Facilitated Reversible Formation of Amides from Carboxylic Acids in Aqueous Solutions III

NOTES: Formation of Amide- and Imide-Linked Degradation Products Between the Peptide Drug Oxytocin and Citrate in Citrate-Buffered Formulations

“…6 Using aniline as a model compound, the authors showed that heating aqueous solutions of amines buffered in citric acid over the pH range 2.0–4.5 leads to the formation of amide and cyclic imide derivatives. A generalized mechanism for their formation is given in Figure 3 6,7. More recently, amides have been shown to form from 5‐aminosalicylic acid formulated in citrate buffer at pH 4.8, both under accelerated stress conditions (70°C) and at room temperature after extended storage 8.…”

“… 6,7. More recently, amides have been shown to form from 5aminosalicylic acid formulated in citrate buffer at pH 4.8, both under accelerated stress conditions (70 • C) Formation of symmetrical and unsymmetrical anhydrides from citrate.…”

Rate of Anhydride Formation in Tartrate Buffer System

“…The rate of disappearance of aniline in 0.5 M tartrate buffer system was followed in a manner already described in a previous paper (3). The study was run under air rather than nitrogen since no differences were noted for this system.…”

“…The theoretical basis of the following treatment has been reported elsewhere (2,3); references should be made for detail to the earlier works. Typical AN-AN, values plotted against time are shown in Fig.…”