Mechanosynthesis Of A Coamorphous Formulation Of Creatine With Citric Acid And Humidity-Mediated Transformation Into A Cocrystal

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