Solvation Stability Research Articles

Structural Characterization and Rationalization of Formation, Stability, and Transformations of Benperidol Solvates

Experimental and theoretical characterization and studies of phase transitions and stability of the solvates obtained in solvate screening of the pharmaceutical compound benperidol were performed to rationalize and understand the solvate formation, stability, and phase transitions occurring during their desolvation. The solvate screening revealed that benperidol can form 11 solvates, including two sets of isostructural solvates. The analysis of the solvate crystal structures and molecular properties indicated that benperidol solvate formation is mainly driven by the complications during packing of benperidol molecules in an energetically efficient way in the absence of solvent molecules, as well as by the compensation of an insufficient number of hydrogen bond donor moieties. Analysis of solvate structures, particularly those of isostructural solvates, revealed that both the possible interactions and the size and shape of the solvent molecules were important factors in solvate formation. Stability of the ...

The coupling between stability and ion pair formation in magnesium electrolytes from first-principles quantum mechanics and classical molecular dynamics.

In this work we uncover a novel effect between concentration dependent ion pair formation and anion stability at reducing potentials, e.g., at the metal anode. Through comprehensive calculations using both first-principles as well as well-benchmarked classical molecular dynamics over a matrix of electrolytes, covering solvents and salt anions with a broad range in chemistry, we elucidate systematic correlations between molecular level interactions and composite electrolyte properties, such as electrochemical stability, solvation structure, and dynamics. We find that Mg electrolytes are highly prone to ion pair formation, even at modest concentrations, for a wide range of solvents with different dielectric constants, which have implications for dynamics as well as charge transfer. Specifically, we observe that, at Mg metal potentials, the ion pair undergoes partial reduction at the Mg cation center (Mg(2+) → Mg(+)), which competes with the charge transfer mechanism and can activate the anion to render it susceptible to decomposition. Specifically, TFSI(-) exhibits a significant bond weakening while paired with the transient, partially reduced Mg(+). In contrast, BH4(-) and BF4(-) are shown to be chemically stable in a reduced ion pair configuration. Furthermore, we observe that higher order glymes as well as DMSO improve the solubility of Mg salts, but only the longer glyme chains reduce the dynamics of the ions in solution. This information provides critical design metrics for future electrolytes as it elucidates a close connection between bulk solvation and cathodic stability as well as the dynamics of the salt.

Hofmeister ion effects on the solvation and thermal stability of model proteins lysozyme and myoglobin

Circular dichroism (CD) and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopies were used to study how sucrose and salts, NaCl, NaClO4, Na2SO4, CaCl2, MgCl2, MgSO4, and NH4Cl alter lysozyme and myoglobin solvation and thermal stability. Both proteins follow the anionic Hofmeister series in which chaotropes (Cl−, ClO4−) decrease thermal stability, and kosmotropes (SO42−) increase thermal stability. CD spectra showed no significant secondary structural differences at 25 °C that correlate with changes in thermal stability. However, infrared spectra of lysozyme and myoglobin show a downshift in the Amide I′ (backbone CO) vibration and increased 1H/2H exchange in the presence of weakly hydrated, chaotropic anions (Cl−, ClO4−), both of which suggest increased protein solvation in the presence of chaotropes and correlate with decreased protein thermal stability. The presence of strongly hydrated, kosmotropic anions (SO42−) or sucrose prevent the downshift of the Amide I′ vibration in lysozyme and myoglobin and result in decreased 1H/2H exchange, suggesting decreased protein solvation in the presence of kosmotropes, that correlates with increased protein stability. The data show a strong correlation between the level of deuterium exchange and the relative thermal stability in the presence of kosmotropes or chaotropes that does not correlate with secondary structural changes and suggests that Hofmeister ions alter protein solvation. These results also show that a combination of CD and infrared spectroscopy is useful in studying how Hofmeister ions and co-solvents influence protein solvation and thermal stability.

Effect of ionic size on solvate stability of glyme-based solvate ionic liquids.

A series of binary mixtures composed of glymes (triglyme, G3; tetraglyme, G4; pentaglyme, G5) and alkali-metal bis(trifluoromethanesulfonyl)amide salts (M[TFSA]; M = Li, Na, and K) were prepared, and the correlation between the composition and solvate stability was systematically investigated. Their phase diagrams and Raman spectra suggested complexation of the glymes with M[TFSA] in 1:1 and/or 2:1 molar ratio(s). From isothermal stability measurements, it was found that the formation of structurally stable complexes in the solid state did not necessarily ensure their thermal stability in the liquid state, especially in the case of 2:1 complexes, where uncoordinating or highly exchangeable glyme ligands existed in the molten complexes. The phase-state-dependent Raman spectra also supported the presence of free glymes in certain liquid complexes. The effect of the electric field induced by the alkali-metal cations on the oxidative stability of certain glyme complexes was examined by linear sweep voltammetry and quantum chemical calculations. Although the actual oxidative stability of complexes did not necessarily reflect the calculated HOMO energy levels of the glymes, the strong electric field induced by the smaller M(+) cations and proper coordination structures impart high stability to the glyme complexes. The results of thermogravimetry of complexes with different M(+) cations revealed that a balance of competitive interactions of the M(+) ions with the glymes and [TFSA](-) anions predominates the thermal stability.

Structural features and thermal stability of molecular complexes of 25,26,27,28-Tetrahydroxycalix[4]arene with solvents

A single crystal of the complex 25,26,27,28-tetrahydroxycalix[4]arene with hexane is grown via slow evaporation of a solution, and its full structure is determined. A molecular complex of 25,26,27,28-tetrahydroxycalix[4]arene with toluene is prepared for the first time, and its thermal stability is studied. The kinetic curves of the sorption of saturated vapors of acetone, acetonitrile, n-hexane, and toluene on 25,26,27,28-tetrahydroxycalix[4]arene are experimentally obtained. It is shown that the sorption of acetonitrile vapors on 25,26,27,28-tetrahydroxycalix[4]arene is characterized by a pronounced maximum corresponding to a stoichiometry of 1: 1. It is assumed that the structural reorganization of 25,26,27,28-tetrahydroxycalix[4]arene results in the transport of acetonitrile molecules within the molecular crystal, followed by complexation to form a thermodynamically stable hexagonal structure. The high thermal stability of solvates of 25,26,27,28-tetrahydroxycalix[4]arene is found to be due to the strict proportionality of the form and size of a guest molecule to those of the cavity of a host molecule.

Comparison and Rationalization of Droperidol Isostructural Solvate Stability: An Experimental and Computational Study

In order to find a tool for comparison of solvate stability and to rationalize their relative stability, droperidol nonstoichiometric isostructural solvates were characterized experimentally and computationally. For the experimental evaluation of stability, three comparison tools were considered: thermal stability characterized by the desolvation rate, desolvation activation energy, and solvent sorption–desorption isotherms. It was found that the desolvation process was limited by diffusion, and the same activation energy values were obtained for all of the characterized solvates, while the solvent content in the sorption isotherm was determined by the steric factors. Therefore, the only criterion characterizing the solvate stability in this particular system was the thermal stability. It was found that computationally obtained solvent–droperidol and solvent–solvent interaction energies could be used for the rationalization of the isostructural solvate stability in this system and that the solvent–solvent...

Crystal solvates of porphyrins and metalloporphyrins

The published data on the crystal solvates with nonpolar aromatic and electron-donor compounds obtained using different research methods as well as our own experimental results obtained by thermogravimetric analysis of the porphyrins and metalloporphyrins of natural and synthetic origin are generalized. The influence of the molecular structure of the porphyrins and metalloporphyrins on the composition, structural parameters, thermal and energy stability of crystal solvates formed through specific σ-and π-complexes with molecular ligands are considered.

Ion solvation and structural stability in a sodium channel investigated by molecular dynamics calculations

The stability and ion binding properties of the homo-tetrameric pore domain of a prokaryotic, voltage-gated sodium channel are studied by extensive all-atom molecular dynamics simulations, with the channel protein being embedded in a fully hydrated lipid bilayer. It is found that Na+ ion presents in a mostly hydrated state inside the wide pore of the selectivity filter of the sodium channel, in sharp contrast to the nearly fully dehydrated state for K+ ions in potassium channels. Our results also indicate that Na+ ions make contact with only one or two out of the four polypeptide chains forming the selectivity filter, and surprisingly, the selectivity filter exhibits robust stability for various initial ion configurations even in the absence of ions. These findings are quite different from those in potassium channels. Furthermore, an electric field above 0.5V/nm is suggested to be able to induce Na+ permeation through the selectivity filter.

X-ray Diffraction, FT-IR, and 13C CP/MAS NMR Structural Studies of Solvated and Desolvated C-Methylcalix[4]resorcinarene

Solid C-methylcalix[4]resorcinarene solvated by acetonitrile and water (CAL-Me) and then modified by slow solvent evaporation (CAL-Me*) was studied using single-crystal and powder X-ray diffraction, FT-IR, and (13)C CP/MAS NMR. The CAL-Me solvate crystallizes in the monoclinic P2(1)/n space group with three CH(3)CN and two H(2)O molecules in the asymmetric part of the unit cell. The CAL-Me molecules adopt a typical crown conformation with all of the hydroxyl groups of the aryl rings oriented up and all of the methyl groups disposed down (the rccc isomeric form). The crystalline network is formed by resorcinarene, CH(3)CN, and H(2)O molecules and assembled by intermolecular hydrogen bonds and weak C-H...A or C-H...pi interactions. The desolvated CAL-Me* loses its crystalline character and becomes partly amorphous. It is devoid of CH(3)CN and deficient in water. However, the resorcinarene molecules still remain in the crown conformation supported by intramolecular hydrogen bonds, while intermolecular hydrogen bonds are considerably disintegrated. The work directs general attention to the problem of stability and polymorphism of resorcinarene solvates. It shows that the joint use of diffractometric and spectroscopic methods is advantageous in the structural studies of complex crystalline macromolecular systems. On the other hand, the solid-state IR and NMR spectroscopic analyses applied in tandem have been found highly beneficial to elucidate the disordered structure of poorly crystalline, desolvated resorcinarene.

Computational Modeling of Carbohydrate-Recognition Process in E-Selectin Complex: Structural Mapping of Sialyl Lewis X onto Ab Initio QM/MM Free Energy Surface

To advance our knowledge of carbohydrate recognition by lectins, we propose a systematic computational modeling strategy to identify complex sugar-chain conformations on the reduced free energy surface (FES). We selected the complex of E-selectin with sialyl Lewis X (denoted E-selectin/SLe(x) complex) as a first target molecule. First, we introduced the reduced 2D-FES that characterizes conformational changes in carbohydrate structure as well as the degree of solvation stability of the carbohydrate ligand, and evaluated the overall free energy profile by classical molecular dynamics simulation combined with ab initio QM/MM energy corrections. Second, we mapped flexible carbohydrate structures onto the reduced QM/MM 2D-FES, and identified the details of molecular interactions between each monosaccharide component and the amino acid residues at the carbohydrate-recognition domain. Finally, we confirmed the validity of our modeling strategy by evaluating the chemical shielding tensor by ab initio QM/MM-GIAO computations for several QM/MM-refined geometries sampled from the minimum free energy region in the 2D-FES, and compared this theoretical averaging data with the experimental 1D-NMR profile. The model clearly shows that the binding geometries of the E-selectin/SLe(x) complex are determined not by one single, rigid carbohydrate structure but rather by the sum of averaged conformations fluctuating around the minimum free energy region. For the E-selectin/SLe(x) complex, the major molecular interactions are hydrogen bonds between Fuc and the Ca(2+) binding site in the carbohydrate-recognition domain, and Gal is important in determining the ligand specificity.

Evaluation of the Use of Ea (Activation Energy) as a Quantitative Indicator of Physical Stability of Indomethacin Solvates: Methanolate and Tertiary Butyl Alcohol Solvate

The purpose of this research is to study the use of Ea as a measure of the energy barrier to the solid-state desolvation of two indomethacin solvates: tert-butyl alcohol (TBA) solvate and methanolate. The desolvation of these solvates was studied over a range of temperatures (60−120 °C) by isothermal thermogravimetric analysis. Intimately mixing 15% α and γ seeds with the two solvates was carried out in order to assess the effect of seeding/nucleation on desolvation. The results suggest that solid-state desolvation predominantly proceeded by a nucleation-limited mechanism as described by the Avrami−Erofeev kinetics equation. On the basis of the equation, an “isokinetic” range was identified between 60−80 °C for the methanolate and 60−90 °C for the TBA solvate, and the dominant mechanism of desolvation remained unchanged. The Arrhenius activation energies (Ea) were 27.9 and 16.6 kcal/mol for the methanol and TBA solvates, respectively. In the “isokinetic” range, Ea values of 36.9 and 15.5 kcal/mol, respect...

Stabilization of quinapril by incorporating hydrogen bonding interactions

In the present study stability of various known solvates of quinapril hydrochloride has been compared with nitromethane solvate. Nitromethane solvate was found to be more stable compared to other known solvates. Single crystal X-ray diffraction analysis of quinapril nitromethane solvate shows intermolecular hydrogen bonding between quinapril molecule and nitromethane. Stabilization of quinapril by forming strong hydrogen bonding network as in case of co-crystals was further studied by forming co-crystal with tris(hydroxymethyl)amino methane. Quinapril free base forms a stable salt with tris(hydroxymethyl)amino methane not reported earlier. Quinapril tris(hydroxymethyl)amino methane salt found to be stable even at 80° for 72 h i.e. hardly any formation of diketopiperazine and diacid impurity. As expected single crystal X-ray diffraction analysis reveals tris(hydroxymethyl)amino methane salt of quinapril shows complex hydrogen bonding network between the two entities along with ionic bond. The properties of this stable salt - stable in solid as well as solution phase, might lead to an alternate highly stable formulation.

Stability of Solvates and Packing Systematics of Nine Crystal Forms of the Antipsychotic Drug Aripiprazole

A comprehensive characterization (thermal, spectroscopic, crystallographic, temperature- and moisture-dependent stability, and transition characteristics) of solvates of aripiprazole (APZ) with methanol (1:1), ethanol (2:1), dichloroethane (2:1), and a monohydrate is presented. To gain insight into packing similarities and differences, the four hydrate/solvate crystal structures and five APZ modifications were compared using the program XPac. It was found that all forms apart from the hydrate are based on either a common dimeric or catemeric motif of H-bonded APZ molecules, and this analysis confirmed also the isostructurality of the three solvates and pointed to possible mechanisms for the desolvation of the solvates and the transformation between forms X° and I. The fact that the intermolecular interactions in the monohydrate are completely different from those found in the isostructural solvates was further confirmed by analyzing the Hirshfeld fingerprint plots. The desolvation of all solvated forms re...

Solvation structure and stability of hypervalent NH 4(CH 3OH) m(NH 3) n clusters

Ionization potentials (IPs) of NH 4(CH 3OH) m (NH 3) n radicals produced by an ArF excimer laser photolysis of ammonia–methanol mixed clusters are determined by the photoionization threshold measurements. The observed IPs show the different evolutions with increasing the number of ammonia and methanol solvents. The IPs are also examined by ab initio calculations, which suggest that the hydrogen bond network is dominant in the case of adding methanol. Moreover, the lack of NH 4 ( CH 3 OH ) m + ( m ⩾ 1) signals indicates that they have very short lifetimes (<4 ns) due to a fast elimination of hydrogen-atom from NH 4 radical via tunneling.

Differential Solvation and Tautomer Stability of a Model Base Pair within the Minor and Major Grooves of DNA

2-(2'-Hydroxyphenyl)benzoxazole (HBO) may be used as a model base pair to study solvation, duplex environment, and tautomerization within the major and minor groves of DNA duplexes. In its ground state, HBO possesses an enol moiety which may be oriented syn or anti relative to the imino nitrogen of the benzoxazole ring. In the absence of external hydrogen-bond donors and acceptors HBO exists as the internally hydrogen-bonded syn-enol, a mimic of the rare base pair tautomer found in DNA, which may be photoinduced to tautomerize and form the keto tautomer, a mimic of the dominant base pair tautomer. Previously, we demonstrated that when incorporated into DNA such that the enol moiety is positioned in the major groove, HBO is not solvated, exists exclusively as the internally hydrogen-bonded syn-enol which is efficiently photoinduced to tautomerize, and the corresponding keto tautomer is preferentially stabilized. In stark contrast, we now show that when HBO is incorporated in DNA such that the enol moiety is positioned in the minor groove, the enol tautomer is preferentially stabilized. Molecular dynamics simulations suggest that this results from the formation of a stable hydrogen-bond between the HBO enol and the O4' atom of an adjacent nucleotide, an H-bond acceptor that is only available in the minor groove. The differential stabilization of the enol and keto tautomers in the major and minor grooves may reflect the functions for which these environments evolved, including duplex replication, stability, and recognition.

Salt-dependent studies of NADP-dependent isocitrate dehydrogenase from the halophilic archaeon Haloferax volcanii.

The salt-dependent stability of recombinant dimeric isocitrate dehydrogenase [ICDH; isocitrate: NADP oxidoreductase (decarboxylating), EC 1.1.1.42] from the halophilic archaeon Haloferax volcanii (Hv) was investigated in various conditions. Hv ICDH dissociation/deactivation was measured to probe the respective effect of anions and cations on stability. Surprisingly, enzyme stability was found to be mainly sensitive to cations and very little (or not) sensitive to anions. Divalent cations induced a strong shift of the active/inactive transition towards low salt concentration. A high resistance of Hv ICDH to chemical denaturation was also found. The data were analysed and are discussed in the framework of the solvation stability model for halophilic proteins.

Solvation properties and stability of ribonuclease A in normal and deuterated water studied by dielectric relaxation and differential scanning/pressure perturbation calorimetry

A change in solvent can have dramatic effects on the physico-chemical properties of a protein and its stability. In this paper we demonstrate by a study of solutions of the enzyme ribonuclease A (RNase A) in normal water (H2O) and deuterated water (D2O), to what extend a solvent isotopic substitution affects the structural and dynamic properties of a protein and its stability. Differential scanning calorimetry (DSC) indicates a shift of the transition temperature from the native to the unfolded state from about 62°C in H2O to 66°C in D2O. Pressure perturbation calorimetry (PPC), a relatively new and efficient technique, is used to study the volumetric properties of RNase A in its native and unfolded state. In PPC, the coefficient of thermal expansion of the partial volume of the protein, α, is deduced from the heat consumed or produced after small isothermal pressure jumps (±5 bar). α and its temperature coefficient, dα/dT, strongly depend on the interaction of the protein with the solvent at the protein–solvent interface. Both quantities are markedly affected by H2O/D2O substitution. Dielectric spectroscopy in the MHz and GHz regime is used to characterize the H2O/D2O isotope effect upon the tumbling time and dipole moment of the protein. The analysis of the isotope effects gives evidence for a decrease of the dipole moment and hydrodynamic radius of the protein in D2O. An intriguing result is that the observed changes in thermodynamic properties reflect not only a stronger and more compact hydration in D2O, but also an increase in protein compactness. A similar result is obtained from dielectric relaxation experiments on another small globular protein, ubiquitin.

New solid solvates of C 60 and C 70 fullerenes: The relationship between structures and lattice energies

The goal of this study was to establish the relationship between the X-ray and the thermodynamic data on fullerene’s solvated crystals. X-ray diffraction study of 12 solid solvates of C 60 and C 70 with different aromatic solvents have been performed. It has been demonstrated that the solid solvates under consideration were typical van-der-Waals complexes with the negative excess volumes, packing coefficients from 0.72 to 0.78, stable due to the formation of the fullerene to solvent bonds, reasonably described by six to 12 Lennard–Jones potentials. The atom–atom potential method has been used to describe both the crystal structures and the thermodynamics of the solid solvates. The minimization of the lattice energy with respect to the cell and rigid body parameters ( T=0 K) has led to the crystal structures very close to the experimental ones. The minimum energies found have reasonably reproduced the calorimetric lattice energies of the solvates. The theory has also demonstrated its ability to account for the trends in thermodynamic stability of solid solvates, e.g., has predicted correctly the low stability of the hypothetical monoclinic solvate C 60·2C 6H 14.

Solid-State Stability of Indomethacin Solvates

Desolvation kinetics of two indomethacin (IMC) solvates namely methanolate and tert−butyl alcohol (TBA) solvate were studied at 60–100 °C by isothermal thermogravimetric analysis. The solvates can transform to one of two true polymorphic forms, α or γ Solid-state desolvation of IMC predominantly proceeds by a nucleation-limited mechanism as described by Avrami-Erofeev kinetics. The activation energies of desolvation as determined from these kinetic data were 34 1 kcal/mol and 17.6 kcal/mol for the methanol and TBA solvates respectively. The rank order of activation energy correlates well with the hydrogen-bonding strength and the crystal packing of the solvates. The methanolate desolvates to the metastable a form, whereas the TBA solvate desolvates to the equilibrium γ form at all the temperatures studied.

Thermochemical Investigation of Some Selected Solvates of Calix[4]resorcinarene

Lipophilic calix[4]resorcinarene derived from lauryl aldehyde forms stable crystalline solvates with a range of organic solvents: acetone, 1,4-dioxane, methylethylvketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, butyronitrile, methanol, 1,2-dimethoxybenzene and acetonitrile. The composition and thermal stability of these solvates was followed by thermogravimetric method, indicating a stoichiometry ranging from 1 to 3 (calixresorcinarene/solvent). The activation energy was evaluated for the selected solvates. Molecular modelling, using Hyperchem 5.0 software, was applied to the selected solvates.