Search

Two bipyridine isomers (2,2′- and 4,4′-), used as coformers and ligands in coordination chemistry, were subjected to solid form screening and crystal structure prediction. One anhydrate and a formic acid disolvate were crystallized for 2,2′-bipyridine, whereas multiple solid-state forms, anhydrate, dihydrate, and eight solvates with carboxylic acids, including a polymorphic acetic acid disolvate, were found for the 4,4′-isomer. Seven of the solvates are reported for the first time, and structural information is provided for six of the new solvates. All twelve solid-state forms were investigated comprehensively using experimental [thermal analysis, isothermal calorimetry, X-ray diffraction, gravimetric moisture (de)sorption, and IR spectroscopy] and computational approaches. Lattice and interaction energy calculations confirmed the thermodynamic driving force for disolvate formation, mediated by the absence of H-bond donor groups of the host molecules. The exposed location of the N atoms in 4,4′-bipyridine facilitates the accommodation of bigger carboxylic acids and leads to higher conformational flexibility compared to 2,2′-bipyridine. For the 4,4′-bipyridine anhydrate ↔ hydrate interconversion hardly any hysteresis and a fast transformation kinetics are observed, with the critical relative humidity being at 35% at room temperature. The computed anhydrate crystal energy landscapes have the 2,2′-bipyridine as the lowest energy structure and the 4,4′-bipyridine among the low-energy structures and suggest a different crystallization behavior of the two compounds., The solid form landscapes of 2,2′- and 4,4′-bipyridine were explored experimentally and computationally. The position of the nitrogen atoms defines not only the conformational flexibility of the molecule but also the crystallization behavior. 4.4′-Bipyridine was found to be more prone to solvate (including hydrate) formation than its 2,2′-isomer.

The reversible solid-state phase transformation between the neat forms II and III of dapsone (DDS) was studied using thermal analytical methods, variable temperature X-ray diffraction and solid-state modeling at the electronic level. The first order III ↔ II phase transformation occurs at 78 ± 4 °C with a heat of transition of 2 kJ mol–1 and a small hysteresis. The two isosymmetric polymorphs (both P212121) differ only in movement of layers of molecules and show a small variation in conformation. The combination of variable-temperature single-crystal structure determinations and pair-wise intermolecular energy calculations allowed us to unravel the single-to-single crystal transformation at a molecular level, to estimate the molecular contributions to the heat of transformation and to rationalize why the room and low temperature form III is the less dense polymorphic form, which is a rare phenomenon in enantiotropically related pairs of polymorphs in molecular crystals.

New polymorphs of thymine emerged in an experimental search for solid forms, which was guided by the computationally generated crystal energy landscape. Three of the four anhydrates (AH) are homeoenergetic (A° – C) and their packing modes differ only in the location of oxygen and hydrogen atoms. AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Anhydrates AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Analysis of the crystal energy landscape for alternative AH C hydrogen bonded ribbon motifs identified a number of different packing modes, whose 3D structures were calculated to deviate by less than 0.24 kJ mol–1 in lattice energy. These structures provide models for stacking faults. The three anhydrates A° – C show strong similarity in their powder X-ray diffraction, thermoanalytical and spectroscopic (IR and Raman) characteristics. The already known anhydrate AH A° was identified as the thermodynamically most stable form at ambient conditions; AH B and AH C are metastable but show high kinetic stability. The hydrate of thymine is stable only at water activities (aw) > 0.95 at temperatures ≤ 25 °C. It was found to be a stoichiometric hydrate despite being a channel hydrate with an unusual water:thymine ratio of 0.8:1. Depending on the dehydration conditions, either AH C or AH D is obtained. The hydrate is the only known precursor to AH D. This study highlights the value and complementarity of simultaneous explorations of computationally and experimentally generated solid form landscapes of a small molecule anhydrate ↔ hydrate system.

Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, poorly water-soluble, zwitterionic compound, has enabled the finding and characterization of its anhydrate polymorphs, including the thermodynamic room temperature form. Crystal structures of the novel forms were determined by combining laboratory powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all experimental forms but also predicted the correct stability order, which was experimentally confirmed by measurements of the heat of hydration., A computationally driven experimental search for anhydrate and hydrate solid forms of creatine enabled the finding and characterization (structure and stability) of its three polymorphs and the monohydrate. The computational method not only found the experimental forms but also correctly predicted the stability order, which was experimentally confirmed by measurements of the heat of hydration.

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 N,N-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 p-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., An extensive experimental screen, coupled with a computational study, revealed seven new solid-state forms of β-resorcylic acid. The known, stable polymorph II° shows a reversible phase transformation to the new, kinetically stable, probably disordered high temperature form I. The study provides a consistent picture of the solid-state of β-resorcylic acid.

Six of the more easily accessible forms of phenobarbital (Pbtl-I, II, III, IV, V, VI) were characterized by a variety of analytical methods (thermal analysis, solution calorimetry, X-ray diffraction methods, infrared, Raman and solid-state NMR spectroscopy), in order to get a clear picture of this complex polymorphic system and to eliminate severe inconsistencies in the existing data. On the basis of the thermochemical data and stability studies, we were able to clarify the thermodynamic relationships of the six forms with the aid of a semi-schematic energy/temperature diagram. The order of the thermodynamic stability at 20 °C was established as I > II > III > IV > V/VI, but forms I and II are energetically almost indistinguishable. This study provides a comprehensive description about the production, identification, and transformation pathways of the six polymorphs and discusses the structural origins for some of the unique solid-state phenomena of this important drug compound.

Six metastable polymorphs (V, VII−XI) of phenobarbital (Pbtl) were produced by melt crystallization via seeding with corresponding isomorphic barbiturate homologues, following the teachings of earlier thermoanalytical studies of isopolymorphic relationships and utilizing the melting phase diagrams of Pbtl admixtures with various 5,5-substituted barbituric acid derivatives. The Pbtl forms and their solid solutions were analyzed with hot-stage microscopy, powder X-ray diffraction, and infrared spectroscopy. The crystal structures of several isomorphic homologues were determined to assess the structural features of the metastable Pbtl polymorphs. In contrast to Pbtl-V, VIII, and IX, which could be isolated as a single component phase, Pbtl-VII, X, and XI could only be stabilized in the presence of one of the isomorphic additives. Form Pbtl-V, the most stable form among the six metastable polymorphs, is structurally similar to Pbtl-IV and was crystallized by seeding with co-crystals of Pbtl/rutonal (3:1). Pbt...

Three polymorphs of the calcimimetic cinacalcet hydrochloride were characterized by a variety of methods including thermal analysis (hot-stage microscopy and differential scanning calorimetry), vibrational spectroscopy (FT-IR and FT-Raman spectroscopy), and X-ray diffractometry (powder and single crystal). The crystal structures of all polymorphs have been determined either from single crystals (form III°) or from powder data (forms I and II). Forms III° and I both exhibit an orthorhombic cell with space group P212121, whereas form II crystallizes in the triclinic space group P1. All three polymorphs show basically the same hydrogen-bond synthon, and the structural differences are associated with conformational changes. In contrast to form III°, form II shows two conformationally different molecules, and in the high temperature form I the phenyl moiety is dynamically disordered. Among the three enantiotropically related polymorphs, form III° (Tfus: 165 °C) is the thermodynamically stable modification belo...

An intriguing example of conformational and color polymorphism is observed in p-tolyl-(2,4,6-trinitrophenyl)-amine (picryltoluidine, PT), which forms two crystalline modifications, the red form I R and the orange form II O . Solvated crystals with a PT/solvate ratio of 1:1 (pyridine) or 2:1 (benzene, chlorobenzene, toluene, or xylene) were obtained only from aromatic solvents, albeit with some difficulty, from aromatic solvents. The crystallization from all other tested solvents produced either a highly pure phase or a mixture of the two anhydrous forms. Single crystal structure determinations were carried out on the seven solid forms, along with a characterization by thermal analysis (hot stage microscopy, DSC, TGA), vibrational spectroscopy (IR, Raman) and X-ray powder diffraction. The PT molecules in all structures exhibit intramolecular N−H···O bonds. The different colors are attributed to intramolecular electronic effects due to an increased delocalization of the secondary amino nitrogen lone-pair el...

The structural and thermodynamic features of three polymorphic forms of the local anesthetic drug oxybuprocaine hydrochloride (OBPHC) were characterized by hot-stage microscopy, differential scanning calorimetry (DSC), pycnometry, Fourier transform infrared spectroscopy (FTIR), FT-Raman and solid-state NMR (SSNMR) spectroscopy as well as X-ray powder and single-crystal diffractometry. Mod II° crystallizes in the space group P21/n, is present in commercial products, and is the thermodynamically stable form at room temperature. Mod II° shows an endothermic transformation to mod I (mp 160 °C) at about 135 °C, indicating an enantiotropic relationship between these forms. Mod I (space group I2/a) shows a high kinetic stability and does not transform back to the more stable mod II° below the thermodynamic transition temperature (∼90 °C) on storage but does so in a solution-mediated process. Cooling mod I below −30 °C results in mod III (P21/a). This transition (Ttrs: −33 °C) is highly reversible, proving the en...

The crystal structures of seven fundamental N-aminoazolium and N,N‘-diaminoazolium chlorides were determined by single-crystal X-ray diffraction. Their hydrogen-bonding networks and lattice architectures are discussed. Lattice energies were also calculated. Powder diffraction patterns of the bulk materials were consistent with those calculated from single-crystal diffraction data.

The dehydration of a thiamine hydrochloride (vitamin B1) hydrate, commonly referred to as the monohydrate, was investigated by solid-state NMR (SSNMR) and X-ray diffraction (XRD) techniques. The hydrate can be classified as a nonstoichiometric solvate since the water content depends on the water vapor pressure of the surrounding atmosphere and essentially maintains the three-dimensional molecular arrangement upon dehydration. Thus, we were able to determine the crystal structures of both the hydrate and the isomorphic desolvate with one single crystal. The loss of water leads to a shrinkage of the unit cell volume of about 5% and to a slight increase in the free volume. This is also accompanied by an increase in molecular motion as is demonstrated by SSNMR 1H and 13C T1 measurements. The largest change in T1 was observed for the carbons of the hydroxyethyl functional group that is hydrogen bonded to the water molecules in the hydrate. This investigation confirms that an increase in free volume results in ...

This paper reports the hitherto undetermined, but previously predicted, high temperature γ-form of the amino acid d,l-norleucine. The transition to the γ-form proceeds at 391 K and has been characterized by X-ray diffraction, hot-stage microscopy, and differential scanning calorimetry. A detailed structural comparison has been made with the redetermined α- and γ-forms, which reveals a relative movement of layers within the crystal lattice and a concomitant torsional motion in the molecular structure.