Preformulation investigation. I. Relation of salt forms and biological activity of an experimental antihypertensive.

The intrinsic dissolution rates of monohydrochloride, dihydrochloride, and disulfate salts and free base of an antihypertensive were studied. The comparative hypotensive activity of these compounds was studied in anesthetized dogs. The hypotensive responses were also compared to a large number of renal hypertensive dogs who had received a placebo treatment. The results from the anesthetized dog study indicate that the hypotensive potencies of the three salts do not differ from each other; however, the intrinsic dissolution rates of the dihydrochloride and disulfate salts are 54 and 42 times greater, respectively, than that observed with the monohydrochloride salt. These findings seem to indicate the oversensitivity of the in vitro dissolution method in reflecting the in vivo hypotensive activity of the compound. The free base failed to produce a significant dose-response curve in the anesthetized dog study as well as in the renal hypertensive dog study. This is attributed and correlated to the fact that the in vitro dissolution rate of the free base is very low in magnitude as compared to its corresponding salts. The results point out that in searching for a potential candidate of a drug substance, it is advisable to study routinely the effect of the salt form on the biological response.