Stoichiometric and Nonstoichiometric Hydrates of Brucine

The complex interplay of temperature and water activity (<i>a</i>_w)/relative humidity (RH) on the solid form stability and transformation pathways of three hydrates (<b>HyA</b>, <b>HyB</b>, and <b>HyC</b>), an isostructural dehydrate (<b>HyA</b>_<b>dehy</b>), an anhydrate (<b>AH</b>), and amorphous brucine has been elucidated and the transformation enthalpies quantified. The dihydrate (<b>HyA</b>) shows a nonstoichiometric (de)­hydration behavior at RH < 40% at 25 °C, and the removal of the water molecules results in an isomorphic dehydrate structure. The metastable dehydration product converts to <b>AH</b> upon storage at the driest conditions or to <b>HyA</b> if exposed to moisture. <b>HyB</b> is a stoichiometric tetrahydrate. The loss of the water molecules causes <b>HyB</b> to collapse to an amorphous phase. Amorphous brucine transforms to <b>AH</b> at RH < 40% RH and a mixture of hydrated phases at higher RH values. The third hydrate (<b>HyC</b>) is only stable at RH ≥ 55% at 25 °C and contains 3.65–3.85 mol equiv of water. Dehydration of <b>HyC</b> occurs in one step at RH < 55% at 25 °C or upon heating, and <b>AH</b> is obtained. The <b>AH</b> is the thermodynamically most stable phase of brucine at RH < 40% at 25 °C. Depending on the conditions, temperature, and <i>a</i>_w, each of the three hydrates becomes the thermodynamically most stable form. This study demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the stability ranges and transition behavior between the solid forms of compounds with multiple hydrates

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<p>The observed moisture- and temperature dependent transformations of the dapsone (4,4′-diaminodiphenyl sulfone, DDS) 0. 33-hydrate were correlated to its structure and the number and strength of the water-DDS intermolecular interactions. A combination of characterization techniques was used, including thermal analysis (hot-stage microscopy, differential scanning calorimetry and thermogravimetric analysis), gravimetric moisture sorption/desorption studies and variable humidity powder X-ray diffraction, along with computational modeling (crystal structure prediction and pair-wise intermolecular energy calculations). Depending on the relative humidity the hydrate contains between 0 and 0.33 molecules of water per molecule DDS. The crystal structure is retained upon dehydration indicating that DDS hydrate shows a non-stoichiometric (de)hydration behavior. Unexpectedly, the water molecules are not located in structural channels but at isolated-sites of the host framework, which is counterintuitively for a hydrate with non-stoichiometric behavior. The water-DDS interactions were estimated to be weaker than water-host interactions that are commonly observed in stoichiometric hydrates and the lattice energies of the isomorphic dehydration product (hydrate structure without water molecules) and (form III) differ only by ~1 kJ mol⁻¹. The computational generation of hypothetical monohydrates confirms that the hydrate with the unusual DDS:water ratio of 3:1 is more stable than a feasible monohydrate structure. Overall, this study highlights that a deeper understanding of the formation of hydrates with non-stoichiometric behavior requires a multidisciplinary approach including suitable experimental and computational methods providing a firm basis for the development and manufacturing of high quality drug products.</p

Why Do Hydrates (Solvates) Form in Small Neutral Organic Molecules? Exploring the Crystal Form Landscapes of the Alkaloids Brucine and Strychnine

Computational methods were used to generate and explore the crystal structure landscapes of the 2 alkaloids strychnine and brucine. The computed structures were analyzed and rationalized by correlating the modeling results to a rich pool of available experimental data. Despite their structural similarity, the 2 compounds show marked differences in the formation of solid forms. For strychnine, only 1 anhydrous form is reported in the literature and 2 new solvates from 1,4-dioxane were detected in the course of this work. In contrast, 22 solid forms are known so far to exist for brucine, comprising 2 anhydrates, 4 hydrates (<b>HyA</b> – <b>HyC</b> and a 5.25-hydrate), 12 solvates (alcohols and acetone), and 4 heterosolvates (mixed solvates with water and alcohols). For strychnine, it is hard to produce any solid form other than the stable anhydrate, while the formation of specific solid state forms of brucine is governed by a complex interplay between temperature and relative humidity/water activity and it is rather a challenge to avoid hydrate formation. Differences in crystal packing and the high tendency for brucine to form hydrates are not intuitive from the molecular structure alone, as both molecules have hydrogen bond acceptor groups but lack hydrogen bond donor groups. Only the evaluation of the crystal energy landscapes, in particular, the close-packed crystal structures and high-energy open frameworks containing voids of molecular (water) dimensions, allowed us to unravel the diverse solid state behavior of the 2 alkaloids at a molecular level. In this study we demonstrate that expanding the analysis of anhydrate crystal energy landscapes to higher energy structures and calculating the solvent-accessible volume can be used to estimate non-stoichiometric or channel hydrate (solvate) formation, without explicitly computing the hydrate/solvate crystal energy landscapes

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

Four Polymorphs of Methyl Paraben: Structural Relationships and Relative Energy Differences

Four polymorphic forms of methyl paraben (methyl 4-hydroxybenzoate, <b>1</b>), denoted <b>1-I</b> (melting point 126 °C), <b>1-III</b> (109 °C), <b>1</b>-<b>107</b> (107 °C), and <b>1</b>-<b>112</b> (112 °C), have been investigated by thermomicroscopy, infrared spectroscopy, and X-ray crystallography. The crystal structures of the metastable forms <b>1-III</b>, <b>1</b>-<b>107</b>, and <b>1</b>-<b>112</b> have been determined. All polymorphs contain the same O–H···OC connected catemer motif, but the geometry of the resulting H-bonded chain is different in each form. The <i>Z</i>′ = 3 structure of <b>1-I</b> (stable form; space group <i>Cc</i>) contains local symmetry elements. The crystal packing of each of the four known crystal structures of <b>1</b> was compared with the crystal structures of 12 chemical analogues. Close two-dimensional relationships exist between <b>1</b>-<b>112</b> and a form of methyl 4-aminobenzoate and between <b>1</b>-<b>107</b> and dimethyl terephthalate. The lattice energies of the four methyl paraben structures have been calculated with a range of methods based on ab initio electronic calculations on either the crystal or single molecule. This shows that the differences in the induction energy of the different hydrogen-bonded chain geometries have a significant effect on relative lattice energies, but that conformational energy, repulsion, dispersion, and electrostatic also contribute

The Complexity of Hydration of Phloroglucinol: A Comprehensive Structural and Thermodynamic Characterization

Hydrate formation is of great importance as the inclusion of water molecules affects many solid state properties and hence determines the required chemical processing, handling, and storage. Phloroglucinol is industrially important, and the observed differences in the morphology and diffuse scattering effects with growth conditions have been scientifically controversial. We have studied the anhydrate and dihydrate of phloroglucinol and their transformations by a unique combination of complementary experimental and computational techniques, namely, moisture sorption analysis, hot-stage microscopy, differential scanning calorimetry, thermogravimetry, isothermal calorimetry, single crystal and powder X-ray diffractometry, and crystal energy landscape calculations. The enthalpically stable dihydrate phase is unstable below 16% relative humidity (25 °C) and above 50 °C (ambient humidity), and the kinetics of hydration/dehydration are relatively rapid with a small hysteresis. A consistent atomistic picture of the thermodynamics of the hydrate/anhydrate transition was derived, consistent with the disordered single X-ray crystal structure and crystal energy landscape showing closely related low energy hydrate structures. These structures provide models for proton disorder and show stacking faults as intergrowth of different layers are possible. This indicates that the consequent variability in crystal surface features and diffuse scattering with growth conditions is not a practical concern

The Complexity of Hydration of Phloroglucinol: A Comprehensive Structural and Thermodynamic Characterization

Hydrate formation is of great importance as the inclusion of water molecules affects many solid state properties and hence determines the required chemical processing, handling, and storage. Phloroglucinol is industrially important, and the observed differences in the morphology and diffuse scattering effects with growth conditions have been scientifically controversial. We have studied the anhydrate and dihydrate of phloroglucinol and their transformations by a unique combination of complementary experimental and computational techniques, namely, moisture sorption analysis, hot-stage microscopy, differential scanning calorimetry, thermogravimetry, isothermal calorimetry, single crystal and powder X-ray diffractometry, and crystal energy landscape calculations. The enthalpically stable dihydrate phase is unstable below 16% relative humidity (25 °C) and above 50 °C (ambient humidity), and the kinetics of hydration/dehydration are relatively rapid with a small hysteresis. A consistent atomistic picture of the thermodynamics of the hydrate/anhydrate transition was derived, consistent with the disordered single X-ray crystal structure and crystal energy landscape showing closely related low energy hydrate structures. These structures provide models for proton disorder and show stacking faults as intergrowth of different layers are possible. This indicates that the consequent variability in crystal surface features and diffuse scattering with growth conditions is not a practical concern

Crystal Polymorphs of Barbital: News about a Classic Polymorphic System

Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted <b>I</b>⁰, <b>III</b>, <b>IV</b>, and <b>V</b>) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications <b>I</b>⁰, <b>III</b>, and <b>V</b> are enantiotropically related to one another. Polymorph <b>IV</b> is enantiotropically related to <b>V</b> and monotropically related to the other two forms. The transition points for the pairs <b>I</b>⁰/<b>III</b>, <b>I</b>⁰/<b>V</b>, and <b>III</b>/<b>IV</b> lie below 20 °C, and the transition point for <b>IV</b>/<b>V</b> is above 20 °C. At room temperature, the order of thermodynamic stability is <b>I</b>⁰ > <b>III</b> > <b>V</b> > <b>IV</b>. The metastable modification <b>III</b> is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N–H···OC hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph <b>IV</b>

Impact of Molecular Flexibility on Double Polymorphism, Solid Solutions and Chiral Discrimination during Crystallization of Diprophylline Enantiomers

The polymorphic behavior of racemic and enantiopure diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformational degrees of freedom of the substituent that carries the only two H-bond donor groups might be related to the versatile crystallization behavior of DPL. The control of these equilibria and the use of a suitable solvent allowed the design of an efficient protocol for the preparative resolution of racemic DPL via preferential crystallization. Therefore, the resolution of DPL enantiomers despite the existence of a racemic compound stable at any temperature demonstrates that the detection of a stable conglomerate is not mandatory for the implementation of preferential crystallization

New High-Pressure Gallium Borate Ga₂B₃O₇(OH) with Photocatalytic Activity

The new high-pressure gallium borate Ga₂B₃O₇(OH) was synthesized in a Walker-type multianvil apparatus under high-pressure/high-temperature conditions of 10.5 GPa and 700 °C. For the system Ga–B–O–H, it is only the second known compound next to Ga₉B₁₈O₃₃(OH)₁₅·H₃B₃O₆·H₃BO₃. The crystal structure of Ga₂B₃O₇(OH) was determined by single-crystal X-ray diffraction data collected at room temperature. Ga₂B₃O₇(OH) crystallizes in the orthorhombic space group <i>Cmce</i> (<i>Z</i> = 8) with the lattice parameters <i>a</i> = 1050.7(2) pm, <i>b</i> = 743.6(2) pm, <i>c</i> = 1077.3(2) pm, and <i>V</i> = 0.8417(3) nm³. Vibrational spectroscopic methods (Raman and IR) were performed to confirm the presence of the hydroxyl group. Furthermore, the band gap of Ga₂B₃O₇(OH) was estimated via quantum-mechanical density functional theory calculations. These results led to the assumption that our gallium borate could be a suitable substance to split water photocatalytically, which was tested experimentally