Tenoxicam (TNX) is a new non-steroidal anti-inflammatory drug that shows a superior anti-inflammatory effect and has the advantages of a long half-life period, a fast onset of action, a small dose, complete metabolism, and good tolerance. Some compounds often have tautomerism, and different tautomers exist in different crystalline forms. TNX is such a compound and has three tautomers. TNX always exists as the zwitterionic form in cocrystals. When the salt is formed, TNX exists in the enol form, which exhibits two conformations depending on whether a proton is gained or lost. Currently, the crystal structure of the keto form is not in the Cambridge Structural Database (CSD). Based on the analysis of existing crystal structures, we derived a simple rule for what form of TNX exists according to the pKa value of the cocrystal coformer (CCF) and carried out validation tests using three CCFs with different pKa values, including p-aminosalicylic acid (PAS), 3,5-dinitrobenzoic acid (DNB), and 2,6-dihydroxybenzoic acid (DHB). The molecular surface electrostatic potential (MEPS) was combined with the pKa rule to predict the interaction sites. Finally, two new cocrystals (TNX-PAS and TNX-DNB) and one salt (TNX-DHB) of TNX were obtained as expected. The differences between the cocrystals and salt were distinguished by X-ray diffraction, vibration spectra, thermal analysis, and dissolution measurements. To further understand the intermolecular interactions in these cocrystals and salt, the lattice energy and energy decomposition analysis (EDA) were used to explain them from the perspective of energy. The results suggest that the melting point of the CCF determines that of the cocrystal or salt, the solubility of the CCF itself plays an important role, and the improvement of the solubility after salt formation is not necessarily better than that of API or its cocrystals.

Two novel co-crystals of naproxen (NPX) were designed and prepared at a stoichiometric ratio of 1:1, namely, naproxen–caprolactam (NPX–CPL) and naproxen–oxymatrine (NPX–OMT). The characteristics of the co-crystals were evaluated in terms of stability and solubility studies. In terms of solubility, in four kinds of solvent systems with different pH, the solubility of NPX–OMT was significantly improved compared with that of NPX, whereas the NPX–CPL showed advantages in acidic solvent systems, indicating that the co-crystals can be applied to concoct preparations depending on therapeutic purposes. Furthermore, the experimental results of the thermal analysis showed that the co-crystal NPX–OMT had better thermal stability than the co-crystal NPX–CPL. Finally, as a complement to the single crystal X-ray diffraction (SC XRD) method, the theoretical calculation based on density functional theory (DFT) was also used to reveal the intermolecular interaction of the co-crystals at the molecular level and visually display the difference between them.

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are class II biopharmaceutics classification system drugs. The poor aqueous solubility of NSAIDs can lead to limited bioavailability after oral administration. Metformin (MET), a small-molecule compound, can be used in crystal engineering to modulate the physicochemical properties of drugs and to improve the bioavailability of orally administered drugs, according to the literature research and preliminary studies. We synthesized two drug–drug molecular salts (ketoprofen–metformin and phenylbutazone–metformin) with NSAIDs and thoroughly characterized them using SCXRD, PXRD, DSC, and IR analysis to improve the poor solubility of NSAIDs. In vitro evaluation studies revealed that the thermal stability and solubility of NSAIDs-MET were substantially enhanced compared with those of NSAIDs alone. Unexpectedly, an additional increase in permeability was observed. Since the structure determines the properties, the structure was analyzed using theoretical calculations to reveal the intermolecular interactions and to explain the reason for the change in properties. The salt formation of NSAIDs with MET could substantially increase the bio-absorption rate of NSAIDs, according to the in vivo pharmacokinetic findings, which provides an experimental basis for developing new antipyretic and analgesic drugs with rapid onset of action.

This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug–drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET–RHE (1:1), MET–RHE–H₂O (1:1:1), MET–RHE–ethanol–H₂O (1:1:1:1), and MET–RHE–acetonitrile (2:2:1) were obtained, indicating the polymorphism of salts formed by MET and RHE. The structures were analyzed by the combination of characterization experiments and theoretical calculation, and the formation mechanism of polymorphism was discussed. The obtained results of in vitro evaluation showed that MET–RHE had a similar hygroscopicity with metformin hydrochloride (MET·HCl), and the solubility of the component of RHE increased by approximately 93 times, which laid a foundation for improving the bioavailability of MET and RHE in vivo. The evaluation of hypoglycemic activity in mice (C57BL/6N) indicated that MET–RHE exhibited better hypoglycemic activity than the parent drugs and the physical mixtures of MET and RHE. The above findings demonstrate that this study achieved the complementary advantages of MET and RHE through the multicomponent pharmaceutical salification technique, and provides new possibilities for the treatment of diabetic complications.