Crystal Engineering Approach Research Articles

Designing Metallogelators Derived from NSAID-based Zn(II) Coordination Complexes for Drug-Delivery Applications.

A crystal engineering approach has been invoked to design a new series of eight Zn(II) coordination complexes derived from various non-steroidal anti-inflammatory drugs (NSAIDs), namely diclofenac (DIC), ibuprofen (IBU), naproxen (NAP), flufenamic acid (FLU) and meclofenamic acid (MEC), and two co-ligands, namely N-phenyl-3-pyridylamide (3-Py) and N-phenyl-4-pyridylamide (4-Py), and Zn(NO3 )2 as potential supramolecular gelators. Half of the coordination complexes thus synthesized were able to form aqueous gels (MG-3-PyMEC, MG-3-PyDIC, MG-4-PyNAP and MG-4-PyMEC). Single-crystal structures of all eight complexes revealed that they possessed a gelation-inducing 1D hydrogen-bonded network including amide…amide synthon in some cases, which supported strongly the design principles based on which these complexes were synthesized. Interestingly, one such metallogelator complex, namely 3-PyMEC, showed an intriguing anticancer property against a human breast cancer cell line (MDA-MB-231), as revealed by both MTT and cell migration assays.

Drug-Drug Binary Solids of Nitrofurantoin and Trimethoprim: Crystal Engineering and Pharmaceutical Properties.

With the aim of developing multidrug solids through a tuned crystal engineering approach, we have selected two antiurinary infective drugs, namely, nitrofurantoin (NF) and trimethoprim (TMP) and isolated eight binary drug-drug solid solvates along with a nonsolvated cocrystal. Crystal structure analyses were performed for eight of these solids and rationalized in terms of known supramolecular synthons formed by pyrimidine, imide, and amine functionalities. Notably, the TMP-NF anhydrous cocrystal and its ionic cocrystal hydrate exhibit enhanced equilibrium solubilities compared to pure NF or the simple NF hydrate. Furthermore, the ionic cocrystal hydrate exhibits greater antibacterial activity against the Gram-negative bacteria, E. coli, compared to the parent TMP and NF at the lowest concentration of 3.9 μg/mL. This study indicates initial pathways using the cocrystal methodology that would help to eventually arrive at an antiurinary cocrystal with optimal properties.

Semicoordination Bond Breaking and Halogen Bond Making Change the Supramolecular Architecture of Metal-Containing Aggregates

The complex [Ni(S2COEt)2] (1) and 1,4-diiodotertafluorobenzene (1,4-FIB) or 1,3,5-triiodotrifluorobenzene (1,3,5-FIB) were cocrystallized to form solid adducts 1·2(1,4-FIB) and 1·2(1,3,5-FIB), respectively; the structures of the adducts were studied by X-ray crystallography. The introduction of any one of the FIBs dramatically changed the supramolecular architecture of 1, and the structure-directing interactions changed from predominantly Ni···S semicoordination (in 1) to I···S halogen bonding between an FIB and the electron-donating S atoms of 1 (in the adducts). The semicoordination bond breaking and halogen bond making upon the interaction of 1 with the FIBs make the employed crystal engineering approach relevant (or even similar) to the molecular synthesis of metal species. The DFT study indicates that the strength of both types of interactions in the adducts are comparable (−3.0 to −4.9 kcal/mol and −4.3 to −4.9 kcal/mol) but very different in regard to their physical nature. If the electrostatics determine the I···S halogen bonds, the Ni···S semicoordination bonding is basically dominated by orbital effects.

Development of L-Lysine Amino Acid-Based Co-Crystal of Telmisartan Using Crystal Engineering Approach to Improve Solubility, Dissolution, and Micrometric Properties.

To develop a co-crytsal of Telmisartan for enhancing its solubility in water. Intermolecular interaction happens in crystal packing; it utilizes and helps to understand the design of new solid with their respective chemical and physical properties called crystal engineering. It is a blueprint of molecular solids with specific chemical and physical properties through an understanding and handling of intermolecular interaction for increasing the solubility, in case of poor water-soluble drugs. The study was taken under consideration with an aim to generate and synthesize a cocrystal form of Telmisartan (TEL) with L-lysine to improve its water solubility, dissolution, and micrometric properties. Using dry grinding technique, solvent evaporation and cooling crystallization, the results revealed a generation of co-crystals with enhanced solubility by liquid drop grinding method. Hence, this process was further explored to investigate various formulations and process parameters that could significantly affect the crystal solubility, dissolution, and micrometric properties. The solubility of TEL co-crystals was enhanced by L-lysine. Further, the optimized batch was subjected to its micrometric evaluation and physiochemical characterization like FT-IR, NMR, PXRD. The result of the micrometric evaluation showed better results as compared to standards. The dissolution studies also showed a better dissolution rate for TEL co-crystal tablets than TEL tablets formulation. Co-crystals of TEL with L-lysine showed better solubility and dissolution rate.

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.

Systematic Design of a Low-Molecular-Weight Gelator and Its Application in the Sensing and Retention of Residual Antibiotics

This work presents step-wise design and synthesis of a set of amide-based compounds, L1 – L3, assisted with the crystal engineering approach. Out of three compounds, L3 suc-cessfully acted as the L...

Fabrication of high efficiency, low-temperature planar perovskite solar cells via scalable double-step crystal engineering deposition method fully out of glove box

Halide perovskite solar cells designed using planar architectures are rapidly becoming of high interest due to their low-temperature fabrication process. As the Electron Selective Layer, SnO2 can enhance charge transfer from perovskite to electron transport layers leading to the reduction of charge accumulation at the interface exploiting the larger band offset with perovskite and a higher electron mobility compared with traditional TiO2. Herein, we developed a method for the fabrication of low-temperature planar PSCs under ambient conditions. The scalable Crystal Engineering approach was successfully applied to fabricate the CH3NH3PbI3 absorbing layer on low-temperature planar SnO2 under atmospheric conditions (fully out of glove-box). Photovoltaic characterization showed high-reproducible hysteresis-free planar perovskite solar cells with a maximum power conversion efficiency of 17.6%. The photophysical properties of the PSCs, evaluated by transient photovoltage and photocurrent analysis, showed the excellent capability of SnO2 to extract charge for perovskite. Non-encapsulated n-i-p planar solar cells indicated promising stability under atmospheric conditions, maintaining 90% of the initial efficiency for more than 1000 h. We demonstrate that the scalable air insensitive crystal engineering method is a promising approach for industrialization and fabrication of high efficiency, air-stable, and low-temperature planar perovskite solar cells with high reproducibility fabrication.

Structural and Functional Characterization of Phosphatidylinositol-Phosphate Biosynthesis in Mycobacteria

In mycobacteria, phosphatidylinositol (PI) acts as a common lipid anchor for key components of the cell wall, including the glycolipids phosphatidylinositol mannoside, lipomannan, and lipoarabinomannan. Glycolipids in Mycobacterium tuberculosis, the causative agent of tuberculosis, are important virulence factors that modulate the host immune response. The identity-defining step in PI biosynthesis in prokaryotes, unique to mycobacteria and few other bacterial species, is the reaction between cytidine diphosphate–diacylglycerol and inositol-phosphate to yield phosphatidylinositol-phosphate, the immediate precursor to PI. This reaction is catalyzed by the cytidine diphosphate–alcohol phosphotransferase phosphatidylinositol-phosphate synthase (PIPS), an essential enzyme for mycobacterial viability. Here we present structures of PIPS from Mycobacterium kansasii with and without evidence of donor and acceptor substrate binding obtained using a crystal engineering approach. PIPS from Mycobacterium kansasii is 86% identical to the ortholog from M. tuberculosis and catalytically active. Functional experiments guided by our structural results allowed us to further characterize the molecular determinants of substrate specificity and catalysis in a new mycobacterial species. This work provides a framework to strengthen our understanding of phosphatidylinositol-phosphate biosynthesis in the context of mycobacterial pathogens.

Improving thermal efficiency of hydrate-based heat engine generating renewable energy from low-grade heat sources using a crystal engineering approach

The development of the eco-friendly technology generating energy will be a gradual requirement all over the world to replace thermal power releasing CO2 and nuclear power for which the wastes are disposed of with great difficultly. The hydrate-heat engine is a new cycle obtaining mechanical work from temperature differences that normally cannot generate energy, for example, heat differences between the top and bottom seawater. Although the hydrate cycle is a more sustainable power generation system than typically used Rankine cycle from the aspect of using environmental harmless working media, this new cycle has an issue as the low thermal efficiency. To increase the thermal efficiency, the performance of the hydrate-based heat engine utilizing structure II and H hydrates is theoretically evaluated for various models of low-grade heat sources. The results showed that the structure II and H hydrates formed by adding large guest molecule compounds to a second small guest gas system were effective in improving thermal efficiency. Especially, the double hydrate with Kr and cyclopentane enable the hydrate cycle to perform as efficiently as Rankine cycle, having the thermal efficiency around 3.0%, for the ocean thermal energy conversion in the temperature range from 282 K to 293 K.

Mechanical Flexibility of Molecular Crystals Achieved by Exchanging Hydrogen Bonding Synthons

Tuning the mechanical properties of crystalline materials is alluring and has captivated the interest of material scientists. Here, we have demonstrated a crystal engineering approach to introduce ...

Formation of Diacerein − fumaric acid eutectic as a multi-component system for the functionality enhancement

The present study aimed to enhance physico-mechanical properties of poorly soluble drug Diacerein (DIA) using crystal engineering approach. Fumaric acid (FMA) was competent enough to generate a novel solid form of DIA by acetone assisted grinding method and was fully characterized. A lower melting depression and maximum enthalpy of fusion resulted from phase diagram and Tammann's triangle of binary system revealed the formation of eutectic mixture with molar ratio of 1: 2 (DIA: FMA). It was further confirmed by PXRD and FT-IR spectra. The topographical differences were observed in case of eutectic by SEM analysis imparting its better flow and packability. Pharmaceutical behaviors in terms of solubility, dissolution, tabletability, compressibility and stability suggested superior functionality of eutectic compared to DIA alone. Pharmacokinetic study of eutectic demonstrated 1.77 times greater bioavailability. Thus, the concept of crystal engineering was successful to prepare DIA-FMA eutectic as a potential way for improving material functionality.

Solution-based heteroepitaxial growth of stable mixed cation/anion hybrid perovskite thin film under ambient condition via a scalable crystal engineering approach

The performance of perovskite solar cells is under direct control of the perovskite film quality and controlling the crystalinity and orientation of solution-processed perovskite film is a fundamental challenge. In this study, we present a scalable fabrication process for heteroepitaxial growth of mixed-cation hybrid perovskites (FA1-x-yMAxCsy)Pb(I1-xBrx)3 in ambient atmospheric condition by using a Crystal Engineering (CE) approach. Smooth and mesoporous thin film of pure crystalline intermediate phase of PbX2.2DMSO is formed by deposition of supersaturated lead/cesium halides solution. Kinetically fast perovskite nucleation is achieved by rapid intercalation of formamidinium iodide (FAI) and methylammonium bromide (MABr) into the intermediate layer trough solvent assisted SN1 ligand exchange. Finally, heteroepitaxially perovskite growth is accomplished via Volmer−Weber crystal growth mechanism. All the layers are deposited under atmospheric condition (relative humidity (RH) 50–75%) with high reproducibility for various device and module dimensions. In particular, perovskite solar modules (Pmax ~550 mW) are successfully fabricated by blade coating under atmospheric condition. The CE approach remarkably improves the device performance by reaching a power conversion efficiency of 18.4% for small area (0.1 cm2), 16.5% on larger area (1 cm2) devices, and 12.7% and 11.6% for blade-coated modules with an active area of 17 and 50 cm2, respectively. Non-encapsulated triple cation solar cells and modules show promising stability under atmospheric shelf life and light soaking conditions.

Improvement in Pharmacokinetic Parameters of Ibuprofen by Crystal Engineering Approach

Improvement in Pharmacokinetic Parameters of Ibuprofen by Crystal Engineering Approach

A preformulation co-crystal screening case study: Polymorphic co-crystals of an imidazopyridazine antimalarial drug lead with the coformer succinic acid

A crystal engineering approach combined with experimental screening methods was employed as a preformulation step for producing expectedly useful forms of a novel antimalarial drug lead (MMV652103). In previous experiments, this drug lead had shown promise both in vitro and in vivo against the human malaria parasite Plasmodium falciparum. Various new forms of MMV652103 were produced earlier, including co-crystals, a salt, polymorphs and a hydrated form and these were reported elsewhere. Three distinct new forms are reported here, of which two are conformational and synthon (2:1) co-crystal polymorphs produced with the coformer succinic acid, while the third is a co-crystal with a different stoichiometric ratio (1:1) of the same components. The crystal structures of the co-crystal polymorphs were elucidated by single-crystal X-ray diffraction. The different forms were also characterised by powder X-ray diffraction, Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, hot stage microscopy, differential thermal analysis, differential scanning calorimetry, thermogravimetric analysis and in some cases variable-temperature powder X-ray diffraction. It was determined that the polymorphs are monotropically related. Methods were developed to prepare each of these forms reproducibly and rapidly identify each form.

Implication of Coformer Structural Diversity on Cocrystallization Outcomes of Telmisartan with Improved Biopharmaceutical Performance.

Crystal engineering approach was utilized for the development of different multicomponent solid forms of telmisartan (TEL) to improve its oral bioavailability. In this context, two cocrystals, gentisic acid (GA) and maleic acid (MA), while two eutectic mixtures, para-aminobenzoic acid (PABA) and adipic acid (AA), were successfully prepared and characterized by different analytical tools. Both the cocrystals exhibited characteristic heterosynthons, viz. OHacid⋯Narom and OHacid⋯O, to propagate new network. Structural features of coformers has been correlated with the outcomes of cocrystallization approach. Coformers having auxiliary functionality in addition to complementary functional groups have high propensity to generate cocrystals. However, multicomponent where auxiliary functionality is lacking, such combinations, is shown to form eutectic mixtures owing to strong homomeric interaction. Besides, the developed cocrystals and eutectic mixtures showed higher aqueous solubility (3-5.5-fold) and intrinsic dissolution rate (1-2.6-fold) over pure TEL. In vivo studies also revealed significant improvement in relative bioavailability (2-2.6-fold). The study also shed light on the implications of eutectic mixtures in mitigating the solubility issues of drugs which are often considered negative results of cocrystallization strategy.

N-(thiazol-2-yl)benzamide derivatives as a new series of supramolecular gelators: Role of methyl functionality and S⋯O interaction

A new series of N-(thiazol-2-yl) benzamide derivatives were synthesized, characterized and investigated for their gelation behavior with the aim to elucidate the role of methyl functionality and multiple non-covalent interactions on gelation/non-gelation behavior using Crystal engineering approach. Interestingly, two amides, namely, 3-methyl-N-(thiazol-2-yl) benzamide (1c) and 3-methyl-N-(5-methylthiazol-2-yl) benzamide (3c) displayed gelation behavior towards ethanol/water and methanol/water mixture with good stability and low minimum gelator concentration (MGC). The single crystal structure of gelator (1c) displayed the helical assembly driven by π-π interaction along with cyclic N–H⋯N and S⋯O interaction, whereas single crystal structure of gelator (3c) displayed 2D hydrogen bonded network without any π-π interaction.

New Insights into Photochromic Properties of N-Salicylideneaniline Derivatives Using a Cocrystal Engineering Approach

In this contribution, we aim to modify the photochromic properties of anils using a crystal engineering approach. Previous work has shown cocrystallization to alter the photochromic behavior of anils. Here, a full screening of 15 anil derivatives (including 8 newly described anils) with 21 coformers (carboxylic acids, amides, and halogenated benzene derivatives) was performed, resulting in 89 new anil cocrystals. This large amount of results allows drawing statistically valid insights on the complex photochromic mechanism providing evidence of a continuous phenomenon instead of the classic binary photochromic/nonphotochromic one. This is supported by the discovery of “weakly photochromic compounds” presented in this contribution. All the results allowed confirming that an enol-imine character is a requirement and that reducing the amount of short contacts involving the moieties of interest is an interesting way to fine-tune properties as this acts on both electronic and structural aspects. Following this “continuous hypothesis”, the role of the dihedral angle has been explored and shown to be related to the intensity of photochromism instead of being determinant for its occurrence. In addition, in this contribution, we present a novel way of interpreting DRS (diffuse reflectance spectroscopy) data.

Multicomponent solid forms of the uric acid reabsorption inhibitor lesinurad and cocrystal polymorphs with urea: DFT simulation and solubility study.

Lesinurad (systematic name: 2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid, C17H14BrN3O2S) is a selective uric acid reabsorption inhibitor related to gout, which exhibits poor aqueous solubility. High-throughput solid-form screening was performed to screen for new solid forms with improved pharmaceutically relevant properties. During polymorph screening, we obtained two solvates with methanol (CH3OH) and ethanol (C2H5OH). Binary systems with caffeine (systematic name: 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, C8H10N4O2) and nicotinamide (C6H6N2O), polymorphs with urea (CH4N2O) and eutectics with similar drugs, like allopurinol and febuxostat, were prepared using the crystal engineering approach. All these novel solid forms were confirmed by XRD, DSC and FT-IR. The crystal structures were solved by single-crystal and powder X-ray diffraction. The crystal structures indicate that the lesinurad molecule is highly flexible and the triazole moiety, along with the rotatable thioacetic acid (side chain) and cyclopropane ring, is almost perpendicular to the planar naphthalene moiety. The carboxylic acid-triazole heterosynthon in the drug is interrupted by the presence of methanol and ethanol molecules in their crystal structures and forms intermolecular macrocyclic rings. The caffeine cocrystal maintains the consistency of the acid-triazole heterosynthons as in the drug and, in addition, they are bound by several auxiliary interactions. In the binary system of nicotinamide and urea, the acid-triazole heterosynthon is replaced by an acid-amide synthon. Among the urea cocrystal polymorphs, Form I (P-1, 1:1) consists of an acid-amide (urea) heterodimer, whereas in Form II (P21/c, 2:2), both acid-amide heterosynthons and urea-urea dimers co-exist. Density functional theory (DFT) calculations further support the experimentally observed synthon hierarchies in the cocrystals. Aqueous solubility experiments of lesinurad and its binary solids in pH 5 acetate buffer medium indicate the apparent solubility order lesinurad-urea Form I (43-fold) > lesinurad-caffeine (20-fold) > lesinurad-allopurinol (12-fold) ≃ lesinurad-nicotinamide (11-fold) > lesinurad, and this order is correlated with the crystal structures.

A de novo strategy for predictive crystal engineering to tune excitonic coupling

In molecular solids, the intense photoluminescence (PL) observed for solvated dye molecules is often suppressed by nonradiative decay processes introduced by excitonic coupling to adjacent chromophores. We have developed a strategy to avoid this undesirable PL quenching by optimizing the chromophore packing. We integrated the photoactive compounds into metal-organic frameworks (MOFs) and tuned the molecular alignment by introducing adjustable “steric control units” (SCUs). We determined the optimal alignment of core-substituted naphthalenediimides (cNDIs) to yield highly emissive J-aggregates by a computational analysis. Then, we created a large library of handle-equipped MOF chromophoric linkers and computationally screened for the best SCUs. A thorough photophysical characterization confirmed the formation of J-aggregates with bright green emission, with unprecedented photoluminescent quantum yields for crystalline NDI-based materials. This data demonstrates the viability of MOF-based crystal engineering approaches that can be universally applied to tailor the photophysical properties of organic semiconductor materials.

Spherical Cocrystallization—An Enabling Technology for the Development of High Dose Direct Compression Tablets of Poorly Soluble Drugs

Spherical cocrystallization (SCC), an integrated crystal and particle engineering approach, was successfully applied to generate spherical cocrystal agglomerates (SCA) between a poorly soluble drug...