Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical.

Five anhydrate polymorphs (forms I-V) and the isomorphic dehydrate (Hydehy) of dapsone (4,4'-diaminodiphenyl sulfone or DDS) were prepared and characterized in an interdisciplinary experimental and computational study, elucidating the kinetic and thermodynamic stabilities, solid form interrelationships, and structural features of the known forms I-IV, the novel polymorph form V, and Hydehy. Calorimetric measurements, solubility experiments, and lattice energy calculations revealed that form V is the thermodynamically stable polymorph from absolute zero to at least 90 °C. At higher temperatures, form II, and then form I, becomes the most stable DDS solid form. The computed 0 K stability order (lattice energy calculations) was confirmed with calorimetric measurements as follows, V (most stable) > III > Hydehy > II > I > IV (least stable). The discovery of form V was complicated by the fact that the metastable but kinetically stabilized form III shows a higher nucleation and growth rate. By combining laboratory powder X-ray diffraction data and ab initio calculations, the crystal structure of form V ( P21/ c, Z' = 4) was solved, with a high energy DDS conformation allowing a denser packing and more stable intermolecular interactions, rationalizing the formation of a high Z' structure. The structures of the forms I and IV, only observed from the melt and showing distinct packing features compared to the forms II, III, and V, were derived from the computed crystal energy landscapes. Dehydration modeling of the DDS hydrate led to the Hydehy structure. This study expands our understanding about the complex crystallization behavior of pharmaceuticals and highlights the big challenge in solid form screening, especially that there is no clear end point.

Understanding the Role of Water in 1,10-Phenanthroline Monohydrate.

The solid forms emerging from an experimental screening programme of 1,10-phenanthroline (o-phen), a heavily used bidentate ligand, and interconversion pathways of its two neat forms, the monohdyrate (Hy1) and four solvates with acetone, chloroform, dichloromethane and 1,2-dichloroethane are described. The solvates, identified and characterised with thermoanalyical methods, are unstable when removed from the mother liquor and desolvate at room temperature depending on the relative humidity (RH) to anhydrate I° (AH I°) or transform to Hy1. At ambient conditions Hy1, a stoichiometric channel hydrate, is the thermodynaically most stable o-phen solid form. The enthalpically stabilised Hy1 melts at 102 °C or dehydrates to AH I° at RH < 10% at 25 °C. The potential energy difference between Hy1 and AH I° was calculated to be approx. 15 kJ mol-1. The second anhydrate polymorph (AH II) can be obatined from the quench cooled melt of o-phen, but is unstable at ambient conditions and transforms wihtin minutes to either AH I° or Hy1. The two neat polymorphs are enantiotropically related and water-free o-phen transforms to Hy1 at RH > 16%. The structural and stablity features of the solid forms, in paricular Hy1, are unravelled by a combination of experimental (thermal analysis, moisture sorption/desorption and storage experiments, infrared spectroscopy and powder X-ray diffraction) and computational modelling (crystal structure prediction and lattice energy calculations), providing a consistent picture why o-phen forms a very stable Z' = 3 channel hydrate.

New Insights into Solid Form Stability and Hydrate Formation: o-Phenanthroline HCl and Neocuproine HCl.

The moisture- and temperature dependent stabilities and interrelation pathways of the practically relevant solid forms of o-phenanthroline HCl (1) and neocuproine HCl (2) were investigated using thermal analytical techniques (HSM, DSC and TGA) and gravimetric moisture sorption/desorption studies. The experimental stability data were correlated with the structural changes observed upon dehydration and the pairwise interaction and lattice energies calculated. For 1 the monohydrate was identified as the only stable form under conditions of RH typically found during production and storage, but at RH values >80% deliquescence occurs. The second compound, 2, forms an anhydrate and two different hydrates, mono- (2-Hy1) and trihydrate (2-Hy3). The 2-Hy1 structure was solved from SCXRD data and the anhydrate structure derived from a combination of PXRD and CSP. Depending on the environmental conditions (moisture) either 2-Hy1 or 2-Hy3 is the most sable solid form of 2 at RT. The monohydrates 1-Hy1 and 2-Hy1 show a high enthalpic stabilization (≥20 kJ mol-1) relative to the anhydrates. The anhydrates are unstable at ambient conditions and readily transform to the monohydrates even in the presence of traces of moisture. This study demonstrates how the right combination of experiment and theory can unravel the properties and interconversion pathways of solid forms.

Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms.

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.

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 Cmce (Z = 8) with the lattice parameters a = 1050.7(2) pm, b = 743.6(2) pm, c = 1077.3(2) pm, and V = 0.8417(3) nm(3). 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.

4-Aminoquinaldine monohydrate polymorphism: Prediction and impurity aided discovery of a difficult to access stable form.

Crystal structure prediction studies indicated the existence of an unknown high density monohydrate structure (Hy1B°) as global energy minimum for 4-aminoquinaldine (4-AQ). We thus performed an interdisciplinary experimental and computational study elucidating the crystal structures, solid form inter-relationships, kinetic and thermodynamic stabilities of the stable anhydrate (AH I°), the kinetic monohydrate (Hy1A ) and this novel monohydrate polymorph (Hy1B°) of 4-AQ. The crystal structure of Hy1B° was determined by combining laboratory powder X-ray diffraction data and ab initio calculations. Dehydration studies with differential scanning calorimetry and solubility measurements confirmed the result of the lattice energy calculations, which identified Hy1B° as the thermodynamically most stable hydrate form. At 25 °C the equilibrium of the 4-AQ hydrate/anhydrate system was observed at an aw (water activity) of 0.14. The finding of Hy1B° was complicated by the fact that the metastable but kinetically stable Hy1A shows a higher nucleation and growth rate. The presence of an impurity in an available 4-AQ sample facilitated the nucleation of Hy1B°, whose crystallisation is favored under hydrothermal conditions. The value of combining experimental with theoretical studies in hydrate screening and characterisation, as well as the reasons for hydrate formation in 4-AQ, are discussed.

Solid state forms of 4-aminoquinaldine - From void structures with and without solvent inclusion to close packing.

Polymorphs of 4-aminoquinaldine (4-AQ) have been predicted in silico and experimentally identified and characterised. The two metastable forms, AH (anhydrate) II and AH III, crystallise in the trigonal space group [Formula: see text] and are less densely packed than the thermodynamically most stable phase AH I° (P21/c ). AH II can crystallise and exist both, as a solvent inclusion compound and as an unsolvated phase. The third polymorph, AH III, is exclusively obtained by desolvation of a carbon tetrachloride solvate. Theoretical calculations correctly estimated the experimental 0K stability order, confirmed that AH II can exist without solvents, gave access to the AH III structure, and identified that there exists a subtle balance between close packing and number of hydrogen bonding interactions in the solid state of anhydrous 4-AQ. Furthermore, the prevalence of void space and solvent inclusion in [Formula: see text] structures is discussed.

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 P212121. 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.

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 I(0), III, IV, and V) 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 I(0), III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I(0)/III, I(0)/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I(0) > III > V > IV. The metastable modification III 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 IV.

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.

Telaprevir: helical chains based on three-point hydrogen-bond connections.

The crystal structure of the title compound [systematic name: (1S,3aR,6aS)-2-((2S)-2-{[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino}-3,3-dimethylbutanoyl)-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide], C(36)H(53)N(7)O(6), contains two independent molecules, which possess distinct conformations and a disordered cyclopenta[c]pyrrolidine unit. In the crystal, molecules are linked into helical chains via three-point N-H···O hydrogen-bond connections in which three NH and three carbonyl groups per molecule are utilized. The chiralities of the six stereocentres per molecule inferred from this study are in agreement with the synthetic procedure.

Alogliptin and its benzoate salt.

The crystal structure of the free base of the antidiabetic drug alogliptin [systematic name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile], C18H21N5O2, displays a two-dimensional N-H···O hydrogen-bonded network. It contains two independent molecules, which have the same conformation but differ in their hydrogen-bond connectivity. In the crystal structure of the benzoate salt (systematic name: (3R)-1-{3-[(2-cyanophenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl}piperidin-3-aminium benzoate), C18H22N5O2(+)·C7H5O2(-), the NH3(+) group of the cation is engaged in three intermolecular N-H···O hydrogen bonds to yield a hydrogen-bonded layer structure. The benzoate salt and the free base differ fundamentally in the conformations of their alogliptin moieties.

Stable polymorph of morphine.

In the stable polymorph of the title compound, C17H19NO3 [systematic name: (5α,6α)-7,8-didehydro-4,5-ep-oxy-17-methyl-morphinan-3,6-diol], the mol-ecular conformation is in agreement with the characteristics of previously reported morphine forms. The molecule displays the typical T-shape and its piperidine ring adopts a slightly distorted chair conformation. Inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into helical chains parallel to the b axis. Intra-molecular O-H⋯O hydrogen bonds are also observed.

Iclaprim mesylate displaying a hydrogen-bonded mol-ecular tape.

The title compound, 2,6-di-amino-5-[(2-cyclo-propyl-7,8-dimeth-oxy-2H-1-benzo-pyran-5-yl)meth-yl]pyrimidin-1-ium methane-sulfonate, C19H23N4O3 +·CH3O3S-, is a salt made up from a protonated iclaprim mol-ecule and a mesylate anion. The pyrimidine and chromene units of the iclaprim mol-ecule form an orthogonal arrangement [inter-planar angle of 89.67 (6)°], and the 3-nitro-gen position of the pyrimidine ring is protonated. Four distinct N-H⋯O inter-actions and an additional N-H⋯N hydrogen bond connect iclaprim and mesylate mol-ecules to one another, resulting in an infinite hydrogen-bonded mol-ecular tape structure. The central section of the tape is formed by a sequence of fused hydrogen-bonded rings involving four distinct ring types.

Two polymorphs and the diethylammonium salt of the barbiturate eldoral.

Polymorph (Ia) of eldoral [5-ethyl-5-(piperidin-1-yl)barbituric acid or 5-ethyl-5-(piperidin-1-yl)-1,3-diazinane-2,4,6-trione], C(11)H(17)N(3)O(3), displays a hydrogen-bonded layer structure parallel to (100). The piperidine N atom and the barbiturate carbonyl group in the 2-position are utilized in N-H···N and N-H···O=C hydrogen bonds, respectively. The structure of polymorph (Ib) contains pseudosymmetry elements. The two independent molecules of (Ib) are connected via N-H···O=C(4/6-position) and N-H···N(piperidine) hydrogen bonds to give a chain structure in the [100] direction. The hydrogen-bonded layers, parallel to (010), formed in the salt diethylammonium 5-ethyl-5-(piperidin-1-yl)barbiturate [or diethylammonium 5-ethyl-2,4,6-trioxo-5-(piperidin-1-yl)-1,3-diazinan-1-ide], C(4)H(12)N(+)·C(11)H(16)N(3)O(3)(-), (II), closely resemble the corresponding hydrogen-bonded structure in polymorph (Ia). Like many other 5,5-disubstituted derivatives of barbituric acid, polymorphs (Ia) and (Ib) contain the R(2)(2)(8) N-H···O=C hydrogen-bond motif. However, the overall hydrogen-bonded chain and layer structures of (Ia) and (Ib) are unique because of the involvement of the hydrogen-bond acceptor function in the piperidine group.

Morphine hydro-chloride anhydrate.

In the title mol-ecular salt [systematic name: (5α,6α)-7,8-didehydro-4,5-ep-oxy-17-methyl-morphinan-3,6-diol hydro-chloride], C17H20NO3(+)·Cl(-), the conformation of the morphinium ion is in agreement with the characteristics of the previously reported morphine forms [for example, Gylbert (1973 ▶). Acta Cryst. B29, 1630-1635]. In the crystal, the cations and chloride anions are linked into a helical chain propagating parallel to the b-axis direction by N-H⋯Cl and O-H⋯Cl hydrogen bonds. The title salt and the morphine monohydrate [Bye (1976 ▶) Acta Chem. Scand.30, 549-554] display very similar one-dimensional packing modes of their morphine components.

Tetra-gonal polymorph of 5,5-dichloro-barbituric acid.

The tetra-gonal polymorph of 5,5-dichloro-barbituric acid (m.p. 478 K), C(4)H(2)Cl(2)N(2)O(3), forms an N-H⋯O hydrogen-bonded tape structure along [001]. Two tapes related by a twofold rotation axis are associated via Cl⋯O contacts [3.201 (1) Å], and four such chain pairs are arranged around a fourfold roto-inversion axis. The crystal structures of the monoclinic and ortho-rhom-bic polymorphs have been reported previously [Gelbrich et al. (2011 ▶). CrystEngComm, 13, 5502-5509].

Crystal structure, PIXEL calculations of inter-molecular inter-action energies and solid-state characterization of the herbicide isoxaflutole.

In the isoxaflutole mol-ecule {systematic name: (5-cyclo-propyl-1,2-oxazol-4-yl)[2-(methyl-sulfon-yl)-4-(tri-fluoro-meth-yl)phen-yl]methanone; C15H12F3NO4S}, the 1,2-oxazole and methanone fragments form an almost coplanar unit, whereas the methanone and phenyl mean planes are inclined by an angle of more than 60°. This conformation differs fundamentally from all other known examples of the 1,2-oxazol-4-yl(phen-yl)methanone fragment and is ascribed to the presence of the bulky methyl-sulfonyl para substituent at the phenyl ring. PIXEL calculations reveal that the largest contributions to the stabilization of the crystal persist within a columnar arrangement of mol-ecules along the twofold screw axis and in inter-actions between adjacent columns related by an inversion operation. Both these intra-column and inter-column motifs are dominated by the dispersion energy term but also display additional significant stabilization effects as a result of three short inter-molecular C-H⋯O contacts involving the methane-sulfonyl-O atoms.

A tale of two polymorphic pharmaceuticals: pyrithyldione and propyphenazone and their 1937 co-crystal patent.

A co-crystal of two polymorphic active pharmaceutical ingredients (APIs), first reported and patented in 1937, has been prepared and thoroughly characterised, including crystal structure analysis. The existence of four crystal forms of one of the APIs, the sedative and hypnotic active pharmaceutical ingredient 3,3-diethyl-2,4(1H,3H)-pyridinedione, pyrithyldione (PYR), and of three crystal forms of the co-crystal-forming second API, the non-steroidal anti-inflammatory drug 1,2-dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenyl-3H-pyrazol-3-one, propyphenazone (PROP), has been reported previously, but they have only been partly characterised. For both compounds, none of the metastable forms exist at room temperature. DSC, hot-stage microscopy, X-ray diffraction and powder synchrotron X-ray diffraction were employed to characterise the polymorphic forms and to determine the crystal structures of forms I-III of PYR and forms I and II of PROP.

Plumeridoid C from the Amazonian traditional medicinal plant Himatanthus sucuuba.

The stereochemistry of the iridoid plumeridoid C, C(15)H(18)O(7), was established by X-ray single-crystal structure analysis, giving (2'R,3R,4R,4aS,7aR)-methyl 3-hydroxy-4'-[(S)-1-hydroxyethyl]-5'-oxo-3,4,4a,7a-tetrahydro-1H,5'H-spiro[cyclopenta[c]pyran-7,2'-furan]-4-carboxylate. The absolute structure of the title compound was determined on the basis of the Flack x parameter and Bayesian statistics on Bijvoet differences. The hydrogen-bond donor and acceptor functions of the two hydroxy groups are employed in the formation of O-H···O-bonded helical chains.