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.

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.

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.

The study of correlations between hydrogen bonding characteristics in liquid, sub- and supercritical methanol. Molecular dynamics simulations and Raman spectroscopy analysis.

Molecular dynamics (MD) studies of hydrogen bonding (H-bonding) in liquid, sub- and supercritical methanol have been performed in a wide range of thermodynamic parameters of state, using various potential models and two H-bond criteria. It was shown that there is the universal correlation between the average number of H-bonds per molecule (n(HB)) and the mole fraction of H-bonded molecules (X(HB)) for the studied thermodynamic parameters of state. The same feature was observed for the correlations between fractions of molecules forming one (f1), two (f2), three (f3) H-bonds and X(HB). These correlations served to fit experimental Raman spectra of methanol recorded under sub- and supercritical conditions. The advantage of the approach used here is that f1, f2, f3 values have a clear physical meaning and are dependent on the values of state parameters.