ON THE PH-DEPENDENT DEGRADATION OF 15(S)-15-METHYL-PROSTAGLANDIN F2-ALPHA (CARBOPROST)

Acid-catalyzed degradation of the methyl ester of 15(R)-15-methyl-pros taglandin F-2 alpha (2b) in acetonitrile afforded methyl 9 alpha 11 ph a-dihydroxy-15-methylprosta-5(Z),13,15-trienoate (3b) as the main prod uct. Treatment of 2b with acidified methanol resulted in the formation of methyl 1S(R,S)-9 alpha,11 alpha-dihydroxy-15-methoxy-15-methylpros ta-5 (Z),13(E)-dienoate (4b,5b) as well as methyl 13(R,S)-9 alpha,11 a lpha-dihydroxy-13-methoxy-15-methylprosta-5 (Z),14(E,Z)-dienoate (6b). In acidified aqueous 1,2-dimethoxyethane, 2b underwent epimerization into the corresponding 15(S) derivative (Ib), solvolysis into methyl 1 3(R,S)-9 alpha,11 3-trihydroxy-15-methylprosta-5(Z),14(E,Z)-dienoate ( 9b), and dehydration into methyl 9 alpha,11 alpha-dihydroxy-15-methyl- prostaglandin ,13,15-trienoate (3b). The same products, as the free ac ids, were formed from 15(S)-15-methyl-prostaglandin F-2 alpha (Carbopr ost, 1) upon treatment with acid in the solvents indicated. Degradatio n of the tromethamine salt of 15(S)-15-methyl-prostaglandin F-2 alpha (1c) in aqueous buffers was studied as a function of time, temperature , and pH. A gradual increase in stability of 1c was observed when the pH values of the buffers used were increased from 7.3 to 9.1 and highe r. As a result of the stability tests, it was concluded that 1c may be stored at 37 degrees C in tromethamine buffer, pH 9.55, for at least 1 year with less than 3-4% degradation.