Enthalpy-Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem.

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

Singular value decomposition analysis of the secondary structure features contributing to the circular dichroism spectra of model proteins.

Amyloid fibril formation occurs in restricted environment, such as the interface between intercellular fluids and bio-membranes. Conformational interconversion from α-helix to ß-structure does not progress in fluids; however, it can occur after sedimentary aggregation during amyloid fibril formation induced by heat treatment of hen egg white lysozyme (HEWL). Secondary structures of various proteins and denatured proteins titrated with 2,2,2-trifluoroethanol (TFE) were examined using their CD spectra. Gaussian peak/trough and singular value decompositions (SVD) showed that the spectral pattern of the α-helix comprised a sharp trough at wavelength 207 nm and a broad trough at 220 nm. Conversely, we distinguished two patterns for ß-sheet-a spread barrel type, corresponding to ConA, and a tightly weaved type, corresponding to the soybean trypsin inhibitor. Herein, we confirmed that the spectral/conformational interconversion of the heat-treated HEWL was not observed in the dissolved fluid.

Molecular recognizable ion-paired complex formation between diclofenac/indomethacin and famotidine/cimetidine regulates their aqueous solubility.

This study focused on the physicochemical interactions between acidic and basic drugs in aqueous solutions. Their ion pair interactions were evaluated in an in vitro study. The model non-steroid anti-inflammatory drugs (NSAIDs), indomethacin (INM) and diclofenac (DIC), were used as acidic and hydrophobic drugs, whereas cimetidine (CIM), famotidine (FAM), and imidazole (IMD) were used as basic additives with heterocyclic moieties. The drug mixtures were evaluated by thermal analysis, dissolution test, nuclear magnetic resonance (NMR) spectroscopy, and mass spectroscopy. The fusion enthalpy of DIC-CIM, INM-CIM, and INM-arginine (ARG) sample was calculated based on melting temperature transformation. The DIC mixture with CIM, IMD, antipyrine (ANT), and ARG showed enhanced solubility, whereas the DIC-FAM mixture sample showed a decreased solubility. Electrospray ionization mass spectroscopy was carried out to detect binary mixtures. The interactions in DIC-FAM mixture sample were found between the carboxyl group of DIC and the amine groups of FAM by NMR. These findings were suggested that DIC-FAM mixture samples construct ion pair complexes based on the theory of Bjerrum. Moreover, the acid model drug and basic model drug also can be constructed 1:1 complexes that affects their solubility in the solvent of water type.

Effects of ionic and reductive atmosphere on the conformational rearrangement in hen egg white lysozyme prior to amyloid formation.

In this study, the combined effects of pH and salt concentration on the aggregation and amyloid formation of a charge-bearing protein (hen egg white lysozyme, HEWL) were investigated, as well as the inhibition of amyloid formation by using dithiothreitol (DTT) as a denaturing agent. Amyloid formation was found to depend on the ion strength and pH of the sample solution. Rather than the total charge, the partial charge of the amyloid related residues contributes to amyloid formation at pH < isoelectric point (pI). On the other hand, at pH> pI HEWL only undergoes alkaline denaturation regardless of the ionic strength. The effect of adding different amounts of DTT at different times on amyloid formation was also investigated. These results suggested that the positions of charges on a protein and the protein secondary structure are critical for protein aggregation and amyloid formation.

Melting Process of the Peritectic Mixture of Lidocaine and Ibuprofen Interpreted by Site Percolation Theory Model.

Eutectic mixtures are often used in the design and delivery of drugs. In this study, we examined the peritectic mixture of lidocaine (LDC) and ibuprofen (IBP) using differential scanning calorimetry, Raman spectroscopy, and microscopy. The obtained phase diagram showed that as the mixture was heated, first LDC melted at 293 K, then IBP dissolved in the liquefied LDC at 310 K, and finally all remaining crystals melted. In the 1H NMR spectra, the signals of the carboxyl group in IBP and amide or amine group in LDC shifted to the low magnetic field in the IBP/LDC mixtures, because of the intermolecular interaction between these moieties. Using FTIR spectroscopy, the kinetic "reaction" order of the melting process in the mixtures with excess LDC, equimolar, and excess IBP was determined to be +1/2, -1/2, and 0, respectively. The 2 contacts between the liquidus line and the higher melting line at 310 K at IBP molar fractions of 1/3 and of 2/3 were explained on the basis of the site percolation theory.