Structure elucidation and quantification of impurities formed between 6-aminocaproic acid and the excipients citric acid and sorbitol in an oral solution using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy

• Published in: Journal of pharmaceutical and biomedical analysis 2015-03, Vol.107, p.333-340
• Main Authors: Schou-Pedersen, Anne Marie V., Cornett, Claus, Nyberg, Nils, Østergaard, Jesper, Hansen, Steen Honoré
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aminocaproic Acid - chemistry; Chemistry, Pharmaceutical - methods; Citric acid; Citric Acid - chemistry; Drug Contamination; Drug–excipient compatibility; Excipients - chemistry; High-performance liquid chromatography; Magnetic Resonance Spectroscopy - methods; Mass spectrometry; Mass Spectrometry - methods; Nuclear magnetic resonance spectroscopy; Pharmaceutical Solutions - chemistry; Sorbitol - chemistry; Temperature
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2015.01.022

•6-aminocaproic acid, citric acid and sorbitol were investigated at 20 and 50–80°C.•An amide reaction product, dimer and caprolactam were identified with HR–MS and NMR.•Minor amounts of degradation products of 6-aminocaproic acid were also observed.•The stability study at 80°C represents normal storage conditions at 20°C. Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50°C, 60°C, 70°C and 80°C as well as at 20°C. It has previously been reported that the commonly employed citric acid is a reactive excipient, and it is therefore important to thoroughly investigate a possible reaction between 6-aminocaproic acid and citric acid. The current study revealed the formation of 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid between 6-aminocaproic acid and citric acid by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectroscopy (NMR). Less than 0.03% of 6-aminocaproic acid was converted to 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid after 30 days of storage at 80°C. Degradation products of 6-aminocaproic acid were also observed after storage at the applied temperatures, e.g., dimer, trimer and cyclized 6-aminocaproic acid, i.e., caprolactam. No reaction products between d-sorbitol and 6-aminocaproic acid could be observed. 3-Hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid, dimer and caprolactam were also observed after storage at 20°C for 3 months. The findings imply that an oral solution of 6-aminocaproic acid is relatively stable at 20°C at the pH values 4.00 and 5.00 as suggested in the USP for oral formulations. Compliance with the ICH guideline Q3B is expected.