Salt or Cocrystal Puzzle Solved by Mechanochemistry: The Role of Solvent in the Pamoic Acid Case Study.

Many drugs are nowadays marketed as salts. Cocrystallization is also emerging as a convenient tool to modify in vivo activity of pharmacologically active compounds. Given the marked difference in physicochemical properties between salts and cocrystals, the possibility of obtaining crystalline systems composed of the same building blocks in their neutral or charged form is desirable. Pamoic acid (PAM) is widely used in pharmaceutical formulation as pamoate salt, and we here propose a unique synthetic strategy to obtain a cocrystal of PAM rather than a salt by tuning mechanochemical conditions. Our findings have been corroborated by means of computational analyses, relating to the noncovalent interactions in the crystal structure with the formation of the different crystalline forms. A detailed analysis of the structure containing PAM in its neutral, anionic or dianionic form present in the Cambridge Structural Database (CSD) helped generalizing our results.