Influence of pH, temperature and buffers on cefepime degradation kinetics and stability predictions in aqueous solutions

Fubara, Josephine O.; Notari, Robert E.

doi:10.1021/js980170y

Cited by 44 publications

(24 citation statements)

References 6 publications

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“…An increase of pH has also been recently reported during cefepime degradation in buffered saline solution (12). On the other hand, evidence for both acid-and base-catalyzed degradation of cefepime has been reported earlier (9).…”

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Pitfalls in Cefepime Titration from Human Plasma: Plasma- and Temperature-Related Drug Degradation In Vitro

Bugnon

Giannoni

Majcherczyk

et al. 2002

Antimicrob Agents Chemother

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While developing a high-pressure liquid chromatography assay for cefepime in plasma, we observed significant drug degradation at 20 and 37°C but not at 4°C. This plasma-related degradation persisted after protein removal. This warrants caution regarding cefepime assays for pharmacokinetic and pharmacodynamic studies of cefepime in vitro and in vivo.While a high-pressure liquid chromatography (HPLC) method to measure levels of cefepime in plasma was being validated, significant plasma-dependent and temperature-dependent degradation of cefepime was observed. Since this might bias cefepime determination in clinical samples, the degradation process was further explored. Experiments were performed in the presence or absence of plasma and at temperatures of 4, 20, and 37°C. In the presence of plasma, maintaining the temperature at 4°C was critical to avoid degradation. At higher temperatures, conforming either to bench-top storage (20°C) or incubation at physiological temperature (37°C), rapid degradation occurred.Methods and experimental design. Cefepime was obtained from Bristol-Myers Squibb AG (Sermoneta, Italy). Deionized water (Ͼ16 M⍀ ⅐ cm) was used. Healthy volunteers' plasma (stored at Ϫ30°C) was obtained from 450-ml individual blood collection bags (Fenwal, Baxter, Volketswil, Switzerland) containing 63 ml of a solution of citric acid (15.6 mM), sodium citrate (90 mM), sodium dihydrogenophosphate (16.1 mM), dextrose (160 mM), and adenine (2 mM).All samples were initially prepared at 4°C. Before HPLC determination, plasma was deproteinized either by precipitation followed by back extraction or by ultrafiltration. For precipitation, 500 l of plasma was mixed with 500 l of acetonitrile, allowed to stand for 10 min, and centrifuged at 15,000 ϫ g for another 10 min. For back extraction, 500 l of the deproteinized supernatant was mixed with 1 ml of methylene chloride, allowed to stand for 10 min, and centrifuged as described above. The supernatant was injected into the HPLC. Ultrafiltration was performed as described elsewhere (10).Cefepime was separated on a C 18 column (LC 18 , 15 cm by 4.6 mm; Supelco, Bellefonte, Pa.), using a Merck-Hitachi HPLC LaChrom system (Hitachi Instruments, Ichige Hitachinaka, Japan) with a diode array detection. The mobile phase (1 ml/min) comprised 92% volume of 0.2 M borate adjusted to pH 6.8 (20°C) with NaOH and 8% volume of methanol. Samples were sealed to prevent evaporation and kept at a controlled temperature (Peltier cooler; Labsource, Reinach, Switzerland) until their automated injection (50 l). Cefepime was quantified by computing the area under the peak from the 260-nm absorption signal. Calibration curves, consisting of seven standards (0.5 to 200 mg/liter) were prepared daily and assayed both at the beginning and the end of the procedure. Linearity, extraction recovery, intrarun and interrun coefficients of variation and accuracy, limit of detection (LOD), and limit of quantification (LOQ) were determined (14).Assay validation. The basic performance of the method was excell...

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“…It is also stable when kept in H 2 O solution at room temperature (9) or in plasma at 4°C (7). However, it is unstable in plain serum during bench-top storage (7).…”

mentioning

confidence: 99%

Pitfalls in Cefepime Titration from Human Plasma: Plasma- and Temperature-Related Drug Degradation In Vitro

Bugnon

Giannoni

Majcherczyk

et al. 2002

Antimicrob Agents Chemother

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“…[31][32][33][34] The automated solution stability method can be applied to determine a stability-pH profile of drug candidates. Three compounds were used to prototype the applica- was used to compensate for evaporation.…”

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Development and Application of an Automated Solution Stability Assay for Drug Discovery

Di¹,

Kerns²,

Hong³

et al. 2006

SLAS Discovery

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Screening of solution stability provides an early alert on potential liabilities of drug candidates so that strategies can be developed to overcome the challenges. A fully automated solution stability assay has been developed to accelerate traditional manual operation. The assay uses the advanced capabilities of a high-performance liquid chromatography instrument that is present in many pharmaceutical research laboratories. The samples are prepared automatically by a temperature-controlled autosampler. The samples are delivered to the stability matrices, mixed, incubated, and injected at selected time points during the reaction time course. This automated process occurs without operator intervention, thus allowing 96 experiments to be run with 0.5 h of a scientist's time compared to 8 h for the same study when performed manually. Automation not only eliminates the manual operation but also improves accuracy and throughput. The assay protocol has been optimized to achieve homogenous mixing and eliminate carryover. The assay is robust, flexible, and high throughput. It can be used to study stability for a large number of samples under multiple incubation conditions and has a wide range of applications in drug discovery and development, such as screening compound stability in biological assay media, obtaining a stability-pH profile, surveying compound stability in physiological fluids, and performing development forced degradation and excipient compatibility. (Journal of Biomolecular Screening 2006:40-47)

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“…on May 9, 2018 by guest http://aac.asm.org/ tration (14,28,43). These studies, however, (i) used more diluted solutions, (ii) had the drug prepared in buffered media (which are not available to clinicians in a pharmaceutically validated form and may also not be sufficient in view of the high drug concentrations needed for the projected clinical use), and (iii) were not specifically designed to test the drug stability under pertinent conditions of clinical use.…”

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confidence: 99%

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Viaene

Chanteux

Servais

et al. 2002

Antimicrob Agents Chemother

177

123

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The stability of antipseudomonal ␤-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), and azlocillin (128 g/liter) remained 90% stable for up to more than 24 h at 37°C (mezlocillin [128 g/liter] was stable at 25°C but not at 37°C). Ceftazidime (120 g/liter), cefpirome (32 g/liter), and cefepime (50 g/liter) remained 90% stable for up to 24, 23.7, and 20.5 h at 25°C but only for 8, 7.25, and 13 h at 37°C, respectively. The control of temperature therefore appears to be critical for all three cephalosporins that cannot be recommended for use in portable pumps carried under clothes for prolonged periods for reasons of stability. Cefpirome and cefepime solutions developed an important color change (from light yellow to dark red) upon exposure when stored at 30°C or higher. Degradation of ceftazidime was accompanied by the liberation of pyridine which, at 37°C, was in excess of what is allowed by the U.S. Pharmacopeia, i.e., 1.1 mg/liter, after 8 and 12 h for drug concentrations of 12 and 8.3%, respectively. Imipenem and meropenem are too unstable (10% degradation at 25°C after 3.5 and 5.15 h, respectively) to be recommended for use by continuous infusion. Faropenem, examined in comparison with imipenem and meropenem, proved as stable as aztreonam or piperacillin.␤-Lactams are one of the most typical antibiotic classes for which the pharmacodynamic data, collected in vitro, as well as in animal studies, clearly indicate a potential advantage of a continuous infusion over the more conventional, discrete mode of administration (see references 6, 22, 23, 38, and 41 for reviews). Accordingly, several clinical trials have been initiated over the last half-decade, most notably in difficult-to-treat situations such as suspected gram-negative infections in critically ill patients (3), severe infections in intensive care patients (8,16,21,24,37), septicemia (1), severe sepsis (20), and cystic fibrosis (29,40). Yet, as clearly pointed out by one of the first promoters of the continuous infusion of ␤-lactams (6), this mode of administration, through programmable pumps or other similar devices, requires the drug to remain sufficiently stable in solution over the projected duration of the infusion. In a previous study (30), we examined the stability of ceftazidime in solution and found it to be critically dependent on the temperature within the 20 to 37°C range (68 to 99°F). This sets clear limitations on the potential use of ceftazidime by continuous infusion if administrations every 24 h are contemplated without periodic changes of the solutions. Chemical considerations suggest that the stability of the main ␤-lactams currently registered for human medicine use may vary to a meaningful extent. Unfortunately, these variations, and their consequences as far as continuous infu...

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Influence of pH, temperature and buffers on cefepime degradation kinetics and stability predictions in aqueous solutions

Cited by 44 publications

References 6 publications

Pitfalls in Cefepime Titration from Human Plasma: Plasma- and Temperature-Related Drug Degradation In Vitro

Pitfalls in Cefepime Titration from Human Plasma: Plasma- and Temperature-Related Drug Degradation In Vitro

Development and Application of an Automated Solution Stability Assay for Drug Discovery

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

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