Novel salts and cocrystals of the antifolate drug trimethoprim and their role in the enhancement of solubility and dissolution

Trimethoprim (TMP) is a BCS class II anti-folate drug with poor aqueous solubility. Four new crystal structures of TMP were developed in this work using a supramolecular synthon approach with coformers theophylline-7-acetic acid (T7A), 5-fluorouracil (5FU), catechol (CAT) and thymine (THY). The carboxylate or amide or hydroxyl groups present on coformer structures aided in generating heterosynthons with the aminopyrimidine ring of TMP. TMP-T7A and TMP-5FU existed as salts, whereas TMP-CAT and TMP-THY-H2O formed as cocrystals. The crystal packing, melting behavior, solubility and dissolution profiles of all four systems were investigated in this study. The cocrystal hydrate (TMP-THY-H2O) displayed lowest melting and TMP-T7A salt displayed the highest melting temperature. Various factors, including the nature of coformers (acidic/basic/ionizable/non-ionizable), pH and pK(a), altered the aqueous solubility of TMP. Among the four systems, TMP-T7A, which possesses the aminopyrimidinium-carboxylate synthon, showed highest solubility compared with the structures containing aminopyrimidinium-amide/hydroxyl synthons.