Investigation of Some Complexes Formed in Solution by Caffeine†

Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals

“…108 A clinical study using the cocrystal showed that it was tolerated in "unusually large amounts in man" and elicited the "typical theophylline response." 108 In the 1950s, Higuchi used solubility measurements to search for complex formation in solution between caffeine and a number of pharmaceutically active or acceptable compounds such as benzoic acid, benzoate ion, 109 aspirin, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, salicylic acid, salicylate ion, butyl paraben, 110 sulfathiazole, sulfadiazine, 4-aminobenzoic acid, benzocaine, phenobarbital, and barbital. 111 Ultimately, he found and isolated cocrystals of caffeine and gentisic acid that had stoichiometries of 1:1 and 1:2 (caffeine/ gentisic acid).…”

Cocrystal Intrinsic Dissolution Behavior Using a Rotating Disk

“…Such complexes or associations can be utilized to manipulate pharmaceutically relevant properties 1 and have led to the design of new materials called cocrystals. 2 Complexation has been widely used in crystal engineering to create new solid materials with improved physicochemical properties.…”

Characterization of Complex Formation Between Small Molecules by Membrane Permeation Measurements

“…20,30, and 35'. 6 The small difference between the experimental results and those predicted from theoretical calculations based on a 1 : 1 stoichiometric ratio and corrected for caffeine dimerization cannot be ascribed to the fact that tetramer formation of caffeine was neglected in the calculations. Correction for the latter would actually increase somewhat the difference between the experimental and theoretical results.…”

“…Correction for the latter would actually increase somewhat the difference between the experimental and theoretical results. 6 The linearity of the solubility phase diagram (Fig. 2) indicates that the stoichiometry with respect to the caffeine component is 1 in this concentration range (12).…”