THE PH-STABILITY AND ACID DEGRADATION OF THE MACROLIDE ANTIBIOTIC, JOSAMYCIN

The influence of pH, ionic strength and buffer concentration on the st ability of josamycin has been investigated. The pH-rate profile for jo samycin over the pH range 1-12 was characterised and the equation desc ribing the profile determined. Results indicated that josamycin is sub ject to specific acid catalysis whilst catalysis in alkali media appea red to be more complex. The rate constant for catalysis by hydronium i on (k(H)) was 54.11 M-1 .h-1 and the rate constant for catalysis by hy droxide ion (k(OH)) was 60.35 M-1 . h-1. Catalysis due to water was in significant and the water catalysed rate constant was found to be 3.37 x 10(-5) h-1. The pH of maximum stability was determined as pH 6.5 wh ilst 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 subjec t to a significant primary salt effect; however, no secondary salt eff ect was evident. Concentration vs. time profiles for josamycin in acid ic media were biphasic which indicated that the degradation reaction d id not follow a simple pathway whereby josamycin degrades directly to products. Further investigations suggest that josamycin undergoes a re versible isomerisation step, with subsequent degradation of josamycin and possibly its isomer, by cleavage of the mycarose moiety to desmyca rose compounds. Studies to determine the stability of josamycin in sim ulated gastric fluids demonstrated that acid degradation could be appr eciable after oral administration. However, extensive degradation in v ivo will only occur at the most acidic gastric pH's of about pH 1.0 to 2.0.