Mechanosynthesis of a Coamorphous Formulation of Creatine with Citric Acid and Humidity-Mediated Transformation into a Cocrystal

Creatine is recognized as a dietary staple among athletes, with two supplement formulations currently available on the United States market: creatine monohydrate and hydrochloride. has relatively low aqueous solubility, which hampers its ease of preparation by consumers. hydrochloride excellent solubility; however, it exhibits strong acidic taste potentially harmful effects dental health. Herein, we report mechanochemical synthesis 1:1 coamorphous formulation citric acid, a-CCA. Milling anhydrous acid yielded a-CCA, was found to be structurally stable under dry conditions. Upon exposure humid air, a-CCA rapidly converted into cocrystalline formulation, c-CCA. Correspondingly, milling at least one source present monohydrate, resulted in direct mechanosynthesis cocrystal. The crystal structure solved refined from powder X-ray diffraction data, obtained solution evaluated energy minimization calculations. Close inspection hydrogen-bonding network revealed presence zwitterionic form neutral molecule. Additionally, solid cocrystal were studied infrared spectroscopy, differential scanning calorimetry, thermogravimetry. solubility (32.0(8) g/L) determined ∼2.5× higher compared that commercial (13.3(6) g/L). ∼10× less simple, efficient, scalable method preparation, phase-purity high degree crystallinity ambient conditions, increased (compared monohydrate) decreased acidity hydrochloride) render creatine:citric an improved marketable formulation.