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.

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.

Ab Initio Study of Structural Features and H-Bonding in Alkylammonium-Based Protic Ionic Liquids.

The structural and energetic characteristics of protic ionic liquids (PILs) based on ethyl-, diethyl-, or triethylammonium cations with anions of phosphorus, trifluoroacetic, or p-toluenesulfonic acids have been investigated by density functional theory calculations at the B3LYP/6-31++G(d,p) level of theory. As a result of the interaction between acid and alkylamine, the H-bonded molecular complexes or H-bonded ion pairs have been obtained. The increasing number of ethyl groups attached to the nitrogen atom of amine and H-bond donor ability of acid causes a stronger H-bonding interaction leading to the formation of ion pairs. For all systems, the proton transfer between ion pairs and molecular complexes has been examined. Solvation effects have been also investigated using the solvent polarizable continuum model (CPCM).

Ab initio molecular dynamics study of H-bonding and proton transfer in the phosphoric acid-N,N-Dimethylformamide system.

Car-Parrinello molecular dynamics simulations of phosphoric acid (H3PO4)-N,N-dimethylformamide (DMF) mixtures over the whole composition range have been carried out. It has been found that the neutral molecules are the dominant species in this system. The concentration dependences of the average number of H-bonds per proton acceptor atom in P=O and C=O groups as well as per proton donor atom in DMFH+ ions towards phosphate species have been discussed. The H-bonding between components in all investigated mixtures of H3PO4 and DMF is possible. A significant fraction of the protonated DMF forms appears at phosphoric acid mole fraction higher than 0.37, indicating a high probability of proton transfer from phosphate species to oxygen atoms in C=O groups. The intermolecular proton transfer between phosphate species themselves is mainly observed when xH3PO4 > 0.19. Satisfactory agreement with available experimental data for structural characteristics of the investigated system was obtained.