Experimental and Computational Hydrate Screening: Cytosine, 5‑Flucytosine, and Their Solid Solution

The structural, temperature-, and moisture-dependent stability features of cytosine and 5-flucytosine monohydrates, two pharmaceutically important compounds, were rationalized using complementary experimental and computational approaches. Moisture sorption/desorption, water activity, thermal analysis, and calorimetry were applied to determine the stability ranges of hydrate ↔ anhydrate systems, while X-ray diffraction, IR spectroscopy, and crystal structure prediction provided the molecular level understanding. At 25 °C, the critical water activity for the cytosine hydrate ↔ anhydrate system is ∼0.43 and for 5-flucytosine ∼0.41. In 5-flucytosine the water molecules are arranged in open channels; therefore, the kinetic desorption data, dehydration at < 40% relative humidity (RH), conform with the thermodynamic data, whereas for the cytosine isolated site hydrate dehydration was observed at RH < 15%. Peritectic dissociation temperatures of the hydrates were measured to be 97 and 84 °C for cytosine and 5-flucytosine, respectively, and the monohydrate to anhydrate transition enthalpies to be around 10 kJ mol^–1. Computed crystal energy landscapes not only revealed that the substitution of C5 (H or F) controls the packing and properties of cytosine/5-flucytosine solid forms but also have enabled the finding of a monohydrate solid solution of the two substances, which shows increased thermal- and moisture-dependent stability compared to 5-flucytosine monohydrate

Structural, Spectroscopic, and Computational Studies on Tl₄Si₅O₁₂: A Microporous Thallium Silicate

Single crystals of the previously unknown thallium silicate Tl₄Si₅O₁₂ have been prepared from hydrothermal crystallization of a glassy starting material at 500 °C and 1kbar. Structure analysis resulted in the following basic crystallographic data: monoclinic symmetry, space group <i>C</i>2/<i>c</i>, <i>a</i> = 9.2059(5) Å, <i>b</i> = 11.5796(6) Å, <i>c</i> = 13.0963(7) Å, β = 94.534(5)°. From a structural point of view the compound can be classified as an interrupted framework silicate with Q³- and Q⁴-units in the ratio 2:1. Within the framework 4-, 6-, and 12-membered rings can be distinguished. The framework density of 14.4 T-atoms/1000 ų is comparable with the values observed in zeolitic materials like Linde type A, for example. The thallium cations show a pronounced one-sided coordination each occupying the apex of a distorted trigonal TlO₃ pyramid. Obviously, this reflects the presence of a stereochemically active 6s² lone pair electron. The porous structure contains channels running along [110] and [−1 1 0], respectively, where the Tl⁺ cations are located for charge compensation. Structural investigations have been completed by Raman spectroscopy. The interpretation of the spectroscopic data and the allocation of the bands to certain vibrational species have been aided by DFT calculations, which were also employed to study the electronic structure of the compound

Insights into Hydrate Formation and Stability of Morphinanes from a Combination of Experimental and Computational Approaches

Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl^– counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group <i>P</i>2₁2₁2₁. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of the different compounds exhibit only little structural variation. Anhydrous polymorphs were detected for all compounds except ethylmorphine (one anhydrate) and its hydrochloride salt (no anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential scanning and isothermal calorimetry were employed to estimate the heat of the hydrate ↔ anhydrate phase transformations, indicating an enthalpic stabilization of the respective hydrate of 5.7 to 25.6 kJ mol^–1 relative to the most stable anhydrate. These results are in qualitative agreement with static 0 K lattice energy calculations for all systems except morphine hydrochloride, showing the need for further improvements in quantitative thermodynamic prediction of hydrates having water···water interactions. Thus, the combination of a variety of experimental techniques, covering temperature- and moisture-dependent stability, and computational modeling allowed us to generate sufficient kinetic, thermodynamic and structural information to understand the principles of hydrate formation of the model compounds. This approach also led to the detection of several new crystal forms of the investigated morphinanes

Insights into Hydrate Formation and Stability of Morphinanes from a Combination of Experimental and Computational Approaches

Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl^– counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group <i>P</i>2₁2₁2₁. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of the different compounds exhibit only little structural variation. Anhydrous polymorphs were detected for all compounds except ethylmorphine (one anhydrate) and its hydrochloride salt (no anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential scanning and isothermal calorimetry were employed to estimate the heat of the hydrate ↔ anhydrate phase transformations, indicating an enthalpic stabilization of the respective hydrate of 5.7 to 25.6 kJ mol^–1 relative to the most stable anhydrate. These results are in qualitative agreement with static 0 K lattice energy calculations for all systems except morphine hydrochloride, showing the need for further improvements in quantitative thermodynamic prediction of hydrates having water···water interactions. Thus, the combination of a variety of experimental techniques, covering temperature- and moisture-dependent stability, and computational modeling allowed us to generate sufficient kinetic, thermodynamic and structural information to understand the principles of hydrate formation of the model compounds. This approach also led to the detection of several new crystal forms of the investigated morphinanes

Nanoindentation, High-Temperature Behavior, and Crystallographic/Spectroscopic Characterization of the High-Refractive-Index Materials TiTa₂O₇ and TiNb₂O₇

Colorless single crystals, as well as polycrystalline samples of TiTa₂O₇ and TiNb₂O₇, were grown directly from the melt and prepared by solid-state reactions, respectively, at various temperatures between 1598 K and 1983 K. The chemical composition of the crystals was confirmed by wavelength-dispersive X-ray spectroscopy, and the crystal structures were determined using single-crystal X-ray diffraction. Structural investigations of the isostructural compounds resulted in the following basic crystallographic data: monoclinic symmetry, space group <i>I</i>2<i>/m</i> (No. 12), <i>a</i> = 17.6624(12) Å, <i>b</i> = 3.8012(3) Å, <i>c</i> = 11.8290(9) Å, β = 95.135(7)°, <i>V</i> = 790.99(10) ų for TiTa₂O₇ and <i>a</i> = 17.6719(13) Å, <i>b</i> = 3.8006(2) Å, <i>c</i> = 11.8924(9) Å, β = 95.295(7)°, <i>V</i> = 795.33(10) ų, respectively, for TiNb₂O₇, <i>Z</i> = 6. Rietveld refinement analyses of the powder X-ray diffraction patterns and Raman spectroscopy were carried out to complement the structural investigations. In addition, <i>in situ</i> high-temperature powder X-ray diffraction experiments over the temperature range of 323–1323 K enabled the study of the thermal expansion tensors of TiTa₂O₇ and TiNb₂O₇. To determine the hardness (<i>H</i>), and elastic moduli (<i>E</i>) of the chemical compounds, nanoindentation experiments have been performed with a Berkovich diamond indenter tip. Analyses of the load–displacement curves resulted in a hardness of <i>H</i> = 9.0 ± 0.5 GPa and a reduced elastic modulus of <i>E</i>_r = 170 ± 7 GPa for TiTa₂O₇. TiNb₂O₇ showed a slightly lower hardness of <i>H</i> = 8.7 ± 0.3 GPa and a reduced elastic modulus of <i>E</i>_r = 159 ± 4 GPa. Spectroscopic ellipsometry of the polished specimens was employed for the determination of the optical constants <i>n</i> and <i>k</i>. TiNb₂O₇ as well as TiTa₂O₇ exhibit a very high average refractive index of <i>n</i>_D = 2.37 and <i>n</i>_D = 2.29, respectively, at λ = 589 nm, similar to that of diamond (<i>n</i>_D = 2.42)

Mechanical Properties, Quantum Mechanical Calculations, and Crystallographic/Spectroscopic Characterization of GaNbO₄, Ga(Ta,Nb)O₄, and GaTaO₄

Single crystals as well as polycrystalline samples of GaNbO₄, Ga­(Ta,Nb)­O₄, and GaTaO₄ were grown from the melt and by solid-state reactions, respectively, at various temperatures between 1698 and 1983 K. The chemical composition of the crystals was confirmed by wavelength-dispersive electron microprobe analysis, and the crystal structures were determined by single-crystal X-ray diffraction. In addition, a high-P–T synthesis of GaNbO₄ was performed at a pressure of 2 GPa and a temperature of 1273 K. Raman spectroscopy of all compounds as well as Rietveld refinement analysis of the powder X-ray diffraction pattern of GaNbO₄ were carried out to complement the structural investigations. Density functional theory (DFT) calculations enabled the assignment of the Raman bands to specific vibrational modes within the structure of GaNbO₄. To determine the hardness (<i>H</i>) and elastic moduli (<i>E</i>) of the compounds, nanoindentation experiments have been performed with a Berkovich diamond indenter tip. Analyses of the load–displacement curves resulted in a high hardness of <i>H</i> = 11.9 ± 0.6 GPa and a reduced elastic modulus of <i>E</i>_r = 202 ± 9 GPa for GaTaO₄. GaNbO₄ showed a lower hardness of <i>H</i> = 9.6 ± 0.5 GPa and a reduced elastic modulus of <i>E</i>_r = 168 ± 5 GPa. Spectroscopic ellipsometry of the polished GaTa_0.5Nb_0.5O₄ ceramic sample was employed for the determination of the optical constants <i>n</i> and <i>k</i>. GaTa_0.5Nb_0.5O₄ exhibits a high average refractive index of <i>n</i>_D = 2.20, at λ = 589 nm. Furthermore, <i>in situ</i> high-temperature powder X-ray diffraction experiments enabled the study of the thermal expansion tensors of GaTaO₄ and GaNbO₄, as well as the ability to relate them with structural features

Conformational Flexibility and Cation–Anion Interactions in 1-Butyl-2,3-dimethylimidazolium Salts

The butyl group in 1-butyl-2,3-dimethylimidazolium (BMMI) salts, a common group of low-melting solids, was found to exhibit different conformations in the solid state. Crystal structures of pure BMMI azide, thiocyanate, propynoate, hexachlorocerate­(IV), chlorocyanocuprate­(I), nonachlorodititanate­(IV), and mixed azide/chloride and cyanide/chloride salts were determined by single crystal X-ray diffraction, and their butyl chain conformations were examined. The twist angle of the C­(α)–C­(β) bond out of the plane of the imidazole ring ranges from 57° to 90°, whereas the torsion angle along the C­(α)–C­(β) bond determines the overall conformation: 63° to 97° (gauche) and 170° to 179° (trans). The preferred conformations of the butyl group are trans–trans and gauche–trans, but trans–gauche and gauche–gauche were also observed. More than one conformer was present in disordered structures. Numerous polar hydrogen bonds between cations and anions were identified. Five structures exhibit stacking of the aromatic imidazole systems, indicated by parallel alignment of pairs of cations with short centroid–centroid distances due to π–π interactions, which is surprisingly frequent. Not only imidazole ring protons are involved in the formation of short CH···X hydrogen bonds, but also interactions between methylene and methyl groups of the alkyl chain and the anion are visible. Hirshfeld surface analysis revealed that nonpolar H···H contacts represent the majority of interactions. The volume-based lattice potential energy, enthalpy, entropy, and free energy were calculated by density functional theory. Calculated and experimental molecular volumes in the range from 0.27 to 0.70 nm³ agreed favorably, thus facilitating reliable predictions of volume-derived properties

New Solvates of an Old Drug Compound (Phenobarbital): Structure and Stability

The solvent formation of phenobarbital, an important drug compound with an unusually complex polymorphic behavior, was studied in detail. Monosolvates with acetonitrile, nitromethane, dichloromethane, and 1,4-dioxane were produced and characterized by single-crystal and powder X-ray diffraction, thermoanalytical methods, FT-IR, Raman, and solid-state NMR spectroscopy. Thermal desolvation of these compounds yields mainly mixtures of polymorphs <b>III</b>, <b>II</b>, and <b>I</b>. At a low relative humidity (25 °C) the solvates transform to polymorph <b>III</b>, and at higher relative humidity the monohydrate and the metastable polymorphs <b>IV</b> and <b>VI</b> can be present as additional desolvation products. These results highlight the potential complexity of desolvation reactions and illustrate that a tight control of ambient conditions is a prerequisite for the production of phase-pure raw materials of drug compounds. Transformation in aqueous media results in the monohydrate. Below room temperature, the 1,4-dioxane monosolvate undergoes a reversible single-crystal-to-single-crystal phase transition due to the ordering/disordering of 50% of its solvent molecules. Dipolar-dephasing NMR experiments show that the solvent molecules are relatively mobile. Deuterium NMR spectra reinforce that conclusion for the dioxane solvent molecules. The crystal structure of an elusive 1,4-dioxane hemisolvate was also determined. This study clearly indicates the existence of “transient solvates” of phenobarbital. The formation of unstable phases of this kind must be considered in order to better understand how different solvents affect the crystallization of specific polymorphs

Solid-State Forms of β-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be?

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with <i>N</i>,<i>N</i>-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the <i>p</i>-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found

Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate

The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at <i>a</i>_w (water activity) = 0.15 at 25 °C. Structures have been derived from single crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher energy structure on a computationally generated crystal energy landscape, which has the anhydrate crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)­sorption, and thermo-analytical methods with the computationally generated crystal energy landscape and lattice energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two monotropically related dimethyl sulfoxide monosolvates were found in the accompanying solid form screen