Cyclooxygenase-1-selective inhibitor SC-560

In the title compound, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), C17H12ClF3N2O, a COX-1-selective inhibitor, the dihedral angles between the heterocycle and the chlorobenzene and methoxybenzene rings are 41.66 (6) and 43.08 (7)°, respectively. The dihedral angle between the two phenyl rings is 59.94 (6)°. No classic hydrogen bonds are possible in the crystal, and intermolecular interactions must be mainly of the dispersion type. This information may aid the identification of dosage formulations with improved oral bioavailability....
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Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters...

The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug-polymer systems is of interest to optimize the formulation of such systems. The purpose of this work was to develop experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers. MATERIALS AND METHODS: The thermodynamics of mixing several amorphous drugs with amorphous polymers was estimated by coupling solution theory with experimental data. The entropy of mixing was estimated using Flory-Huggins lattice theory. The enthalpy of mixing and any deviations from the entropy as predicted by Flory-Huggins lattice theory were estimated using two separate experimental techniques; (1) melting point depression of the crystalline drug in the presence of the amorphous polymer was measured using differential scanning calorimetry and (2) determination of the solubility of the drug in 1-ethyl-2-pyrrolidone. The estimated activity coefficient was used to calculate the free energy of mixing of the drugs in the polymers and the corresponding solubility. RESULTS: Mixtures previously reported as miscible showed various degrees of melting point depression while systems reported as immiscible or partially miscible showed little or no melting point depression. The solubility of several compounds in 1-ethyl-2-pyrrolidone predicts that most drugs have a rather low solubility in poly(vinylpyrrolidone). CONCLUSIONS: Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug-polymer mixtures and the thermodynamic driving force for crystallization....
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Crystallization Force-A Density Functional Theory Concept for Revealing Intermolecular Interactions and Molecular Packing in Organic Crystals...

Organic molecules are prone to polymorphic formation in the solid state due to the rich diversity of functional groups that results in comparable intermolecular interactions, which can be greatly affected by the selection of solvent and other crystallization conditions. Intermolecular interactions are typically weak forces. such as van der Waals and stronger short-range ones including hydrogen bonding, that are believed to determine the packing of organic molecules during the crystal-growth process. A different packing of the same molecules leads to the formation of a new crystal structure. To disclose the underlying causes that drive the molecule to have various packing motifs in the solid state, an electronic concept or function within the framework of conceptual density functional theory has been developed. namely, crystallization force. The concept aims to describe the local change in electronic structure as a result of the self-assembly process of crystallization and may likely quantity the locality of intermolecular interactions that directs the molecular packing in a crystal. To assess the applicability of the concept, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, so-called ROY, which is known to have the largest number of solved polymorphs. has been examined. Electronic calculations were conducted on the seven available crystal structures as well as on the single molecule. The electronic structures were analyzed and crystallization force values were obtained. The results indicate that the crystallization forces are able to reveal intermolecular interactions in the crystals, in particular, the close contacts that are formed between molecules. Strong correlations exist between the total crystallization force and lattice energy of a crystal structure, further suggesting the underlying connection between the crystallization force and molecular packing....
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Polymorphism of a Simple Organic Amide

Glycolanilide (2-hydroxy-N-phenylacetamide), a simple amide, may be reproducibly crystallized in either of two polymorphic forms. The crystal and molecular structures of each polymorph have been determined, revealing that the two polymorphs differ in the extent and arrangement of intermolecular hydrogen bonding. The more stable polymorph displays one-dimensional chains linked through hydrogen bonds between the amide carbonyl and the alpha-hydroxyl group. In the metastable polymorph, analogous chain structures are overlain with cyclic hydrogen-bonded amide dimers, with an additional set of hydrogen bonding contacts joining the chain and cyclic motifs....
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Polymorphism and Phase Behaviors of 2-(Phenylamino)nicotinic Acid...

The discovery and phase transition studies of four polymorphs of 2-(phenylamino)nicotinic acid are described in this report. The four polymorphs were crystallized from solution under different conditions. All polymorphs differ in the degree of conjugation of the two aromatic rings and thus are of conformational polymorphism. Three of the four modifications have more than one conformer in the asymmetric unit. Due to the difference in conformation, all polymorphs display distinctive colors as well as different hydrogen-bonding arrangements. Phase behaviors of the four forms were studied by differential scanning calorimetry and hot-stage microscopy, indicating that metastable forms underwent phase transition to the stable one initiated by mechanical perturbation in solution or assisted by heating in the solid state. As such, this polymorphic system exhibits polychromism, conformational isomorphism, thermochromism, and mechanochromism. It may be valuable for further solid-state structure-property relationship studies....
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An Investigation into the Influence of Counterion on the Properties of Some Amorphous Organic Salts...

Amorphous solids and crystalline salts are both of interest as a means of improving the dissolution characteristics and apparent solubility of poorly water soluble active pharmaceutical ingredients which have low bioavailability in humans. The theory and selection of both crystalline drug substance salt forms and amorphous products have been extensively studied. However, less is known about the impact of different counterions on the properties of amorphous drug substance salts. In this study, several salts of either nicardipine or propranolol were prepared and characterized with respect to glass transition temperature, crystallization tendency and moisture sorption behavior. Although the moisture sorption behavior and crystallization tendency varied depending on the counterion used, no trends were readily apparent. The glass transition temperature was found to be dependent on the counterion used to form the salt, and was higher in all instances for the salts than for the neutral compound. Several molecular descriptors were calculated for the various counterions, and multivariate analysis was used to build a model that successfully correlated T(g) with a number of these parameters. Important parameters which influenced T(g) included counterion pK(a) and electrophilicity index. In conclusion, it is apparent that, as for crystalline salts, the counterion has an effect on the properties of amorphous materials....
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Receptor-Independent, Direct Membrane Binding Leads to Cell-Surface Lipid Sorting and Syk Kinase Activation in Dendritic Cells...

Binding of particulate antigens by antigen-presenting cells is a critical step in immune activation. Previously, we demonstrated that uric acid crystals are potent adjuvants, initiating a robust adaptive immune response. However, the mechanisms of activation are unknown. By using atomic force microscopy as a tool for real-time single-cell activation analysis, we report that uric acid crystals could directly engage cellular membranes, particularly the cholesterol components, with a force substantially stronger than protein-based cellular contacts. Binding of particulate substances activated Syk kinase-dependent signaling in dendritic cells. These observations suggest a mechanism whereby immune cell activation can be triggered by solid structures via membrane lipid alteration without the requirement for specific cell-surface receptors, and a testable hypothesis for crystal-associated arthropathies, inflammation, and adjuvanticity....
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Polymorphism of an organic system effected by the directionality of hydrogen-bonding chains...

Four polymorphs of 2-[methyl(phenyl)amino] nicotinic acid were discovered, and their single crystal structures were obtained at 90 K. In addition, one monohydrate and one salt were also crystallized and measured. Among the crystal structures, there are 17 crystallographically independent conformations. More interestingly, the four anhydrate forms are tessellated similarly by stacking of one-dimension hydrogen-bonding chains and, yet, the directionalities of the hydrogen-bonding chains are unique in each polymorph....
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Materials engineering of solid-state dosage forms

Organic crystalline materials play a central role in the pharmaceutical industry as well as in fine chemicals. Physicochemical properties not only affect formulation and production, but also the performance and stability of products. Because the majority of pharmaceutical materials are solid and most of the solid are crystalline, controlling crystal growth and consequent materials properties of drug substances and excipients has become one of essential tasks in the industry, demanding a considerable amount of investment and posing significant challenges for scientists. Crystal size and shape are known to have a great influence on formulation and unit operations including flow, blending, granulation and compaction. Uncontrolled and unpredictable properties may lead to product failure such as content inconsistency (e.g., sub- and super-potency) of solid dosage forms, cited as one of the main reasons for product recall by the FDA, which are often caused by segregation and poor flowability. Furthermore, being unable to identify or select a suitable polymorphic form of a drug makes its products susceptible to phase transformation, and consequently difficult to meet dissolution and bioavailability requirements, likely putting patients’ life in jeopardy and throwing a company into a market crisis....
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Further understanding of the thermal motions of atoms in aspirin and acetaminophen crystals with conceptual density functional theory...

Following up on a previous report, further correlations between force constants of thermal motions of atoms in aspirin and acetarninophen single crystals and nuclear Fukui functions have been identified. It is believed that the energy barrier of the thermal vibration of one atom in an organic crystal is mainly dominated by the soft-soft type of interatomic interactions, which may be characterized by the nuclear Fukui functions....
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The polymorphism of indomethacin: An analysis by density functional theory calculations...

Indomethacin exhibits conformational polymorphism. Crystal structures of two polymorphs have been solved bearing different molecular conformations. Herein, the conformational variance in the crystals was examined by density functional theory (DFT) calculations in order to understand the mutual influence between electronic structures and crystal packing.
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Visualizing the locality of intermolecular interactions in organic crystals...

Density functional theory (DFT) provides a rigorous theoretical framework for analyzing and interpreting electronic structures of molecules and crystals. One electron density-based concept is the Fukui function, which describes the responding sensitivity of a molecular system to electronic perturbations. As a local property, the Fukui function is directly associated with local polarizability, so it may be capable of describing the intermolecular interaction in an organic crystal with regard to molecular packing. Herein, we demonstrate such an application to the aspirin single crystal and discuss potentials of the DFT-based concepts for studying electronic structures of organic crystals....
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The confusion of indexing aspirin crystals

Much of the existing literature dealing with crystalline aspirin is vague or ambiguous with regard to indexing of the crystal faces. The inconsistency with which the indices of the dominant faces have been assigned leads to confusion in analysis of surface properties. To clarify this, we have conducted crystal growth experiments on aspirin, and indexed the crystal faces with X-ray diffraction (XRD), paying special attention to the placement of symmetry elements. The space group was confirmed as P2(1)/c, and the dominant face was (100). Contact angle measurements made on the two major faces of aspirin indicate the (100) face to be more hydrophobic than the (001) face, likely due to the acetyloxy moiety, not the carboxyl, exposed on the (100)....
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2,4,6-Trimethylanilinium chloride

The title compound, C9H14N+·Cl-, is a hydrochloric acid salt of 2,4,6-trimethylaniline. In the crystal structure, all the hydrogen-bond donors and acceptors are involved in hydrogen bonds. The packing can be described as columns, two ion-pairs wide, propagating along the a axis. The columns are formed through N-HCl hydrogen bonds linking pairs of cations and anions around centers of symmetry and further connecting these pairs in the [100] direction. In addition, the aromatic rings on each side of the columns are stacked above each other, indicating - stacking (the distance between aromatic rings is 4.811 Å)....
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6-Oxo-1,6-dihydropyridine-3-carboxylic acid

The title compound, C6H5NO3, commonly known as 6-hydroxynicotinic acid, is found to be a tautomer of it. Four molecules, all adopting a planar conformation, are found in the asymmetric unit. The compound forms hydrogen-bonded sheets parallel to the [ 001] direction via intermolecular N-H center dot center dot center dot O and O-H center dot center dot center dot O hydrogen bonds. Each sheet consists of interconnected dimers created by R-2(2)(8) N-H center dot center dot center dot O hydrogen-bonded motifs and infinite chains formed by C( 7) hydrogen-bonded motifs. Alternatively, these sheets can be viewed as infinitely fused 32-membered hydrogen-bonded rings....
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3-Carboxy-2-(2,6-dimethylphenylamino)pyridinium trifluoroacetate...

In the title compound, C14H15N2O2+ center dot C2F3O2-, the two aromatic rings of the cation are almost perpendicular to each other. The cations and anions are connected through hydrogen bonds into a one-dimensional network. There is an intramolecular N-H center dot center dot center dot O hydrogen bond between the secondary amine group and the carboxylic acid group.
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