Studies of "drug-drug" multi-component crystals of trimethoprim and probenecid

• Two multi-component crystals TMP-PRO and TMP-PRO H 2 O of TMP and PRO were synthesized for the first time;. • The obtained multi-component crystals were characterized and analyzed by various methods, and further studied by means of quantum chemistry;. • The dehydration phenomenon and process ofTMP-PRO H 2 O salt dihydrate were studied and monitored by various methods;. • The use of PRO in line with GRAS safety certification as a ligand, and may play a better drug synergy, in line with the concept of green chemistry. Trimethoprim (TMP) is a synthetic broad-spectrum antimicrobial agent. The powders of TMP-PRO and TMP-PRO H 2 O, two multi-component crystals of trimethoprim (TMP) and the probenecid (PRO), were prepared by slurry suspension. In this study, solid state characterization and analysis of the obtained crystal powders have been carried out. Relevant computational analyses were also performed, such as Hirshfeld surface (HS) analysis to elucidate the types of interactions between TMP-PRO and TMP-PRO H 2 O, and molecular electrostatic potential surface (MEPs) analysis to analyze the formation of multi-component crystals. Atoms in molecules (AIM) and independent gradient model based on Hirshfeld partition (IGMH) were used to analyze the intermolecular and intramolecular interactions within two multi-component crystals, and it was found that hydrogen bond plays an important role in the formation and stability of the multi-component crystals. In addition, the solubility of the prepared crystals was tested in pH 6.8 buffer, pure water and pH 1.2 buffer. It was found that the solubility decreased compared to the raw TMP. In the pH 6.8 buffer, the release rates of salts and hydrates were reduced to 0.69 and 0.61 times that of TMP, respectively. From this, the good slow-release performance was found. The kinetic models were used to evaluate the release data, and it was demonstrated that the release of TMP and multi-component crystals is mainly through a non-Fickian diffusion mechanism. The successful preparation of TMP-PRO and TMP-PRO H 2 O can broaden the clinical application of TMP to a certain extent.