Additive perturbed molecular assembly in two-dimensional crystals: differentiating kinetic and thermodynamic pathways

During attempts to produce novel two-dimensional cocrystals by coadsorbing components in a binary mixture, the formation of a metastable form was observed in analogy to the phenomenon of additive-induced polymorph formation reported in three-dimensional crystallization. Mechanistic insights into this phenomenon were gained through the use of scanning tunneling microscopy and several adsorbate/additive combinations. One additive plays a critical role in forming a disordered assembly through a process that is primarily kinetic whereas another additive thermodynamically stabilized an intermediate form, resulting in interrupting a phase transformation to a more stable form. These additive effects elucidate one of the potential pathways to kinetically isolate a metastable polymorph formed during cocrystallization in three-dimensional crystallization.     

Identification of an Overlooked Halogen-Bond Synthon and Its Application in Designing Fluorescent Materials

Research on new supramolecular synthons facilitates the progress of materials design. Herein, the ability of sp² carbonyl oxygen atoms to act as halogen-bond acceptors was established through cocrystallization. Four sets of carbonyl compounds, including aldehydes, ketones, esters, and amides, were selected as halogen-bond acceptors. In the absence of strong hydrogen bonds, 14 out of 16 combinations of halogen-bond donors and acceptors could form cocrystals, whereby the supramolecular synthon C=O ⋅⋅⋅ X acts as the main interaction. Further, the geometric parameters of the C=O ⋅⋅⋅ X interaction were statistically revealed on the basis of the crystallographic database. The bifurcated interaction mode that has been observed in other halogen-bond synthons rarely occurs in the case of C=O ⋅⋅⋅ X. The robustness of C=O ⋅⋅⋅ X makes its application in crystal engineering possible and opens up new opportunities in designing multicomponent fluorescent materials, as indicated by multicolor emission of cocrystals D through C=O ⋅⋅⋅ X interactions.     

Andrographolide: Solving Chemical Instability and Poor Solubility by Means of Cocrystals

The bioactive agent andrographolide was screened with pharmaceutically acceptable coformers to discover a novel solid form that will solve the chemical instability and poor solubility problems of this herbal medicine. Liquid‐assisted grinding of andrographolide with GRAS (generally regarded as safe) coformers in a fixed stoichiometry resulted in cocrystals with vanillin (1:1), vanillic acid (1:1), salicylic acid (1:1), resorcinol (1:1), and guaiacol (1:1). All the crystalline products were characterized by thermal, spectroscopic, and diffraction methods. Interestingly, even though the cocrystals are isostructural, their physicochemical properties are quite different. The andrographolide–salicylic acid cocrystal completely inhibited the chemical transformation of andrographolide to its inactive sulfate metabolite, and moreover, the cocrystal exhibited a dissolution rate that was three times faster and a drug release that was two times higher than pure andrographolide.     

Uncovering the Intramolecular Emission and Tuning the Nonlinear Optical Properties of Organic Materials by Cocrystallization

The spectroscopic and photophysical properties of organic materials in the solid‐state are widely accepted as a result of their molecular packing structure and intermolecular interactions, such as J‐ and H‐aggregation, charge‐transfer (CT), excimer and exciplex. However, in this work, we show that Spe‐F₄DIB cocrystals (SFCs) surprisingly retain the energy levels of photoluminescence (PL) states of Spe crystals, despite a significantly altered molecular packing structure after cocrystallization. In comparison, Npe‐F₄DIB cocrystals (NFCs) with new spectroscopic states display different spectra and photophysical behaviors as compared with those of individual component crystals. These may be related to the molecular configuration in crystals, and we propose Spe as an “intramolecular emissive” material, thus providing a new viewpoint on light‐emitting species of organic chromophores. Moreover, the nonlinear optical (NLO) properties of Npe and Spe are firstly demonstrated and modulated by cocrystallization. The established “molecule‐packing‐property” relationship helps to rationally control the optical properties of organic materials through cocrystallization.     

Co-crystallisation as a modular approach to the discovery of spin-crossover materials

Herein we present co-crystallisation as a strategy for materials discovery in the field of switchable spin crossover (SCO) systems. Using [Fe(3-bpp)₂]·2A (where 3-bpp = 2,6-bis(pyrazol-3-yl)pyridine, A = BF₄⁻/PF₆⁻) as a starting point, a total of 11 new cocrystals have been synthesised with five different dipyridyl coformers. Eight of these systems show spin crossover behaviour, and all show dramatically different switching properties from the parent complex. The cocrystals have been studied by variable temperature single-crystal X-ray diffraction and SQUID magnetometry to develop structure–property relationships. The supramolecular architecture of the cocrystals depends on the properties of the coformer. With linear, rigid coformer molecules leading to 1D supramolecular hydrogen-bonded chains, while flexible coformers form 2D sheets and bent coformers yield 3D network structures. The SCO behaviour of the cocrystals can be modified through changing the coformer and thus co-crystallisation presents a rapid, facile and highly modular tool for the discovery of new switchable materials. The wider applicability of this strategy to the design of hybrid multifunctional materials is also discussed.

The switching behaviour of spin crossover cocrystals can be modified through changing the coformer and thus co-crystallisation presents a rapid, facile and highly modular tool for the discovery of new switchable materials.     

New Screening Protocol for Effective Green Solvents Selection of Benzamide,Salicylamide and Ethenzamide

New protocol for screening efficient and environmentally friendly solvents was proposed and experimentally verified. The guidance for solvent selection comes from computed solubility via COSMO-RS approach. Furthermore, solute-solvent affinities computed using advanced quantum chemistry level were used as a rationale for observed solvents ranking. The screening protocol pointed out that 4-formylomorpholine (4FM) is an attractive solubilizer compared to commonly used aprotic solvents such as DMSO and DMF. This was tested experimentally by measuring the solubility of the title compounds in aqueous binary mixtures in the temperature range between 298.15 K and 313.15 K. Additional measurements were also performed for aqueous binary mixtures of DMSO and DMF. It has been found that the solubility of studied aromatic amides is very high and quite similar in all three aprotic solvents. For most aqueous binary mixtures, a significant decrease in solubility with a decrease in the organic fraction is observed, indicating that all systems can be regarded as efficient solvent-anti-solvent pairs. In the case of salicylamide dissolved in aqueous-4FM binary mixtures, a strong synergistic effect has been found leading to the highest solubility for 0.6 mole fraction of 4-FM.     

Crystal Engineering of Stable Temozolomide Cocrystals

The antitumor prodrug temozolomide (TMZ) decomposes in aqueous medium of pH≥7 but is relatively stable under acidic conditions. Pure TMZ is obtained as a white powder but turns pink and then brown, which is indicative of chemical degradation. Pharmaceutical cocrystals of TMZ were engineered with safe coformers such as oxalic acid, succinic acid, salicylic acid, d,l ‐malic acid, and d,l ‐tartaric acid, to stabilize the drug as a cocrystal. All cocrystals were characterized by powder X‐ray diffraction (PXRD), single crystal X‐ray diffraction, and FT‐IR as well as FT‐Raman spectroscopy. Temozolomide cocrystals with organic acids (pK_a 2–6) were found to be more stable than the reference drug under physiological conditions. The half‐life (T_1/2) of TMZ–oxalic and TMZ–salicylic acid measured by UV/Vis spectroscopy in pH 7 buffer is two times longer than that of TMZ (3.5 h and 3.6 h vs. 1.7 h); TMZ–succinic acid, TMZ–tartaric acid, and TMZ–malic acid also exhibited a longer half‐life (2.3, 2.5, and 2.8 h, respectively). Stability studies at 40 °C and 75 % relative humidity (ICH conditions) showed that hydrolytic degradation of temozolomide in the solid state started after one week, as determined by PXRD, whereas its cocrystals with succinic acid and oxalic acid were intact at 28 weeks, thus confirming the greater stability of cocrystals compared to the reference drug. The intrinsic dissolution rate (IDR) profile of TMZ–oxalic acid and TMZ–succinic acid cocrystals in buffer of pH 7 is comparable to that of temozolomide. Among the temozolomide cocrystals examined, those with succinic acid and oxalic acid exhibited both an improved stability and a comparable dissolution rate to the reference drug.     

Imatinib mesylate cocrystals: synthesis, screening, and preliminary characterization

Abstract  

Drug–drug cocrystals of imatinib mesylate with several cocrystal formers, i.e. 5-chlorouracil, 5-fluorouracil, hydroxyurea, 5-fluorocytosine, N-acetylcytosine, chlorogenic acid, dacarbazine, curcumin, creatine, orotic acid, l-cysteine, glutathione, and caffeic acid, were prepared from mixtures by cogrinding or solvent cocrystallization. The samples prepared were analyzed by FTIR, DSC, and XRPD. Formation of cocrystals with different stoichiometry was observed. Novel cocrystals of imatinib mesylate with 5-fluorouracil or hydroxyurea were identified, characterized, and selected by the solid form screening approach. These cocrystals were non-hygroscopic and chemically and physically stable to thermal stress under the testing conditions.     

New Cocrystals of Antipsychotic Drug Aripiprazole: Decreasing the Dissolution through Cocrystallization

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI₂-RSV₁·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI₂-RSV₁·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.     

Syntheses,Crystal Structures,and Properties of Two Novel CL‐20‐based Cocrystals

In recent years, cocrystallization has emerged as an effective way of tuning the properties of compounds and has been widely used in the field of energetic materials. In this study, we have prepared two novel cocrystals of CL‐20 and methylimidazole, including a 1:2 CL‐20 / 2‐mercapto‐1‐methylimidazole ( 1 ) and a 1:4 CL‐20 / 4‐methyl‐5‐nitroimidazole ( 2 ). Cocrystal 1 has good physical and detonation properties (ρ₁ = 1.652 g · cm^–3, D₁ = 7073 m · s^–1, P₁ = 21.6 GPa); however, cocrystal 2 shows higher properties (ρ₂ = 1.680 g · cm^–3, D₂ = 7945 m · s^–1, P₂ = 27.4 GPa). The performance of both cocrystals is better than those of TNT. Thermal performance suggests that both the cocrystals have moderate thermal stabilities. Cocrystal 1 decomposes at 164.9 °C and cocrystal 2 has an exothermic peak at 221 °C. Both cocrystals are insensitive energetic explosives (IS > 40 J, FS > 360 N). Methylimidazole compounds are rarely used as coformers to form cocrystals with CL‐20, which possess good properties for a range of potential applications. Herein, we provide new possible directions for enriching cocrystal speciation.     

Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids

A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors. The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride. On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water.     

Experimental validation of theoretical potassium and sodium cation affinities of amides by mass spectrometric kinetic method measurements

In this study the theoretical Gaussian-2 K(+)/Na(+) binding affinities (enthalpies) at 0 K (in kJ mol(-1)) for six amides in the order: formamide (109.2/138.5) < N-methylformamide (117.7/148.6) < acetamide (118.7/149.5) < N,N-dimethylformamide (123.9/156.4) < N-methylacetamide (125.6/157.7) < N,N-dimethylacetamide (129.2/162.6), reported previously (Siu et al., J. Chem. Phys. 2001; 114: 7045-7051), were validated experimentally by mass spectrometric kinetic method measurements. By monitoring the collision-induced dissociation (CID) of K(+)/Na(+)-bound heterodimers of the amides, the relative affinities were shown to be accurate to within +/-2 kJ mol(-1). With these six theoretical K(+)/Na(+) binding affinities as reference values, the absolute K(+)/Na(+) affinities of imidazole, 1-methylimidazole, pyridazine and 1,2-dimethoxyethane were determined by the extended kinetic method, and found to be consistent (to within +/-9 kJ mol(-1)) with literature experimental values obtained by threshold-CID, equilibrium high-pressure mass spectrometry, and Fourier transform ion cyclotron resonance/ligand-exchange equilibrium methods. A self-consistent resolution is proposed for the inconsistencies in the relative order of K(+)/Na(+) affinities of amides reported in the literature. These two sets of validated K(+) and Na(+) affinity values are useful as reference values in kinetic method measurements of K(+)/Na(+) affinity of model biological ligands, such as the K(+) affinities of aliphatic amino acids.     

Effects of Cocrystallization on the Structure and Properties of Melt-Cast Explosive 2,4-Dinitroanisole: A Computational Study

Melt-cast explosive 2,4-dinitroanisole (DNAN) crystal and its cocrystals DNAN/1,3-dinitrobenzene (DNB) and DNAN/2-nitroaniline (NA) were used to identify the effects of cocrystallization on the crystal structure, non-covalent interactions, and melting points of the DNAN crystal through density functional theory and molecular dynamics. The components DNB and NA with subtle structure variations between the nitro group and amino group can significantly affect the non-covalent interactions, especially the π-π stacking and H-bonds, which can lead to different crystal stacking styles. The melting points of the DNAN crystal are decreased through the cocrystallization, which expands the utilization of the DNAN-based melt cast explosives. Our study deciphers the effects caused by the cocrystallization on the structure and properties of melt cast explosives and may help to design and optimize novel melt-cast explosives.     

Spin-polarized conceptual density functional theory study of the regioselectivity in ring closures of radicals

The regioselectivity of ring-forming radical reactions is investigated within the framework of the so-called spin-polarized conceptual density functional theory. Two different types of cyclizations were studied. First, a series of model reactions of alkyl- and acyl-substituted radicals were investigated. Next, attention was focused on the radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals (a three-step mechanism). In both of these reactions, the approaching radical (carbon or nitrogen centered) adds to a carbon-carbon double bond within the same molecule to form a radical ring compound. In this process, the number of electrons is changing from a local point of view (a charge transfer occurs from one part of the molecule to another one) at constant global spin number Ns (both the reactant and the product ring compound are in the doublet state). It is shown that the experimentally observed regioselectivities for these ring-closure steps can be predicted using the spin-polarized Fukui functions for radical attack, f0NN(r).     

Intermolecular Charge-Transfer Interactions Facilitate Two-Photon Absorption in Styrylpyridine–Tetracyanobenzene Cocrystals

Cocrystals of 4-styrylpyridine and 1,2,4,5-tetracyanobenzene were successfully prepared by supramolecular self-assembly. Donor–acceptor interactions between the molecular components are the main driving force for self-assembly and contribute to intermolecular charge transfer. The cocrystals possess two-photon absorption properties that are not observed in the individual components; suggesting that two-photon absorption originates from intermolecular charge-transfer interactions in the donor–acceptor system. The origin of two-photon absorption in multichromophore systems remains under-researched; thus, the system offers a rare demonstration of two-photon absorption by cocrystallization. Cocrystal engineering may facilitate further design and development of novel materials for nonlinear optical and optoelectronic applications.     

Construction of anomalously bent biphenyl structure using conformational properties of calix[4]amide

C_2v-symmetrical cyclic tetramers of aromatic amides were simply synthesized in moderate yield by condensation reaction of N,N′-dimethyl-1,3-phenylenediamine and isophthalic acid derivatives using dichlorotriphenylphosphorane. The calix[4]amides exist in 1,3-alternate structure with cis conformation of tertiary aromatic amides, which were shown to be a versatile scaffold leading to a bowl-shaped macrocyclic compound possessing a anomalously strained structure, a bent hinge angle between two aromatic ring planes of biphenyl moiety, via an intramolecular ligation reaction.     

Diastereoselective synthesis of atropisomers containing two non-biaryl stereogenic axes: stereochemical relay through stereogenic centres in dihydrostilbene-2,2'-dicarboxamides

Addition of laterally lithiated tertiary aromatic amides to benzaldimines controls the formation of a new stereogenic centre adjacent to the benzaldimine aromatic ring. Drawing on the fact that such amino-substituted stereogenic centres may themselves control the conformation of amides, with amido-substituted benzaldimines we found it becomes possible to relay stereochemistry from one amide to another via this intervening stereogenic centre. A group of dihydrostilbene-2,2'-dicarboxamide derivatives bearing one or two stereogenic axes are made by this method, which demonstrates the use of combined kinetic and thermodynamic control for the relay of stereochemical information.     

The cocrystallization of polymers: Polyethylene and its copolymers

In a continuation of our study of the molecular constitution requirements for the cocrystallization of chemically similar polymeric species, we have directed attention to both homopolymer-copolymer mixtures and copolymer mixtures of polyethylene. Molecular weight and composition fractions were used exclusively. Molecular weights of the components were matched so that attention is given to the influence of chain structure. Differential scanning calorimetry and selective extraction techniques were used to assess whether cocrystallization occurs. Linear polyethylene, and random copolymers which contained up to 2 mol% of either ethyl or acetate branches, cocrystallize upon rapid crystallization from the melt. When the branching content becomes greater than about 3 mol%, cocrystallization does not occur. Copolymers containing about 1–2 mol% are found to cocrystallize with one another. However, copolymers containing higher counit contents do not cocrystallize with one another or with samples containing a smaller amount of counit. These results can be explained on the basis of the concentration of eligible sequences that are available for crystallization.     

Investigation into the structures and physicochemical properties of multi-component crystals of voriconazole

Voriconazole (VZL) is a second-generation and broad-spectrum triazole against fungal infections. Being a BCS (biopharmaceutics classification system) class II compound, the poor aqueous solubility has limited its bioavailability and clinical efficacy. Aims to overcome this disadvantage, a cocrystallization strategy based on crystal engineering principles has resulted in five new multi-component crystals of VZL with maleic acid, L-tartaric, protocatechuic, gallic, and 3,5-dinitrobenzoic acids. Structure analysis revealed that the hydroxyl/carboxylic acid···triazole N₃ hydrogen bonding interaction appears as a main supramolecular heterosynthon in the VZL multi-component crystals with organic acids. And VZL molecule has a flexible conformation in each of the five multi-component structures. The newly synthesized multi-component crystals showed impressive solubility improvement compared to that of the raw material of VZL. Molecular electrostatic potential surfaces (MEPS) analysis based on density functional (DFT) calculations revealed that hydrogen bond interactions in cocrystals mainly involved pairwise interactions in the global maxima and minima sites, but this rule is not always followed. This study indicates the potential of cocrystals to improve the solubility and dissolution rate of VZL     

芳醚酮大环封端聚酰亚胺的合成与交联

本文制备了一种含硫醚键环状芳醚酮单体, 并将其引入聚酰亚胺中, 在不存在引发剂的条件下, 能开环交联反应制备出全芳香高热稳定的可交联聚酰亚胺.