Overcoming stability challenges during continuous intravenous administration of high-dose amoxicillin using portable elastomeric pumps

• Published in: PloS one 2019-08, Vol.14 (8), p.e0221391
• Main Authors: Binson, Guillaume, Grignon, Claire, Le Moal, Gwenaël, Lazaro, Pauline, Lelong, Jérémy, Roblot, France, Venisse, Nicolas, Dupuis, Antoine
• Format: Article
• Language: English
• Subjects: Adverse drug reactions; Allergy; Amoxicillin; Amoxicillin - administration & dosage; Amoxicillin - adverse effects; Amoxicillin - analysis; Amoxicillin - chemistry; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - analysis; Anti-Bacterial Agents - chemistry; Antibiotics; Antimicrobial agents; Bacterial Infections - drug therapy; Biology and Life Sciences; Care and treatment; Chemistry, Pharmaceutical; Communicable diseases; Complications and side effects; Corrosion resistance; Degradation; Degradation products; Dose-Response Relationship, Drug; Drug dosages; Drug Stability; Elastomers; Endocarditis; High performance liquid chromatography; Hospitals; Human health and pathology; Humans; Hypersensitivity; Infectious diseases; Infusion; Infusion Pumps; Infusions, Intravenous - instrumentation; Intravenous administration; Life Sciences; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Medical treatment; Medicine and Health Sciences; Metabolites; Organic chemistry; Penicillin; Penicillins; Pharmaceutical sciences; Pharmacy; Physical Sciences; Pulmonary arteries; Pumps; Research and Analysis Methods; Risk factors; Solubility; Spectroscopy; Stability analysis; Studies; Temperature; Temperature effects; Time Factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0221391

While treatment of serious infectious diseases may require high-dose amoxicillin, continuous infusion may be limited by lack of knowledge regarding the chemical stability of the drug. Therefore, we have performed a comprehensive study so as to determine the chemical stability of high-dose amoxicillin solutions conducive to safe and effective continuous intravenous administration using portable elastomeric pumps. First, amoxicillin solubility in water was assessed within the range of 25 to 300 mg/mL. Then, amoxicillin solutions were prepared at different concentrations (25, 50, 125, 250 mg/mL) and stored in different conditions (5±2°C, 25±1°C, 30±1°C and 37±1°C) to investigate the influence of concentration and temperature on the chemical stability of amoxicillin. Finally, its stability was assessed under optimized conditions using a fully validated HPLC-UV stability-indicating method. Degradation products of amoxicillin were investigated by accurate mass determination using high-resolution mass spectrometry. Amoxicillin displayed limited water solubility requiring reconstitution at concentrations below or equal to 150 mg/mL. Amoxicillin degradation were time, temperature as well as concentration-dependent, resulting in short-term stability, in particular at high concentrations. Four degradation products of amoxicillin have been identified. Among them, amoxicilloic acid and diketopiperazine amoxicillin are at risk of allergic reaction and may accumulate in the patient. Optimized conditions allowing for continuous infusion of high-dose amoxicillin has been determined: amoxicillin should be reconstituted at 25 mg/mL and stored up to 12 hours at room temperature (22 ± 4°C) or up to 24 hours between 4 and 8°C.