Crystal Packing Arrangement Research Articles

An integrated approach combining experimental, informatics and energetic methods for solid form derisking of PF-06282999

The landscapes of observed and predicted three-dimensional crystal packing arrangements of small-molecule drug candidates can be complex. The possible appearance of a more thermodynamically stable solid form during drug development has led to the digital workflow of informatics-based risk assessments, named a Solid Form Health Check. Herein, we describe the use of a combined approach consisting of experiments, informatics together with energetic calculations in analysis of four competing polymorphs of PF-06282999, a myeloperoxidase (MPO) inhibitor with conformational flexibility and multiple plausible hydrogen bond networks. This combined approach offered a comprehensive understanding of the solid form structure, properties, and performance, ensuring robust solid form derisking and selection.

Coumarin-Phosphazenes: Enhanced Photophysical Properties from Hybrid Materials.

Phosphazenes have drawn a great deal of interest over the past 20 years as a potentially useful building block for the fabrication of fluorescent materials. The main objective of this work is to explore novel derivatives produced by coumarins, a class of chemicals well-known for their photophysical importance, and cyclophosphazenes. UV absorbance, fluorescence emission, quantum yield, and lifetime measurements were conducted to comprehend the optical properties. Furthermore, single-crystal X-ray analysis and theoretical calculations were carried out to confirm the structure of the molecule. The obtained findings collectively confirm the commendable optical properties exhibited by the studied compounds. Moreover, a detailed study of the crystal packing arrangement of DPP-Et-Kum-Et compound crystallized in the P21/n monoclinic space group revealed the presence of stacking interactions between the nonplanar conjugated benzene rings of the coumarins and the rigid diphenyl groups attached to the phosphazene ring. The crystal structure of the DPP-Kum-Me-Me compound is mainly based on classical C-H···O intermolecular hydrogen bonding interactions with an average distance of 2.52 Å. Importantly, the calculated absorption spectra of the compounds are in close agreement with the experimental data, further supporting their interesting electronic properties. Given that the DPP-Et-Kum-Et and DPP-Kum-Et compounds have the theoretically lowest band gaps (4.31 and 4.30 eV, respectively), the activation energies of these compounds were determined by an impedance analyzer using dc conductance values measured at different temperatures. The calculated activation energies for DPP-Et-Kum-Et and DPP-Kum-Et are 104.49 and 100.92 meV, respectively. The results demonstrate that both theoretical and experimental calculations are in agreement with each other and that the DPP-Kum-Et compound has the lowest conductivity.

Insights on molecular modeling and supramolecular arrangement of bilastine polymorphs.

The advancement in the development of second-generation drugs in the field of antihistamines represents a significant milestone in the management of allergic diseases, targeting the effects of histamine. The efficacy of bilastine in treating allergic disorders has sparked interest in investigating its polymorphism, a crucial property that impacts quality, safety, and effectiveness as per regulatory guidelines. This study examines the polymorphism of bilastine, focusing on two crystalline forms labeled as Form I and Form II. Utilizing advanced analytical techniques, the research explores the structural characteristics and molecular interactions within these forms. Geometric parameters, such as bond lengths, bond angles, and torsion angles, are examined to comprehend molecular conformations and crystal packing arrangements. Hydrogen bonding, covalent bonds, and van der Waals forces contribute to the unique supramolecular arrangements in these forms.This study provides a significant contribution to understanding bilastine's polymorphism, offering critical insights to researchers and regulatory bodies to ensure the quality, efficacy, and safety of antihistamine products. The molecular conformation of two bilastine forms was obtained through DFT with the exchange-correlation functional M06-2X and the 6-311 + + G(d,p) basis set, and the results were compared with the experimental X-ray. The atomic coordinates were obtained directly from the crystalline structures, and charge transfer was also investigated using frontier molecular orbitals (HOMO and LUMO), and MEP map in order to evaluate the energies associated with charge transfers and regions of high electron affinity. The geometric and topological parameters and intermolecular interactions in the crystals were analyzed using Hirshfeld Surface.

Crystal Polymorph Search in the NPT Ensemble via a Deposition/Sublimation Alchemical Path.

The formulation of active pharmaceutical ingredients involves discovering stable crystal packing arrangements or polymorphs, each of which has distinct pharmaceutically relevant properties. Traditional experimental screening techniques utilizing various conditions are commonly supplemented with in silico crystal structure prediction (CSP) to inform the crystallization process and mitigate risk. Predictions are often based on advanced classical force fields or quantum mechanical calculations that model the crystal potential energy landscape but do not fully incorporate temperature, pressure, or solution conditions during the search procedure. This study proposes an innovative alchemical path that utilizes an advanced polarizable atomic multipole force field to predict crystal structures based on direct sampling of the NPT ensemble. The use of alchemical (i.e., nonphysical) intermediates, a novel Monte Carlo barostat, and an orthogonal space tempering bias combine to enhance the sampling efficiency of the deposition/sublimation phase transition. The proposed algorithm was applied to 2-((4-(2-(3,4-dichlorophenyl)ethyl)phenyl)amino)benzoic acid (Cambridge Crystallography Database Centre ID: XAFPAY) as a case study to showcase the algorithm. Each experimentally determined polymorph with one molecule in the asymmetric unit was successfully reproduced via approximately 1000 short 1 ns simulations per space group where each simulation was initiated from random rigid body coordinates and unit cell parameters. Utilizing two threads of a recent Intel CPU (a Xeon Gold 6330 CPU at 2.00 GHz), 1 ns of sampling using the polarizable AMOEBA force field can be acquired in 4 h (equating to more than 300 ns/day using all 112 threads/56 cores of a dual CPU node) within the Force Field X software (https://ffx.biochem.uiowa.edu). These results demonstrate a step forward in the rigorous use of the NPT ensemble during the CSP search process and open the door to future algorithms that incorporate solution conditions using continuum solvation methods.

X-ray diffraction, structural analysis, quantum reactivity studies, molecular interactions, spectroscopic insights and antiepileptic activities of [Cu(C7N4H8O2)2(NO3)(H2O)2]NO3 hybrid material by molecular docking

Epilepsy is a neurological disorder which is attributed to unprovoked recurrent seizures. It is a dangerous disease that affects men, women and children of all ages. This present investigation aims to uncover new opportunities for designing potential drugs for epilepsy treatment. To achieve this goal, the synthesized [Cu(C7N4H8O2)2(NO3)(H2O)2]NO3, [Cu(Tphyl)2(H2O)2(NO3)]NO3, with Tphyl = Theophylline, material was experimentally and theoretically employed within the framework of density functional theory (DFT) computation. The Hirshfeld surface analysis, combined with the fingerprint plot, is widely employed to understand the interactions within the crystal packing of the [Cu(Tphyl)2(H2O)2(NO3)]NO3 complex. The analysis unveils the presence of intermolecular hydrogen bonds (O-H...O) and intramolecular hydrogen bonds (C-H...O and C-H...N) in the crystal packing arrangements. While the fingerprint plots reveal various types of interactions and their relative prevalence within the complex, butclearly show that O...H 25.2%, H...O 22.2%, and H...H 20.8% interactions are the predominant forces within the complex. The molecular docking result reveal five conventional hydrogen bonds with best binding pose of -4.1 kcal/mol and -4.8 kcal/mol for 5y30 and 5y2z proteins when docked with [Cu(Tphyl)2(H2O)2(NO3)]NO3 ligand. Therefore, we can conclude that if the [Cu(Tphyl)2(H2O)2(NO3)]NO3 ligand is employed as an antiepileptic drug, it would likely be more effective than the conventional drug. Hence, [Cu(Tphyl)2(H2O)2(NO3)]NO3–5y2z and [Cu(Tphyl)2(H2O)2(NO3)]NO3–5y31 are recommended as potential therapeutic candidates for antiepileptic treatment.

1D and 2D Coordination Polymers of Calcium with Nonsteroidal Anti-Inflammatory Drugs: Synthesis, Crystal Structures, Hirshfeld Surfaces, Antimicrobial and Antioxidant Activities.

Four alkaline earth metal complexes of ketoprofen (Hket) and indomethacin (Hind) were synthesized and characterized: [Ca(ket)2(H2O)2]n (1), [Mg(ket)2(H2O)2] (2), [Ca(ind)2(EtOH)2]n (3), and [Mg(ind)2(EtOH)2] (4). All compounds were studied by elemental analysis (EA), flame atomic absorption spectrometry (FAAS), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). Crystal structures of 1 and 3 were determined by single crystal X-ray diffraction technique T=100 K. The structure of 1 is dominated by a one-dimensional coordination polymer, while 3 is formed by a two-dimensional layer stabilized by the calcium zig-zag chains and π⋅⋅⋅π stacking interactions. Crystal packing arrangements were characterized by fingerprint plots (FPs) that were derived from the Hirshfeld surfaces (HSs). The antioxidant and antimicrobial activities of complexes were evaluated against Gram-positive and Gram-negative bacteria as well as yeasts.

Synthesis and characterization of a new copper-based polyoxomolybdate and its catalytic activity for azide-alkyne cycloaddition reaction under UV light irradiation

A new organic-functionalized Cu-based Anderson-type polyoxomolybdate, namely (C7H15N4)2[Na(H2O)4]2[C6H12CuMo6N2O24]·2(H2O) (CuII-POM), was synthesized via a simple one-pot reaction and subsequently characterized using a range of analytical and spectral techniques. Structural investigation by single crystal X-ray diffraction analysis revealed that the polyanion component of the synthesized compound (i.e. [C6H12CuMo6N2O24]4−) possesses a δ-isomer Anderson-type structure, which is surrounded by four lattice water molecules and four [C7H15N4–NaH15(H2O)8]4+ cations in the crystal packing arrangement. The resulting double-sided tris-functionalized Anderson-type compound can function as highly effective heterogeneous photocatalysts for the copper(I)-catalyzed Huisgen azide-alkyne cycloaddition (Cu-AAC) reaction of terminal alkyne, benzyl halides, and sodium azide (acts as the azidonation and reducing agent) in aqueous media. Ultraviolet light irradiation enhances the catalytic activity of CuII-POM ~ 4.4 times of the “off” situation under reaction conditions of 0.00239 mmol cat., 80 °C, 8 h, 2 mL H2O, So that the isolated yields for the AAC reaction involving a variety of terminal alkynes and benzyl halides using the CuII-POM catalyst ranged between 19–97%. The current study is the first report about using an efficient and economical Cu(II)-POM/UV/NaN3 catalytic system in the Cu-AAC reaction and reveals its significant potential for applying to other Cu(I)-catalyzed reactions.

Theoretical investigations of the substituent effect on the opto-electronic properties of the linearly fused napthadithiophene-based molecules.

The optoelectronic and charge transport properties of eight linearly fused Napthadithiophene (NDT) molecules with different electron-withdrawing (EWG) and electron-donating (EDG) substituents are studied using the density functional theory (DFT) methods. The effect of the substitution of EWG and EDG on the molecular structure, frontier molecular orbitals, ionization energy, electron affinity, reorganization energy, crystal packing, and charge carrier mobility are studied. The crystal structure simulation method is used to optimize the possible crystal packing arrangements for the studied molecules. The energy and distribution of electron density on the frontier molecular orbitals are strongly influenced by the substitution of EWG and EDG, thereby changes in the absorption spectrum and charge transport properties. The unsubstituted NDT molecule possesses a maximum hole mobility of 2.8 cm2 V-1 s-1, which is due to the strong intermolecular interactions. Therefore, the NDT molecule can be used as a p-type semiconducting material. Among the studied molecules, the CCH-substituted NDT molecule, NDT-CCH, possesses a higher electron mobility of 1.13 cm2 V-1 s-1. The C2H5-substituted NDT molecule, NDT-C2H5, possesses ambipolar behavior with mobility of 4.77 × 10-2 cm2 V-1 s-1 and 1.70 × 10-2 cm2 V-1 s-1 for hole and electron, respectively.

Spin crossover of a Fe(II) mononuclear complex induced by intermolecular factors involving chloride and solvent ordering.

Two new salts of a mononuclear tripodal Fe(II) complex were prepared, using ClO4- and Cl-. The ClO4- sample (1) remained HS at low temperatures, similar to the previously reported BF4- analogue. Crystallising with the Cl- anion (2) led to a markedly different crystal packing arrangement, and engendered SCO activity. This has been correlated to the lower crystal packing density in 2 and the coordination complex conformational differences arising due to the packing motifs of 1 and 2. Further, solvent ordering effects have been proposed to facilitate spin transition behaviour in 2.

What is isostructurality? Questions on the definition.

Investigation of isostructurality leads to a deeper understanding of close-packing principles and contributes to the ability of crystal engineering. A given packing motif may tolerate small molecular changes within a limit. Slight alterations of a crystal packing arrangement are carried out in order to fine-tune the structural and macroscopic properties, keeping the balance of the spatial requirements and electrostatic effects of the altered molecules in the crystals, preserving their isostructurality. Even so, the definition of isostructurality is not explicit about several issues. Are the corresponding structures required to have the same stoichiometry, Z', symmetry elements and the same space group? Because it is not obvious in the definition, studies on structure analysis and software calculating various numerical descriptors developed for the quantitative comparison of the degree of similarity of isostructural crystals self-define their criteria. The extent of the difference between corresponding crystal structures referred to as isostructural is not limited. Should it be determined numerically? There is nothing in the definition about a demand for similar supramolecular arrangements in isostructural crystals. Should the similarity of supramolecular interactions be a criterion of isostructurality? The definition of isostructurality deserves reconsideration regarding symmetry, measure of similarity and formation of supramolecular interactions.

3D Ag(I) coordination polymer sandwiched by water-muconate anionic layers: Synthesis, structure, Hirshfeld surface analysis, binding with BSA, and photocatalytic activity

The sonochemical reaction between silver salt, 1,3-bis(4-pyridylpropane (bpp) and trans,trans-muconic acid (H2muc) formed an Ag(I) coordination polymer with a 3D supramolecular sandwich architecture, {[Ag8(bpp)8(H2O)3].(muc)4.29(H2O)}n, (1) consisting of the silver-bpp cationic host that alternates with 2D water–muc guest anionic layers. The latter is formed by H-bonded water molecules-anions comprising hexagonal (H2O)6 clusters. The Hirshfeld surface and fingerprint plots have been used to quantify the weak intermolecular interactions in the crystal packing arrangement. The study showed that intermolecular hydrogen bonds are the most critical in constructing the titled supramolecular complex, accounting for 51.2% of the total Hirshfeld surface. Several spectrofluorimetric methods have been employed to investigate the binding interaction between Bovine Serum Albumin (BSA) and the titled complex. The complex induced significant fluorescence quenching of BSA, indicating a strong binding affinity for the protein. Static or ground state complex formation was envisaged as the primary quenching mechanism when the complex interacts with BSA. In addition, the Ag compound also offers photocatalytic properties by degrading the toxic organic methylene blue dye.

Charge Transfer and Optical Characteristics of cyclopenta-diene based Oligomers

1,4-bis(2-(cyclopenta-1,3-dien-1-yl)ethyl)cyclopenta-1,3-diene [CCD] is one of the interesting oligomer with high charge carrier mobility and chemical stability. Based on the density functional theory (DFT), the electronic characteristics of four CCD molecules with various hetero atom substituents are investigated. The electronic of four CCD molecules with different hetero atom substituents are explored based on the density functional theory (DFT). The effects of substituents on the molecular structure, molecular orbitals, ionization energies, electron affinities, reorganization energy and crystal packing are analysed in detail to clarify the structure-property relationship of the studied molecules. The different crystal packing arrangements and intermolecular interactions of the studied molecules lead to differences in transfer integrals when introducing different substituents to the CCD molecule.

Revealing intermolecular coupling effects on vibrational spectra with infrared-reflectance absorbance analysis of perylene diimide thin films

Intermolecular interactions govern the optical and electronic properties of organic semiconductor thin films. Optimizing the function of molecular devices such as organic solar cells and light emitting diodes relies on understanding structural effects in a heterogeneous film environment. Because organic thin films are typically more disordered than inorganic crystalline semiconductors, advanced techniques are often needed to sufficiently characterize these materials. However, polarized infrared reflectance measurements are a benchtop method that can provide well-resolved vibrational spectra with specificity in their molecular orientation. By using infrared reflectance-absorbance spectroscopy (IRRAS) we relate the effects of intermolecular packing geometry on thin film vibrational spectra of perylene diimide (PDI), a prototypical molecular semiconductor. We analyze a suite of PDIs with differing sidechain substitutions, which adopt distinct crystal packing arrangements in thin films, by comparison of the reflectance spectra to isotropic KBr mixtures. We observe differences in the degree of Davydov splitting as a function of displacement along the short and long molecular axes and the π-π stacking distance that are evident in either the symmetric or anti-symmetric CO stretching frequencies of the solid. The four PDIs also display changes in relative intensity between the two modes that indicate different average molecular orientations.

Pore topology analysis in porous molecular systems.

Porous molecular materials are constructed from molecules that assemble in the solid-state such that there are cavities or an interconnected pore network. It is challenging to control the assembly of these systems, as the interactions between the molecules are generally weak, and subtle changes in the molecular structure can lead to vastly different intermolecular interactions and subsequently different crystal packing arrangements. Similarly, the use of different solvents for crystallization, or the introduction of solvent vapour, can result in different polymorphs and pore networks being formed. It is difficult to uniquely describe the pore networks formed, and thus we analyse 1033 crystal structures of porous molecular systems to determine the underlying topology of their void spaces and potential guest diffusion networks. Material-agnostic topology definitions are applied. We use the underlying topological nets to examine whether it is possible to apply isoreticular design principles to porous molecular materials. Overall, our automatic analysis of a large dataset gives a general insight into the relationships between molecular topologies and the topological nets of their pore network. We show that while porous molecular systems tend to pack similarly to non-porous molecules, the topologies of their pore distributions resemble those of more prominent porous materials, such as metal-organic frameworks and covalent organic frameworks.

One-dimensional stacking array of 10,20-diphenyl-5,15-diazaporphyrin metal complexes

We prepared a free-base 10,20-diphenyl-5,15-diazaporphyrin and its Ni(II), Cu(II), Pd(II), and Pt(II) complexes. These molecules uniformly form an infinite one-dimensional [Formula: see text]-stacking array in the solid state. The four-fold intermolecular hydrogen bonding interactions between the meso-nitrogen atom of the diazaporphyrin core and the ortho-hydrogen atom of the phenyl substituent dominate the crystal packing arrangement. The present study revealed that the meso-nitrogen atom of diazaporphyrins would be used as an inherent hydrogen bonding acceptor to construct supramolecular assemblies.

Supramolecular assemblies in the molecular complexes of 4-cyanophenylboronic acid with different N-donor ligands.

Molecular complexes of 4-cyanophenylboronic acid (CB) with various N-donor compounds having different conformational features, for example, rigid (1,10-phenanthroline (110phen), 4,7-phenanthroline (47phen), 1,7-phenanthroline (17phen) and acridine (acr)) and linear (1,2-bis(4-pyridyl)ethane (bpyea), 1,2-bis(4-pyridyl)ethene (bpyee) and 4,4'-azopyridine (azopy)), have been reported. In all complexes, the -B(OH)2 moiety is found to be in a syn-anti confirmation, with the exception of structures containing 110phen, bpyee, and azopy, wherein, syn-syn conformation is observed. Further, CB molecules remain intact in all structures except in the complexes with some linear N-donor ligands, wherein -B(OH)2 transforms to monoester (-B(OH)(OCH3)) prior to the formation of corresponding molecular complexes. In such boronic monoester complexes, the conformation of -B(OH)(OCH3) is syn-anti with respect to the -OH and -OCH3 groups. Also, complexes mediated by azopy and bpyee exist in both hydrated and anhydrous forms. In these anhydrous structures, the recognition pattern is through homomeric (juxtaposed -CN and -B(OH)2) as well as heteromeric (between hetero N-atom and -B(OH)2) O-H⋯N hydrogen bonds, while only heteromeric O-H⋯N hydrogen bonds hold co-formers in all other structures. Depending upon the conformational features of both co-formers, molecules are packed in crystal lattices in the form of stacked layers, helical chains, and crossed ribbons. All structures are fully characterized by single-crystal X-ray diffraction and phase purity is established by powder X-ray diffraction. Additionally, correlation among structures is explained by calculating a similarity index and performing a Hirshfeld surface analysis to quantify the strength and effectiveness of different types of intermolecular bonds that stabilize these structures along with the presentation of energy frameworks, representing the strength of the interactions in the form gradient cylinders. Also, the morphology of each complex was computed by BFDH methodology to correlate with the actual crystal morphology and packing arrangement.

Highly soluble Ni(II) dithienylnorcorrole

Recently, norcorrole Ni(II) complexes have received much attention because they exhibit peculiar solid-state structures and fascinating electronic properties originating from their distinct antiaromatic character. In this work, we have prepared a norcorrole Ni(II) complex with 5-hexylthien-2-yl substituents at the meso-positions, of which the antiaromatic nature was evaluated by 1H NMR analysis as well as NICS and ACID calculations. The X-ray diffraction analysis elucidated its molecular structure and crystal packing arrangement. Crystal packing structures of Ni(II) meso-di(5-methylthien-2-yl)norcorrole and Ni(II) meso-di(5-hexylthien-2-yl)norcorrole were markedly different. The latter provided a polar crystal because of the unidirectional alignment of 5-hexylthien-2-yl groups in the solid state.

Formulation Strategies to Improve the Stability and Handling of Oral Solid Dosage Forms of Highly Hygroscopic Pharmaceuticals and Nutraceuticals.

Highly hygroscopic pharmaceutical and nutraceutical solids are prone to significant changes in their physicochemical properties due to chemical degradation and/or solid-state transition, resulting in adverse effects on their therapeutic performances and shelf life. Moisture absorption also leads to excessive wetting of the solids, causing their difficult handling during manufacturing. In this review, four formulation strategies that have been employed to tackle hygroscopicity issues in oral solid dosage forms of pharmaceuticals/nutraceuticals were discussed. The four strategies are (1) film coating, (2) encapsulation by spray drying or coacervation, (3) co-processing with excipients, and (4) crystal engineering by co-crystallization. Film coating and encapsulation work by acting as barriers between the hygroscopic active ingredients in the core and the environment, whereas co-processing with excipients works mainly by adding excipients that deflect moisture away from the active ingredients. Co-crystallization works by altering the crystal packing arrangements by introducing stabilizing co-formers. For hygroscopic pharmaceuticals, coating and co-crystallization are the most commonly employed strategies, whereas coating and encapsulation are popular for hygroscopic nutraceuticals (e.g., medicinal herbs, protein hydrolysates). Encapsulation is rarely applied on hygroscopic pharmaceuticals, just as co-crystallization is rarely used for hygroscopic nutraceuticals. Therefore, there is potential for improved hygroscopicity reduction by exploring beyond the traditionally used strategy.

Variations on a theme: crystal forms of the amino-acid transporter MhsT.

The bacterial amino-acid transporter MhsT from the SLC6A family has been crystallized in complex with different substrates in order to understand the determinants of the substrate specificity of the transporter. Surprisingly, crystals of the different MhsT-substrate complexes showed interrelated but different crystal-packing arrangements. Space-group assignment and structure determination of these different crystal forms present challenging combinations of pseudosymmetry, twinning and translational noncrystallographic symmetry.

Structure determination and Hirshfeld surface analysis of new cocrystal and salt forms of 5-aminotetrazole with hydroxy- and nitro-substituted carboxylic acids.

Two new crystalline solids, namely, 5-aminotetrazole-3,5-dihydroxybenzoic acid-water (1/4/6), CH3N5·4C7H6O4·6H2O (I), and 5-aminotetrazolium 3,5-dinitrosalicylate, CH4N5+·C7H3N2O7- (II), have been synthesized and characterized by single-crystal X-ray diffraction and Hirshfeld surface analysis. The crystal packing arrangements of I and II are governed by N-H...O and O-H...O hydrogen-bonding interactions. In cocrystal I, adjacent acid molecules are linked through O-H...O hydrogen bonds, forming a dimer with an R22(8) motif. In salt II, the tetrazolium cation and acid anion are linked through N-H...O hydrogen bonds to also form a dimer with an R22(8) motif. Further N-H...O and O-H...O hydrogen bonds help to stabilize the crystal packing, along with aromatic π-π stacking interactions in I and carbonyl...π interactions in II. The Hirshfeld surface analysis and fingerprint plots reveal that O...H/H...O interactions contribute 34.4% of the total interactions in the crystal packing of cocrystal I and 36.7% in salt II.