Cocrystal Solvate Research Articles

Unravelling Guest Dynamics in Crystalline Molecular Organics Using 2H Solid-State NMR and Molecular Dynamics Simulation.

2H solid-state NMR and atomistic molecular dynamics (MD) simulations are used to understand the disorder of guest solvent molecules in two cocrystal solvates of the pharmaceutical furosemide. Traditional approaches to interpreting the NMR data fail to provide a coherent model of molecular behavior and indeed give misleading kinetic data. In contrast, the direct prediction of the NMR properties from MD simulation trajectories allows the NMR data to be correctly interpreted in terms of combined jump-type and libration-type motions. Time-independent component analysis of the MD trajectories provides additional insights, particularly for motions that are invisible to NMR. This allows a coherent picture of the dynamics of molecules restricted in molecular-sized cavities to be determined.

Combining a Drug and a Nutraceutical: A New Cocrystal of Praziquantel and Curcumin

This study explores the co-crystallization between the drug praziquantel (PZQ) and the nutraceutical curcumin (CU). The investigation revealed two novel solid forms: a cocrystal solvate with ethyl acetate and a non-solvated cocrystal. This novel drug–nutraceutical cocrystal is a praziquantel–curcumin (2:1) cocrystal. The cocrystal solvate has ethyl acetate molecules occupying the voids with minimal interactions within the crystal lattice. The application of heat treatment induces solvent removal and prompts the transition to the non-solvated cocrystal, as highlighted by variable-temperature X-ray powder diffraction (VT-XRPD). Thermal analyses demonstrate the stability of the cocrystal solvate up to approximately 100 °C, beyond which it transforms into the non-solvated phase, which eventually melts at 130 °C.

Two-component Supramolecular Adduct based on Hydroxyl Substituted Triptycene with 4,4’-bipyridine: Crystal Structure Analysis

A new cocrystal solvate possessing 2,7,14-trihydroxytriptycene (THT) and 4,4′-bipyridine (bpy) was grown from a MeOH solution by solvent evaporation to form THT·0.5bpy·MeOH·H2O (1).The crystal structure of 1 was determined by single-crystal X-ray diffraction in the monoclinic space group C2/c. In the new cocrystal solvate (1), the asymmetric unit consists of one unit of THT, a half unit of disordered bpy, one unit of a water molecule and one MeOH molecule. A 2D supramolecular architecture is observed in (1) linking THT, bpy and solvent water molecules via classical O-H···N and O-H···O hydrogen bonds. The MeOH and water molecules entrapped in (1) form stabilizing hydrogen bondswith the surrounding “trimeric cocrystals.” Furthermore, we investigated whether these hydrogen bonds stabilize the crystal packing. The calculations were carried out using Hydrogen Bond Statistics and Full Interaction Maps packages, and the results exhibit common bonding behaviour in terms of bond distances and strength.

Multicomponent Solvate Crystals of 3,5-Dinitrobenzoic Acid and Acetamide and CSD Analysis of Solvates.

Twelve multicomponent solvate crystals (cocrystal solvates) of 3,5-dinitrobenzoic acid and acetamide were synthesized via slow evaporation method. All crystalline materials were characterized by single-crystal X-ray diffraction. All cocrystal solvates are isostructural, and crystal packing forms continuous channels where some solvent molecules are connected via weak intermolecular interactions with 3,5-dinitrobenzoic acid and acetamide. All multicomponent solvate crystals encompass amide-amide dimer homo synthons and form R22 (8) motifs. Moreover, the phase purity of solvate crystals was analyzed by powder X-ray diffraction. Further, most of the cocrystal solvates were analyzed by nuclear magnetic resonance and differential scanning calorimetry. Cambridge structural database analysis categorizes solvate propensity in single-crystal structures. The importance of hydrogen bond donor/acceptor nature, size, and shape of solvents is also discussed in the context of crystallization and crystal packing.

Supramolecular Tuning of Spin Crossover Properties in Isostructural Cocrystal Solvates

In order to improve strategies for the design of spin-crossover materials, it is necessary to develop and understand structure–property relationships, and this is best achieved by obtaining isostructural materials. In this work we synthesized a series of four isostructural cocrystal solvates using the [Fe(3-bpp)2][A]2 complex and the 2,2-dipyridyl disulfide coformer in methanol and ethanol (A = BF4– or PF6–). The spin-crossover properties of the materials were determined by variable temperature single-crystal X-ray diffraction. They show the same SCO behavior but with shifted spin-crossover temperatures, which has been related to the hydrogen bond basicity, pKBHX of the anions, and solvents present. This relationship between hydrogen bond basicity and the spin-crossover transition temperature offers a design strategy for the supramolecular tuning of spin-crossover properties in specific isostructural materials.

Enantioselectivity of chiral dihydromyricetin in multicomponent solid solutions regulated by subtle structural mutation.

Multicomponent crystals of a chiral drug with non-chiral components have attracted increasing attention in the application of enantiomer purification and regulation of the physicochemical properties of crystalline materials. Crystalline solid solutions provide opportunities for fine-tuning material properties because of continuously adjustable component stoichiometry ratios. The synthesis, crystal structure, thermodynamics and solid-state enantioselectivity of a series of multicomponent crystals of chiral dihydromyricetin (DMY) with caffeine (CAF) or theophylline (THE) were investigated and the results reveal how the subtle change of molecular structure of the coformer dictates the enantiomer selectivity in multicomponent cocrystals. A series of multicomponent cocrystal solvates of chiral DMY with CAF and THE were synthesized by the slurry cocrystallization method in acetonitrile. Although most racemic mixtures crystallize as racemic compounds or conglomerates, both DMY-CAF and DMY-THE crystallize as chiral solid solutions, unveiled by pseudo-binary melt phase diagrams and pseudo-ternary solution phase diagrams. Crystal structures of Rac-DMY-CAF, R,R-DMY-CAF, Rac-DMY-THE and R,R-DMY-THE are reported for the first time via single-crystal X-ray diffraction, displaying two distinct types of solid solution differing in mixing scale of enantiomers spanning several orders of magnitude. Surprisingly, this remarkable impact on enantiomer discrimination was simply achieved by the reduction of a methyl group of CAF to the THE coformer, which was further rationalized from their crystal structures and intermolecular interactions. Collectively, this work has demonstrated that a subtle change in the molecular structure of a coformer can regulate enantioselectivity in crystalline materials, guiding the purification of chiral racemic compounds via the cocrystallization method and the design of solid-solution crystalline materials.

Cocrystallization of lenvatinib and temozolomide to improve the performance in terms of stability, dissolution, and tabletability

Cocrystallization of two anti-melanoma drugs, lenvatinib and temozolomide, resulted in two drug–drug cocrystal solvates presenting improved performance in terms of stability, dissolution, and tabletability, which show great potential to be developed as a drug combination.

Exploring the influence of crystal packing on the optical-physical property of quercetin-based binary and ternary solid forms

The co-crystallization of quercetin (Qur) with a flexible molecule 4-(4-pyridinyldisulfanyl) pyridine (DPDS) in different solvents and conditions was investigated, yielded five multi-component crystalline phases and characterized with X-ray diffractions and thermal analysis. Although the crystal system of Qur-DPDS-MeOH and Qur-DPDS-Dioxane is the same, the desolvation results revealed that Qur-DPDS-MeOH transformed to Qur-DPDS when MeOH solvent molecules escape from the lattice, while Qur-DPDS-Dioxane transformed to Qur-DPDS-II through a similar process, which is same with Qur-DPDS-THF. These two cocrystal polymorphs Qur-DPDS and Qur-DPDS-II obey an enantiotropic relationship. Moreover, the formation of cocrystal solvates improves the packing efficiency of crystals. Crystal structure analysis showed that hydrogen bonds and conformations of the corresponding parent molecules play a major role in molecular assembly and crystal packing patterns, thus bring different physicochemical properties. Finally, the fluorescence spectra and quantum-chemical calculations were carried out to explore the difference in the optical-physical properties.

Phase transitions in flexible crystals of cocrystal solvate of caffeine

Phase transitions in flexible crystals of cocrystal solvate of caffeine

Playing with Isostructurality from Binary Cocrystals to Ternary Cocrystal Solvates of Quercetin: Tuning Colors of Pigment

Playing with Isostructurality from Binary Cocrystals to Ternary Cocrystal Solvates of Quercetin: Tuning Colors of Pigment

Influence of Multiple Binding Sites on the Supramolecular Assembly of N-[(3-pyridinylamino) Thioxomethyl] Carbamates.

In this study, we investigated how the presence of multiple intermolecular interaction sites influences the heteromeric supramolecular assembly of N-[(3-pyridinylamino) thioxomethyl] carbamates with fluoroiodobenzenes. Three targets—R-N-[(3-pyridinylamino) thioxomethyl] carbamate (R = methyl, ethyl, and isobutyl)—were selected and crystallized, resulting in three parent structures, five co-crystals, and one co-crystal solvate. Three hydrogen-bonded parent crystal structures were stabilized by N-H···N hydrogen bonding and assembled into layers that stacked on top of one another. Molecular electrostatic potential surfaces were employed to rank binding sites (Npyr > C=S > C=O) in order to predict the dominant interactions. The N-H⋯H hydrogen bond was replaced by I⋯Npyr in 3/6 cases, I⋯C=S in 4/6 cases, and I⋯O=C in 1 case. Interestingly, the I⋯C=S halogen bond coexisted twice with I⋯Npyr and I⋯O=C. Overall, the MEPs were fairly reliable for predicting co-crystallization outcomes; however, it is crucial to also consider factors such as molecular flexibility. Finally, halogen-bond donors are capable of competing for acceptor sites, even in the presence of strong hydrogen-bond donors.

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation.

Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

Structure analysis and insight into hydrogen bond and van der waals interactions of etoricoxib cocrystals and cocrystal solvate

Etoricoxib (ETR) is a non-ionizable BCS class II drug with no typical hydrogen bond donors and low solubility in water. Cocrystal was proved to be a good strategy to improve bioavailability. In this work, the excess enthalpy (△Hex) was used to shorten the time of the screening of ETR cocrystals. Six cocrystals of ETR and one cocrystal solvate have been synthesized and characterized. The dissolution experiments showed that all cocrystals performed a higher apparent solubility compared with ETR Form Ⅴ. To gain insight into the intermolecular interactions of cocrystals, the crystal structures have been solved by single crystal X-ray diffraction and other analysis methods. The average local ionization energy (ALIE) analysis shows that pyridine nitrogen is more susceptible to be attacked by the electrophiles than sulfonyl oxygen. Therefore, O-H···N rather than O-H···O hydrogen bond dominates the formation of supramolecular synthons. Van der Waals (vdW) force is another main driving force that works together with hydrogen bonds to form basic units of ETR-CT cocrystal and ETR-HQ-MeOH cocrystal solvate. The hydrogen bond strength of all the ETR cocrystals and cocrystal solvate was calculated by atoms-in-molecules theory, which was rationalized by natural population analysis. Overall, our work presents the structure analysis of six newly formed ETR cocrystals and one cocrystal solvate, which provides a deeper insight into intermolecular interactions of cocrystals at the molecular level.

Structural systematics in isomorphous binary co-crystal solvates comprising 2,2′-dithiodibenzoic acid, 4-halobenzoic acid and dimethylformamide (1 : 1 : 1), for halide = chloride, bromide and iodide

The enhanced steric and bonding influences exerted by iodide are not sufficient to perturb isostructurality in a series of ternary crystals that differ only in the halide substituent, i.e. X = Cl, Br and I.

Mechanochemical synthesis, thermoanalytical study and characterization of new multicomponent solid forms of norfloxacin with saccharin

Cocrystallization is a very efficient strategy to improve the physicochemical properties of bioactive agents. A new norfloxacin (NOR)–saccharin cocrystal and a cocrystal–solvate were synthesized through the mechanochemical method (neat and liquid-assisted grinding), and the characterization was performed by thermal analysis (TG–DTA, DSC and DSC microscopy), infrared vibrational spectroscopy and powder X-ray diffraction. Moreover, solubility experiments carried out in water and buffer solutions (pH 3.0, 6.1 and 8.5) showed that norfloxacin has an aqueous solubility 3.5 times higher when cocrystallized with saccharin than in its pristine state, and an inverted pH-dependency compared to NOR alone (2 times higher in 6.1, slightly increase in pH 3.0, and a decrease of 0.7 times in 8.5 buffer solution). Furthermore, the solvate–cocrystal has a water solubility 2.3 times higher than NOR and the same solubility in 6.1 buffer solution than the cocrystal (2 times higher than NOR alone).

Phototriggered Guest Release from a Nonporous Organic Crystal: Remarkable Single-Crystal-to-Single-Crystal Transformation of a Binary Cocrystal Solvate to a Ternary Cocrystal.

The development of organic solids for applications in materials science requires a fundamental understanding of how close packing of molecules can affect structure and function. We report here nonporous organic crystals that release entrapped guest molecules upon application of UV light. We show components of binary cocrystal solvates to undergo an intermolecular photoreaction to generate ternary cocrystals that results in release of entrapped solvent molecules. The phototriggered guest release occurs in a single-crystal-to-single-crystal transformation that is in the absence pores and channels in the solid. The cocrystals are composed of a tetratopic hydrogen-bond-acceptor molecule synthesized in the solid state. The UV-light results in [2 + 2] photodimerization of an isocoumarin to generate a ternary cocrystal with cyclobutane molecules that support guest release.

Enabling Cocrystallization of Challenging Systems: Passing through a Stable Cocrystal Solvate as a Pathway to Strenuous Cocrystal Forms

Caffeine and maleic acid can form various cocrystal forms, which is a potential route to avoiding hydration issues of caffeine. This particular system was intensively studied as it not only shows cocrystal polymorphism but also stoichiometrically diverse cocrystals with a 1:1 maleic acid: caffeine (MC) and a 1:2 maleic acid:caffeine (MC2) form already identified. A cocrystallization process for MC was already developed. However, a process leading to pure MC2 remained a challenge, as the stability zone of the MC2 suspension is very narrow in most solvents. In this paper, we propose an alternative crystallization pathway toward this crystal form, passing through a stable solvate. Indeed, we identified a novel cocrystal solvate of MC2 (MC2·MeCN) in acetonitrile at 9 °C. This cocrystal solvate is characterized by a large stability zone in the ternary phase diagram, and consequently, a crystallization process leading to this form can easily be devised. Upon filtration, and exposure to ambient atmosphere, MC2·MeCN is quickly desolvated leading to the pure MC2 cocrystal phase. In this contribution, we therefore show that cocrystal phases, which are seemingly strenuous to crystallize from solution, can be accessed by thinking out-of-the-box and using the properties of unexpected alternative phases.

Influence of crystal packing on the thermal properties of cocrystals and cocrystal solvates of olanzapine: insights from computations

A multicomponent supramolecular host with adaptive guest accommodation abilities is observed in the cocrystal solvates of the olanzapine–hydroquinone system.

A 1:1:1 co-crystal solvate comprising 2,2'-di-thiodi-benzoic acid, 2-chloro-benzoic acid and N,N-di-methyl-formamide: crystal structure, Hirshfeld surface analysis and computational study.

The asymmetric unit of the three-component title compound, 2,2'-di-thiodi-benzoic acid-2-chloro-benzoic acid-N,N-di-methyl-formamide (1/1/1), C14H10O4S2·C7H5ClO2·C3H7NO, contains a mol-ecule each of 2,2'-di-thiodi-benzoic acid (DTBA), 2-chloro-benzoic acid (2CBA) and di-methyl-formamide (DMF). The DTBA mol-ecule is twisted [the C-S-S-C torsion angle is 88.37 (17)°] and each carb-oxy-lic group is slightly twisted from the benzene ring to which it is connected [CO2/C6 dihedral angles = 7.6 (3) and 12.5 (3)°]. A small twist is evident in the mol-ecule of 2CBA [CO2/C6 dihedral angle = 4.4 (4)°]. In the crystal, the three mol-ecules are connected by hydrogen bonds with the two carb-oxy-lic acid residues derived from DTBA and 2CBA forming a non-symmetric eight-membered {⋯HOCO}2 synthon, and the second carb-oxy-lic acid of DTBA linked to the DMF mol-ecule via a seven-membered {⋯HOCO⋯HCO} heterosynthon. The three-mol-ecule aggregates are connected into a supra-molecular chain along the a axis via DTBA-C-H⋯O(hydroxyl-2CBA), 2CBA-C-H⋯O(hydroxyl-DTBA) and DTBA-C-H⋯S(DTBA) inter-actions. Supra-molecular layers in the ab plane are formed as the chains are linked via DMF-C-H⋯S(DTBA) contacts, and these inter-digitate along the c-axis direction without specific points of contact between them. A Hirshfeld surface analysis points to additional but, weak contacts to stabilize the three-dimensional architecture: DTBA-C=O⋯H(phenyl-DTBA), 2CBA-Cl⋯H(phenyl-DTBA), as well as a π-π contact between the delocalized eight-membered {⋯HOC=O}2 carb-oxy-lic dimer and the phenyl ring of 2CBA. The latter was confirmed by electrostatic potential (ESP) mapping.

Piroxicam–clonixin drug–drug cocrystal solvates with enhanced hydration stability

Piroxicam and clonixin can form drug–drug crystalline complexes with the help of suitable solvent molecules.