Solid State Polymorphism Research Articles

Structural investigation of anionic cyclometalated Pt(II)-tetrabromocatecholate complexes: quasi-halogen bonding and elusive polymorphism at play

Four unusual anionic heteroleptic cyclometalated monomeric Pt(II) complexes bearing the aromatic tetrabromocatecholate dianion (Br4cat) and either benzo[h]quinoline H(bzq) (1), (2,4-difluorophenyl)-pyridine H(F2ppy) (2), 2-phenylpyridine H(ppy) (3) or 2,2’-thienylpyridine H(thpy) (4) as the cyclometalating ligand were synthesized, precipitated as NBu4 + salts and recrystallized from acetone solutions. Single-crystal XRD investigation indicated that in the crystal structures of 1–4 the monoanionic [(C∧N)Pt(Br4cat)]− [(C∧N) = bzq (1), F2ppy (2), ppy) (3), thpy (4α, 4β)] moieties engage in various intermolecular interactions, including π-π stacking and Br···Br contacts (mostly of quasi-type II), which ultimately determine their aggregation into 2D (1) or 3D (2–4) supramolecular networks, albeit without short Pt···Pt contacts. A combined PXRD and DSC analysis of both microcrystalline powders and single-crystals of 1–4 unequivocally revealed the occurrence of solid-state polymorphism for 1, 3 and 4. Efforts to grow single-crystals of more than just one form of 1 and 3 were unsuccessful. Conversely, two polymorphs of 4 (4α and 4β) could be isolated and studied. The deep structural investigation of 1–4 put forward herein contributes validating the hypothesized reasons behind the significant enhancement of luminescence in the solid-state previously reported for this series of heteroleptic cyclometalated Pt(II) monomers.

Conformations in Solution and in Solid-State Polymorphs: Correlating Experimental and Calculated Nuclear Magnetic Resonance Chemical Shifts for Tolfenamic Acid

A new approach for quantitively assessing putative crystal structures with applications in crystal structure prediction (CSP) is introduced that is based upon experimental solution- and magic-angle spinning (MAS) solid-state NMR data and density functional theory (DFT) calculation. For the specific case of tolfenamic acid (TFA), we consider experimental solution-state NMR for a range of solvents, experimental MAS NMR of polymorphs I and II, and DFT calculations for four polymorphs. The change in NMR chemical shift observed in passing from the solution state to the solid state (ΔδExperimental) is calculated as the difference between 1H and 13C experimental solid-state chemical shifts for each polymorphic form (δSolidexpt) and the corresponding solution-state NMR chemical shifts (δSolutionexpt). Separately, we use the gauge-included projector augmented wave (GIPAW) method to calculate the NMR chemical shifts for each form (δSolidcalc) and for TFA in solution (δSolutioncalc) using the dynamic 3D solution conformational ensemble determined from NMR spectroscopy. The calculated change in passing from the solution state to the solid state (ΔδCalculated) is then calculated as the difference of δSolidcalc and δSolutioncalc. Regression analysis for ΔδCalculated against ΔδExperimental followed by a t-test for statistical significance provides a robust quantitative assessment. We show that this assessment clearly identifies the correct polymorph, i.e., when comparing ΔδExperimental based on the experimental MAS NMR chemical shifts of form I or II with ΔδCalculated based on calculated chemical shifts for polymorphs I, II, III, and IV. Complementarity to the established approach of comparing δSolidexpt to δSolidcalc is explored. We further show that our approach is applicable if there are no solid-state crystal structure data. Specifically, δSolidcalc in ΔδCalculated is replaced by the chemical shift for an isolated molecule with a specific conformation. Sampling conformations at specific 15° angle values and comparing them against experimental 13C chemical shift data for forms I and II identifies matching narrow ranges of conformations, successfully predicting the conformation of tolfenamic acid in each form. This methodology can therefore be used in crystal structure prediction to both reduce the initial conformational search space and also quantitatively assess subsequent putative structures to reliably and unambiguously identify the correct structure.

Interaction potentials for modelling GaN precipitation and solid state polymorphism

We outline a molecular mechanics model for the interaction of gallium and nitride ions ranging from small complexes to nanoparticles and bulk crystals. While the current GaN force fields allow the modelling of either bulk crystals or single ions dispersed in solution, our model covers both and hence paves the way to describing aggregate formation and crystal growth processes from molecular simulations. The key to this is the use of formal +3 and −3 charges on the gallium and nitride ions, whilst accounting for the charge transfer in GaN crystals by means of additional potential energy terms. The latter are fitted against experimental data of GaN in the wurtzite structure and benchmarked for the zinc-blende and rock-salt polymorphs. Comparison to quantum chemical references and experiment shows reasonable agreement of structures and formation energy of [GaN]n aggregates, elastic properties of the bulk crystal, the transition pressure of the wurtzite to rock-salt transformation and intrinsic point defects. Furthermore, we demonstrate force field transferability towards the modelling of GaN nanoparticles from simulated annealing runs.

Structural and Optoelectronic Properties of the α-, β-, and γ-Glycine Polymorphs and the Glycine Dihydrate Crystal: A DFT Study

Density functional calculations were performed to study the properties of the three main glycine solid-state polymorphs α, β, and γ and the glycine dihydrate (GDH) crystal. Optimized unit cell geometries, Kohn–Sham electron energy bands, electron densities of states, population charges, carrier effective masses, optical absorption, and complex dielectric functions were obtained for each glycine system using a GGA functional plus the TS dispersion correction, leading to lattice parameters very close to the experimental values. The theoretical fundamental gaps of all glycine crystals are indirect and near 5 eV. The carrier effective masses are anisotropic and especially heavy (∼26 free electron masses at most) for holes in the case of the GDH crystal. The optical absorption and the dielectric function are very sensitive to the polarization of light in all glycine-based crystals.

Dynamics of Dimethylbutanols in Plastic Crystalline Phases by Field Cycling 1H NMR Relaxometry.

2,2-Dimethylbutan-1-ol (2,2-DM-1-B), 3,3-dimethylbutan-1-ol (3,3-DM-1-B), and 3,3-dimethylbutan-2-ol (3,3-DM-2-B) show a rich solid-state polymorphism, which includes one or more plastic crystalline phases (also referred to as orientationally disordered crystalline (ODIC) phases) and glass of the liquid or ODIC phases. In this work, the dynamics of the three isomeric alcohols was investigated in the liquid and plastic crystalline phases by fast field cycling 1H NMR relaxometry in the temperature range between 213 and 303 K. The analysis of the nuclear magnetic relaxation dispersion curves (i.e., longitudinal relaxation rate R1 vs 1H Larmor frequency) acquired for the different alcohols at different temperatures gave quantitative information on internal motions, overall molecular reorientations, and molecular self-diffusion. Self-diffusion coefficients were also determined in the liquid phase and in some ODIC phases of the samples from the trends of 1H R1 as a function of the frequency square root at low frequencies. Remarkable changes in the temperature trends of correlation times and self-diffusion coefficients were found at the transition between the liquid and the ODIC phase for 2,2-DM-1-B and 3,3-DM-1-B, and between ODIC phases for 3,3-DM-2-B, the latter sample showing a markedly different dynamic and phase behavior.

Low-temperature dynamics of (S)-4-(1-methylheptyloxy)-4ʹ-cyanobiphenyl (8*OCB) and (S)-4-(2-methylbutyl)-4ʹ-cyanobiphenyl (5*CB) in disordered crystalline and glassy phases

ABSTRACTThe inelastic neutron scattering (INS) spectra were measured for two materials of chiral molecules: (S)-4-(1-methylheptyloxy)-4ʹ-cyanobiphenyl (8*OCB) and (S)-4-(2-methylbutyl)-4ʹ-cyanobiphenyl (5*CB), revealing solid state polymorphism with two partially disordered crystalline phases I and II and glassy state of liquid and of crystalline phase in each substance. The experiments were performed in the energy range up to 30 µeV in the temperature range from 4 to 35 K. For 8*OCB the elastic scans were measured as well up to 300 K illustrating well the phase diagram. For all solid phases of both substances in the µeV range of INS spectra, the existence of the excess density of vibrational states over that typical for fully ordered crystalline phases was evidenced. Contribution of this so-called boson peak occurred to be much larger in glass of isotropic phase than in the phase II and glass of phase I of 8*OCB, while for 5*CB it was larger in the phase I and glass of phase II than in glass of cholesteric phase. The quasi-elastic broadening of elastic peak corresponding to stochastic reorientations in the ns time scale was detected for both substances. Comparison of the results obtained for glassy and crystalline phases of 8*OCB and 5*CB compounds have been given and confronted with those obtained previously in meV energy range.

Cu(II) complexes of cytosine and 1-methylcytosine with bromide: old motifs and new structures

The preparation from aqueous solutions and crystal structures of the compounds trans-[Cu(1-Mecyt)2Br2] (1), trans-[Cu(cyt)2Br2] (2), [Cu(cyt)4]Br2·2H2O (3), and [Cu(cyt)Br3][Hcyt] (4) (where 1-Mecyt = 1-Methylcytosine and cyt = cytosine) is reported. Compounds 1 and 2 are made of trans-CuL2Br2 molecules [L = 1-Mecyt (1) or cyt (2)]. In 1, the coordination geometry around the central Cu(II) is distorted square pyramidal, while in 2 no such distortion is observed. Two solid-state polymorphs of 1 have been isolated, 1a and 1b, both of which contain no crystallization solvent and thus only differ in the relative disposition of vicinal [Cu(1-Mecyt)2Br2] units through space. As far as we know, 1 is the first example of a 1:2 Cu(II) complex with 1-Mecyt showing a trans arrangement of the ligands. The obtaining of 2 is also worth of note, as this species was previously reported as elusive. Compound 3 comprises tetra-cytosine-Cu(II) cations and bromides, these latter building, together with water molecules, a H-bonded tetrameric [Ow2Br2] motif. Compound 4 is constituted by [Cu(cyt)Br3]− anions and Hcyt+ cations, the cytosinium cations being in the outer metal coordination sphere. Likely, a pH-mediated equilibrium between 2 and 4 exists, 4 being only observable in traces as the neutral 1:2 complex with two metal–cyt direct bonds (2) is the thermodynamically favored product.

Structural Polymorphism as the Result of Kinetically Controlled Self-Assembly.

Traditionally, the goal of self-assembly and supramolecular chemistry is to engineer an equilibrium structure with a desired geometry and functionality; this is achieved through careful choice of molecular monomers, growth conditions, and substrate. Supramolecular assemblies produced under nonequilibrium conditions, in contrast, can form metastable structures with conformations quite different from those accessible in equilibrium self-assembly. The study of nonequilibrium growth of clusters potentially impacts the study of nucleation in atmospheric aerosols, nucleation in organic crystallization, and mesoscale organization for systems ranging from biological molecules to molecular electronics. In our experiments, we prepare surface monolayers of small organic and organometallic molecules through direct injection of a solution onto a substrate in high vacuum. During this process, the rapid evaporation of small solution droplets in high vacuum can lead to nonequilibrium growth conditions. The resulting structures are then characterized by scanning tunneling microscopy. Among the features observed in these experiments are cyclic, hydrogen-bonded pentamers. For carboxylic acids, the two-molecule ring dimer is the common binding motif. Large, cyclic hydrogen-bonded systems are uncommon, especially so for rings with five members. Despite this, pentagonal clusters appear to be a general phenomenon for systems containing adjacent strong and weak hydrogen-bonding elements on five-member aromatic rings. Regular pentamers have been observed as metastable structures for ferrocenecarboxylic acid, indole-2-carboxylic acid, and isatin (1-H-indole-2,3-dione). Electronic structure calculations confirm the relative stability of these structures with respect to the dimer or catemer conformations which are observed in the solid-state crystal structures. For ferrocenecarboxylic acid, cyclic pentamers undergo further self-assembly, resulting in long-range order in conjunction with local 5-fold rotational symmetry. This system is the first reported self-assembled molecular quasicrystal, and it remains the only example of a hydrogen-bonded quasicrystal. This supramolecular structure forms as a result of the cocrystallization of hydrogen-bonded cyclic pentamers with intercalated molecular dimers. The shared bonding to a single dimer is responsible for locking the adjacent pentamers in specific distances and orientations, which produces the quasicrystal. Careful analysis of experimental data provides evidence that, in some cases, metastable clusters are formed in solution and then subsequently adsorb on the surface. This is a unusual mechanism for supramolecular assembly, and it has important implications for understanding questions in crystal growth, namely: what the initial stages of crystal growth are as molecules are first precipitating from solution; what role the solvent plays in determining crystal structure; and whether solvent-mediated clustering is important in the broader phenomenon of solid-state polymorphism.

5-Methylhydantoin: From Isolated Molecules in a Low-Temperature Argon Matrix to Solid State Polymorphs Characterization.

The molecular structure, vibrational spectra and photochemistry of 5-methylhydantoin (C4H6N2O2; 5-MH) were studied by matrix isolation infrared spectroscopy and theoretical calculations at the DFT(B3LYP)/6-311++G(d,p) theory level. The natural bond orbital (NBO) analysis approach was used to study in detail the electronic structure of the minimum energy structure of 5-MH, namely the specific characteristics of the σ and π electronic systems of the molecule and the stabilizing orbital interactions. UV irradiation of 5-MH isolated in argon matrix resulted in its photofragmentation through a single photochemical pathway, yielding isocyanic acid, ethanimine, and carbon monoxide, thus following a pattern already observed before for the parent hydantoin and 1-methylhydantoin molecules. The investigation of the thermal properties of 5-MH was undertaken by differential scanning calorimetry (DSC), polarized light thermal microscopy (PLTM) and Raman spectroscopy. Four different polymorphs of 5-MH were identified. The crystal structure of one of the polymorphs, for which it was possible to grow up suitable crystals, was determined by X-ray diffraction (XRD). Two of the additional polymorphs were characterized by powder XRD, which confirmed the molecules pack in different crystallographic arrangements.

Novel fluorescent liquid crystal containing azobenzene and stilbene moieties-synthesis, mesogenic and spectroscopic studies

This paper presents synthesis and characterization of new rigid core dye composed of two chromophore moieties such as azobenzene and stilbene parts. During this study liquid-crystalline properties was investigated and found as expected. An additional and unforeseen phenomenon of solid state polymorphism was also noticed. Furthermore, fluorescent properties were examined and confirmed by the fluorescence spectroscopy. This initial study gave very interesting and promising results which can be basis for further studies of such new type of azo-stilbene based substances.

The generalized maximum hardness principle revisited and applied to solids (Part 2).

Building on Part 1 devoted to atoms and molecules (PCCP, in press 2017), we now focus on the crystal structure and electronic properties of solids as viewed from the Maximum Hardness Principle (MHP), first formulated by Pearson in 1987. The focus is on cases where nuclear potential acting on electrons does not remain constant and where substantial modifications of the nuclear geometry take place (Generalized MHP, GMHP). We present an overview of important manifestations of the (G)MHP for solids such as (i) a tendency of metals and doped-semiconductors to undergo superconducting transition at low temperatures, (ii) propensity of many types of alloys to develop a band gap or a pseudo-gap, (iii) preference for preserving the noble gas (octet, doublet) configuration of main block element ions in the solid state, (iv) preference of Jahn-Teller systems for band-gap-opening vibronic-coupling-related lattice distortions, (v) pressure phenomena leading to localization of the electronic density, (vi) tendency to annihilate the null band gap via phase separation (while preserving the nominal chemical composition), (vii) absence of a large number of families of high-TC superconductors, (viii) resistance of most stable systems to chemical doping, etc. GMHP turns out to be an important qualitative guide in studies of solid state polymorphism and electronic phenomena. Exceptions from (G)MHP are discussed, and a more restrictive formulation of the principle is proposed.

Conformational Energy Landscape of the Ritonavir Molecule.

Conformational polymorphism of ritonavir, a well-known pharmaceutical drug, is intricately linked to its efficacy in the treatment of acquired immunodeficiency syndrome (AIDS). Polymorphic transition from the crystalline form I to form II leads to the loss of bioactivity. The constituent ritonavir molecules adopt a trans configuration about the carbamate torsion angle in the form I crystal, and a cis configuration in the form II crystal. Investigating the energetics and mechanistic features of conformational transitions at the single molecule level is a key step toward decoding the complex features of the solid state polymorphism. In this work, we employ the energy landscape framework to investigate the conformational transitions of an isolated ritonavir molecule. The landscape is explored using discrete path sampling (DPS) and visualized in terms of disconnectivity graphs. We identify two distinct funnels corresponding to the two molecular forms that are identified by crystallography. The two regions can be reliably distinguished using the carbamate torsion angle, and the corresponding interconversion rates are predicted to follow Arrhenius behavior. The results provide mechanistic insight into pathways for cis ↔ trans interconversion at the molecular level and may also help in elucidating the polymorphic transitions in the crystal state.

Conducting Reflective, Hands-On Research with Advanced Characterization Instruments: A High-Level Undergraduate Practical Exploring Solid-State Polymorphism

An undergraduate practical exercise has been designed to provide hands-on, instrument-based experience of advanced characterization techniques. A research experience approach is taken, centered around the concept of solid-state polymorphism, which requires a detailed knowledge of molecular and crystal structure to be gained by advanced analytical techniques normally considered as the preserve of a research facility. Powder and single crystal diffraction techniques are primarily required and implemented via the unique approach of the students themselves using benchtop instruments dedicated to teaching, as opposed to more complex and difficult to access research instruments. Furthermore, the manual instructions for performing the practical are delivered via an adapted Electronic Laboratory Notebook system where, for each specific aspect of the practical, students note their intentions, actions, observations, and inferences. Assessors can access the notebooks and provide targeted online feedback for each ind...

Solid-State Investigation of Polymorphism and Tautomerism of Phenylthiazole-thione: A Combined Crystallographic, Calorimetric, and Theoretical Survey

In the context of solid-state polymorphism, a detailed crystallographic and theoretical investigation has been carried out on a dimorphic phenylthiazole-derived compound (4-phenylthiazole-2-thiol, labeled here as compound 1), considered here as a potential lead compound, for which we discovered original polymorphic behavior. A detailed crystallographic study and calorimetric investigation permit us to assess the monotropic relationship between polymorphic forms, and ab initio quantum methods, combined with Monte Carlo polymorphic prediction, allow rationalization of the thiol-thione tautomeric preferential character of the compound. The experimental and theoretical conclusions prove once more that in an early process of lead compound optimization, a combination of solid-state analysis and phase prediction with modeling methods can be a fast and efficient tool to select/disable a particular compound, in addition to well-known potential alert flags such as adsorption–distribution–metabolism–excretion/toxico...

Dy, Tb, Gd and Eu complexes with low melting point and magnetic behavior

Three new complexes based on lanthanide(III) tetrakis(β-diketonate) with a tetraalkylphosphonium as counterion [P6,6,6,14][Ln(NTA)4] (Ln=Dy (1), Tb (2), Gd (3); NTA=naphthoyltrifluoroacetone; P6,6,6,14=trihexyl(tetradecyl)phosphonium) were synthesized. The complexes were fully characterized and their spectroscopic, thermal and magnetic properties were evaluated, together with the Eu (4) analogue. The Dy (1) compound showed solvatochromic properties, the Tb (2) compound presented an unprecedented solid state polymorphism never observed in an organometallic compound and all complexes presented paramagnetic behavior with no interactions between the magnetic moments.

Solid-state investigation on a new dimorphic substituted N-salicylidene compound: insights into its thermochromic behaviour

The solid-state polymorphism behaviour of a new thermochromic mechanosynthesized compound derived fromortho-vanillin is investigated through SCXRD andab initioprediction methods.

Solid-State Supramolecular Synthesis Based on the N–H…O Heterosynthon: An Approach to Solve the Polymorphism Problem in Famotidine

Famotidine (FMT), a histamine H2 -receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single-crystal X-ray diffraction reveals that (FMT)(+) in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three-dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)(+) side chain. Nonconventional π-stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT.

The risk of recrystallization: changes to the toxicity and morphology of pyrimethamine.

Pyrimethamine, an anti-malarial agent known to exhibit solid state polymorphism, may be purified by means of recrystallization. Recrystallization may alter the solid state chemistry of pharmaceuticals, which may impact the toxicity and/or manufacturability thereof. We evaluated the risks associated with the recrystallization of pyrimethamine. Pyrimethamine was recrystallized using several organic solvents. X-ray diffraction, thermal analysis, infra-red spectroscopy, microscopy, flowability -, solubility and dissolution testing as well as computational work were employed to evaluate the recrystallized products. A toxic solvatomorph of pyrimethamine (Pyr-MeOH) was found to be the product from methanol recrystallization. The elucidation of - and the elaboration on the unique characteristics of Pyr-MeOH provides the pharmaceutical industry with several means to identify Pyr-MeOH and to distinguish it from the pharmaceutically preferred anhydrous form (Pyr). Thermal methods of analysis found that the toxicity of Pyr-MeOH may be reversed by overcoming a desolvation activation energy of 148 kJ/mol. In addition it was found that recrystallization altered the morphology of Pyr. Angle of repose and tapped density determinations identified that the different morphologies of Pyr displayed differences in powder flow and compressibility behaviour and In Silico calculations were successful in rendering morphologies resembling that found experimentally. We present a solvatomorph of pyrimethamine and provide several characteristic means to identify this unwanted toxic form and quantified the energy required to overcome its toxicity. In addition we describe that Pyr may present in different morphologies and show how it may impact the manufacturability thereof.

Molecular dynamics of 4-cyano-3-fluorophenyl 4-butylbenzoate (4CFPB) glass-forming liquid crystal in unidirectional silicon nanopores

Complex dynamics of 4-cyano-3-fluorophenyl 4-butylbenzoate (4CFPB) in cylindrical non-intersecting nanopores, mean diameters 6 nm and 8 nm was studied by broadband dielectric spectroscopy. For relaxation processes ascribed to the flip-flop, reptation-like and collective motions, the short- and long-range time correlations were estimated and discussed. Size effect and differences in ordering of molecules in pores during cooling and heating runs were found. On cooling, vitrification occurred in pores, similarly as in bulk, while on heating two-step ordering of molecules along pore walls was evidenced by subsequent diminishing of ε″max(T). Explanation based on data concerning solid state polymorphism of 4CFPB in bulk is given.

Time-Dependent Solid-State Polymorphism of a Series of Donor–Acceptor Dyads

In order to exploit the use of favorable electrostatic interactions between aromatic units in directing the assembly of donor-acceptor (D-A) dyads, the present work examines the ability of conjugated aromatic D-A dyads with symmetric side chains to exhibit solid-state polymorphism as a function of time during the solid formation process. Four such dyads were synthesized and their packing in the solid-state from either slower (10-20 days) or faster (1-2 days) evaporation from solvent was investigated using single crystal X-ray analysis and powder X-ray diffraction. Two of the dyads exhibited tail-to-tail (A-A) packing upon slower evaporation from solvent and head-to-tail (D-A) packing upon faster evaporation from solvent. A combination of single crystal analysis and XRD patterns were used to create models wherein a packing model for the other two dyads is proposed. Our findings suggest that while side chain interactions in asymmetric aromatic dyads can play an important role in enforcing segregated D-A dyad assembly, slowly evaporating symmetrically substituted aromatic dyads allows for favorable electrostatic interactions between the aromatic moieties to facilitate the organization of the dyads in the solid-state.