Shape and size mimicry in the design of ternary molecular solids: towards a robust strategy for crystal engineering

2- and 5-methylresorcinol form co-crystals with 4,4'-bipyridine in which some of the bipyridine molecules are loosely bound. These molecules can be replaced with other molecules of a similar shape and size to give a general method for the engineering of a ternary co-crystal.     

Structural rationalisation of co-crystals formed between trithiocyanuric acid and molecules containing hydrogen bonding functionality

Crystallisation of trithiocyanuric acid (TTCA) from various organic solvents that have hydrogen bonding capability (acetone, 2-butanone, dimethylformamide, dimethyl sulfoxide, methanol and acetonitrile) leads to the formation of co-crystals in which the solvent molecules are incorporated together with TTCA in the crystal structure. Structure determination by single-crystal X-ray diffraction reveals that these co-crystals can be classified into different groups depending upon the topological arrangement of the TTCA molecules in the crystal structure. Thus, three different types of single-tape arrangements of TTCA molecules and one type of double-tape arrangement of TTCA molecules are identified. In all co-crystals, hydrogen-bonding interactions are formed through the involvement of N-H bonds of TTCA molecules in these tapes and the other molecule in the co-crystal. Detailed rationalisation of the structural properties of these co-crystals is presented.     

Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co-Crystals

Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry—X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.     

Periodic DFT Study of the Effects of Co-Crystallization on a N-Salicylideneaniline Molecular Switch

This work aims at better understanding the complex effects of co-crystallization on a single salicylideneaniline molecular switch, (E)-2-methoxy-6-(pyridine-3-yliminomethyl)phenol (PYV3), which can tautomerize between an enol and a keto form. A combination of periodic boundary conditions DFT and molecular wavefunction calculations has been adopted for examining a selection of PYV3 co-crystals, presenting hydrogen bonds (H-bonds) or halogen bonds (X-bonds), for which X-ray diffraction data are available. Three aspects are targeted: i) the energy (H-bond strength, enol to keto relative energy, and geometry relaxation energies), ii) the geometrical structure (PYV3 to co-crystal and enol to keto geometrical variations), and iii) the electron distribution (PYV3 to co-crystal and enol to keto Mulliken charge variations). These allow i) explaining the preference for forming H-bonds with the nitrogen of the pyridine of PYV3 with respect to the oxygens and the importance of the crystal field, ii) distinguishing the peculiar behavior of the SulfonylDiPhenol (SDP) coformer, which stabilizes the keto form of PYV3, iii) describing the relative stabilization of the enol form upon co-crystallization (with the exception of SDP) and therefore iv) substantiating the co-crystallization-induced reduction of thermochromism observed for several PYV3 co-crystals.     

Co-crystal structure of mixed molecules of methyl 2-(3-chloro-4-methyl-2-oxo-2H-chromen-7-yloxy)acetate and 2-(2-aminophenyl)benzothiazole

A co-crystal is obtained in a methanolic solution from methyl 2-(3-chloro-4-methyl-2-oxo-2H-chromen-7-yloxy)acetate and 2-(2-aminophenyl)benzothiazole. In the crystal these molecules are connected via usual N-H…O and weak C-H…O H-bonds. The co-crystals are very stable.     

Macrocycle Co-Crystals Showing Vapochromism to Haloalkanes

Organic co-crystal engineering is a promising method to make multifunctional materials. Here, the marriage of macrocyclic chemistry and co-crystal engineering provides a smart strategy to build vapochromic materials. The macrocycle co-crystals (MCCs) were constructed from π-electron rich pillar[5]arene (P5) and an electron-deficient pyromellitic diimide derivative (PDI) on a 10 g scale. MCCs of P5-PDI are in red owing to the formation of a charge-transfer (CT) complex. After solvent removal, a white crystalline solid with a new structure (P5-PDIα) is yielded, which exhibits selective vapochromic responses to volatile organic compounds (VOCs) of haloalkanes, accompanied by color changes from white to red or orange. Powder and single-crystal X-ray diffraction analyses reveal that the color changes are attributed to the vapor-triggered solid-state structural transformation to form CT co-crystals. Coating films of P5 and PDI on glass showed a visible vapochromic behavior with good reversibility.     

Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening

In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.     

Co-crystals of ethenzamide with 2-nitrobenzoic acid - Conformational analysis,MD simulations and DFT investigations

In crystal engineering and pharmaceutical chemistry, co-crystals have a wide range of applications. Ethenzamide (EA) is found to form co-crystal with 2-nitrobenzoic acid (NBA). Geometry properties like stability energy, charge distribution, bond length, electronic properties and thermodynamic characteristics have been analyzed. The C–H?O hydrogen bond involves C–H of EA and oxygen of NBA. Configuration with the angle, N3–C4–C5–C6 gives the lowest energy conformation. Partition coefficient value suggests that EA-NBA has pharmaceutics behavior. RMSD values show the simulation's relative stability and the complexes, remained stable throughout.     

Intermolecular Forces Driving Hexamethylenetetramine Co-Crystal Formation,a DFT and XRD Analysis

Interest in co-crystals formation has been constantly growing since their discovery, almost a century ago. Such success is due to the ability to tune the physical-chemical properties of the components in solid state by avoiding a change in their molecular structure. The properties influenced by the co-crystals formation range from an improvement of mechanical features and chemical stability to different solubility. In the scientific research area, the pharmacological field is undoubtedly one of those in which an expansion of the co-crystal knowledge can offer wide benefits. In this work, we described the crystalline structure of hexamethylenetetramine co-crystallized with the isophthalic acid, and we compared it with another co-crystal, showing the same components but different stoichiometry. To give a wider overview on the nature of the interactions behind the observed crystal packing and to rationalize the reasons of its formation, a computational analysis on such structures was carried out.     

Identification of a new co-crystal of salicylic acid and benzamide of pharmaceutical relevance

Raman spectroscopy, X-ray powder diffraction/X-ray crystallography and differential scanning calorimetry have been used to study the phenomenon of co-crystal formation in stoichiometric mixtures of salicylic acid with benzamide. Raman spectroscopy was particularly useful for the characterization of the products and was used to determine the nature of the interactions in the co-crystals. It was observed that little change in the vibrational modes associated with the phenyl groups of the respective reactants took place upon co-crystal formation, but changes in intensities of the vibrational modes associated with the amide and the carboxylic acid groups were observed upon co-crystal formation. Several new vibrational bands were identified in the co-crystal which were not manifested in the physical mixture of both components and could be used as diagnostic features of co-crystal formation.     

Anticancer potential of novel 5-Fluorouracil co-crystals against MCF7 breast and SW480 colon cancer cell lines along with docking studies

In the present investigation, 5-Fluorouracil co-crystals with four cyclic dimers of amino acids (Glycine, Tryptophane, Leucine and Alanine conformers are prepared via co-crystallization route, with an aim to improve its anticancer effectiveness and to minimize its associated drawbacks. The prepared co-crystals were characterized by FTIR and PXRD techniques. FTIR revealed the presence of respective functional groups in the prepared co-crystals. Frequencies (v) of NH (3416 cm^?1) and carbonyl group (1671 cm^?1) in the 5-Fu (FTIR) spectrum were considerably moved in all co-crystal’s spectra exhibiting the development of new interactions. 5-Fu peak at 2θ = 28.48° was visibly transformed in the co-crystal’s graphs of PXRD. MTT assays was studied on MCF7 breast and SW480 colon cancer cell lines using 0.78 to 200 μg mL^?1 dose concentration. Co-crystals with Tryptophane and Leucine cyclic dimers revealed highest potential (99 % and 100 %) respectively, against colon cancer cell line Likewise Alanine and Tryptophane dimers furnished promising efficiency (100 %) against MCF7 cell line Genetic Optimization for Ligand Docking/GOLD was applied to evaluate the latent anti-tumor behaviors against the proteins [C-myc. (PDB ID: 6G6K, Thymidylate synthase (PDB ID:1HVY) and protein kinase (PDB ID: 2X18). Results revealed that the developed 5-Fluorouracil co-crystals have promising antitumor efficacy as compared to already reported 5-Fu co-crystals and 5-Fu alone.     

Challenges and Progress in Nonsteroidal Anti-Inflammatory Drugs Co-Crystal Development

Co-crystal innovation is an opportunity in drug development for both scientists and industry. In line with the “green pharmacy” concept for obtaining safer methods and advanced pharmaceutical products, co-crystallization is one of the most promising approaches to find novel patent drugs, including non-steroidal anti-inflammatory drugs (NSAID). This kind of multi-component system improves previously poor physicochemical and mechanical properties through non-covalent interactions. Practically, there are many challenges to find commercially viable co-crystal drugs. The difficulty in selecting co-formers becomes the primary problem, followed by unexpected results, such as decreased solubility and dissolution, spring and parachute effect, microenvironment pH effects, changes in instability, and polymorphisms, which can occur during the co-crystal development. However, over time, NSAID co-crystals have been continuously updated regarding co-formers selection and methods development.     

Model pharmaceutical co-crystallization: Guest-directed assembly of caffeine and aromatic tri-hydroxy and dicarboxylic acids into different heteromolecular hydrogen bonding networks in solid state

Three model pharmaceutical caffeine-containing co-crystals of 1,3,5-trihydroxybenzene (phloroglucinol), isophthalic acid and 5-hydroxyisophthalic acid were synthesized and characterized via single-crystal X-ray diffraction. The three crystalline forms reported are an anhydrous co-crystal and other two are co-crystal hydrates. Also their binding properties were studied by UV-vis analysis. In each of these structures, an organised intermolecular hydrogen bonding motif was observed. A comparison of hydrogen bonding motifs in the crystal sheets was presented.     

Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge

Induced fit or protein flexibility can make a given structure less useful for docking and/or scoring. The 2015 Drug Design Data Resource (D3R) Grand Challenge provided a unique opportunity to prospectively test optimal strategies for virtual screening in these type of targets: heat shock protein 90 (HSP90), a protein with multiple ligand-induced binding modes; and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), a kinase with a large flexible pocket. Using previously known co-crystal structures, we tested predictions from methods that keep the receptor structure fixed and used (a) multiple receptor/ligand co-crystals as binding templates for minimization or docking (“close”), (b) methods that align or dock to a single receptor (“cross”), and (c) a hybrid approach that chose from multiple bound ligands as initial templates for minimization to a single receptor (“min-cross”). Pose prediction using our “close” models resulted in average ligand RMSDs of 0.32 and 1.6 Å for HSP90 and MAP4K4, respectively, the most accurate models of the community-wide challenge. On the other hand, affinity ranking using our “cross” methods performed well overall despite the fact that a fixed receptor cannot model ligand-induced structural changes,. In addition, “close” methods that leverage the co-crystals of the different binding modes of HSP90 also predicted the best affinity ranking. Our studies suggest that analysis of changes on the receptor structure upon ligand binding can help select an optimal virtual screening strategy.     

(Solid + liquid) phase diagram for (indomethacin + nicotinamide)-methanol or methanol/ethyl acetate mixture and solubility behavior of 1:1 (indomethacin + nicotinamide) co-crystal at T = (298.15 and 313.15) K

(Solid + liquid) equilibrium data for indomethacin (IMC) and nicotinamide (NCT) in both methanol (MeOH) and methanol/ethyl acetate (EA) mixture were determined using a static method at T = (298.15 and 313.15) K under atmospheric pressure. The 1:1 (IMC + NCT) co-crystal and IMC·MeOH were found in both systems under conditions investigated. The solubility of the 1:1 (IMC + NCT) co-crystal was correlated using a mathematical model consisting of both solubility product and a complexation process. Solubility of (IMC + NCT) co-crystals as a function of co-former (NCT) concentration was evaluated. It was found that temperature has a significant effect on the formation of methanol solvate in the systems investigated. Solvate formation could be suppressed either by increasing temperature or using solvent mixtures. Additionally, the solvent mixture could level out the solubility differences between IMC and NCT, resulting in larger and more symmetric regions for the (IMC + NCT) co-crystal, which would be helpful to the development of the co-crystallization process for the 1:1 (IMC + NCT) co-crystal.     

Achieving dynamic behaviour and thermal expansion in the organic solid state via co-crystallization

Thermal expansion involves a response of a material to an external stimulus that typically involves an increase in a crystallographic axis (positive thermal expansion (PTE)), although shrinking with applied heat (negative thermal expansion (NTE)) is known in rarer cases. Here, we demonstrate a means to achieve dynamic molecular motion and thermal expansions in organic solids via co-crystallizations. One co-crystal component is known to exhibit dynamic behaviour in the solid state while the second, when varied systematically, affords co-crystals with linear thermal expansion coefficients that range from colossal to nearly zero. Two co-crystals exhibit rare NTE. We expect the approach to guide the design of molecular solids that enable predesigned motion related to thermal expansion processes.     

Structural properties of a family of hydrogen-bonded co-crystals formed between gemfibrozil and hydroxy derivatives of t-butylamine, determined directly from powder X-ray diffraction data

We report the formation and structural properties of co-crystals containing gemfibrozil and hydroxy derivatives of t-butylamine H₂NC(CH₃)_3−n(CH₂OH)_n, with n=0, 1, 2 and 3. In each case, a 1:1 co-crystal is formed, with transfer of a proton from the carboxylic acid group of gemfibrozil to the amino group of the t-butylamine derivative. All of the co-crystal materials prepared are polycrystalline powders, and do not contain single crystals of suitable size and/or quality for single crystal X-ray diffraction studies. Structure determination of these materials has been carried out directly from powder X-ray diffraction data, using the direct-space Genetic Algorithm technique for structure solution followed by Rietveld refinement. The structural chemistry of this series of co-crystal materials reveals well-defined structural trends within the first three members of the family (n=0, 1, 2), but significantly contrasting structural properties for the member with n=3.     

Conformational polymorphism in bicalutamide: a quantum chemical study

Bicalutamide is an anti-neoplastic drug widely used for the treatment of prostate cancer and it exhibits conformational polymorphism. Three crystal structures of bicalutamide are reported as racemic mixtures, two of which are polymorphs. In addition, three co-crystals are also reported—two with organic coformers and one with adrenoreceptor (the macromolecular target). All the reported structures show significant conformational differences. Quantum chemical B3LYP/6-31+G(d,p) analysis has been carried out to understand the interplay of intra- and intermolecular interactions leading to the conformational preferences in this molecule. The difference between the two polymorphic forms has been traced to the C5–S8–C11–C12 torsional angle. Inside the cavity of androgen receptor, a completely different conformation is found but it does not correspond to any local minima on the potential energy surface of the drug. A relatively rigid torsional angle C11–C12–C15–N17 is also expected due to a strong five-membered ring intramolecular hydrogen bond (H–O13–C12–C15–O16), which has been reported to be desirable; quantum chemical analysis revealed that this rigidity is of the order of 11 kcal/mol. Ab initio calculations demonstrate that polymorphs and polymorphic co-crystals differ in the extent of intra- and intermolecular hydrogen bonding interactions. The strength of the intermolecular interactions associated with these structures is analyzed in terms of energy release due to dimerization.     

Carboxylic acid–pyridine supramolecular heterocatemer in a co-crystal

Robustness of carboxylic acid–pyridine supramolecular heterosynthon was examined in three 1:2 binary co-crystals of 4,4′-bipyridine with monocarboxylic acids, (4,4′-bipyridine)·(dl-hydroxyphenylacetic acid)₂, 1; (4,4′-bipyridine)_0.5·(4-bromonaphthalene-1-carboxylic acid), 2 and (4,4′-bipyridine)_0.5·(4-methylbenzoic acid), 3. All the three co-crystals form “two-component supermolecules” (consisting of one molecule of 4,4′-bipyridine and two molecules of the relevant carboxylic acid) stabilized through carboxylic acid–pyridine heterosynthons. Co-crystals 1 and 2 exhibits the expected carboxylic acid–pyridine dimer (heterodimer I) whereas co-crystal 3 forms a novel carboxylic acid–pyridine catemer (heterocatemer II).     

One class classification as a practical approach for accelerating π–π co-crystal discovery

The implementation of machine learning models has brought major changes in the decision-making process for materials design. One matter of concern for the data-driven approaches is the lack of negative data from unsuccessful synthetic attempts, which might generate inherently imbalanced datasets. We propose the application of the one-class classification methodology as an effective tool for tackling these limitations on the materials design problems. This is a concept of learning based only on a well-defined class without counter examples. An extensive study on the different one-class classification algorithms is performed until the most appropriate workflow is identified for guiding the discovery of emerging materials belonging to a relatively small class, that being the weakly bound polyaromatic hydrocarbon co-crystals. The two-step approach presented in this study first trains the model using all the known molecular combinations that form this class of co-crystals extracted from the Cambridge Structural Database (1722 molecular combinations), followed by scoring possible yet unknown pairs from the ZINC15 database (21 736 possible molecular combinations). Focusing on the highest-ranking pairs predicted to have higher probability of forming co-crystals, materials discovery can be accelerated by reducing the vast molecular space and directing the synthetic efforts of chemists. Further on, using interpretability techniques a more detailed understanding of the molecular properties causing co-crystallization is sought after. The applicability of the current methodology is demonstrated with the discovery of two novel co-crystals, namely pyrene-6H-benzo[c]chromen-6-one (1) and pyrene-9,10-dicyanoanthracene (2).

Machine learning using one class classification on a database of existing co-crystals enables the identification of co-formers which are likely to form stable co-crystals, resulting in the synthesis of two co-crystals of polyaromatic hydrocarbons.