Cocrystal Engineering Research Articles

Pillar[5]arene-Based Ion-Pair Recognition for Encapsulation of a Stilbazolium-Type Dye with Enhanced Photophysical Properties and Nonlinear Optical Activity.

Constructing organic composite materials through molecular recognition has emerged as an important theme in materials science. Here we report an ion-pair recognition system involving the use of a propoxylated pillar[5]arene (PrP5) to modulate the solid-state photophysical properties of dye trans-4'-(dimethylamino)-N-methyl-4-stilbazolium hexafluorophosphate (DMASP). Single crystal X-ray diffraction analysis reveals that the dye guest DMASP is encapsulated by PrP5 to form a 2 : 1 host-guest complex 2PrP5⸧DMASP in the crystalline state. The macrocyclic skeleton of PrP5 imposes restrictions on the intramolecular motions of the dye guest, leading to a significant enhancement of its fluorescence emission. Additionally, within the 2PrP5⸧DMASP complex crystal structure, DMASP molecules are found to display two possible opposite orientations in the one-dimensional channels formed by PrP5 molecules. This arrangement is believed to alter the overall solid-state packing structure of DMASP, thereby activating its nonlinear optical activity. This work not only reports a novel ion-pair molecular recognition system based on pillararenes but also provides valuable insights into the modulation of the crystalline state photophysical properties of organic dyes via cocrystal engineering.

Cocrystal formulation design of 4-Aminosalicylic acid and isoniazid via spray-drying based on a ternary phase diagram toward simultaneous pulmonary delivery

Cocrystal engineering is a potent strategy for enhancing drug properties, but its application in spray-drying has been limited. Furthermore, concurrently introducing two drugs and realizing simultaneous pharmacological effects at the target site is challenging. This is particularly evident for oral formulations designed for systemic use, but the local administration of drugs at the target site displays the potential to overcome this problem. Herein, we investigated the potential of cocrystallization principles for use in developing dry powder inhaler formulations of anti-tuberculosis drugs. We focused on the formation of cocrystals of 4-aminosalicylic acid (PAS) and isoniazid (INH), which are crucial components of tuberculosis treatment. Via spray-drying, we successfully produced spray-dried particles of PAS-INH that exhibited hydrogen bonding interactions between the molecules. Aerosolization performance evaluation with an Andersen Cascade Impactor (ACI) confirmed the concurrent deposition of both drugs, highlighting the potential of our particle design for use in the co-delivery of PAS-INH. Furthermore, simulated lung dissolution studies using the ACI and Transwell inserts revealed synchronized dissolution patterns, indicating promising prospects for use in effective drug delivery. This innovative approach to tuberculosis therapy has significant implications for improving treatment efficacy and enhancing patient adherence, potentially revolutionizing tuberculosis treatment.

Organic cocrystals: From high‐performance molecular materials to multi‐functional applications

AbstractAdvancements in organic electronics are propelling the development of new material systems, where organic materials stand out for their unique benefits, including tunability and cost‐effectiveness. Organic single crystals stand out for their ordered structure and reduced defects, enhancing the understanding of the relationship between structure and performance. Organic cocrystal engineering builds upon these foundations, exploring intermolecular interactions within multicomponent‐ordered crystalline materials to combine the inherent advantages of single‐component crystals. However, the path to realizing the full potential of organic cocrystals is fraught with challenges, including structural mismatches, unclear cocrystallization mechanisms, and unpredictable property alterations, which complicate the effective cocrystallization between different molecules. To deepen the understanding of this promising area, this review introduces the mechanism of organic cocrystal formation, the various stacking modes, and different growth techniques, and highlights the advancements in cocrystal engineering for multifunctional applications. The goal is to provide comprehensive guidelines for the cocrystal engineering of high‐performance molecular materials, thereby expanding the applications of organic cocrystals in the fields of optoelectronics, photothermal energy, and energy storage and conversion.

ADVANCES IN COCRYSTALS OF ANTICANCER AGENTS: FORMULATION STRATEGIES AND THERAPEUTIC IMPLICATIONS

Cancer remains one of the most pressing health concerns worldwide, driving continuous efforts in pharmaceutical research to develop more effective treatments. In the ever-evolving landscape of cancer therapy, cocrystals stand as promising contenders, offering enhanced solubility, stability, and bioavailability to traditional anticancer agents. Co-crystallization, a strategy emerging at the nexus of pharmaceutical and crystal engineering. From the fundamental principles of cocrystal engineering to advanced spectroscopic and crystallographic methodologies, each aspect is meticulously dissected to unveil the transformative potential of cocrystals in oncology. The review elucidates the transformative potential of cocrystals in oncology, highlighting their capacity to revolutionize drug delivery and efficacy. Recent advancements in the field are comprehensively examined, showcasing the promising role of anticancer cocrystals in paving the way for novel therapeutic strategies and improved patient outcomes. Cocrystals represent a promising avenue in cancer therapy, offering significant enhancements to traditional anticancer agents. Through a comprehensive exploration of recent advancements, this article navigates the complex terrain of anticancer cocrystals, drug-drug cocrystals, paving the way for novel therapeutic strategies and improved patient outcomes.

Searching new cocrystal structures of CL-20 and HMX via evolutionary algorithm and machine learning potential

In this work, we report the discovery of energy cocrystals using an efficient iterative workflow combining an evolutionary algorithm and a machine learning potential (MLP). The compound 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) has attracted significant attention owing to its higher energy density than traditional energetic materials. However, the higher sensitivity has limited its applications. An important way to reduce its sensitivity involves cocrystal engineering with traditional explosives. Many cocrystal structures are expected to be composed of these two components. We developed an efficient iterative workflow to explore the phase space of CL-20 and 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane (HMX) cocrystals using an evolutionary algorithm and an MLP. The algorithm was based on the Universal Structure Predictor: Evolutionary Xtallography (USPEX) software, and the MLP was the reactive force field with neural networks (ReaxFF-nn ) model. A set of high-density cocrystal structures was produced through this workflow; these structures were further checked via first-principles geometry optimizations. After careful screening, we identified several high-density cocrystal structures with densities of up to 1.937 g/cm3 and HMX: CL-20 ratios of 1:1 and 1:2. The influence of hydrogen bonds on the formation of high-density cocrystals was also discussed, and a roughly linear relationship was found between energy and density.

Simultaneous Enhancement of Thermal Stability and Preferred Isomer Enrichment in Difenoconazole: the Dual Facets of Cocrystal Engineering

Simultaneous Enhancement of Thermal Stability and Preferred Isomer Enrichment in Difenoconazole: the Dual Facets of Cocrystal Engineering

Nucleic-acid-base photofunctional cocrystal for information security and antimicrobial applications

Cocrystal engineering is an efficient and simple strategy to construct functional materials, especially for the exploitation of novel and multifunctional materials. Herein, we report two kinds of nucleic-acid-base cocrystal systems that imitate the strong hydrogen bond interactions constructed in the form of complementary base pairing. The two cocrystals studied exhibit different colors of phosphorescence from their monomeric counterparts and show the feature of rare high-temperature phosphorescence. Mechanistic studies reveal that the strong hydrogen bond network stabilizes the triplet state and suppresses non-radiative transitions, resulting in phosphorescence even at 425 K. Moreover, the isolation effects of the hydrogen bond network regulate the interactions between the phosphor groups, realizing the manipulation from aggregation to single-molecule phosphorescence. Benefiting from the long-lived triplet state with a high quantum yield, the generation of reactive oxygen species by energy transfer is also available to utilize for some applications such as in photodynamic therapy and broad-spectrum microbicidal effects. In vitro experiments show that the cocrystals efficiently kill bacteria on a tooth surface and significantly help prevent dental caries. This work not only provides deep insight into the relationship of the structure-properties of cocrystal systems, but also facilitates the design of multifunctional cocrystal materials and enriches their potential applications.

Achieving High-Temperature Phosphorescence by Organic Cocrystal Engineering.

Organic phosphors offer a promising alternative in optoelectronics, but their temperature-sensitive feature has restricted their applications in high-temperature scenarios, and the attainment of high-temperature phosphorescence (HTP) is still challenging. Herein, a series of organic cocrystal phosphors are constructed by supramolecular assembly with an ultralong emission lifetime of up to 2.16 s. Intriguingly, remarkable stabilization of triplet excitons can also be realized at elevated temperature, and green phosphorescence is still exhibited in solid state even up to 150 °C. From special molecular packing within the crystal lattice, it has been observed that the orientation of isolated water cluster and well-controlled molecular organization via multiple interactions can favor the structural rigidity of cocrystals more effectively to suppress the nonradiative transition, thus resulting in efficient room-temperature phosphorescence and unprecedented survival of HTP.

Achieving High‐Temperature Phosphorescence by Organic Cocrystal Engineering

AbstractOrganic phosphors offer a promising alternative in optoelectronics, but their temperature‐sensitive feature has restricted their applications in high‐temperature scenarios, and the attainment of high‐temperature phosphorescence (HTP) is still challenging. Herein, a series of organic cocrystal phosphors are constructed by supramolecular assembly with an ultralong emission lifetime of up to 2.16 s. Intriguingly, remarkable stabilization of triplet excitons can also be realized at elevated temperature, and green phosphorescence is still exhibited in solid state even up to 150 °C. From special molecular packing within the crystal lattice, it has been observed that the orientation of isolated water cluster and well‐controlled molecular organization via multiple interactions can favor the structural rigidity of cocrystals more effectively to suppress the nonradiative transition, thus resulting in efficient room‐temperature phosphorescence and unprecedented survival of HTP.

Control of Regioselectivity in the Dimerization of trans-Cinnamic Acid and Its Derivatives Using Cocrystal Engineering

Control of Regioselectivity in the Dimerization of <i>trans</i>-Cinnamic Acid and Its Derivatives Using Cocrystal Engineering

Separation of benzene and toluene associated with vapochromic behaviors by hybrid[4]arene-based co-crystals

The combination of macrocyclic chemistry with co-crystal engineering has promoted the development of materials with vapochromic behaviors in supramolecular science. Herein, we develop a macrocycle co-crystal based on hybrid[4]arene and 1,2,4,5-tetracyanobenzene that is able to construct vapochromic materials. After the capture of benzene and toluene vapors, activated hybrid[4]arene-based co-crystal forms new structures, accompanied by color changes from brown to yellow. However, when hybrid[4]arene-based co-crystal captures cyclohexane and pyridine, neither structures nor colors change. Interestingly, hybrid[4]arene-based co-crystal can separate benzene from a benzene/cyclohexane equal-volume mixture and allow toluene to be removed from a toluene/ pyridine equal-volume mixture with purities reaching 100%. In addition, the process of adsorptive separation can be visually monitored. The selectivity of benzene from a benzene/cyclohexane equal-volume mixture and toluene from a toluene/ pyridine equal-volume mixture is attributed to the different changes in the charge-transfer interaction between hybrid[4]arene and 1,2,4,5-tetracyanobenzene when hybrid[4]arene-based co-crystal captures different vapors. Moreover, hybrid[4]arene-based co-crystal can be reused without losing selectivity and performance. This work constructs a vapochromic material for hydrocarbon separation.

Efficient cocrystal coformer screening based on a Machine learning Strategy: A case study for the preparation of imatinib cocrystal with enhanced physicochemical properties

Cocrystal engineering, which involves the self-assembly of two or more components into a solid-state supramolecular structure through non-covalent interactions, has emerged as a promising approach to tailor the physicochemical properties of active pharmaceutical ingredient (API). Efficient coformer screening for cocrystal remains a challenge. Herein, a prediction strategy based on machine learning algorithms was employed to predict cocrystal formation and seven reliable models with accuracy over 0.890 were successfully constructed. Imatinib was selected as the model drug and the models established were applied to screen 31 potential coformers. Experimental verification results indicated RF-8 is the optimal model among seven models with an accuracy of 0.839. When the seven models were combined for coformer screening of Imatinib, the combinational model achieved an accuracy of 0.903, and eight new solid forms were observed and characterized. Benefiting from intermolecular interactions, the obtained multicomponent crystals displayed enhanced physicochemical properties. Dissolution and solubility experiments showed the prepared multicomponent crystals had higher cumulative dissolution rate and remarkably improved the solubility of imatinib, and IM-MC exhibited comparable solubility to Imatinib mesylate α form. Stability test and cytotoxicity results showed that multicomponent crystals exhibited excellent stability and the drug-drug cocrystal IM-5F exhibited higher cytotoxicity than pure API.

Anion-Counterion Strategy toward Organic Cocrystal Engineering for Near-Infrared Photothermal Conversion and Solar-Driven Water Evaporation.

An anion-counterion strategy is proposed to construct organic mono-radical charge-transfer cocrystals for near-infrared photothermal conversion and solar-driven water evaporation. Ionic compounds with halogen anions as the counterions serve as electron donors, providing the necessary electrons for efficient charge transfer with unchanged skeleton atoms and structures as well as the broad red-shifted absorption (200-2000 nm) and unprecedented photothermal conversion efficiency (~90.5 %@808 nm) for the cocrystals. Based on these cocrystals, an excellent solar-driven interfacial water evaporation rate up to 6.1±1.1 kg ⋅ m-2 ⋅ h-1 under 1 sun is recorded due to the comprehensive evaporation effect from the cocrystal loading in polyurethane foams and chimney addition, such performance is superior to the reported results on charge-transfer cocrystals or other materials for solar-driven interfacial evaporation. This prototype exhibits the great potential of cocrystals prepared by the one-step mechanochemistry method in practical large-scale seawater desalination applications.

Halogen-bonded charge-transfer co-crystal scintillators for high-resolution X-ray imaging.

The development of high-quality organic scintillators encounters challenges primarily associated with the weak X-ray absorption ability resulting from the presence of low atomic number elements. An effective strategy involves the incorporation of halogen-containing molecules into the system through co-crystal engineering. Herein, we synthesized a highly fluorescent dye, 2,5-di(4-pyridyl)thiazolo[5,4-d]thiazole (Py2TTz), with a fluorescence quantum yield of 12.09%. Subsequently, Py2TTz was co-crystallized with 1,4-diiodotetrafluorobenzene (I2F4B) and 1,3,5-trifluoro-2,4,6-triiodobenzene (I3F3B) obtaining Py2TTz-I2F4 and Py2TTz-I3F3. Among them, Py2TTz-I2F4 exhibited exceptional scintillation properties, including an ultrafast decay time (1.426 ns), a significant radiation luminescence intensity (146% higher than Bi3Ge4O12), and a low detection limit (70.49 nGy s-1), equivalent to 1/78th of the detection limit for medical applications (5.5 μGy s-1). This outstanding scintillation performance can be attributed to the formation of halogen-bonding between I2F4B and Py2TTz. Theoretical calculations and single-crystal structures demonstrate the formation of halogen-bond-induced rather than π-π-induced charge-transfer cocrystals, which not only enhances the X-ray absorption ability and material conductivity under X-ray exposure, but also constrains molecular vibration and rotation, and thereby reducing non-radiative transition rate and sharply increasing its fluorescence quantum yields. Based on this, the flexible X-ray film prepared based on Py2TTz-I2F4 achieved an ultrahigh spatial resolution of 26.8 lp per mm, underscoring the superiority of this strategy in developing high-performance organic scintillators.

Dual-rotor strategy for organic cocrystals with enhanced near-infrared photothermal conversion.

Organic cocrystal engineering provides a promising route to promote the near-infrared (NIR) light harvesting and photothermal conversion (PTC) abilities of small organic molecules through the rich noncovalent bond interactions of D/A units. Besides, the single-bond rotatable groups known as "rotors" are considered to be conducive to the nonradiative transitions of the excited states of organic molecules. Herein, we propose a single-/double-bond dual-rotor strategy to construct D-A cocrystals for NIR PTC application. The results reveal that the cocrystal exhibits an ultra-broadband absorption from 300 nm to 2000 nm profiting from the strong π-π stacking and charge transfer interactions, and the weakened p-π interaction. More importantly, the PTC efficiency of cocrystals at 1064 nm in the NIR-II region can be largely enhanced by modulating the number of rotor groups and the F-substituents of D/A units. As is revealed by fs-TA spectroscopy, the superior NIR PTC performance can be attributed to the nonradiative decays of excited states induced by the free rotation of the single-bond rotor (-CH3) from the donors and the inactive double-bond rotor ([double bond, length as m-dash]C(C[triple bond, length as m-dash]N)2) being in the active form of [-C(C[triple bond, length as m-dash]N)2] in the excited states from the acceptors. This prototype displays a promising route to extend the functionalization of small organic molecules based on organic cocrystal engineering.

Quercetin-maleic acid co-crystal engineering using solvent evaporation to ıncrease quercetin solubility

Quercetin-maleic acid co-crystal engineering using solvent evaporation to ıncrease quercetin solubility

Crystal clear: unveiling giant birefringence in organic-inorganic cocrystals.

Coplanar groups with large anisotropic polarizability are suitable as birefringence-active groups for investigating compounds with significant birefringence. In this study, the organic coplanar raw reagent, o-C5H5NO (4HP), was selected as an individual complement. Utilizing the cocrystal engineering strategy, we successfully designed two cocrystals: [LiNO3·H2O·4HP]·4HP (Li-4HP2) and [Mg(NO3)2·6H2O]·(4HP)2 (Mg-4HP), and one by-product: LiNO3·H2O·4HP (Li-4HP), which were grown using a mild aqua-solution method. The synergy of the coplanar groups of NO3 - and 4HP in the structures resulted in unexpectedly large birefringence values of 0.376-0.522@546 nm. Furthermore, the compounds exhibit large bandgaps (4.08-4.51 eV), short UV cutoff edges (275-278 nm), and favorable growth habits, suggesting their potential as short-wave UV birefringent materials.

Molecule configurations modulate packing array and charge transfer in cocrystal engineering

Molecule configurations modulate packing array and charge transfer in cocrystal engineering

Novel jellyfish-shaped resorcin[4]arene macrocyclic cocrystal via collaboration of macrocyclic chemistry and co-crystal engineering: Insight into structural, noncovalent interactions and computational chemistry

The collaboration of macrocyclic chemistry and co-crystal engineering has witnessed rapid development in recent years for the creation of functional solid-state. Here, we report the construction of novel jellyfish-like co-crystal derived from macrocyclic resorcin[4]arenes (R4A) serving as a bell and (Z)-3-(pyridine-4-yl)-2-(4-(pyridine-4-yl)phenyl)acrylonitrile (PPPA) molecules acting as a tentacle through the precise engineering of supramolecular interactions. The co-crystal structure was comprehensively investigated using single crystal X-ray diffraction (SXRD), X-ray powder diffraction (XRD), Infrared spectroscopy (IR) and molecular modeling. The packing pattern of the co-crystal structure shows the inclusion-of acetone solvent that connects the neighboring R4A cavitands into high order linear structure stabilized by multiple C–H⋯O, hydrogen bonds and C–H⋯π interactions. Interestingly, jellyfish like architecture is obtained by the interaction of PPPA with R4A molecules through collaborative C–H⋯O, CH⋯N and OH⋯N Hydrogen bonds. Additionally, the HOMO-LUMO, molecular electrostatic potential (MESP), Interaction region indicator (IRI) analysis, and Localized orbital locator (LOL) were collectively employed to provide comprehensive insights into the electronic structure and reactivity of the studied compound. Hirshfeld surface analysis in combination with 2D fingerprints plots were carried out to get insight into the role of various non-covalent routs in the formation cocrystal packing. This strategy will guide any future synthetic endeavors aimed at engineering supramolecular interactions on demand using macrocycle chemistry and co-crystal engineering for the development of promising novel functional materials.

Cocrystal screening of anticancer drug p-toluenesulfonamide and preparation by supercritical antisolvent process

p-Toluenesulfonamide (PTS) is a new anticancer drug in development. Its poor dissolution behavior complicates the design and development of the formulation process. The present study aimed to improve the dissolution profile of PTS by using a cocrystal engineering approach. Cocrystal screening of PTS with commonly used coformers was investigated, including 4,4′-bipyridine, nicotinamide, isonicotinamide, and sulfacetamide. According to the results of PXRD, FTIR, DSC, and elemental analyzer, a cocrystal of PTS with coformer 4,4′-bipyridine in a stoichiometric ratio of 2:1 was first disclosed. The single crystal of this cocrystal was then prepared, and the crystallographic data were identified and reported. In addition, an intensified crystallization technique, the supercritical antisolvent (SAS) process, was applied to produce this cocrystal using CO2 as the antisolvent. The effect of SAS process parameters was studied, including the operating temperature, operating pressure, solution flow rate, and nozzle diameter. Optimized SAS conditions were proposed for cocrystal preparation, yielding a total powder recovery of approximately 70% and a purity level of up to 90%. Furthermore, according to the results of the dissolution rate study, the dissolution rate of SAS-produced cocrystal was enhanced considerably about 375 times compared to the physical mixture.