Baicalein (Bai) is one of the most important bioactive flavonoids isolated from the well-known traditional Chinese medicine called “Huang Qin”. Though it has broad therapeutic capability, the bioavailability is limited due to its poor solubility. In this study, we aimed to modulate its solubility through cocrystallization. Cocrystals of Bai with isoniazide (Inia), isonicotinamide (Inam), caffeine (Caf), and theophylline (Tph) were obtained. And different cocrystallization methods lead to different cocrystal phases for Inam and Tph. These cocrystals were characterized using powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, dynamic vapor sorption, and Fourier transform infrared spectroscopy. Among all the cocrystals studied, BaiCaf is found to be superior in powder dissolution and pharmacokinetic behavior. Area under the curve values of BaiCaf is improved by a factor of 4.1, and the bioavailability of baicalein is thus expected to be accordingly increased. Given that Caf is a central nervous system stimulant available in many prescription and nonprescription medications, BaiCaf can be a promising alternative solid form of Bai to be developed.

A machine-learning model trained on the whole Cambridge Structural Database was developed to assist high-throughput cocrystal screening. With only 2D structures taken as inputs, the probability of cocrystal formation is returned for two given molecules. All of the cocrystal records in the CSD were used as positive samples, while negative samples were constructed by randomly combining different molecules into chemical pairs. Our model showed a prediction ability comparable with that of a widely used ab initio method in a head-to-head comparison test. Both experimental and virtual cocrystal screening against captopril were conducted at the same time to further validate the model. Two cocrystals of captopril with L-proline and sarcosine were obtained and characterized by PXRD, DSC, and FT-IR. These two coformers were also successfully predicted by our model. These results suggest that the tool we developed can be used to effectively guide coformer selection in the discovery of new cocrystals.

Scheme S1. Library of coformers. Scheme S2. Polarizing microscopy pictures of (a) MD• 1-HNA, (b) MD• 6-HNA, and (c) MD• Sul.

Four cocrystals of the anti-tuberculosis drug pyrazinamide (PZA) with adipic acid (1), sebacic acid (2), trans-aconitic acid (3), and citric acid (4) were successfully designed and synthesised. Their structures were determined by single-crystal X-ray diffraction, in which 1 and 2 displayed one-dimensional chain structures, while 3 and 4 formed two-dimensional hydrogen bonded frameworks between PZA and the coformers. The equilibrium solubility and intrinsic dissolution rate (IDR) of the four cocrystals and PZA itself were then determined. The results demonstrate that 3 and 4 exhibit superior solubility and IDR relative to PZA.

Two-in-one bending properties were achieved by a crystal engineering strategy of introducing a spring-like backbone in the structure.

A new conformational polymorph of VD 3 containing a pure α conformer was prepared and fully characterized. Chemical stability and hygroscopicity are compared with the marketed solid-state form (form A, two conformers α/β, 1 : 1). The results indicate that crystallization of VD 3 needs to be controlled to avoid the unstable polymorph.

Intrauterine adhesion (IUA) is characterized by endometrial fibrosis, which ultimately leads to menstrual abnormalities, infertility, and recurrent miscarriages. The Shh/Gli2 pathway plays a critical role in tissue fibrogenesis and regeneration; Gli2 activation induces profibrogenic effects in various tissues, such as the liver and kidney. However, the role of Gli2 in endometrial fibrosis remains unknown. The purpose of this study was to test the hypothesis that activated Gli2 promotes endometrial fibrosis. Endometrial samples from moderate and severe IUA patients exhibited significantly enhanced expression of Gli2 compared with normal endometrial samples and mild IUA samples. Transfection with overactive Gli2 plasmids induced higher fibrosis-related protein expression, while blocking Gli2 signaling with cyclopamine caused the opposite effect in endometriotic stromal cells (ESCs), including inducing cell-cycle arrest. Menstrual-derived stem cell conditioned medium (MenSCs-CM) reduced endometrial fibrosis by reducing Gli2 protein levels and causing cell-cycle arrest in ESCs through granulocyte-colony stimulating factor (G-CSF). The effect was weakened after neutralization with a G-CSF antibody. Gli2 overexpression reduced the effects of MenSC-CM and G-CSF on fibrosis and cell-cycle progression in vitro. The antifibrotic effect of G-CSF was also observed in murine model. These findings demonstrate that Gli2 signaling promotes endometrial fibrosis, and the inhibition of Gli2 through MenSCs-secreted G-CSF may be of therapeutic value for managing endometrial fibrosis.

Nicorandil (NCD) is a chemically unstable drug and sensitive to humidity, heat, and mechanical stress in manufacturing processes. In this work, the cocrystals of NCD with organic acids were designed and synthesized to enhance the stability of NCD. Cocrystals of NCD with 1-hydroxy-2-naphthoic acid, salicylic acid, 3-hydroxybenzoic acid, and 2,5-dihydroxybenzoic acid were obtained. Hydrothermal stability study showed that cocrystals performed with remarkable stability advantages compared with pure NCD. On the basis of mechanism research, the stability improvements of NCD molecules can be attributed to the realignments of NCD molecules in cocrystals. After the formation of cocrystals, the novel packing styles of NCD break the selfcatalyzed decomposition process in pure NCD structure. Moreover, intrinsic dissolution rate characterizations showed that the formation of cocrystals could also optimize the dissolution behavior of NCD to realize the objective of sustained release.