It is well known that daidzein has various significant medicinal values and health benefits, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, cholesterol lowering, neuroprotective, cardioprotective and so on. To our disappointment, poor solubility, low permeability and inferior bioavailability seriously limit its clinical application and market development. To optimize the solubility, permeability and bioavailability of daidzein, the cocrystal of daidzein and piperazine was prepared through a scientific and reasonable design, which was thoroughly characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Combining single-crystal X-ray diffraction analysis with theoretical calculation, detailed structural information on the cocrystal was clarified and validated. In addition, a series of evaluations on the pharmacogenetic properties of the cocrystal were investigated. The results indicated that the cocrystal of daidzein and piperazine possessed the favorable stability, increased solubility, improved permeability and optimized bioavailability of daidzein. Compared with the parent drug, the formation of cocrystal, respectively, resulted in 3.9-, 3.1-, 4.9- and 60.8-fold enhancement in the solubility in four different media, 4.8-fold elevation in the permeability and 3.2-fold in the bioavailability of daidzein. Targeting the pharmaceutical defects of daidzein, the surprising elevation in the solubility, permeability and bioavailability of daidzein was realized by a clever cocrystal strategy, which not only devoted assistance to the market development and clinical application of daidzein but also paved a new path to address the drug-forming defects of insoluble drugs.

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.

To reduce the hygroscopicity of betaine (BET), three co-crystals were synthesized: betaine-3,5-dihydroxybenzoic acid (BET-3,5-DHB), betaine-2,4-dihydroxybenzoic acid (BET-2,4-DHB), and betaine-3-hydroxybenzoic acid (BET-3-HDB). BET, commonly present in natural products, is used to treat homocysteine methyltransferase and has additional benefits such as hepatoprotective and neuroprotective properties. However, BET is extremely hygroscopic. Three cocrystals are acquired to address the problem. Comprehensive characterization, such as X-ray diffraction analysis, spectral analysis and thermal analysis, were conducted for co-crystals and BET. Based on the evaluation results for dynamic vapor sorption, the three co-crystals, especially BET-3-HDB, significantly reduce BET’s hygroscopicity. At 90% RH, the weight changes of BET-2,4-DHB (0.36%), BET-3,5-DHB (1.79%) and BET-3-HDB (0.32%) are 306.9, 61.7, and 345.3 times greater than those of the raw material BET, respectively. Hygroscopicity results from BET’s ability to easily create hydrogen bonding interactions with water molecules due to its carboxylate ions. Nevertheless, carboxylate ions establish hydrogen bonds with CCFs in co-crystals, lowering BET’s hygroscopicity and minimizing the likelihood of contact with water molecules. The contributions of contacts in the co-crystals are shown by Hirschfeld surface analysis as follows: H-H > O-H > H-O. Coulomb forces are dominant in the co-crystals by 3D energy frameworks.