(23a) Creatine Citric Acid Cocrystals or Creatine Citrate Salts, That Is the Question?

Cocrystals and salts are important classes of multicomponent crystalline materials that can enhance solubility and improve the physical properties of solid forms for pharmaceutical development. It is challenging to determine a priori if salt or cocrystal formation is favored for a specific system for components where similar pKa values exist, as the two are different only by the location of the proton between the acid and base. In this case, the pKa value and the crystalline environment determine the extent of proton transfer. Proton transfer must be complete for the crystalline solid to form a salt, but this transfer does not occur for cocrystals. Single crystal X-ray diffraction (SC-XRD) and spectroscopic techniques such as IR and solid-state NMR can be used to unambiguously determine if proton transfer has occurred in these crystalline solids and scientists use these tools to identify if a new crystalline form is a cocrystal or salt.

A recently published manuscript reports¹ that creatine, one of the most frequently used fitness supplements, and citric acid can form a cocrystal; however, previous publications^2,3 suggest that the two components form a salt instead. Since the pKa differences between creatine and citric acid suggest that salt formation is more likely, we set out to determine which reports were correct. Both experimental and computational approaches were investigated. In this pursuit, a novel solid form of a creatine citric acid cocrystal was synthesized and demonstrated to be thermodynamically-preferred over the known cocrystal form. Single crystal X-ray diffraction confirmed the new crystal form is indeed a cocrystal. The crystal structures of the two polymorphs of the creatine citric acid cocrystal revealed that they are composed of strong intermolecular interactions in which citric acid is in the neutral state and creatine in the zwitterionic form. Free energy calculations confirmed experimental observations that the newly discovered cocrystal is thermodynamically-favored over the earlier polymorph.

This creatine citric acid crystalline system is an interesting test case and highlights difference in pKa between ionizable groups may not necessarily be sufficient to classify a multicomponent solid salt or a cocrystal. In these situations, analytical techniques (e.g. crystallography, spectroscopy, etc.) and/or computational approaches are required to provide unambiguous confirmation.