0 Intermolecular complexation between a mixture of the comparatively water-insoluble alkaloids comprising 9,lOdihydroergotoxine and several xanthines was investigated. Substantial elevations of aqueous solubility of dihydroergotoxine in 0.1 N HCl and in pH 6.65 phosphate buffer was observed in most of the cases examined. This incongruity in the normally expected solubility data may be attributed to a mutual influence between the ergot derivative and the xanthine under consideration. Dissolution studies indicated a generally enhanced first-order rate of solution in the presence of xanthine which seems to evidence some "driving force" pulling the drug into solution. Partitioning rates (aqueous to chloroform) are usually increased when xanthine is added to the 9,10-dihydroergotoxine at pH 6.65 and the reverse is true in 0.1 N HCl. Biological data in cats and humans are in good agreement with physicochemical work.
Keyphrases 0 Ergot alkaloids, derivatives4omplex formation 0 Dihydroergotoxine-xanthines-interactions 0 Xanthines effectdihydroergotoxine dissolution 0 Partitioning rate, dihydroergotoxine-xanthine effect 0 Biological activity correlationphysicochemical data Caffeine and other naturally occurring xanthines have previously been shown to exhibit exceptional ability for formation of stable complexes with a wide variety of substances (1-3).
Mixtures of ergot alkaloids themselves have been stated to possess a tendency toward facile intermolecular complexation (4).
The interaction of caffeine and ergotamine tartrate in aqueous solution was observed in this laboratory and is exemplified by: (a) an increased solubility of the alkaloid in the presence of caffeine; (b) an increased dissolution rate constant for the ergot alkaloid in the combination over pure ergotamine; and (c) increased or decreased partitioning rates (aqueous to chloroform) of the alkaloid in the presence of caffeine relative to ergotamine tartrate alone depending on the pH studied (5).
This attraction between ergotamine tartrate and caffeine appeared to be an extremely weak one. The isolation of the complex eluded the authors (5). These ill-defined forces may be on the order of those found in dipole-dipole, dipole-induced dipole, and induced dipole-induced dipole systems, but have not been delineated. The two component solubility curves do not lend themselves to stoichiometric analysis (5).
It was speculated at the time that these in vitro results might correlate to some extent with the stated clinical effectiveness (6, 7) of orally administered caffeine, ergotamine tablets, and the caffeine present was functioning by holding the ergotamine in solution in the gut. Consequently, this solubilization of the complex in enteral media was thought probably to provide increased drug activity through ease of absorp-1