Cocrystal Strategy Research Articles

Three new co-crystals of 2,3,5,6-tetramethyl pyrazin with different substituted aromatic compounds _ crystal structure, spectroscopy and Hirshfeld analysis

Co-crystallizations of 2,3,5,6-tetramethyl pyrazin (TMP) with different substituted aromatic compounds [3,5-dinitrosalicylic acid (DNS), 5-chlorosalicylic acid (CSA) and 3,5-dichlorosalicylic acid (DCA)] have been performed, resulting in the formation of three co-crystals (TMP : DNS = 1:1 for 1; TMP : CSA = 1:2 for 2; TMP : DCA = 1:2 for 3). Those newly co-crystals were characterized by single-crystal X-ray diffraction, infrared spectroscopy, thermogravimetric analyses (TGA), UV–Vis spectroscopy and X-ray diffraction (XRD). The Hirshfeld surface analysis revealed that N–H∙∙∙O/O–H∙∙∙N strong hydrogen bonds and other intermolecular interactions such as H∙∙∙H, C–H∙∙∙π, π∙∙∙π and lone-pair∙∙∙π participated in a cooperative way to stabilize the supramolecular structures. Additionally, thermodynamic results indicated that the halogen bonding exerted a positive effect on the stability of co-crystal structures, further improving the release process of pyrazine spices. This work provided a co-crystal strategy for the solidification of liquid pyrazine-related spices for broader applications.

Improving physicochemical properties of Ibrutinib with cocrystal strategy based on structures and natures of the carboxylic acid co-formers

Ibrutinib(IBR) is an irreversible Bruton's tyrosine kinase inhibitor and has been classified as the Biopharmaceutical Classification System (BCS) class Ⅱ drug. The objective of the current study was to improve the physicochemical properties of IBR by co-crystallization. Based on ΔpKa analysis and structure analysis, we reported seven IBR pharmaceutical cocrystals with different structure types of co-formers such as hydroxy-2-naphthoic acids, mono-hydroxybenzoic acids, and aliphatic acids via the slurry method and ultrasonic method. The seven prepared cocrystals were characterized by powder X-ray diffraction(PXRD), differential scanning calorimetry(DSC), thermogravimetric analysis(TGA) and Fourier transform infrared spectroscopy(FT-IR). The solubility and accumulative dissolution of IBR cocrystals were explored. It was found that the solubility and dissolution were optimally increased up to 6.64 times and 1.85 times than that of IBR Form A, respectively. Moreover, all the IBR cocrystals maintained a stable cocrystal state after 90-d under 40 °C/75% RH condition and after 30-d under 60 °C/0% RH condition. According to the results analysis, there may be hydrogen bond(H-bond) and π-π stacking interactions in the IBR cocrystal system. The current study demonstrated that the co-crystallization of IBR with specific co-formers proposed a prospective technology and optional strategy to modify the physicochemical nature of IBR.

Crystal structure, dissolution and hygroscopicity of a novel cocrystal hydrate of berberine hydrochloride with L(+)-lactic acid.

Berberine hydrochloride (BCl) is commercially used to treat diarrhea, diabetes, hyperlipidemia, and cancer. However, BCl suffers from solid state instability, low aqueous solubility, low dissolution rate, and poor bioavailability, which limit its potential application in clinical medicine. In this work, we report a novel cocrystal hydrate of BCl with L(+)-lactic acid (BCl-LA-H₂O), designed to improve its physicochemical properties, thus promoting its application in the pharmaceutical industry. As a result, the cocrystal strategy improved the solubility, dissolution, melting point, and hygroscopicity of BCl, which indicated that the BCl-LA-H₂O can be used as a better solid form.

Insight from Molecular Packing: Charge Transfer and Emission Modulation through Cocrystal Strategies

Charge transfer (CT), occurring from donor to acceptor involving π electrons, plays a significant role in regulating the emission of materials. Especially, in multicomponent systems, the CT degree depends on not only the electron rich-deficient abilities of components but also the molecular packing. Herein, three novel cocrystals (BPPa-2I, BPPa-3I, and BPPa-TCNB) based on BPPa, 2I (diiodo-tetrafluorobenzene), 3I (triiodo-trifluorobenzene), and TCNB (1,2,4,5-tetracyanobenzene) are fabricated through halogen bonding (XB) and CT interactions. The three cocrystals exhibit red-shifted emissions from 470 to 505 nm to 530 nm, covering blue via green to yellow, which are attributed to the enhanced CT degrees. On the basis of crystal structural analysis, the effective distance between two components in molecular packing is responsible for the different CT degrees; that is, a fully face-to-face stacking between donor and acceptor can improve the CT degree more effectively. The present study paves an easy way to construct a “packing-CT degree-emission” relationship.

A co-crystal strategy for the solidification of liquid pyrazine derivatives: X-ray structures and Hirshfeld surface analyses

Here we described a co-crystal strategy for the solidification of liquid 2,3-dimethylpyrazine (2,3-DMP), 2,5-dimethylpyrazine (2,5-DMP), 2,6-dimethylpyrazine (2,6-DMP) with the poly-substituted salicylic acids [3,5,6-trichlorosalicylic acid (TCSA) and 3,5-dinitrosalicylic acid (DNSA)] under identical conditions. Those newly grown co-crystals (2,3-DMP:TCSA = 1:1 for 1; 2,5-DMP:TCSA = 1:2 for 2; 2,6-DMP:DNSA = 1:1 for 3) were characterized by single-crystal X-ray diffraction. The structure determination shows that strong O-H⋯N hydrogen bonds play an important role in connection of pyrazine derivatives and poly-substituted salicylic acids. Moreover, aromatic cycle stacking interactions play a crucial role in the 3D supramolecular network. Hirshfeld surfaces and fingerprint plots of the reported co-crystals were analyzed, which showed that O-H⋯N, C-H⋯O, H⋯H, H⋯Cl and aromatic cycle stacking intermolecular interactions are the main stabilizing factors of the co-crystal structures. The melting points studies showed that the co-crystal strategy is effective for solidification of liquid pyrazine derivatives.

Cocrystal Strategy toward Multifunctional 3D‐Printing Scaffolds Enables NIR‐Activated Photonic Osteosarcoma Hyperthermia and Enhanced Bone Defect Regeneration

AbstractMalignant bone tumors are one of the major serious diseases in clinic. Inferior reconstruction of new bone and rapid propagation of residual tumor cells are the main challenges to surgical intervention. Herein, a bifunctional DTC@BG scaffold for near‐infrared (NIR)‐activated photonic thermal ablation of osteosarcoma and accelerated bone defect regeneration is engineered by in situ growth of NIR‐absorbing cocrystal (DTC) on the surface of a 3D‐printing bioactive glass (BG) scaffold. The prominent photothermal conversion performance and outstanding bone regeneration capability of DTC@BG scaffolds originate from the precise tailoring of the bandgap between the electron donors and acceptors of DTC and promote new bone growth performance of BG scaffolds. DTC@BG scaffolds not only significantly promote tumor cell ablation in vitro, but also effectively facilitate bone tumor suppression in vivo. In particular, DTC@BG scaffolds exhibit excellent capability in stimulating osteogenic differentiation and angiogenesis, and finally promote newborn bone formation in the bone defects. This research represents the first paradigm for ablating osteosarcoma and facilitating new bone formation through precise modulation of electron donors and acceptors in the cocrystal, which offers a new avenue to construct high‐efficiency therapeutic platforms based on cocrystal strategy for ablation of malignant bone tumor.

Tunable room temperature phosphorescence and energy transfer in ratiometric co-crystals.

Two co-crystals (BTA-ME-1 and BTA-ME-2) assembled with the same building blocks but in different ratios exhibit alternative stacking modes, relative orientations and aggregation states, leading to color-tunable green and yellow room temperature phosphorescence (RTP) and different intermolecular energy transfer efficiencies, respectively. Based on the time-resolved afterglow properties of the RTP emission, BTA-ME-2 is further applied for signal-visualized information encryption.

Seeking a novel energetic co-crystal strategy through the interfacial self-assembly of CL-20 and HMX nanocrystals

Solvent and heat induced self-assembly to CL-20/HMX co-crystals has been investigated. The mechanism towards such process could be concluded to nanoparticle inducing, oriented aggregation, surface integration and co-crystals assembly.

Cocrystals Strategy towards Materials for Near‐Infrared Photothermal Conversion and Imaging

AbstractA cocrystal strategy with a simple preparation process is developed to prepare novel materials for near‐infrared photothermal (PT) conversion and imaging. DBTTF and TCNB are selected as electron donor (D) and electron acceptor (A) to self‐assemble into new cocrystals through non‐covalent interactions. The strong D–A interaction leads to a narrow band gap with NIR absorption and that both the ground state and lowest‐lying excited state are charge transfer states. Under the NIR laser illumination, the temperature of the cocrystal sharply increases in a short time with high PT conversion efficiency (η=18.8 %), which is due to the active non‐radiative pathways and inhibition of radiative transition process, as revealed by femtosecond transient absorption spectroscopy. This is the first PT conversion cocrystal, which not only provides insights for the development of novel PT materials, but also paves the way of designing functional materials with appealing applications.

Cocrystals Strategy towards Materials for Near-Infrared Photothermal Conversion and Imaging.

A cocrystal strategy with a simple preparation process is developed to prepare novel materials for near-infrared photothermal (PT) conversion and imaging. DBTTF and TCNB are selected as electron donor (D) and electron acceptor (A) to self-assemble into new cocrystals through non-covalent interactions. The strong D-A interaction leads to a narrow band gap with NIR absorption and that both the ground state and lowest-lying excited state are charge transfer states. Under the NIR laser illumination, the temperature of the cocrystal sharply increases in a short time with high PT conversion efficiency (η=18.8 %), which is due to the active non-radiative pathways and inhibition of radiative transition process, as revealed by femtosecond transient absorption spectroscopy. This is the first PT conversion cocrystal, which not only provides insights for the development of novel PT materials, but also paves the way of designing functional materials with appealing applications.

Studies on the synthesis, structural characterization, Hirshfeld analysis and stability of apovincamine (API) and its co-crystal (terephthalic acid: Apovincamine = 1:2)

Apovincamine and the corresponding co-crystal have been synthesized and characterized by single crystal XRD, FT-IR, UV, TGA/DSG. Components of the crystalline phase have also been investigated in terms of their corresponding Hirshfeld surface. In the crystal lattice, a three-dimensional hydrogen-bonded network is observed in the co-crystal, including the formation of a two-dimensional molecular scaffold. Hirshfeld surfaces and fingerprint plots indicate that the structures are stabilized by H⋯H, C−H⋯π, C–H⋯O and O–H⋯N intermolecular interactions. In this work, the co-crystal strategy has been applied successfully to apovincamine. One important parameter, i.e. solubility in water, has also been significantly improved, which proves to be an important factor for bioavailability. Furthermore, DSC/TGA analysis indicates that the co-crystal maintains its crystallinity up to 200°C, suggesting a higher stability of the co-crystal compared to apovincamine.

Indomethacin co-crystals and their parent mixtures: does the intestinal barrier recognize them differently?

Co-crystals are crystalline complexes of two or more molecules bound together in crystal lattices through noncovalent interactions. The solubility and dissolution properties of co-crystals can allow to increase the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). It is currently believed that the co-crystallization strategy should not induce changes on the pharmacological profile of the APIs, even if it is not yet clear whether a co-crystal would be defined as a physical mixture or as a new chemical entity. In order to clarify these aspects, we chose indomethacin as guest poorly aqueous soluble molecule and compared its properties with those of its co-crystals obtained with 2-hydroxy-4-methylpyridine (co-crystal 1), 2-methoxy-5-nitroaniline (co-crystal 2), and saccharine (co-crystal 3). In particular, we performed a systematic comparison among indomethacin, its co-crystals, and their parent physical mixtures by evaluating via HPLC analysis the API dissolution profile, its ability to permeate across intestinal cell monolayers (NCM460), and its oral bioavailability in rat. The indomethacin dissolution profile was not altered by the presence of co-crystallizing agents as physical mixtures, whereas significant changes were observed by the dissolution of the co-crystals. Furthermore, there was a qualitative concordance between the API dissolution patterns and the relative oral bioavailabilities in rats. Co-crystal 1 induced a drastic decrease of the transepithelial electrical resistance (TEER) value of NCM460 cell monolayers, whereas its parent mixture did not evidence any effect. The saccharin-indomethacin mixture induced a drastic decrease of the TEER value of monolayers, whereas its parent co-crystal 3 did not induce any effects on their integrity, being anyway able to increase the permeation of indomethacin. Taken together, these results demonstrate for the first time different effects induced by co-crystals and their parent physical mixtures on a biologic system, findings that could raise serious concerns about the use of co-crystal strategy to improve API bioavailability without performing appropriate investigations.

Synthesis, structural characterization and Hirshfeld analysis studies of three novel co-crystals of trans-4-[(2-amino-3,5-dibrobenzyl) amino] cyclohexanol with hydroxyl benzoic acids

Combination of active pharmaceutical ingredients, trans-4-[(2-amino-3,5-dibrobenzyl) amino] cyclohexanol (AMB) and some organic acids, e.g., p-hydroxybenzoic acid (PHBA), m-hydroxybenzoic acid (MHBA), and 3,4-dihydroxy benzoic acid (DHBA), yield three novel co-crystals characterized by X-ray single-crystal, Fluorescence spectroscopy and thermal analysis (DSC and TGA), which included co-crystal 1 with 2:2: 1 stoichiometry of AMB, PHBA and H2O, co-crystal 2 with 1:1 stoichiometry of AMB and MHBA, and co-crystal 3 with 1:1:1 stoichiometry of AMB, DHBA and CH3OH. Constituents of the co-crystalline phase were also investigated in terms of Hirshfeld surfaces. In the crystal lattice, a three-dimensional hydrogen-bonded network is observed, including formation of a two-dimensional molecular scaffolding motif. Hirshfeld surfaces and fingerprint plots of three co-crystals show that structures are stabilized by H⋯H, N–H⋯O, H⋯Br and C⋯H intermolecular interactions. Besides, the studies of the solubility showed that this co-crystal strategy could promote the solubility of AMB and follow the order: co-crystal 1<co-crystal 2<co-crystal 3.

Naphthalene diimide cocrystals: A facile approach to tune the optical properties

Core-substituted naphthalene diimides are attracting much interest because of their tunable optical properties, which are generally achieved by the elaborate introduction of electron-donating groups into electron-deficient core to form donor–acceptor compounds through the covalent bonds. Here we report that the optical properties of core-unsubstituted naphthalene diimides can be modulated by a facile cocrystal strategy. Based on the X-ray crystallographic and Hirshfeld surface analyses, the π–π interactions have been demonstrated to be the most important factor that answers for the optical properties of naphthalene diimide cocrystals, while other interactions, such as hydrogen bonds and solvation effects, have little impact on their properties but influence π stacking. This insight is of considerable significance for the development of naphthalene diimide based materials in various directions.

Tuning solid-state fluorescence of pyrene derivatives via a cocrystal strategy

1-Acetyl-3-(4-methoxyphenyl)-5-(1-pyrenyl)-pyrazoline (AMPP) was synthesized and crystallized to yield three types of crystals with different host–guest structures: AMPP crystal (I), AMPP–phenol (II) and AMPP–(2-naphthol) cocrystals (III). Twisted π-conjugated structures and different stacking modes of AMPP molecules were found in the three crystals. In crystal I, pyrene fluorophores adopt a face-to-face π-stacked arrangement, while pyrene fluorophores in crystals II and III adopt the monomer arrangements because AMPPs were widely separated by means of entrapment of guest molecules in the two lattices. Investigation of the optical-properties of the three crystals reveals that they are closely related to the arrangements of the pyrene fluorophores. Face-to-face π–π stacking of the pyrene fluorophores in crystal I cause a broad band emission with a red shift of 40–50 nm relative to pyrene fluorescence in solution. However, the emission spectrum of crystal II is similar to that of crystal III; both of them exhibit two sharp bands with a small red shift of 20 nm relative to pyrene fluorescence in solution, which are induced by the monomer arrangements of pyrene fluorophores and overlaps of π-orbitals between benzene and pyrene fluorophores. These results demonstrate that using a cocrystal strategy to regulate packing modes of pyrene fluorophores is an effective way for exploring highly blue-emissive pyrene derivatives.

A Co-Crystal Strategy to Tune the Supramolecular Patterns and Luminescent Properties: Ten Well-Designed Salts Assembled by Arenedisulfonic Acid with Diverse Diamines

Ten salts assembled by arenedisulfonic acid with hydrazine, flexible aliphatic diamines, rigid and semirigid aromatic diamines, namely, (H2HA)2+·(NDS)2– (1), (H2EDA)2+·(NDS)2– (2), (H2PDA)2+·(NDS)2– (3), (H2BTDA)2+·(NDS)2– (4), (H2BDMA)2+·(NDS)2–·2H2O (5), 2(o-HBDA)+·(NDS)2– (6), (m-H2BDA)2+·(NDS)2– (7), (H2MBDA)2+·(NDS)2–·3H2O (8), (H2SDA)2+·(NDS)2–·H2O (9), and 2(HSDA)+·(NDS)2–·H2O (10) (H2NDS = 1,5-naphthalenedisulfonic acid, HA = hydrazine, EDA = 1,2-ethanediamine, PDA = 1,3-propanediamine, BTDA = 1,4-butanediamine, BDMA = 1,3-benzenedimethanamine, o-BDA = 1,2-benzenediamine, m-BDA = 1,3-benzenediamine, MBDA = 4-methyl-1,3-benzenediamine, SDA = 4,4′-sulfonyldiamiline), have been constructed and characterized by elemental analysis, infrared, thermogravimetric analysis, phospholuminescence, and powder and single-crystal X-ray diffraction. Structural analyses indicate that the nature of the diamines can effectively influence the final structures of the salts through diverse noncovalent bonding interactio...

A cocrystal strategy for the precipitation of liquid 2,3-dimethyl pyrazine with hydroxyl substituted benzoic acid and a Hirshfeld surfaces analysis of them

We here report the cocrystal strategy for the precipitation of liquid 2,3-dimethyl pyrazine (2,3-DMP) with the hydroxyl substituted benzoic acids: salicylic acid (SA), m-hydroxybenzoic acid (MHBA) and p-hydroxybenzoic acid (PHBA) under identical conditions, and obtained three cocrystals (cocrystal 1–3), respectively. Their crystal structures were characterized by single-crystal X-ray diffraction, IR spectra, differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), hot stage microscopy (HSM) and X-ray powder diffraction (XRPD). Wherein, 1 forms a 1 : 2 2,3-DMP : SA cocrystal; 2 forms a 1 : 1 2,3-DMP : MPHA cocrystal and 3 forms a 1 : 1 : 1 2,3-DMP : PHBA : H2O cocrystal. The structure determination shows that the three cocrystals are all primarily stabilized by a strong O–H⋯N hydrogen bonding interaction between 2,3-DMP and the hydroxyl substituted benzoic acid. We also prepared and analysed Hirshfeld surfaces and fingerprint plots of the reported cocrystals and reveal that the structures are stabilized by H⋯H, O–H⋯N, O–H⋯N, C–H⋯π, π⋯π and lone-pair⋯π intermolecular interactions. Additionally, what is interesting is that cocrystal 2 sublimes half the 2,3-DMP at about 110 °C during the heating procedure, while the other half sublimes at about 226 °C, which was confirmed by the XRPD measurement. This may be developed for the controlled release of 2,3-DMP.

What have We Learned about Topochemical Diacetylene Polymerizations?

A series of five polydiacetylenes have been synthesized via topochemical polymerizations of the corresponding monomers. The requisite structural parameters for the polymerization were achieved by the use of a host–guest co-crystal strategy. The atom trajectories of the polymerization reactions are discussed.