Chemical Incompatibility Between Procainamide Hydrochloride and Glucose Following Intravenous Admixture

Abstract

The chemical reaction between procainamide hydrochloride and glucose following admixture to glucose infusion has been investigated. Substantial amounts (10-15% after 10 h at room temperature) of the procainamide is lost with the formation of a mixture of the corresponding alpha- and beta-glucosylamines. The chemical identity of the latter compounds was confirmed by 13C and 1H nuclear magnetic resonance spectroscopy.

Glycosylation of Aromatic Amines I: Characterization of Reaction Products and Kinetic Scheme

“…The m/z of 393 in the mass spectra for the two products corresponds to molecular ion plus sodium. Though the expected products were the glycosylamines, as has been reported for reactions of amines with sugars (6,8,26) this was further confirmed using UV and NMR spectroscopy. The two products showed similar UV spectral properties to that of kynurenine.…”

“…The aromatic amine pK a was estimated to be 1.84 at 40°C using UV spectroscopy. Kynurenine is a weakly basic aromatic amine similar in basicity with primary aromatic amine-containing drugs such as sulfamethoxazole (pKa=1.69) (6), procainamide (pKa= 2.75) (26), benzocaine (pKa=2.49), or procaine (pKa=2.28) (35) to name a few (31). The alpha amine pK a value was determined to be 9.05 at 40°C by potentiometric titration.…”

“…For example, the reversible formation of glycosylamines for procainamide in the presence of 5% dextrose solution was reported in water (24,25). In another study, a 20-30% procainamide potency loss (aromatic amine pK a =2.75) in 24 h was reported following admixing with glucose solutions (26). The formation of glucosylamines has also been reported for the oral suspension of sulfamethoxazole (aromatic amine pK a =1.69) in the presence of glucose and a limit for the amount of glycosylamines allowed in the suspension has been reported for such formulations (27).…”

Glycosylation of aromatic amines II: Kinetics and mechanisms of the hydrolytic reaction between kynurenine and glucose

“…Although numerous examples of pharmaceutically relevant compounds reacting with reducing sugars have been reported in the recent literature,11–18 mechanistic studies involving reducing sugars and weakly basic aromatic amines (p K a 1–3) have not been extensively studied. In general, aliphatic and aromatic amines react with the reactive carbonyls of reducing sugars to form imines (acyclic form), which exist in equilibrium with the glycosylamines (reduced cyclic form) 19, 20.…”

Glycosylation of aromatic amines III: Mechanistic implications of the pH-dependent glycosylation of various aromatic amines (kynurenine, 2′-aminoacetophenone, daptomycin, and sulfamethoxzaole)

“…Glycosylation and various other carbonyl–amine reactions are of great importance in the design, development, and quality of drug delivery systems by virtue of their potential roles in prodrug synthesis,1, 2 carrier‐linkage design, chemical stability, and excipient–drug interactions 3–6. In this series, we have reported on the methods, reaction schemes, kinetics, and mechanisms of a model aromatic amine glycosylation using glucose isomers and kynurenine 7, 8.…”