title: Physicochemical characterization of creatine N-methylguanidinium salts.
abstract: Creatine is widely used as a dietary supplement for body builders to enhance athletic performance. As the monohydrate, its low solubility in water and high dose lead to water retention and gastrointestinal discomfort. Hence, alternative creatine derivatives with enhanced water solubility and potential therapeutic advantages have been synthesized. As a zwitterionic compound, creatine can form salts at the N-methyl guanidinium or carboxylic acid functional groups. In this study, we determined the aqueous solubilities and partition coefficients of six N-methyl guanidinium salts of creatine compared to those of creatine monohydrate; two of these were new salts, namely, creatine mesylate and creatine hydrogen maleate. The aqueous solubilities of the salts were significantly more than that of creatine monohydrate with the hydrochloride and mesylate being 38 and 30 times more soluble, respectively. The partition coefficients of the creatine salts were very low indicating their relatively high polarity. Permeabilities of creatine pyruvate, citrate, and hydrochloride in Caco-2 monolayers were compared to that of creatine monohydrate. Aside from the creatine citrate salt form that had reduced permeability, there were no significant differences in permeability characteristics in Caco-2 monolayers. Typical of an amphoteric compound, creatine is least soluble in the pH region near the isoelectric point.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Gufford
authors.forename: Kamaraj
authors.initials: K
authors.lastname: Sriraghavan
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Miller
authors.forename: Donald W
authors.initials: DW
authors.lastname: Miller
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Gu
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Robinson
mesh_terms: D054874:Athletic Performance; D018938:Caco-2 Cells; D003401:Creatine / Q000737:chemistry*; D019587:Dietary Supplements; D019791:Guanidine; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010539:Permeability; D012492:Salts / Q000737:chemistry; D012995:Solubility
chemical_list: D012492:Salts; D019791:Guanidine; D003401:Creatine