Conformational Polymorphs Research Articles

Template design based on molecular and crystal structure similarity to regulate conformational polymorphism nucleation: the case of α,ω-alkanedicarboxylic acids

Template design on polymorph control, especially conformational polymorphs, is still in its infancy and the result of polymorph control is often accidental. A method of regulating the crystallization of conformational polymorphs based on the crystal structure similarity of templates and the target crystal form has been developed. Crystal structure similarity was considered to be able to introduce lattice matching (geometric term) with chemical interactions to regulate conformational polymorph nucleation. The method was successfully applied to induce the crystallization of DA7-II [HOOC–(CH2)n−2–COOH (diacids), named DAn, wheren= 7, 9, 15, 17 and II represents the metastable polymorph] on the surface of DA15-II. An analogous two-dimensional plane – the (002) face of both DA15-II and DA7-II – was firstly predicted as the epitaxially attached face with similar lattice parameters and the strongest adsorption energy. The powder DA15-II template with the preferred orientation face in (002) presented much stronger inducing DA7-II ability than the template with other preferred orientation faces. The epitaxial growth of DA7-II on DA15-II through an identical (002) face was clearly observed and verified by the single-crystal inducing experiments. The molecular dynamics simulation results demonstrated that the strong interactions occurred between DA7 molecules and the (002) face of DA15-II. This method has been verified and further applied to the crystallization of DA7-II on the surface of DA17-II and DA9-II on the surface of DA15-II. This study developed a strategy based on structure similarity to regulate the conformational polymorph and verified the significant role of lattice matching and chemical effects on the design and preparation of templates.

Can the Crystal of Conformational Polymorph Nucleate Directly from Its Conformer? The Case of Flufenamic Acid

The combination of solution IR spectroscopy measurement, fast cooling crystallization experiments, conformational search, and molecular computation was investigated in detail in this study to explo...

The influence of microstructure and conformational polymorph on the drop-weight impact sensitivity of δ-phase HMX

ABSTRACT The influence on HMX impact sensitivity resulting from damage due to phase transition versus that of the polymorphic conformer and crystal lattice change in δ-HMX are quantified in this work. Microstructural imaging techniques are used to characterize 30 crystals from three groups of distinctly large and small HMX crystals which have undergone a thermally induced phase transition, as well as some which have undergone spontaneous reversion from -phase. It is found that large HMX crystals incur a significant increase in cracks during the transition from , while much smaller crystals appear to have no distinguishable increase in voids after undergoing a -phase change. Drop-weight impact experiments were performed on 46 to 68 samples from each of six sample types of HMX, three types of which are composed of very small HMX crystals and three of which are composed of large HMX crystals. It is found that small HMX crystals, which do not appear to incur a significant increase in voidspace after undergoing the phase transition, do not have statistically distinguishable changes in drop-weight impact sensitivity between β, δ, or β-reverted phase HMX; however, large crystal HMX impact sensitivity increases significantly when transitioned to δ-phase and furthermore when allowed to revert to β-phase. This indicates that the morphological change is the dominant effect of transformation on impact sensitivity and that the δ-conformer and crystal packing structure have little or no effect on the impact sensitivity of HMX.

Use of additives to regulate solute aggregation and direct conformational polymorph nucleation of pimelic acid.

Understanding the nucleation pathway and achieving regulation to produce the desired crystals are mutually beneficial. The authors previously proposed a nucleation pathway of conformational polymorphs in which solvation and solute self-assembly could affect the result of the conformational rearrangement and further nucleation outcomes. Based on this, herein α,ω-alkanedi-carb-oxy-lic acids (DAn, where n represents the number of carbon atoms in the molecule, n = 2-6, 8-11) were designed as homologous additives to interfere with the self-assembly of pimelic acid (DA7) to further induce the form II compound, which differs from form I only in conformation. Interestingly, longer-chain additives (DA6-11) have a stronger form II-inducing ability than short-chain ones (DA2-4). In addition, an apparent gradient of the degree of interference with solute self-assembly, consistent with form II-inducing ability, was detected by infrared and nuclear magnetic resonance spectroscopy. The calculated molecular electrostatic potential charges also clearly indicate that additive-solute electrostatic interactions gradually increase with increasing carbon chain length of the additives, reaching a maximum value with DA6-11. This novel use of additives demonstrates a direct link between solute aggregation and conformational polymorph nucleation.

Two conformational polymorphs of 4-methylhippuric acid.

4-Methylhippuric acid {systematic name: 2-[(4-methylbenzoyl)amino]ethanoic acid}, a p-xylene excreted metabolite with a backbone containing three rotatable bonds (R-bonds), is likely to produce more than one stable molecular structure in the solid state. In this work, we prepared polymorph I by slow solvent evaporation (plates with Z' = 1) and polymorph II by mechanical grinding (plates with Z' = 2). Potential energy surface (PES) analysis, rotating the molecule about the C-C-N-C torsion angle, shows four conformational energy basins. The second basin, with torsion angles near -73°, agree with the conformations adopted by polymorph I and molecules A of polymorph II, and the third basin at 57° matched molecules B of polymorph II. The energy barrier between these basins is 27.5 kJ mol-1. Superposition of the molecules of polymorphs I and II rendered a maximum r.m.s. deviation of 0.398 Å. Polymorphs I and II are therefore true conformational polymorphs. The crystal packing of polymorph I consists of C(5) chains linked by N-H...O interactions along the a axis and C(7) chains linked by O-H...O interactions along the b axis. In polymorph II, two molecules (A with A or B with B) are connected by two acid-amide O-H...O interactions rendering R22(14) centrosymmetric dimers. These dimers alternate to pile up along the b axis linked by N-H...O interactions. A Hirshfeld surface analysis localized weaker noncovalent interactions, C-H...O and C-H...π, with contact distances close to the sum of the van der Waals radii. Electron density at a local level using the Quantum Theory of Atoms in Molecules (QTAIM) and the Electron Localization Function (ELF), or a semi-local level using noncovalent interactions, was used to rank interactions. Strong closed shell interactions in classical O-H...O and N-H...O hydrogen bonds have electron density highly localized on bond critical points. Weaker delocalized electron density is seen around the p-methylphenyl rings associated with dispersive C-H...π and H...H interactions.

Unforeseen crystal forms of the natural osmolyte floridoside

Floridoside (2-α-O-D-galactopyranosyl glycerol) is a glycerol glycoside that is biosynthesised by most species of red algae and has been implicated as an intracellular regulator of various homeostatic functions. Here, we report the identification of two unforeseen crystal forms of the ubiquitous natural osmolyte floridoside including a seemingly unheralded second anhydrous conformational polymorph and the unambiguous description of an elusive monohydrated variant. By employing a variety of thermal and spectroscopic techniques, we begin to explore both their macro and molecular physicochemical properties, which are notably different to that of the previously reported polymorph. This work advances the characterisation of this important natural biomolecule which could aid in facilitating optimised utilisation across a variety of anthropocentric applications and improve comprehension of its role in-vivo as a preeminent compatible solute.

Conformational polymorphism in a cobalt(II) dithiocarbamate complex.

Two conformational polymorphs of (N,N-dibutyldithiocarbamato-κ2S,S')[tris(3,5-diphenylpyrazol-1-yl-κN2)hydroborato]cobalt(II), [Co(C45H34BN6)(C9H18NS2)] or [TpPh2Co(S2CNBu2)], 1, are accessible by recrystallization from dichloromethane-methanol to give orthorhombic polymorph 1a, while slow evaporation from acetonitrile produces triclinic polymorph 1b. The two polymorphs have been characterized by IR spectroscopy and single-crystal X-ray crystallography at 150 K. Polymorphs 1a and 1b crystallize in the orthorhombic space group Pbca and the triclinic space group P-1, respectively. The polymorphs have a trans (1a) and cis (1b) orientation of the butyl groups with respect to the S2CN plane of the dithiocarbamate ligand, which results in an intermediate five-coordinate geometry for 1a and a square-pyramidal geometry for 1b. Hirshfeld surface analysis reveals minor differences between the two polymorphs, with 1a exhibiting stronger C-H...S interactions and 1b favouring C-H...π interactions.

Conformation Directed Interaction Anisotropy Leading to Distinct Bending Behaviors of Two ROY Polymorphs

Two conformational polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) exhibited similar morphology but strikingly different mechanical flexibility, where the yellow needl...

Polymorphism in the Anti-inflammatory Drug Flunixin and Its Relationship with Clonixin

Crystallization of the nonsteroidal anti-inflammatory drug (NSAID) flunixin in acetone and in acetone–hexane produced two conformational polymorphs, as predicted by hydrogen-bond propensity analyse...

Probing the structural pathway of conformational polymorph nucleation by comparing a series of α,ω-alkanedicarboxylic acids.

Herein the nucleation pathway of conformational polymorphs was revealed by studying the relationships and distinctions among a series of α,ω-alkanedicarboxylic acids [HOOC-(CH2) n-2-COOH, named DAn, where n = 5, 7, 9, 11, 13, 15] in the solid state and in solution. Their polymorphic outcomes, with the exception of DA5, show solvent dependence: form I with conformation I crystallizes from solvents with hydrogen-bond donating (HBD) ability, whereas form II with conformation II crystallizes preferentially from solvents with no HBD ability. In contrast, form II of DA5 does not crystallize in any of the solvents used. Quantum mechanical computation showed that there is no direct conformational link between the solvents and the resultant polymorphic outcomes. Surprisingly, solute aggregates were found in no-HBD solvents by Fourier transform infrared spectroscopy, and only monomers could be detected in HBD solvents, suggesting stronger solvation. Furthermore, it was found that all six compounds including DA5 followed the same pattern in solution. Moreover, crystal-packing efficiency calculations and stability tests stated that dimorphs of DA5 bear a greater stability difference than others. These suggest that the rearrangement from conformation II to I could not be limited by hard desolvation in HBD solvents, where form I was also obtained. In other systems, metastable II was produced in the same solvents, probably as a result of the rearrangement being limited by hard desolvation. In this work, a comparative study uncovers the proposed nucleation pathway: difficulty in desolvation has a remarkable effect on the result of rearrangement and nucleation outcome.

Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated wavefunction methods.

Molecular crystal structure prediction is increasingly being applied to study the solid form landscapes of larger, more flexible pharmaceutical molecules. Despite many successes in crystal structure prediction, van der Waals-inclusive density functional theory (DFT) methods exhibit serious failures predicting the polymorph stabilities for a number of systems exhibiting conformational polymorphism, where changes in intramolecular conformation lead to different intermolecular crystal packings. Here, the stabilities of the conformational polymorphs of o-acetamidobenzamide, ROY, and oxalyl dihydrazide are examined in detail. DFT functionals that have previously been very successful in crystal structure prediction perform poorly in all three systems, due primarily to the poor intramolecular conformational energies, but also due to the intermolecular description in oxalyl dihydrazide. In all three cases, a fragment-based dispersion-corrected second-order Møller-Plesset perturbation theory (MP2D) treatment of the crystals overcomes these difficulties and predicts conformational polymorph stabilities in good agreement with experiment. These results highlight the need for methods which go beyond current-generation DFT functionals to make crystal polymorph stability predictions truly reliable.

Reversible Temperature-Stimulated Single-Crystal-to-Single-Crystal Conformational Polymorph Transformation in Cadmium(II) Coordination Trimer with a Water Vapor Sorption/Desorption Potential

A crystalline cadmium(II) coordination trimer with pyridine-4-propanamide (4-propy), [Cd3Cl4(H2O)4(4-propy)6](CH3CH2COO)2, readily responds to external stimuli while preserving crystal integrity. Two polymorphic forms, Polymorph-I (triclinic form) and Polymorph-II (monoclinic form), undergo a reversible single-crystal-to-single-crystal conformational polymorph transformation upon temperature change, while the triclinic form (Polymorph-I) additionally shows substantial reversible sorption/desorption potential via two pathways, in response to stimulation by (i) elevated temperature, and (ii) reduced pressure. The elucidation of the conformational transformation via a variety of ex situ and in situ methods (SCXRD, VT-PXRD, TG/DSC and VT-IR), complemented by in-depth theoretical studies, suggested that the conformational transformation might be a process that occurs slowly and continuously over a wider temperature range, with different processes (distinctive conformational changes) taking place over different temperature intervals.

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.

\u03b1-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb

Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates.In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.

Solvent vapour induced rare single-crystal-to-single-crystal transformation of stimuli-responsive fluorophore: Solid state fluorescence tuning, switching and role of molecular conformation and substituents

Supramolecular interactions and molecular conformations play significant role on producing fluorescent polymorphs with tunable emission in the solid state from single fluorophore. External stimuli-induced structural transformation from one polymorph to another polymorph without losing single crystalline character (single-crystal-to-single-crystal transition (SC-SC)) provides perfect model to understand the structure-property of molecules in the solid state and designing new functional fluorescent materials. Herein we have tailored the substituent groups in the aggregation-induced-emissive (AIE) tetraphenylethylene (TPE) based donor (D)-acceptor (A) fluorophores (TPPA-1-6) and explored fluorescent polymorphs formation and SC-SC transition in the solid state. TPPA-1 showed conformational fluorescent polymorphs via twisted and co-planar conformation between TPE phenyl group and cyanophenyl acceptor phenyl ring. However, single crystal analysis of other derivatives revealed that substituent groups and supramolecular interactions control the molecular conformation and SC-SC transition. Fluorophore with same substituent but positional change also show drastic effect on the fluorescent polymorphs formation and SC-SC transition. Substituents that can form strong intermolecular interactions stabilize the less stable co-planar structure whereas bulky substituents with weak intermolecular interactions produced twisted or both conformers. Photophysical, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimteric (TG) analysis were performed to substantiate and get insight on the structural transformation. The formation of fluorescent polymorphs and SC-SC transition exhibited tunable and switchable solid state fluorescence. The non-planar TPE core has been made use to demonstrate high contrast stimuli induced reversible fluorescence switching. Overall, the present studies attempted to gain information on the structural design for developing SC-SC transforming functional organic fluorescent materials that could be of potential interests for optoelectronic and display devices.

Exfoliating a CdII -Purine Framework: Conversion of Nanosheets-to-Nanofibers and Studies of Elastic and Capacitive Properties.

Layered bulk crystals are amenable to exfoliation to yield 2D nanosheets through isolation and intercalation processes, which could be further converted to 1D nanoscale structures. The latter inherit gross morphological and physical properties associated with the precursor structures. Herein, we report three purine-based crystal structures 1, 2, and 3, where 3 is obtained by a single-crystal-to-single-crystal transformation from 2 and is a conformational polymorph of 1. Next, we describe the sonication-assisted liquid exfoliation of 1, a CdII -purine coordination framework, into nanosheets and nanofibers in a solvent-dependent process. The exfoliation was carefully studied at low temperatures to ascertain this unique conversion. This work also features the determination of the Young's modulus and surface potential of the bioinspired CdII -based nanostructures by using amplitude modulation-frequency modulation atomic force microscopy and Kelvin probe force microscopy, respectively, revealing their interesting elastic and capacitive properties for their possible use in electronics and energy devices. Electron impedance spectroscopy measurements further established a higher value of capacitance for the exfoliated CdII framework as compared to the ligand alone.

Exploring concomitant/conformational dimorphism in a difluoro-substituted phosphoramidate derivative.

The concomitant occurrence of dimorphs of diphenyl (3,4-difluorophenyl)phosphoramidate, C18H14F2NO3P, was observed via a solution-mediated crystallization process with variation in the symmetry-free molecules (Z'). The existence of two forms, i.e. Form I (block, Z' = 1) and Form II (needle, Z' = 2), was characterized by single-crystal X-ray diffraction, differential scanning calorimetry and powder X-ray diffraction. Furthermore, a quantitative analysis of the energetics of the different intermolecular interactions was carried out via the energy decomposition method (PIXEL), which corroborates with inputs from the energy framework and looks at the topology of the various intermolecular interactions present in both forms. The unequivocally distinguished contribution of strong N-H...O hydrogen bonds along with other interactions, such as C-H...O, C-H...F, π-π and C-H...π, mapped on the Hirshfeld surface is depicted by two-dimensional fingerprint plots. Apart from the major electrostatic contribution from N-H...O hydrogen bonds, the crystal structures are stabilized by contributions from the dispersion energy. The closely related melting points and opposite trends in the calculated lattice energies are interesting to investigate with respect to the thermodynamic stability of the observed dimorphs. The significant variation in the torsion angles in both forms helps in classifying them in the category of conformational polymorphs.

Orientation-dependent conformational polymorphs in two similar pyridine/pyrazine phenolic esters

The ring orientations in the conformational polymorphs of two similar pyridine/pyrazine phenolic esters were investigated to explore the effect of supramolecular assemblies in the solid state.

Polymorphism in a Rotaxane Molecule: Intra- and Intermolecular Understanding

Polymorphs have been widely studied since different crystalline phases of the same compound may have distinct properties. Macromolecules are an area of major study with just a few polymorphs reported. This investigation presents the first case of polymorphism in a [2]rotaxane molecule. This rotaxane contains a succinamide station bearing nonsymmetric stoppers and a tetralactam macrocycle. A different polymorphic phase is achieved by varying the crystallization solvent. These polymorphs presented relevant differences at the molecular level and were classified as conformational polymorphs. At the supramolecular level, polymorph I is −21 kcal mol–1 more stable than polymorph II. Crystallization mechanisms to assess the stages of the crystallization process were proposed. Similar stabilization of the first nuclei formed was observed to be responsible for the possibility of both forms to coexist. The large differences observed between the polymorphs were not significantly reflected in the types and contributio...

Conformational trimorphism of bis(2,6-dimesitylphenyl)ditelluride

AbstractBesides the previously known α-form (monoclinic,P21/c, Z=4) of bis(2,6-dimesitylphenyl)ditelluride, two new polymorphic modifications, namely the β-form (monoclinic,P21/c, Z=8) and the γ-form (triclinic,P1̅, Z=2), were obtained serendipitously during chemical reactions. In all three modifications, the individual molecules possess significantly different conformations and bond parameters, such as Te–Te bond lengths, C–Te–Te bond angles, C–Te–Te–C torsion angles and intramolecular Menshutkin interactions, which is also reflected in their non-covalent interactions with adjacent molecules in the crystal lattice via London dispersion and electrostatic forces. The interplay between intermolecular and intramolecular forces in these conformational polymorphs was investigated using quantum chemical calculations, which reveal that the β-form should be thermodynamically stable at absolute zero. In contrast, crystallization experiments and thermoanalytical investigations indicate that the α-form is stable at high temperatures and therefore, both forms might be related by enantiotropism.