The pH-stability and acid degradation of the macrolide antibiotic, josamycin

Abstract

The influence of pH, ionic strength and buffer concentration on the stability of josamycin has been investigated. The pH-rate profile for josamycin over the pH range 1–12 was characterised and the equation describing the profile determined. Results indicated that josamycin is subject to specific acid catalysis whilst catalysis in alkali media appeared to be more complex. The rate constant for catalysis by hydronium ion ( k H) was 54.11 M −1 · h −1 and the rate constant for catalysis by hydroxide ion ( k OH) was 60.35 M −1 · h −1. Catalysis due to water was insignificant and the water catalysed rate constant was found to be 3.37 × 10 −5 h −1. The pH of maximum stability was determined as pH 6.5 whilst degradation at pH 1.0 and 12.0 is about five orders of magnitude greater than at pH 6.5. The degradation of josamycin in acid is subject to a significant primary salt effect; however, no secondary salt effect was evident. Concentration vs. time profiles for josamycin in acidic media were biphasic which indicated that the degradation reaction did not follow a simple pathway whereby josamycin degrades directly to products. Further investigations suggest that josamycin undergoes a reversible isomerisation step, with subsequent degradation of josamycin and possibly its isomer, by cleavage of the mycarose moiety to desmycarose compounds. Studies to determine the stability of josamycin in simulated gastric fluids demonstrated that acid degradation could be appreciable after oral administration. However, extensive degradation in vivo will only occur at the most acidic gastric pH's of about pH 1.0 to 2.0.