Revisiting the solid-state landscape of creatine citric acid: A salt or a cocrystal?

Creatine, a widely used sports supplement, has been formulated in several different ways due to its poor solubility profile. Among these, coformulations of creatine and citric acid have been extensively studied, leading to reports of both salt and cocrystal formations. However, the zwitterionic nature of creatine has presented challenges in determining the favored formation and the influencing factors leading to the observation of salt or cocrystal. To address the discrepancies in the literature, our investigation revisited the solid-state landscape of creatine citric acid. In this pursuit, we synthesized a novel solid form - a 1:1 creatine citric acid cocrystal - and performed free energy calculations to confirm its thermodynamic preference over the previously reported cocrystal. We also examined several other methodologies reported to give creatine citric acid salts and obtain cocrystals. Crystal structure analyses of the two polymorphs revealed significant intermolecular interactions between creatine in its zwitterionic form and citric acid in its neutral state. Our experimental and computational findings collectively support the thermodynamic favorability of the newly discovered cocrystal. This cocrystal was characterized using various solid-state analytical techniques, including X-ray diffraction, thermal analysis, IR spectroscopy and computational predictions.