL. The results of particle diameter are presented as MDD. (Figure 2 and Supplementary Materials Figure S1)
- HPLC–HRMS was used to quantify CT concentration in the admixtures. Samples were measured in triplicate. An Infinity II LC system coupled to a 6560-ion mobility QTOF mass spectrometer, both from Agilent Technologies (Santa Clara, CA, USA), was used in positive ionization mode from m/z 100–1700. A Kinetex F5 150 × 2.1 mm, 2.6 µm column from Phenomenex (Torrance, CA, USA) was used with mobile phase A (water and 0.1% formic acid and mobile phase B (Acetonitrile and 0.1% formic acid) at 0.4 mL/min, following the gradient (t(min), %B): (0, 2), (1, 2), (6, 95), (7.5, 95), (7.8, 2), and (10, 2). Samples were diluted 1/10,000 with ultrapure water in three steps and centrifuged at 10,000 rpm at 4 °C for 5 min. The injection volume was 2 µL. Trace chromatograms were extracted with a 3 ppm error at m/z 667.1824 for ceftolozane and m/z 301.0601 for tazobactam. (Figure 3) Calibration standards were prepared in a blank matrix diluted 1/10,000, and the weighting of calibration curves was adjusted (1/x or 1/x2) to obtain accuracies between 80 and 120%. The matrix-matched calibration curve was prepared in a blank sample diluted 1/10,000, which was spiked with standards at five concentrations between 0.1 and 4.5 mg/L. The calibration curve was prepared daily and was injected in triplicate each day of analysis. Regarding selectivity, the ability to distinguish the analyte from other substances was indicated by an absence of the respective peaks at the same retention time as the corresponding standards in trace chromatograms extracted with a 5 ppm error. Accuracy was calculated at the five spiked levels (based on the ratio between the calculated concentration and the spiked concentration) between 90.5 and 101.2% for tazobactam and between 82.6 and 111.1% for ceftolozane. Intra-day repeatability expressed as relative standard deviation (%) between 0.4 and 3.4% for ceftolozane and between 0.1 and 3.3% for tazobactam was obtained. Inter-day repeatability was between 2.1 and 12.8% for ceftolozane and between 0.8 and 15.9% for tazobactam. The limit of detection LOD, defined as S/N = 3, was 10 ng/mL for ceftolozane and 1 ng/mL for tazobactam.
- No changes in visual inspection, defined as a homogeneous admixture with no changes in color, no phase separation, and lack of macroscopic precipitates or gas formation altering the admixture, as assessed by two independent observers against a black-and-white contrast background at t = 0 h and t = 6 h [35].
- No signs of precipitation, emulsion disruption, or presence of particles >5 µm at microscopic inspection.
- No relevant CT concentration changes in the mixture, defined as <20% change at t = 24 h (measured using HPLC–HRMS) [15].
- No relevant particle size changes, defined as MDD ≤ 500 nm in all samples (United States Pharmacopeia), and percentage of particles greater than 5 µm < 0.05% according to the US pharmacopeia method I [38].
4.6. Data Analysis and Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sample | MDD |
---|---|
PN1 | 276.1 ± 7.7 nm |
PN2 | 286.8 ± 4.7 nm |
PN3 | 284.0 ± 6.5 nm |
PN1-bolus1 | 286.5 ± 8.9 nm |
PN2-bolus2 | 284.7 ± 4.6 nm |
PN3-bolus3 | 282.3 ± 6.3 nm |
PN1-IC1 | 279.2 ± 4.0 nm |
PN2-IC2 | 285.4 ± 2.8 nm |
PN3-IC3 | 294.2 ± 7.3 nm |
Sample | Osmolality (mOsm/kg) t = 0 h | Osmolality (mOsm/kg) t = 6 h | Percentage of Initial Osmolality |
---|---|---|---|
PN1 | 1944.3 ± 31.6 | 1931.7 ± 21.1 | −0.7% |
PN2 | 1940 ± 11.1 | 1922.7 ± 23 | −0.9% |
PN3 | 1920.3 ± 17.1 | 1910.3 ± 12.1 | −0.5% |
PN1-bolus1 | 1171 ± 6.6 | 1149 ± 2.6 | −1.9% |
PN2-bolus2 | 1063.3 ± 7.1 | 1053.3 ± 4.6 | −0.9% |
PN3-bolus3 | 1076.3 ± 21 | 1060.3 ± 8.6 | −1.5% |
PN1-IC1 | 1741 ± 23.4 | 1714 ± 5.3 | −1.6% |
PN2-IC2 | 1808 ± 6.6 | 1744.3 ± 11.2 | −3.5% |
PN3-IC3 | 1695.3 ± 16.7 | 1709 ± 12.1 | +0.8% |
Sample | Concentration (mg/mL) t = 0 h | Concentration (mg/mL) t = 24 h | Percentage of the Initial Concentration |
---|---|---|---|
PN1-bolus1 | 8.64 ± 0.32 | 9.08 ± 0.57 | +5% |
PN2-bolus2 | 8.21 ± 0.53 | 9.58 ± 0.61 | +17% |
PN3-bolus3 | 8.45 ± 0.06 | 9.44 ± 0.44 | +12% |
PN1-IC1 | 1.46 ± 0.05 | 1.32 ± 0.01 | −10% |
PN2-IC2 | 1.45 ± 0.04 | 1.35 ± 0.01 | −7% |
PN3-IC3 | 1.81 ± 0.07 | 1.83 ± 0.04 | +1% |
Sample | Concentration (mg/mL) t = 0 h | Concentration (mg/mL) t = 24 h | Percentage of the Initial Concentration |
---|---|---|---|
PN1-bolus1 | 4.25 ± 0.10 | 4.16 ± 0.04 | −2% |
PN2-bolus2 | 4.33 ± 0.23 | 4.37 ± 0.01 | +1% |
PN3-bolus3 | 4.32 ± 0.11 | 4.09 ± 0.28 | −5% |
PN1-IC1 | 0.78 ± 0.01 | 0.78 ± 0.01 | 0% |
PN2-IC2 | 0.80 ± 0.02 | 0.77 ± 0.04 | −4% |
PN3-IC3 | 1.09 ± 0.05 | 1.07 ± 0.02 | −2% |
Sample | Concentration Ratio t = 0 h | Concentration Ratio t = 24 h | Percentage of the Initial Concentration Ratio |
---|---|---|---|
PN1-bolus1 | 2.03 | 2.18 | +7% |
PN2-bolus2 | 1.89 | 2.19 | +16% |
PN3-bolus3 | 1.96 | 2.31 | +18% |
PN1-IC1 | 1.87 | 1.70 | −9% |
PN2-IC2 | 1.81 | 1.75 | −3% |
PN3-IC3 | 1.66 | 1.71 | +3% |
PN | |
---|---|
Volume (mL) | 1615 |
Total calories (kcal) | 1850 |
Non-protein calories (kcal) | 1500 |
Non-protein calories/gN Ratio | 107 |
Glucose (g) | 250 |
Aminoacids (g) | 87.5 |
Nitrogen (g) | 14 |
Lipids (g) | 50 |
Na+ (mEq) | 80 |
K+ (mEq) | 60 |
Ca2+ (mEq) | 9.2 |
Mg2+ (mEq) | 10 |
Phosphate (mEq) | 20 |
Sulphate (mEq) | 5 |
Chlorate (mEq) | 60 |
Acetate (mM) | 50 |
Multivitamin Cernevit® a | 5 mL |
Trace elements Supliven® b | 10 mL |
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De Pourcq, J.T.; Riera, A.; Gras, L.; Garin, N.; Busquets, M.A.; Cardenete, J.; Cardona, D.; Riera, P. Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition. Pharmaceuticals 2024, 17, 896. https://doi.org/10.3390/ph17070896
De Pourcq JT, Riera A, Gras L, Garin N, Busquets MA, Cardenete J, Cardona D, Riera P. Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition. Pharmaceuticals. 2024; 17(7):896. https://doi.org/10.3390/ph17070896
Chicago/Turabian StyleDe Pourcq, Jan Thomas, Adria Riera, Laura Gras, Noe Garin, Maria Antònia Busquets, Joana Cardenete, Daniel Cardona, and Pau Riera. 2024. "Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition" Pharmaceuticals 17, no. 7: 896. https://doi.org/10.3390/ph17070896
APA StyleDe Pourcq, J. T., Riera, A., Gras, L., Garin, N., Busquets, M. A., Cardenete, J., Cardona, D., & Riera, P. (2024). Physicochemical Compatibility of Ceftolozane-Tazobactam with Parenteral Nutrition. Pharmaceuticals, 17(7), 896. https://doi.org/10.3390/ph17070896