Supramolecular Heterosynthons Research Articles

Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation.

Hesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml-1) and rapid first-pass metabolism. Cocrystallization has evolved as a promising approach to generate novel crystal forms of biologically active compounds and enhance the physicochemical properties without covalent modification. In this work, crystal engineering principles were employed to prepare and characterize various crystal forms of HES. Specifically, two salts and six new ionic cocrystals (ICCs) of HES involving sodium or potassium salts of HES were studied using single-crystal X-ray diffraction (SCXRD) or powder X-ray diffraction and thermal measurements. Structures of seven of the new crystalline forms were elucidated by SCXRD, which revealed two families of isostructural ICCs in terms of their crystal packing and confirmed the presence of phenol...phenolate (PhOH...PhO-) supramolecular heterosynthons. Diverse HES conformations were observed amongst these structures, including unfolded and folded (previously unreported) conformations. One ICC, HES with the sodium salt of HES (NESNAH), was scalable to the gram scale and found to be stable after accelerated stability testing (exposure to elevated heat and humidity). HESNAH reached Cmax after 10 min in PBS buffer 6.8 compared with 240 min in pure HES. In addition, relative solubility was observed to be 5.5 times greater, offering the possibility of improved HES bioavailability.

A Failed Cocrystallization Attempt Resulted in Novel First Polymorphic Structure: Crystal Structure and Hirshfeld Surface Analysis of the Polymorph of 4-Oxo-4-(pyridin-2-ylamino)butanoic Acid

An attempt to cocrystallize 4-oxo-4-(pyridin-2-ylamino)butanoic acid (APS) with adipic acid in the ratio 1:1 was made. Solvent assisted grinding followed by solvent evaporation technique using ethanol as solvent yielded single crystals. Single crystal X-ray diffraction (SCXRD) studies of the obtained crystals showed that an attempt to obtain cocrystals has failed and instead has yielded a novel and very first polymorphic structure of APS (1). Compound 1 crystallizes with one molecule in the asymmetric unit in monoclinic P21/n system, whereas, the earlier reported polymorph, 2, crystallizes in triclinic P-1 system with two molecules in the asymmetric unit. The crystal structure of 1 features aminopyridine···carboxylic O-H···N and N-H···O=C interactions between molecules resulting in R2 2(8) supramolecular hetero-synthon, similar to that observed in polymorph 2. The R2 2(8) dimer propagates into a 2D sheet along the body diagonal plane (intersecting a and c axis) via a pair of C-H···O intermolecular interactions having R2 2(14) motif. Polymorph 2, on the other hand, features several C-H···O intermolecular interactions that extends the R2 2(8) supramolecular architecture into complex 1D columns. The Hirshfeld surface analyses including dnorm plots and two dimensional fingerprint analyses were conducted to confirm the presence of various hydrogen bonds/intermolecular interactions existing in the crystal structure of 1. H···H contacts (dispersion interactions) contributes most to the Hirshfeld surface with a contribution of 40.8%, followed by O···H/H···O (28.4%), C···H/H···C (12.4%), N···H/H···N (9.3%) and others (9.1%). Further, the molecular structure, crystal structure and Hirshfeld surfaces including dnorm and fingerprint plots of 1, 2 and a positional isomer 4-oxo-4-(pyridin-3- ylamino)butanoic acid (3) were compared to observe the similarities and differences in the three compounds.

On the inverse correlation between the hydrogen bond strength and chalcogen bond strength in the cyclic supramolecular heterosynthon [–Se–N]⋯[HOOC–

The correlation between two different noncovalent bonds in a cyclic supramolecular heterosynthon has been studied both in the gas phase and in the crystal phase.

Crystal Engineering of Ionic Cocrystals Sustained by Azolium···Azole Heterosynthons.

Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+B-A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+B-C), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31-46 kJ mol-1. The azolium-triazole ICC (A+B-C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.

Conformational Trimorphism in an Ionic Cocrystal of Hesperetin.

We report the existence of conformational polymorphism in an ionic cocrystal (ICC) of the nutraceutical compound hesperetin (HES) in which its tetraethylammonium (TEA+) salt serves as a coformer. Three polymorphs, HESTEA-α, HESTEA-β and HESTEA-γ, were characterized by single-crystal X-ray diffraction (SCXRD). Each polymorph was found to be sustained by phenol···phenolate supramolecular heterosynthons that self-assemble with phenol···phenol supramolecular homosynthons into C 3 2(7) H-bonded motifs. Conformational variability in HES moieties and different relative orientations of the H-bonded motifs resulted in distinct crystal packing patterns: HESTEA-α and HESTEA-β exhibit H-bonded sheets; HESTEA-γ is sustained by bilayers of H-bonded tapes. All three polymorphs were found to be stable upon exposure to humidity under accelerated stability conditions for 2 weeks. Under competitive slurry conditions, HESTEA-α was observed to transform to the β or γ forms. Solvent selection impacted the relationship between HESTEA-β (favored in EtOH) and HESTEA-γ (favored in MeOH). A mixture of the β and γ forms was found to be present following H2O slurry.

Crystal engineering of phenol–phenolate supramolecular heterosynthon

Crystal engineering of phenol–phenolate supramolecular heterosynthon

Trimorphic ionic cocrystals sustained by the phenol–phenolate supramolecular heterosynthon

Trimorphic ionic cocrystals sustained by the phenol–phenolate supramolecular heterosynthon

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 N 3 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 Novel voriconazole multi-component crystals were prepared via liquid-assisted grinding and solvent evaporation method. Cocrystallization technique shows impressive advantages in improving the solubility and dissolution rate of voriconazole.

Crystal Engineering of Ionic Cocrystals Sustained by the Phenol-Phenolate Supramolecular Heterosynthon.

Although crystal engineering strategies are generally well explored in the context of multicomponent crystals (cocrystals) formed by neutral coformers (molecular cocrystals), cocrystals comprised of one or more salts (ionic cocrystals, ICCs) are understudied. We herein address the design, preparation, and structural characterization of ICCs formed by phenolic moieties, a common group in natural products and drug molecules. Organic and inorganic bases were reacted with the following phenolic coformers: phenol, resorcinol, phloroglucinol, 4-methoxyphenol, and 4-isopropylphenol. Nine ICCs were crystallized, each of them sustained by the phenol–phenolate supramolecular heterosynthon (PhOH···PhO–). Such ICCs are of potential utility, and there are numerous examples of phenolic compounds that are biologically active, some of which suffer from low aqueous solubility. The propensity to form ICCs sustained by the PhOH···PhO– supramolecular heterosynthon was evaluated through a combination of Cambridge Structural Database (CSD) mining, structural characterization of nine novel ICCs, and calculation of interaction energies. Our analysis of these 9 ICCs and the 41 relevant entries archived in the CSD revealed that phenol groups can reliably form ICCs through charge-assisted PhOH···PhO– interactions. This conclusion is supported by hydrogen-bond strength calculations derived from CrystalExplorer that reveal the PhOH···PhO– interaction to be around 3 times stronger than the phenol–phenol hydrogen bond. The PhOH···PhO– supramolecular heterosynthon could therefore enable crystal engineering studies of a large number of phenolic pharmaceutical and nutraceutical compounds with their conjugate bases.

Expanding the Supramolecular Toolkit: Computed Molecular and Crystal Properties for Supporting the Crystal Engineering of Higher-Order Molecular Ionic Cocrystals

Over the past 2 decades, significant progress has been made in developing a robust supramolecular toolkit for the crystal engineering of simple binary cocrystals. By contrast, crystal engineering of higher-order molecular ionic cocrystals (ICCs) is not well established. Here, we report the results of the most extensive survey of the molecular and crystal properties of ICCs reported to date and use the resulting data to propose a set of guiding principles to aid the crystallization of molecular ICCs sustained by charge-assisted hydrogen bonding interactions. Using a data set comprising a total of 94 ICC crystal structures, this work reveals that molecular ICCs are favored within a narrow range of the property landscape. Specifically, most of the ICCs in the data set are crystallized using molecules with significantly different polar surface areas. The data also highlight the importance of choosing molecules with a similar number of conformational degrees of freedom when targeting higher-order cocrystals. Molecular ICCs comprising conjugate acid–base fragments are more likely to be observed in crystallization screens when the difference in the ionization constants of the acid–base pair lie within the “gray” zone of the salt–cocrystal continuum. This work also reveals the hierarchy in the supramolecular heterosynthons of molecular ICCs. Finally, periodic dispersion-corrected density functional theory calculations on a limited subset of crystal structures reveals that most of the ICCs surveyed are driven to form on the basis of favorable energetics as indicated by a mean stabilization energy of −5 kJ mol–1.

Nonsteroidal Anti-Inflammatory Drugs–1-Phenylethylamine Diastereomeric Salts: A Systematic Solid-State Investigation

The solid-state investigation of the diastereomeric salts (S)-ibuprofen (S-Ibu), (S)-naproxen, (S-Nap), and (S)-ketoprofen (S-Ket) with (R)-(+)- and (S)-(−)-1-phenylethylamine, R-PEA, and S-PEA respectively, has been carried out by using a combination of experimental and in-silico tools. The focus was on their crystal packing and on the stability/transformation of their solid forms under different experimental conditions with the final aim of extracting useful information on the forces/features which could be exploited for the chiral separation of the corresponding racemic compounds. All the salts are 21-column crystals, each column consisting of API and 1-phenylethylamine ions assembled via the 1-phenylethylammonium-carboxylate supramolecular heterosynthon which originates a R43 (10) pattern, the intercolumns contacts being definitely weaker. In spite of an overall similarity in the crystal packing forces and motifs of the anhydrous salts, the temperature stability range suggests that the homochiral species are the most stable. The fact that the homochiral salt of S-Ket (S-Ket_S-PEA) is stable toward the hydration, at variance with the heterochiral one (S-Ket_R-PEA), further confirms this hypothesis. On the other hand, preliminary sorption tests show that S-Ket and S-Ibu preferentially capture the homochiral PEA (S-Nap is not selective). This behavior has been correlated to the almost planar boundary surfaces which characterize and differentiate the 21 sheets in S-Ket_S-PEA and S-Ibu_S-PEA salts with respect to the corresponding heterochiral ones.

Multicomponent crystals of p-coumaric acid and trans-ferulic acid: structures and physicochemical properties

• P -coumaric and trans-ferulic acids co-crystallised with 4,4’-bipyridine and dioxane. • Only p -coumaric acid co-crystallised with pyridine. • Persistence of carboxylic acid homosynthon for dioxane and pyridine compounds. • Formation of heterosynthons for 4,4’-bipyridine co-crystals. • Greater thermal stability of trans-ferulic acid compounds. p -coumaric acid ( p CA) and trans -ferulic acid (TFA) formed multicomponent crystals with 4,4’-bipyridine (BIPY) and 1,4-dioxane (DX). p CA also co-crystallised with pyridine (PYR). The crystal structures, thermal analysis, Hirshfeld surfaces and Fourier transform infrared spectroscopy of the compounds are presented. Both ( p CA)·(BIPY) and (TFA)·(BIPY) displayed the supramolecular heterosynthons, COOH···N pyr and OH···N pyr . The ( p CA)·(DX), (TFA)·(DX) and ( p CA)·(PYR) crystal structures featured the carboxylic acid homosynthon and the (phenol)OH···O/N heterosynthon. The observed supramolecular synthons can be related to the molecular sizes of the co-crystal formers thus allowing for the design of specific supramolecular motifs. Differential scanning calorimetry (DSC) results showed that (TFA)·(BIPY) has a higher thermal stability than ( p CA)·(BIPY) . The thermal stability of the dioxane and pyridine compounds followed the trend, (TFA)·(DX) > ( p CA)·(DX) > ( p CA)·(PYR) . The greater thermal stability of the TFA co-crystals can be related to the presence of the methoxy group which formed an intramolecular hydrogen bond with the hydroxyl group.

A Robust Supramolecular Heterosynthon Assembled by a Hydrogen Bond and a Chalcogen Bond

The 1:1 and 2:1 cocrystals of isophthalic acid and 2,1,3-benzoselenadiazole have been successfully synthesized and resolved; the noncovalent interactions in the crystal structures have been studied in detail by quantum chemical calculations. In both of the crystal structures, isophthalic acid and 2,1,3-benzoselenadiazole are bound together by a cyclic supramolecular heterosynthon assembled by an O–H···N hydrogen bond and a N–Se···O chalcogen bond. The crystal structures of the 1:1 and 2:1 cocrystals of isophthalic acid and 2,1,3-benzoselenadiazole and the crystal structure of pure isophthalic acid are very similar, which indicates that the [COOH]···[Se−N] cyclic heterosynthon can be an effective alternative to the strong [COOH]2 cyclic homosynthon. The quantum theory of atoms in molecules further recognizes the existence of the hydrogen bond and chalcogen bond. The results of quantum chemical calculations show that the strengths of the π···π stacking interactions in the 1:1 cocrystals of isophthalic acid and 2,1,3-benzoselenadiazole are almost the same as those in the 2:1 cocrystals of isophthalic acid and 2,1,3-benzoselenadiazole, and the strengths of the [COOH]···[Se−N] cyclic heterosynthons (about 9.00 kcal/mol) are less than the strengths of the much stronger [COOH]2 cyclic homosynthons (14.00 kcal/mol). These calculated results are in good agreement with those experimentally observed, demonstrating that, although not as strong as the [COOH]2 cyclic homosynthon, the [COOH]···[Se−N] cyclic heterosynthon can also play a key role in the crystal growth and design.

2D cocrystal engineering: switching the robust carboxylic acid–pyridine supramolecular heterosynthon via an oriented external electric field

The response of 2D cocrystals with the carboxylic acid–pyridine supramolecular heterosynthon to the oriented external electric field is identified on solid surfaces.

Assessment of Effects of Solvents on Cocrystallization by Computational Simulation Approach.

The sole purpose of this study is to improve the solubility and dissolution of telmisartan by cocrystallization technique and apply a computational simulation approach to assess the nature of chemical interactions between telmisartan and coformer as well as the solvent contribution to the molecules for furnishing cocrystallization. The effects of various concentrations of coformer i.e. oxalic acid on physicochemical parameters and drug release were investigated. Solubility studies suggested that cocrystallization technique with oxalic acid helps to increase the solubility of pure telmisartan of about 7 folds and drug release study revealed that telmisartan-oxalic acid cocrystals showed greater dissolution as compared to pure telmisartan. SEM study suggested that prepared telmisartan cocrystals showed rhomboid-shaped crystals with sharp edges and smooth surface. FTIR study revealed that shifting in the vibrational frequencies of C=O group of telmisartan in telmisartan- oxalic acid cocrystal indicates the formation of supra molecular hetero synthon of the cocrystal. DSC and XRD studies confirmed the formation of telmisartan-oxalic acid cocrystals. Computational simulation approach revealed that telmisartan and oxalic acid can interact with each other in the presence of methanol and water where oxalic acid can form interactions principally with the others. The interactions, thereof, may form several associations or bondings in between the drug and carrier modifying the planarity, bond energy, bond angles of both which subsequently lead to cocrystallization. So, the present research concluded that prepared telmisartan-oxalic acid cocrystal is a successful application of crystal engineering approach to improve the physicochemical properties as well as to enhance the solubility and dissolution of telmisartan.

Rational design, supramolecular synthesis and solid state characterization of two bicomponent solid forms of mebendazole

MBZ methyl sulfate and perchlorate were designed based on the statistical probability of the formation of an R22(8) supramolecular heterosynthon.

A new supramolecular heterosynthon [C–I⋯OC(carboxylate)] at work: engineering copper acetate cocrystals

Carboxylate–iodine supramolecular heterosynthons in combination with energy frameworks can be reliably applied in engineering hybrid metal-carboxylate cocrystals.

Cocrystals of diacerein: Towards the development of improved biopharmaceutical parameters.

The effectiveness of Diacerein as an anti-osteoarthritis drug is limited due to its acutely poor aqueous solubility and bioavailability. The present study demonstrates cocrystallization as a successful technique to improve the biopharmaceutical parameters of diacerein. Three cocrystals of diacerein were prepared by an eco-friendly technique with three suitable coformers namely isonicotinamide, nicotinamide, and theophylline. The formation of a new solid phase was inferred from the DSC thermograms and powder diffraction pattern and was supported by FTIR. The crystal structures of the cocrystals determined from the PXRD pattern using Material Studio software. Detailed analysis showed the formation of supramolecular hetero-synthons of complementary functional groups of the coformers with the carbonyl and carboxyl groups of diacerein. The structural conformation of the cocrystalline state was also provided by the shifts in the ssNMR pattern of the cocrystals. The three new cocrystals were found to have a relatively high solubility and intrinsic dissolution rate which showed remarkable improvement in anti-arthritic activity as compared to diacerein. Thus, proving cocrystallization to be a potential solution to the solubility limited bioavailability problems of diacerein.

Crystal structures of salts and cocrystal of 1,3,5-triazine derivatives with thiophene carboxylic acid derivatives: an investigation on supramolecular interactions

Present work gives an account of different types of non covalent interactions encountered in the supramolecular architectures of new salts and cocrystal formed between derivatives of 1,3,5-triazine and thiophene carboxylic acid. The novel salts formed between derivatives of thiophene carboxylic acid and 1,3,5-triazine are 2, 4-diamino-6-methyl-1,3,5-triazin-1-ium 5-carboxythiophene-2-carboxylate monohydrate, C4H8N5+·C6H3O4S1−·H2O (I) and 2,4-diamino-6-methyl-1,3,5-triazin-1-ium 3-bromothiophene-2-carboxylate monohydrate, C4H8N5+·C5H2O2S1Br 1 − ·H2O (II). The new cocrystal is a 1:1 cocrystal formed between 2,4-diamine-6-phenyl-1,3,5-triazine and 2,5-dichlorothiophene-3-carboxylic acid, C9H9N5·C5H2O2S1Cl2 (III). The newly synthesized salts (I and II) and cocrystal (III) have been characterized by single-crystal X-ray diffraction. Supramolecular heterosynthons, homosynthons observed via N–H···O, N–H···N and O–H···N hydrogen bonds are also discussed. Anion···π interaction between carboxylate oxygen and aromatic rings of thiophene and triazine are observed in salt (I). π···π interaction is present between thiophene and triazine rings in salt (II). R 2 2 (8) ring motif is formed in cocrystal (III) via N–H···O and O–H···N hydrogen bonds. Further stabilisation of cocrystal (III) via Cl···O, Cl···Cl interactions as well as π···π interactions (triazine···triazine rings and triazine···phenyl rings) are also investigated.

Lamotrigine: Design and synthesis of new multicomponent solid forms

In this work, a crystal engineering and thermodynamic based approach has been used aiming at contributing to a deeper knowledge of lamotrigine multicomponent solid forms. Two types of co-molecules have been chosen that can give rise to co-crystals with lamotrigine through different supramolecular heterosynthons: the xanthines, theophylline and caffeine, and the three isomeric pyridinecarboxamides. Association with diflunisal, which may result in a salt, was also investigated. Mechanochemistry, differential scanning calorimetry, thermogravimetry, X-ray powder and single crystal diffraction, infrared spectroscopy were the methods used. For all the systems, exploratory neat mechanochemistry experiments, carried out on lamotrigine + co-molecule binary mixtures of different compositions, were not successful in promoting association. From differential scanning calorimetry data and the binary solid-liquid phase diagrams, co-crystals/salts were identified as well as their respective stoichiometry, and a methodology of synthesis was established. For pyridinecarboxamides, molecular recognition is dependent on the position of the amide group in the pyridine ring: co-crystallization did not occur with picolinamide co-former. Both xanthines form co-crystals with lamotrigine, (1:1) with theophylline and (2:1) lamotrigine:caffeine. Additionally, the crystalline structure of a lamotrigine:theophylline 1:1 monohydrate was solved. The (1:1) lamotrigine:theophylline co-crystal converts to this monohydrate in accelerated stability tests. A (1:1) lamotrigine:diflunisal salt was identified, which proved to be stable in accelerated stability assays.