Neutral solutions of aminomethanesulfonates are largely dissociated into hydroxymethylamino compounds and sulfite (and bisulfite) ions. Identical solutions are formed either by dissolving pure crystalline aminomethanesiilfonic acids or by combining the amine, formaldehyde, and sulfite at appropriate pH. Solutions of aminomethanesulfonates can react with an additional molecule of formaldehyde bisutfite to givt a disubstituted amine, which in turn dissociates to give more sutfite ion. Neutral solutions of sodium colistimethate comprise complex equilibria in which individual molecules are substituted by vai ying numbers of methanesulfonate or hydroxyrnethyl groups, possibly as many as 10, but with three or four of these species more highly favored than the rest (possibly for steric as well as statistical reasons). When more than three molecules each of formaldehyde and d f i t e are available for reaction with colistin, no evidence for the existence of free colistin is found. Furthermore, the likelihood for the simultaneous existence of five unreacted amino groups in one molecule is very small. Keyphrases 0 Colistimethate sodium soliitions--equilibria phenomena 0 n-Butylaminomethanesulfonic acid-synthesis, model solutions Equilibrium constants-n-butylaminomethanesulfonic acid solutions 0 Iodine titration-n-butyl iminomethanesulfonic acid, colistimethate solutions 0 IR spectrophotometry-identity, structure 0 NMR spectroscopy-identity, structure 0 Electrophoresis-analysis Methanesulfonation of free amino groups of pharmaceuticals is a technique which has been used for many years in attempts to improve such properties as toxicity (or more precisely, therapeutic ratio), c ompatibility, and solubility, and to eliminate undesired side effects such as pain on injection. A review of many of the classes of drugs subjected to methanesulfonation was published by Logeman and Miori (1). Throughout the years it seems to have been more or less tacitly assumed that these methanesulfonates were physiolcgically active by virtue of slow "hydrolysis" to give 3ack the parent drug. However, this hydrolysis has not been adequately demonstrated.
Sodium colistimethate is a metha~iesulfonate~ derivative of colistin, a basic polypeptide i ntibiotic having five free amino groups (2). This derivative has the sought-for advantages of reduced toxicii y (higher therapeutic ratio) and elimination of pain or injection. Two studies have been reported in which attempts were made to ascertain whether or not the methanesulfonate is hydrolyzed in human serum, and, if so, to what extent and in what form it is excreted in the urine (3, 4). In these studies the investigators succeeded in demonstrating some changes in the form of the dru,;, but the complexity of the problem precluded an exact description of these changes. 1 Coly-Mycin Injectable brand of sodium colistimethate is manu-2 By the term aminomethanesulfonates is meant ;NCHzSOsor factured by Warner-Chilcott Laboratories, Morris PI[ ins, N. J.