Yifei Xie

In this study, crystal engineering was employed to enhance the solubility and druggability of Chrysin (CHR). Four nitrogen heterocyclic compounds, including piperazine (PIP), 4,4'-bipyridine (BIP), imidazole (IMI), and sophoridine (SOP), were investigated using computational screening methodologies. Screening experiments were conducted to validate the computational screening results, and four CHR crystals were successfully prepared, three of which were reported for the first time. The structures of these cocrystals were characterized by using single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), and thermal analysis. The spatial structure, arrangement, interactions, and associations were analyzed. Additionally, physical stability, apparent solubility, and biological evaluation were performed to assess those cocrystals. Finally, the CHR-SOP cocrystal shows a significant improvement in solubility and dissolution rate, making it a promising candidate for further study.

The solid form of the drug can directly affect the physicochemical properties, bioavailability, safety, and efficacy of the drug, and its types mainly include amorphous state, single-component polycrystalline, hydrate, solvate, salt, and cocrystal. Polymorphic drugs are solid drugs whose active ingredients exist in a specific crystalline state. Polymorphic drugs are solid drugs whose active ingredients exist in a specific crystalline state. Drug polymorphism refers to the presence of two or more different crystalline states of the drug. Pharmaceutical cocrystal is a new type of solid form that can improve the stability, solubility, and bioavailability of active pharmaceutical ingredients and many other physicochemical properties. The determination of the crystalline form of a drug and its content is of great significance in ensuring the quality of the polymorphic drug and its safety. In this paper, the quantitative analysis methods of polymorphs and pharmaceutical cocrystals are reviewed, the advantages and disadvantages of various methods are analyzed mainly from three types of techniques, namely, X-ray diffraction, spectroscopy, and thermal analysis, and the specific applications of various methods are commented on through examples. The analytical methods that can effectively determine the content of polymorphic drugs are comprehensively mastered to provide a reference for the establishment of quality standards for polymorphic drugs.

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.

Ligustrazine (TMP) is the main active ingredient extracted from Rhizoma Chuanxiong, which is used in the treatment of cardiovascular and cerebrovascular diseases, with the drawback of being unstable and readily sublimated. Cocrystal technology is an effective method to improve the stability of TMP. Three benzoic acid compounds including P-aminobenzoic acid (PABA), 3-Aminobenzoic acid (MABA), and 3,5-Dinitrobenzoic acid (DNBA) were chosen for co-crystallization with TMP. Three novel cocrystals were obtained, including TMP-PABA (1:2), TMP-MABA (1.5:1), and TMP-DNBA (0.5:1). Hygroscopicity was characterized by the dynamic vapor sorption (DVS) method. Three cocrystals significantly improved the hygroscopicity stability, and the mass change in TMP decreased from 25% to 1.64% (TMP-PABA), 0.12% (TMP-MABA), and 0.03% (TMP-DNBA) at 90% relative humidity. The melting points of the three cocrystals were all higher than TMP, among which the TMP-DNBA cocrystal had the highest melting point and showed the best stability in reducing hygroscopicity. Crystal structure analysis shows that the mesh-like structure formed by the O-H⋯N hydrogen bond in the TMP-DNBA cocrystal was the reason for improving the stability of TMP.

Scutellarin is widely distributed in Scutellaria baicalensis, family Labiatae, and Calendula officinalis, family Asteraceae, and belongs to flavonoids. Scutellarin has a wide range of pharmacological activities, it is widely used in the treatment of cerebral infarction, angina pectoris, cerebral thrombosis, coronary heart disease, and other diseases. It is a natural product with great research and development prospects. In recent years, with in-depth research, researchers have found that wild scutellarin also has good therapeutic effects in anti-tumor, anti-inflammatory, anti-oxidation, anti-virus, treatment of metabolic diseases, and protection of kidney. The cancer treatment involves glioma, breast cancer, lung cancer, renal cancer, colon cancer, and so on. In this paper, the sources, pharmacological effects, in vivo and in vitro models of scutellarin were summarized in recent years, and the current research status and future direction of scutellarin were analyzed. Graphical Abstract

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.

Drug combinations have been the hotspot of the pharmaceutical industry, but the promising applications are limited by the unmet solubility and low bioavailability. In this work, novel cocrystals, consisting of two antithrombotic drugs with poor solubility and low bioavailability in vivo, namely, apixaban (Apx) and quercetin (Que), were developed to discover a potential method to improve the poor solubility and internal absorption of the drug combination. Compared with Apx, the dissolution behavior of Apx–Que (1:1) and Apx–Que–2ACN (1:1:2) was enhanced significantly, while the physical mixture of the chemicals failed to exhibit the advantages. The dissolution improvements of Apx–Que–2ACN could be explained by the fact that the solid dispersion-like structure and column-shaped cage of Que accelerated the access of the solvent to the inner layer of Apx. The fracture of the hydrogen bonds of Apx, which was the joint of the adjacent Que chains, facilitated the break-up of the structures. Besides, the bioavailability of Apx–Que was increased compared with the physical mixture and Apx, and Apx–Que remained stable in high temperature and illumination conditions. Therefore, a drug–drug cocrystal of two antithrombotic agents with poor solubility was developed, which exhibited greatly improved solubility, bioavailability and superior stability, indicating a novel method to overcome the shortages of drug combination.