Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association...

Crystallization from solution involves nucleation and growth; growth conditions greatly influence self-association behaviors of solute molecules in these steps, affecting crystal packing of organic molecules. We examined the role of pre-nucleation association to provide insights into the mutual influence between molecular conformation in solution and packing in the solid state.
read more

Interplay Between Molecular Conformation and Intermolecular Interactions in Conformational Polymorphism: A Molecular Perspective from Electronic Calculations of Tolfenamic Acid...

Tolfenamic acid exhibits conformational polymorphism. The molecules in its two commonly occurred crystal structures form similar hydrogen-bonded dimers but differ in conformation. The conformational variance was analyzed by electronic calculation methods with the aim to unravel intrinsic connection between the conformational flexibility and intermolecular interactions in the polymorphs. The study was conducted mainly by conceptual density functional theory (DFT) and natural bond orbital (NBO) analysis. It is found that the conformational polymorphism is resulted from the energy competition between intramolecular π-conjugation and intermolecular hydrogen bonding. By adapting conformation that departs from being the most energetically stable, tolfenamic acid molecules can strengthen the intermolecular hydrogen-bonding interactions in the crystals. The study illustrates how the molecule's electronic properties are influenced by conformational variation and, inherently, how the intermolecular interactions become regulated. Moreover, understanding molecular interaction and crystal packing necessitates electronic structure calculation and analysis, which can be further facilitated by utilizing DFT and NBO concepts....
read more

Hybrid Nanocrystals: Achieving Concurrent Therapeutic and Bioimaging Functionalities toward Solid Tumors...

Bioimaging and therapeutic agents accumulated in ectopic tumors following intravenous administration of hybrid nanocrystals to tumor-bearing mice. Solid, nanosized paclitaxel crystals physically incorporated fluorescent molecules throughout the crystal lattice and retained fluorescent properties in the solid state. Hybrid nanocrystals were significantly localized in solid tumors and remained in the tumor for several days. An anticancer effect is expected of these hybrid nanocrystals....
read more

Preparation and Antitumor Study of Camptothecin Nanocrystals...

Camptothecin (CPT) is a potent, broad spectrum antitumor agent that inhibits the activity of DNA topoisomerase I. Due to its poor solubility and stability and consequent delivery challenges, its clinical use is nevertheless limited. We aim to use nanocrystal formulation as a way to circumvent the difficult solubilization practice. Specifically, camptothecin nanocrystals were prepared with a sonication-precipitation method without additional stabilizing surfactants. Particle characteristics, cellular cytotoxicity, and animal antitumor effect were examined. CPT nanocrystals were tested to be more potent to MCF-7 cells than CPT solution in vitro. When tested in MCF-7 xenografted BALB/c mice, the CPT nanocrystals exhibited significant suppression of tumor growth. The drug concentration in the tumor was five times more at 24 h by using the nanocrystal treatment than by using the drug salt solution. Storage stability study indicated that the nanocrystals were stable for at least six months. Overall, CPT nanocrystals were considered to be potentially feasible to overcome formulation challenges for drug delivery and to be used in clinic....
read more

Solvatomorphism in (E)-2-(2,6-dichloro- 4-hydroxybenzylidene) hydrazinecarboximidamide...

The structures of orthorhombic (E)-4-(2-{[amino(iminio) methyl]amino}vinyl)- 3,5-dichlorophenolate dihydrate, C8H8Cl2N4O·2H2O, (I), triclinic (E)-4-(2-{[amino(iminio) methyl]amino}vinyl)- 3,5-dichlorophenolate methanol disolvate, C8H8Cl2N4O·2CH4O, (II), and orthorhombic (E)-amino[(2,6-dichloro-4-hydroxystyryl)amino]methaniminium acetate, C8H9Cl2N4O+·C2H3O2-, (III), all crystallize with one formula unit in the asymmetric unit, with the molecule in an E configuration and the phenol H atom transferred to the guanidine N atom. Although the molecules of the title compounds form extended chains via hydrogen bonding in all three forms, owing to the presence of different solvent molecules, those chains are connected differently in the individual forms. In (II), the molecules are all coplanar, while in (I) and (III), adjacent molecules are tilted relative to one another to varying degrees. Also, because of the variation in hydrogen-bond-formation ability of the solvents, the hydrogen-bonding arrangements vary in the three forms....
read more

Phase Transition from Two Z′ = 1 Forms to a Z′ = 2 Form of a Concomitant Conformational Polymorphic System...

Differential scanning calorimetry and hot-stage microscopy revealed two solid−solid phase transitions from two Z′ = 1 polymorphs to a Z′ = 2 form in a concomitant conformational polymorphic system of 2-(mesitylamino)nicotinic acid. Neat grinding and solvent-drop grinding experiments also confirmed that the high Z′ form is thermodynamically stable. The finding adds to a few cases where a high Z′ form is the most thermodynamically stable, apparently running contrary to a common notion that incomplete crystallization tends to produce metastable high Z′ structures. The high Z′ form of 2-(mesitylamino)nicotinic acid may be due to the combination of iso-energetic conformations and better packing. Lattice and conformational energy calculations were performed to provide further information about the intermolecular interactions of the polymorphs. Conformational search is in agreement with the conformers found in the three forms....
read more

Electronic origin of pyridinyl N as a better hydrogen-bonding acceptor than carbonyl O...

A diarylamine compound, 2-(phenylamino)nicotinic acid, can form either the carboxyl acid–acid dimer or acid–pyridine chain in its polymorphic structures. Quantum mechanical calculations indicate that the hydrogen-bonding strength of the heterosynthon is stronger. Conceptual density functional theory is then used to understand the fundamental cause of pyridine N being a better hydrogen-bonding acceptor....
read more

Stability conditions for density functional reactivity theory: An interpretation of the total local hardness...

The second-order Taylor series expansions commonly used in the density functional chemical reactivity theory are used to define local stability conditions for electronic states. Systems which satisfy these conditions are stable to infinitesimal perturbations due to approaching chemical reagents. The basic formalism considered here supersedes previous variational approaches to chemical reactivity theory like the electrophilicity, potentialphilicity, and chargephilicity. The total local hardness emerges naturally in this analysis, and can be clearly interpreted. When the total local hardness is small, the system is relatively insensitive to perturbations. Furthermore, minus the total local hardness is an energetically favorable perturbation of the external potential....
read more

Polymorphism in 2-(4-hydroxy-2,6-dimethylanilino)-5,6-dihydro-4H-1,3-thiazin-3-ium chloride...

Details of the structures of two conformational polymorphs of the title compound, C12H17N2OS+·Cl−, are reported. In form (I) (space group P), the two N—H groups of the cation are in a trans conformation, while in form (II) (space group P21/c), they are in a cis arrangement. This results in different packing and hydrogen-bond arrangements in the two forms, both of which have extended chains lying along the a direction. In form (I), these chains are composed of centrosymmetric R42(18) (N—H...Cl and O—H...Cl) hydrogen-bonded rings and R22(18) (N—H...O) hydrogen-bonded rings. In form (II), the chains are formed by centrosymmetric R42(18) (N—H...Cl and O—H...Cl) hydrogen-bonded rings and by R42(12) (N—H...Cl) hydrogen-bonded rings....
read more

Analysis of Relationships Between Solid-State Properties, Counterion, and Developability of Pharmaceutical Salts...

The solid-state properties of pharmaceutical salts, which are dependent on the counterion used to form the salt, are critical for successful development of a stable dosage form. In order to better understand the relationship between counterion and salt properties, 11 salts of procaine, which is a base, were synthesized and characterized using a variety of experimental and computational methods. Correlations between the various experimental and calculated physicochemical properties of the salts and counterions were probed. In addition to investigating the key factors affecting solubility, the hygroscopicity of the crystalline salts was studied to determine which solid-state and counterion properties might be responsible for enhancements in moisture uptake, thus providing the potential for adverse chemical stability. Multivariate principal components and partial least squares projection to latent structures analyses were performed in an attempt to establish predictive models capable of describing the relationships between these characteristics and both measured and calculated properties of the counterion and salt. Some success was achieved with respect to modeling crystalline salt solubility and the glass transition temperature of the amorphous salts. Through the modeling, insight into the relative importance of various descriptors on salt properties was achieved. The solid-state properties of crystalline and amorphous salts of procaine are highly dependent on the nature of the counterion. Important properties including aqueous solubility, melting point, hygroscopicity, and glass transition temperature were found to vary considerably between the different salts....
read more

Enforcing Molecule’s pi-Conjugation and Consequent Formation of the Acid-Acid Homosynthon over the Acid-Pyridine Heterosynthon in 2-Anilinonicotinic Acids...

Two different synthons, acid-acid and acid-pyridine, are present in the crystal structures of 2-(phenylamino)nicotinic acid. The intermolecular hydrogen-bonding motifs are determined by molecular conformation and conformational energy. By covalently linking electron-withdrawing groups to the phenyl ring, it is possible to strengthen the molecule's global pi-conjugation and thereby lead to only the acid-acid homosynthon in crystal packing and prohibit the competing acid-pyridine heterosynthon....
read more

Physical Characterization of 1,3-dipropyl-8-cyclopentylxanthine (CPX)...

1,3-dipropyl-8-cyclopentylxanthine (CPX) has been shown to stimulate in vitro CFTR activity in a dagger F508 cells. Data from a phase I study demonstrated erratic bioavailability and no measurable clinical response to oral CPX. One cause for its poor bioavailability may have been dissolution rate limited absorption, but there is little published physicochemical data on which to base an analysis. The objective of this study was to determine the solubility and solid-state characteristics of CPX. CPX is a weak acid with pKa of 9.83 and water solubility at pH 7.0 of 15.6 mu M. Both laureth-23 and poloxamer 407 increased the apparent water solubility linearly with increasing concentrations. CPX exists in two crystal forms, one of which (form II) has been solved. Form II is a triclinic crystal with space group P1 and calculated density of 1.278 g/cm(3). X-ray powder diffraction and differential scanning calorimetry studies (DSC) indicated that CPX crystals prepared at room temperature were mixtures of forms I and II. DSC results indicated a melting point of approximately 195A degrees C for form I and 198A degrees C for form II. Thermogravimetric analysis indicated no solvent loss upon heating. Dynamic water vapor sorption data indicated no significant water uptake by CPX up to 90% RH. Analysis of the data indicates that CPX may not be amenable to traditional formulation approaches for oral delivery....
read more

Solid-State Properties of the Cyclooxygenase-1-Selective Inhibitor, SC-560...

Selective inhibition of the cyclooxygenase-1 (COX-1) isoform has been shown to reduce inflammation and tumorigenesis and lack the gastrointestinal toxicity of traditional nonsteroidal anti-inflammatory drugs. The COX-1-selective inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), shown in Fig. 1, was identified as one of several structurally related compounds with varying selectivity for the COX isoforms during the development of the COX-2-selective inhibitor celecoxib (1). From this work, SC-560 was found to be a highly selective and potent inhibitor of COX-1, with in vitro studies showing an IC50 of 0.007 μM for COX-1 and 75 μM for COX-2. In animal studies, SC-560 has been shown to be effective in treating neuroinflammation when administered by injection (2). However, the poor bioavailability that results following oral administration of SC-560 may limit its effectives in treating diseases where COX-1 inhibition would provide efficacy. When administered orally to rats as a suspension in 1% methylcellulose, the mean bioavailability is only 5% of the dose (3). Altering the oral dosage formulation by dissolving in polyethylene glycol 600 improves the bioavailability to only 15% (3). Therefore, additional studies are needed to identify dosage formulations which may improve oral bioavailability. To develop dosage forms and products of a potential drug compound, solid-state properties of the chemical need to be thoroughly examined. One of the basic attributes is the crystal structure of the compound, which determines important physical and chemical properties of the substance, including solubility and dissolution rate. We have solved the crystal structure for SC-560 and reported it elsewhere (4). Herein, we describe additional solid-state properties, including its solubility in water....
read more

Controlled Formation of the Acid-Pyridine Heterosynthon over the Acid-Acid Homosynthon in 2-Anilinonicotinic Acids...

Four substituted 2-anilinonicotinic acids were synthesized, and their crystal structures were analyzed. It was found that by chemically introducing bulky functional groups to the aniline ring of the molecules, it is possible to dislodge the planar conformation due to steric repulsion. As a result, acid-pyridine heterosynthons, not acid-acid homosynthons, are formed in the crystals. The study is believed to offer a refreshing case of how a molecule's conformation can affect intermolecular interactions and consequent crystal packing....
read more

Chargephilicity and chargephobicity: Two new reactivity indicators for external potential changes from density functional reactivity theory...

In analogy to the electrophilicity and the potentialphilicity, we define the chargephilicity and chargephobicity to describe the energetic response of a molecule to a change in its charge distribution. The chargephilicity captures the ‘best’ way to change the underlying charge distribution; the chargephobicity captures the ‘worst’ way to change the underlying charge distribution. The Coulomb potential induced by the linear-response function plays a very important role in this approach, analogous to the role of the hardness for the electrophilicity, the hardness kernel for the Fukui function, and the linear-response function for the potentialphilicity and potentialphobicity....
read more

Potentialphilicity and potentialphobicity: Reactivity indicators for external potential changes from density functional reactivity theory...

In analogy to the electrophilicity, we define potentialphilicity indicators that represent energetically favorable ways to change the external potential of a molecule at fixed electron number. Similarly, we define a potentialphobicity to represent the least favorable way to change the external potential of a molecule. The resulting indicators should be useful for describing how molecular geometries change and predicting favorable and unfavorable ways for a reagent to approach a molecule. The linear response function enters plays a very important role in this approach, analogous to the role of the hardness for the electrophilicity or the hardness kernel for the Fukui function. The mathematical properties of the response function and its implications for these reactivity indicators are discussed in depth. (C) 2009 American Institute of Physics....
read more