Conformational Polymorphs Research Articles

A zeolitic imidazolate framework with conformational variety: conformational polymorphs versus frameworks with static conformational disorder

We show via structural considerations and DFT calculations that for a zeolitic imidazolate framework (ZIF) with sodalite (SOD) topology, [Zn(dcim)2]-SOD (dcim = 4,5-dichloroimidazolate), structural models of an infinite number of hypothetical conformational polymorphs with distinct linker orientations can be generated, which can be interconverted most likely only via reconstructive structural transitions. The relative total energies suggest that some of those polymorphs might be synthetically accessible. Efforts in that direction led to the synthesis of new trigonal 1 and previously known cubic 2 with improved crystallinity. According to structural analyses based on powder X-ray diffraction (PXRD) methods supported by NMR spectroscopy, 1 is the most stable of the theoretically predicted SOD-type framework conformers (isostructural to ZIF-7), whereas 2, at variance to a recent proposal, is a SOD-type material with a high degree of orientational disorder of the dcim linker units. The statistics of the linker orientations in 2 is close to that in 1, indicating that the disorder in 2 is not random. Rather crystals of 2 are likely twins consisting of nanoscopic domains of trigonal 1 that are deformed to a cubic metric, with linker disorder being located in the domain interfaces. As structural differences appear to be more related to characteristics of the real as opposed to the ideal crystal structures, we propose to not consider 1 and 2 as true conformational polymorphs. Systematic investigations of solvent mixtures led to the discovery of intermediate materials of 1 and 2. The PXRD patterns and SEM images indicate that they belong to a complete series of structural intermediates. Differences in the Ar adsorption/desorption behaviours reveal that 1, in contrast to 2, is a flexible ZIF framework.

Crystallization induced enhanced emission in conformational polymorphs of a rotationally flexible molecule

The crystallization of weakly fluorescent 4-amino-2,2′-bipyridine (AMBPY) in solution phase under ambient conditions afforded three conformational polymorphs possessing enhanced emission.

Conformational polymorphism of a twisted conjugated molecule: controllable torsional motion for crystal growth selectivity

Controlling the emergence of the desired polymorphic form in crystal growth is of importance for both understanding the phenomenon of polymorphism and practical applications, but remains a great challenge as well. Herein, two polymorphs of cyano substituted distyrylbenzene (CN-DSB) are obtained as the crystals grow from chlorobenzene solution (Form I, blue fluorescence) and from its vapor (Form II, green fluorescence). Single-crystal X-ray analysis for the two crystal forms shows unambiguous evidence that the distinctive feature of molecules in both crystal forms is their difference in torsion angles of peripheral phenyl segments. A computational study addresses that the controllable growth of polymorphs can be rationalized on the basis of structural relationships with torsion potential under different external conditions. Our demonstration of single-crystal growth by tuning subtle external conditions illustrates a controllable process of obtaining conformational polymorphs.

ChemInform Abstract: Facts and Fictions About Polymorphism

AbstractReview: 119 refs.

Selective crystallization of vitamin D3for the preparation of novel conformational polymorphs with distinctive chemical stability

A new conformational polymorph of VD3 containing a pure α conformer was prepared and fully characterized. Chemical stability and hygroscopicity are compared with the marketed solid-state form (form A, two conformers α/β, 1 : 1). The results indicate that crystallization of VD3 needs to be controlled to avoid the unstable polymorph.

Conformational polymorphs and solid-state polymerization of 9-(1,3-butadiynyl)carbazole derivatives

The novel diacetylenes, 9-(5-(4-nitrophenoxy)penta-1,3-diyn-1-yl)-9H-carbazole (1) and 4-((5-(9H-carbazol-9-yl)penta-2,4-diyn-1-yl)oxy)benzonitrile (2), were prepared and characterized by crystallographic analyses. Compound 1 gave two conformational polymorphs, 1-(I) and 1-(II), whose differences were concluded to originate in intermolecular interactions among nitrophenyl groups. Crystal 1-(I) and 2 had suitable molecular arrangements for solid-state polymerization and polymerized by thermal annealing to give crystalline polydiacetylenes (PDAs). While an arrangement of 1-(II) was unsuitable for the polymerization. The PDAs showed broad absorption from UV to near IR region (ca. 900 nm), suggesting effective expansion of π-conjugated system by carbazolyl groups.

Polymorphism and DFT calculations of 1,4-bis(triisopropylsilyl)buta-1,3-diyne

Two polymorph forms of 1,4-bis(triisopropylsilyl)buta-1,3-diyne were investigated by X-ray analysis. The polymorph grown from acetone solution crystallized in the monoclinic crystal system with one molecule in a general position of the asymmetric unit. A second polymorph grown from acetonitrile and ethanol solutions crystallized in the triclinic crystal system with a molecule located on an inversion center. The two polymorphs have slightly different molecular geometries and crystal packing motifs. The conformations found in these polymorphs were investigated and compared with five other rotamers as possible candidates for conformational polymorphs using DFT calculations.

Hirshfeld surface analysis of sulfameter (polymorph III), sulfameter dioxane monosolvate and sulfameter tetrahydrofuran monosolvate, all at 296 K.

The ability of the antibacterial agent sulfameter (SMT) to form solvates is investigated. The X-ray crystal structures of sulfameter solvates have been determined to be conformational polymorphs. Both 1,4-dioxane and tetrahydrofuran form solvates with sulfameter in a 1:1 molar ratio. 4-Amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide (polymorph III), C11H12N4O3S, (1), has two molecules of sulfameter in the asymmetric unit cell. 4-Amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide 1,4-dioxane monosolvate, C11H12N4O3S·C4H8O2, (2), and 4-amino-N-(5-methoxypyrimidin-2-yl)benzenesulfonamide tetrahydrofuran monosolvate, C11H12N4O3S·C4H8O, (3), crystallize in the imide form. Hirshfeld surface analyses and fingerprint analyses were performed to study the nature of the interactions and their quantitative contributions towards the crystal packing. Finally, Hirshfeld surfaces, fingerprint plots and structural overlays were employed for a comparison of the two independent molecules in the asymmetric unit of (1), and also for a comparison of (2) and (3) in the monoclinic crystal system. A three-dimensional hydrogen-bonding network exists in all three structures, involving one of the sulfone O atoms and the aniline N atom. All three structures are stabilized by strong intermolecular N-H···N interactions. The tetrahydrofuran solvent molecule also takes part in forming significant intermolecular C-H···O interactions in the crystal structure of (3), contributing to the stability of the crystal packing.

Identification of polymorphism in ethylone hydrochloride: synthesis and characterization

Ethylone, a synthetic cathinone with psychoactive properties, is a designer drug which has appeared on the recreational drug market in recent years. Since 2012, illicit shipments of ethylone hydrochloride have been intercepted with increasing frequency at the Canadian border. Analysis has revealed that ethylone hydrochloride exists as two distinct polymorphs. In addition, several minor impurities were detected in some seized exhibits. In this study, the two conformational polymorphs of ethylone hydrochloride have been synthesized and fully characterized by FTIR, FT‐Raman, powder XRD, GC‐MS, ESI‐MS/MS and NMR (13C CPMAS, 1H, 13C). The two polymorphs can be distinguished by vibrational spectroscopy, solid‐state nuclear magnetic resonance spectroscopy and X‐ray diffraction. The FTIR data are applied to the identification of both polymorphs of ethylone hydrochloride (mixed with methylone hydrochloride) in a laboratory submission labelled as 'Ocean Snow Ultra’. The data presented in this study will assist forensic scientists in the differentiation of the two ethylone hydrochloride polymorphs. This report, alongside our recent article on the single crystal X‐ray structure of a second polymorph of this synthetic cathinone, is the first to confirm polymorphism in ethylone hydrochloride. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd. © 2015 Canada Border Services Agency. Drug Testing and Analysis published by John Wiley & Sons, Ltd.

(9-Anthryl)vinyl(9-phenanthryl)vinylbenzene Position Isomers: Intriguing Effects of Molecular Configuration on Polymorphism, Solvatochromism, and Aggregation-Induced Emission Properties

Three [(9-anthryl)vinyl][(9-phenanthryl)vinyl]benzene (APB) position isomers were synthesized and compared. The molecular configuration exhibits an extraordinary ability to affect polymorphism probability, unexpected solvatochromism, and aggregation-induced emission property. With the substitution changing from para-, ortho-, to meta-position, the polymorph number changes from 1, 2, to 3. Both 1,2-APB and 1,3-APB display a temperature-induced crystal-to-crystal phase transition. Furthermore, a pair of concomitant conformational polymorphs were obtained for 1,3-APB. Crystal structure analyses reveal that the steric hindrance between the two substituents leads to different molecular conformation and packing pattern. The unexpected solvatochromism is attributed to the strong electron-withdrawing ability of anthracene against phenanthrene, which produces permanent dipole moment. The solvatochromic degree is determined by the conjugative effect that varies with substitution position. 1,4-APB displays the most ...

New conformational polymorph of hydrochlorothiazide with improved solubility

Context: To characterize a new conformation of hydrochlorothiazide (HCT) with better solubility and establishing its relationship with previously reported form I, obtained during attempted crystallization experiments.Objective: The aim of present investigation is to unveil a new conformational polymorph (form IA) having a higher solubility compared to commercially available form I.Materials and methods: New form (IA) was obtained from slow evaporation as well as by solvent–antisolvent method and was then characterized by DSC, FTIR, PXRD and SCXRD. Equilibrium solubility profile shows that it is more soluble than form I.Results: Appearance of phase transition endotherm at 215.87 °C in DSC spectra indicated the existence of new polymorph which was further confirmed by FTIR and PXRD. Single crystal study showed significant difference in various bond angles and torsion angles of the two forms. The solubility exhibited by form IA was (938 µg/mL) compared to form I (791 µg/mL) in water.Discussion: Complete structural analysis and molecular arrangements in the unit cell along with the DSC and FTIR data confirm the existence of new conformer of HCT.Conclusion: This study reveals the existence of a new conformational polymorph of HCT molecule having higher solubility could prove to be promising in pre-formulation.

Polymorphs of Thiazole-Derived Imines Connected to Hydroxyaromatics

Conformational polymorphs arising from C–N bond rotation of a methylthiazole ring anchored to a nitrogen atom, which is a constituent of a six-membered intramolecularly hydrogen-bonded system, are studied. We have observed two polymorphs each from 2-(E)-[(5-methylthiazol-2-ylimino)methyl]phenol (1) and 1-(E)-[(5-methylthiazol-2-ylimino)methyl]unaphthalen-2-ol (2). Individual polymorphs are distinguished on the basis of their packing patterns and orientations of functional groups. One polymorph of compound 2, namely polymorph 2b, having Z′ = 2, is metastable; this polymorph is generated on heating of polymorph 2a, which has Z′ = 1.

Insight into the conformational polymorph transformation of a block-buster multiple sclerosis drug fingolimod hydrochloride (FTY 720)

Single-crystal structures of fingolimod hydrochloride (FTY 720), a block-buster multiple sclerosis drug, were revealed for the first time in this study. Three different conformational polymorphs (designated as forms I–III) were characterized using a variety of analytical techniques, including single-crystal XRD, VT-PXRD, DSC, HSM, and VT-confocal Raman spectroscopy. A temperature-dependent solid–solid transformation between different conformational polymorphs was observed to be reversible, and the transition process was studied using both VT-PXRD and VT-Raman techniques. Structural analysis revealed that the FTY 720 molecules adopt distinctive conformations in different polymorphs. Single-crystal to single-crystal transformation from form I to II was observed and was closely monitored by X-ray diffraction.

Facts and fictions about polymorphism.

We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not. Whilst the energy difference between polymorphs is usually less than 1 kcal mol(-1), conformational polymorphs are capable of differing by larger values (up to 2.5 kcal mol(-1) in our dataset). As overall statistics, we found that one in three compounds in the CSD are polymorphic whilst at least one in two compounds from the Roche and Lilly set display polymorphism with a higher estimate of up to three in four when compounds are screened intensively. Whilst the statistics provide some guidance of expectations, each compound constitutes a new challenge and prediction and realization of targeted polymorphism still remains a holy grail of materials sciences.

Structures of the conformational isomers and polymorph modifications of N-substituted 2,6-(E,E)-bis(ferrocenylidene)piperid-4-ones: photo- and electrochemically induced E/Z isomerization

Polymorph modifications for title compounds were investigated.

Concomitant conformational dimorphism in 1,2-bis(9-anthryl)acetylene

The structure of a concomitant conformational polymorph of an opto-electronic material raises questions about polymorphism.

Nucleation of Conformational Polymorphs: A Computational Study of Tolfenamic Acid by Explicit Solvation

The nucleation mechanism of polymorph formation remains poorly understood. For conformational polymorphism, the nature and strength of molecular interactions influence the conformation of a molecule, and such interplay between conformation and intermolecular interaction likely plays out through the self-assembling process of nucleation governing the outcome of resultant crystal structures. This study investigates molecular interactions and structural properties of a conformationally flexible molecule, tolfenamic acid, in explicit solvent by means of molecular dynamics and combined quantum mechanics and molecular mechanics methods. The results point out that tolfenamic acid prefers to take a relatively flat conformation, stabilized by intermolecular interactions between the solute and solvent molecules. Tolfenamic acid molecules can also adopt a more twisted conformation in a homodimeric state which exhibits lower solvation energy but greater stability. The computational work unravels the important influence by intermolecular interactions—between the solute and solvent or between the solute and solute—on stabilizing the conformation of solute molecules and, thus, highlights the underlying cooperation between a molecule’s conformation and its intermolecular interaction leading to the nucleation of distinct polymorphic structures.

Polymorphs of 1-(5-Methylthiazol-2-yl)-3-phenylthiourea and Various Anion-Assisted Assemblies of Two Positional Isomers

Orientations of the phenyl group and the intramolecular hydrogen bond play prime roles in the packing patterns of three conformational polymorphs of an unsymmetrical thiourea derivative, 1-(5-methylthiazol-2-yl)-3-phenylthiourea (PTH1). Self-assembly of each polymorph is composed of hydrogen-bonded dimeric motifs held together in head-to-tail arrangement but packed in different manners. Each has an intramolecular N–H···N hydrogen bond between an amide N–H and the nitrogen atom of the 5-methylthiazole unit. The packing pattern of 1-(4-methylthiazol-2-yl)-3-phenylthiourea (PTH2) is composed of dimeric assemblies of PTH2 in head-to-tail fashion. PTH2 is monomorphic as there are intermolecular C–H···S interactions between a C–H bond of the phenyl ring of each molecule and the sulfur atom of the thiocarbonyl group of a neighboring molecule. Such interactions lock the orientation of phenyl group in the solid state. The syn–anti conformation across the thiourea group, originally present in the positional isomers PTH1 and PTH2, is invariably transformed to syn–syn conformation in their salts. The extent of hydration of anions in the salts of PTH1 or PTH2 is dependent on the cation as well as the anion. The chloride salt of PTH1 has a large difference in packing patterns in comparison with the corresponding chloride salt of PTH2; they also differ in the numbers of symmetry-nonequivalent molecules in their respective unit cells. The anhydrous salt of PTH1 with hydrogen bromide having a 1:1 ratio of cation and anion is formed, whereas the bromide salt of PTH2 is a hydrate of composition (HPTH2)2(Br)2·6H2O. This salt has bromide–water clusters in its crystal lattice. Nitric acid reacts with PTH1 under different conditions to form hydrated or anhydrous salts. The hydrated salt (HPTH1)2(NO3)2·H2O has anions bridged by water molecules. The anhydrous nitrate salts of PTH1 and PTH2 are structurally similar in having nitrate···nitrate interactions. The deprotonation of polyacids by PTH1 and PTH2 is selective. The ability to abstract a proton from sulfuric acid to form crystalline salts by PTH1 and PTH2 differs. The sulfate salt (HPTH1)2(SO4) is formed by reaction of sulfuric acid with PTH1, but PTH2 forms the bisulfate salt (HPTH2)HSO4·H2O. PTH1 forms the corresponding dihydrogen phosphate salt upon reaction with orthophosphoric acid; the dihydrogen phosphate anions are held together in the form of cyclic hydrogen-bonded hexameric assemblies in the lattice. Water loss from the assemblies of hydrated salt was determined by thermogravimetry and differential scanning calorimetry and showed that dehydration from anion-assisted assemblies was guided by the cationic host and the type of assembly.

Contrasting Polymorphism of Related Small Molecule Drugs Correlated and Guided by the Computed Crystal Energy Landscape

Solid form screening and crystal structure prediction (CSP) calculations were carried out on two related molecules, 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid (B5) and 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7). Only one anhydrate form was crystallized for B5, whereas multiple solid forms, including three neat polymorphs, were found for DB7. The crystal structure of B5 is P21/n Z′ = 1 with intramolecular hydrogen bonding, whereas Forms I and II of DB7 are conformational polymorphs with distinct Z′ = 1 P1 structures and intermolecular hydrogen bonds. A disordered structure for Form III of DB7 is proposed, based on CSP-generated structures which gave a promising match to the X-ray powder diffraction and solid state NMR data for this metastable form. The differences in the hydrogen bonding and experimental solid form landscapes of the two molecules appear to arise from the dominance of the self-assembly of the benzoisoxazolepiperazinyl an...

In Situ Ultralow-Frequency Raman Tracking of the Polymorphic Transformation of Crystalline 1,1′-Binaphthyl

Extremely low-frequency (LF) Raman spectroscopy that allows for fast access to lattice vibrations with little hindrance of immense Rayleigh scattering was used to track in situ thermally induced polymorphic transformation of crystalline 1,1′-binaphthyl (BN), a fundamental structural unit of specific chiral ligands. BN occurs in two conformational polymorphs, cisoid and transoid forms, with the former being a racemate and the latter being a conglomerate of chiral crystals. Observed LF Raman spectra (from 200 cm–1 down to ∼5 cm–1, equivalent to 0.15 THz), which arise predominantly from lattice vibrations, show markedly different features between the cisoid and transoid forms, making it possible to study their phase transition. A series of LF Raman spectra measured with slow heating of microcrystalline BN reveal that, in contrast to previous studies, the monoclinic cisoid form transforms directly to the tetragonal transoid form in the solid state without formation of any intermediate phase. The present approach is applicable to various phase transition systems, including pharmaceutical compounds, liquid crystals, and polymer films, which conventional X-ray diffraction analysis may not be able to investigate.