Widom Line in Supercritical Water in Terms of Changes in Local Structure: Theoretical Perspective.

Performing molecular dynamics simulations with the TIP4P/2005 water model along 9 isobars (from 175 to 375 bar) in the temperature range between 300 and 1100 K, we have found that the loci of the extrema in the rate of change of specific structural properties can be used to define purely structure-based Widom lines. We have examined several parameters that describe the local structure of water, such as the tetrahedral arrangement, nearest neighbor distance, local density around the molecules, and the size of the largest dense domain. The last two parameters were determined using the Voronoi polyhedral and density-based spatial clustering of applications with noise methods, respectively. By analyzing the moments of the associated distributions, we show that along a given isobar, the temperature at which we observe a maximum in the fluctuation, the rate of change of the average values, or in the skewness values unambiguously determines the Widom line that is in agreement with the experimentally detected, thermodynamic response function-based ones.

Molecular Mechanism of Conformational Crossover of Mefenamic Acid Molecules in scCO2.

In this work, we studied conformational equilibria of molecules of mefenamic acid in its diluted solution in scCO2 under isochoric heating conditions in the temperature range of 140-210 °C along the isochore corresponding to the scCO2 density of 1.1 of its critical value. This phase diagram range totally covers the region of conformational transitions of molecules of mefenamic acid in its saturated solution in scCO2. We found that in the considered phase diagram region, the equilibrium of two conformers is realized in this solution. In the temperature range of 140-180 °C, conformer I related to the first, most stable polymorph of mefenamic acid prevails. In the temperature range of 200-210 °C, conformer II, which is related to the second metastable polymorph becomes dominant. Based on the results of quantum chemical calculations and experimental IR spectroscopy data on the mefenamic acid conformer populations, we classified this temperature-induced conformational crossover as an entropy-driven phenomenon.

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY.

The search for new forms of already known drug compounds is an urgent problem of high relevance as more potent drugs with fewer side effects are needed. The trifluoromethyl group in flufenamic acid renders its chemical structure differently from other fenamates. This modification is responsible for a large number of conformational polymorphs. Therefore, flufenamic acid is a promising structural modification of well-known drug molecules. An effective approach in this field is micronization, employing "green" supercritical fluid technologies. This research raises some key questions to be answered on how to control polymorphic forms during the micronization of drug compounds. The results presented in this work demonstrate the ability of two-dimensional nuclear Overhauser effect spectroscopy to determine conformational preferences of small molecular weight drug compounds in solutions and fluids, which can be used to predict the polymorphic form during the micronization. Quantitative analysis was carried out to identify the conformational preferences of flufenamic acid molecules in dimethyl sulfoxide-d6 medium at 25 °C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 °C and 9 MPa. The data presented allows predictions of the flufenamic acid conformational preferences of poorly soluble drug compounds to obtain new micronized forms.

Molecular Dynamics and Nuclear Magnetic Resonance Studies of Supercritical CO2 Sorption in Poly(Methyl Methacrylate).

The study of supercritical carbon dioxide sorption processes is an important and urgent task in the field of "green" chemistry and for the selection of conditions for new polymer material formation. However, at the moment, the research of these processes is very limited, and it is necessary to select the methodology for each polymer material separately. In this paper, the principal possibility to study the powder sorption processes using 13C nuclear magnetic resonance spectroscopy, relaxation-relaxation correlation spectroscopy and molecular dynamic modeling methods will be demonstrated based on the example of polymethylmethacrylate and supercritical carbon dioxide. It was found that in the first nanoseconds and seconds during the sorption process, most of the carbon dioxide, about 75%, is sorbed into polymethylmethacrylate, while on the clock scale the remaining 25% is sorbed. The methodology presented in this paper makes it possible to select optimal conditions for technological processes associated with the production of new polymer materials based on supercritical fluids.

Study of Dispersions of Carbon Nanotubes Modified by the Method of Rapid Expansion of Supercritical Suspensions.

The effectiveness of carbon nanotubes (CNT) deagglomeration by rapid expansion of supercritical suspensions (RESS) in nitrogen and carbon dioxide fluids was studied in this work. Two different mechanisms of deagglomeration were proposed for these two fluids at various temperature and pressure conditions. Ultrasound attenuation spectroscopy was applied as an express method of determining median diameter and aspect ratio of CNTs. At least twofold reduction of the diameter was shown for CNT bundles processed by RESS technique. Aspect ratio of processed CNTs, calculated from acoustic attenuation spectra, increased to 340. These results were in a good agreement with atomic force microscopy data.

Correlation between the conformational crossover of carbamazepine and its polymorphic transition in supercritical CO2: On the way to polymorph control.

In this paper we have established a correlation between the conformation crossover of carbamazepine and associated polymorph transformation. This was achieved by using a combination of quantum chemical calculations and in situ IR spectroscopy for performing a conformational analysis of carbamazepine molecules in its saturated solution in scCO2 being in permanent contact with the carbamazepine solid form. Using quantum calculations, we determined two carbamazepine conformers, whose spectral signatures were then found in experimental IR spectra. Further analysis of the IR spectra allowed us to quantify the distribution of these conformations in supercritical CO2. We found that this distribution can be changed by heating from 40°C to 110°C along two isochores at 1.1 and 1.3 of the critical CO2 density. Using in situ Raman spectroscopy we proved that the appearing conformational crossover correlates with the polymorphic transformation of the carbamazepine solid form. Moreover, this transformation was proved by the results of IR diffuse reflection spectroscopy.

Application of Chemometrics Approaches to Analysis of Mid-Infrared Spectra of Ibuprofen Diluted in Supercritical Carbon Dioxide.

This work represents a comprehensive analysis of mid-infrared (mid-IR) spectra of ibuprofen diluted in supercritical CO2 (in the temperature range of 40-90 ℃ and at the CO2 density corresponding to 1.3 of its critical value). The study employed mathematical approaches based on data matrix analysis such as two-dimensional cross-correlation analysis (2D-COS) and principal component analysis (PCA). Two-dimensional cross-correlation analysis allowed us to reveal correlations between the spectral contributions constituting the analytical spectral band and assigned to certain ibuprofen conformers, as well as the significance of these correlations. It has been shown that the considerable increase in the total intensity of the analytical spectral band, proportional to the equilibrium ibuprofen concentration in the supercritical CO2 phase, is accompanied by certain redistribution of intensities of the spectral components related to the corresponding conformers. The PCA allowed us to determine the changes of intensities of individual spectral contributions for each thermodynamic point in the considered temperature range. It has been shown that these two complementary methods provide more precise information that may be used as the initial data in the classical analysis of spectral data based on spectral curve deconvolution into individual spectral contributions.

LiCl solvation in N-methyl-acetamide (NMA) as a model for understanding Li(+) binding to an amide plane.

The thermodynamics of ion solvation in non-aqueous solvents remains of great significance for understanding cellular transport and ion homeostasis for the design of novel ion-selective materials and applications in molecular pharmacology. Molecular simulations play pivotal roles in connecting experimental measurements to the microscopic structures of liquids. One of the most useful and versatile mimetic systems for understanding biological ion transport is N-methyl-acetamide (NMA). A plethora of theoretical studies for ion solvation in NMA have appeared recently, but further progress is limited by two factors. One is an apparent lack of experimental data on solubility and thermodynamics of solvation for a broad panel of 1 : 1 salts over an appropriate temperature and concentration range. The second concern is more substantial and has to do with the limitations hardwired in the additive (fixed charge) approximations used for most of the existing force-fields. In this submission, we report on the experimental evaluation of LiCl solvation in NMA over a broad range of concentrations and temperatures and compare the results with those of MD simulations with several additive and one polarizable force-field (Drude). By comparing our simulations and experimental results to density functional theory computations, we discuss the limiting factors in existing potential functions. To evaluate the possible implications of explicit and implicit polarizability treatments on ion permeation across biological channels, we performed potential of mean force (PMF) computations for Li(+) transport through a model narrow ion channel with additive and polarizable force-fields.

The interplay between the paracetamol polymorphism and its molecular structures dissolved in supercritical CO2 in contact with the solid phase: In situ vibration spectroscopy and molecular dynamics simulation analysis.

The aim of this paper is to characterize the distribution of paracetamol conformers which are dissolved in a supercritical CO2 phase being in equilibrium with their corresponding crystalline form. The quantum calculations and molecular dynamics simulations were used in order to characterize the structure and analyze the vibration spectra of the paracetamol conformers in vacuum and in a mixture with CO2 at various thermodynamic state parameters (p,T). The metadynamics approach was applied to efficiently sample the various conformers of paracetamol. Furthermore, using in situ IR spectroscopy, the conformers that are dissolved in supercritical CO2 were identified and the evolution of the probability of their presence as a functions of thermodynamic condition was quantified while the change in the crystalline form of paracetamol have been monitored by DSC, micro IR and Raman techniques. The DSC analysis as well as micro IR and Raman spectroscopic studies of the crystalline paracetamol show that the subsequent heating up above the melting temperature of the polymorph I of paracetamol and the cooling down to room temperature in the presence of supercritical CO2 induces the formation of polymorph II. The in situ IR investigation shows that two conformers (Conf. 1 and Conf. 2) are present in the phase of CO2 while conformer 3 (Conf. 3) has a high probability to be present after re-crystallization.

Computer simulation study of the intermolecular structure of phosphoric acid-N,N-dimethylformamide mixtures.

The structures and energies of the complexes (H3PO4)2, H3PO4-DMF, and (H3PO4)2-DMF were analyzed at the B3LYP level of approximation. It was found that H-bonds form between H3PO4 and DMF molecules, but the strength of the H-bond depends strongly on its molecular environment. Effects of the solvent were taken into account via the CPCM approach. According to the B3LYP-СPCM calculations, the O···O distance in (H3PO4)2-DMF is shorter and its H-bonds are stronger than in the other complexes studied. In order to study the effects of concentration on the intermolecular structure, molecular dynamics simulations of H3PO4-DMF mixtures with mole fractions of acid of <0.1 were performed. The calculations indicated that the largest fraction of the acid protons are involved in hydrogen bonding with oxygen atoms of the DMF molecules. An increased probability of acid-acid hydrogen-bond formation at phosphoric acid mole fractions >0.06 was also noted.

Prediction of cosolvent effect on solvation free energies and solubilities of organic compounds in supercritical carbon dioxide based on fully atomistic molecular simulations.

The solubility of organic compounds in supercritical fluids can be dramatically affected by addition of a suitable cosolvent (entrainer) at small concentrations. This makes the screening of the best-suited cosolvent an important task for the supercritical technology. The present study aims to improve our fundamental understanding of solvation in supercritical CO2 with cosolvents. We address the following questions: (1) How does the solvation free energy depend on the chemical class of an organic solute and the chemical nature of co-solvents? (2) Which intermolecular interactions determine the effect of a cosolvent on the solubility of organic compounds? We performed extensive calculations of solvation free energies of monofunctional organic molecules at infinite dilution in supercritical media by the Bennett's acceptance ratio method based on fully atomistic molecular dynamics sampling. Sixteen monofunctional organic molecules were solvated in pure sc-CO2 and sc-CO2 with addition of 6 molar % of cosolvents of different chemical nature: ethanol, acetone, and n-hexane. Cosolvent-induced solubility enhancement (CISE) factors were also calculated. It was found that formation of significant number of hydrogen bonds between a solute and cosolvent molecules leads to a profound solubility enhancement. The cosolvent effect is proportional to the number of hydrogen bonds. When polar cosolvents do not form hydrogen bonds with solutes, the CISE correlates with the dipole moment of solute molecules. However, the electrostatic interactions have a small impact on the solubility enhancement compared to hydrogen bonding. Addition of a nonpolar cosolvent, n-hexane, has a very little effect on the solvation Gibbs free energy of studied small organic molecules. The observed trends were discussed in line with available experimental data.

Hydrogen bonding analysis of phosphoric acid-N,N-dimethylformamide mixtures.

An analysis of H-bonding in phosphoric acid (H3PO4)-N,N-dimethylformamide (DMF) mixtures was performed across the full range of mixture compositions using the results from molecular dynamics simulations. The distribution of molecules according to the number of H-bonds they formed with OH groups or О(=Р) atoms of acid molecules and О(=С) atoms of DMF molecules was calculated. The dependence of the average number of H-bonds per acid molecule on the concentration when the acid molecule acted as a proton acceptor was discerned, as were the corresponding dependences when the acid molecule acted as a proton donor towards H3PO4 and/or DMF. The dependence of the average number of H-bonds per DMF molecule (which always acted as a proton acceptor) on the concentration was also determined.

The intermolecular structure of phosphoric acid-N,N-dimethylformamide mixtures as studied by computer simulation.

The computer simulation of H(3)PO(4)-N,N-dimethylformamide (DMF) mixtures over the whole concentration range using molecular dynamic (MD) methods has been carried out. The preferential orientations of the nearest neighbors of H(3)PO(4) and DMF molecules were obtained using the ranked radial distribution functions technique. On the basis of MD results, the parameters of hydrogen bonds between molecules in mixture were calculated. The changes of the intermolecular structure of mixture as a function of acid composition over the whole concentration range were analyzed and reported. Analysis of O···H distance distributions and angles between O-H (H(3)PO(4)) and C=O (DMF) or P=O (H(3)PO(4)) vector distributions showed that O(DMF) and O(H(3)PO(4)) may each have two hydrogen bonds.