Quantification of crystallinity during indomethacin crystalline transformation from α- to γ-polymorphic forms and of the thermodynamic contribution to dissolution in aqueous buffer and solutions of solubilizer.

The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form and metastable α-form of INM at various proportions were prepared, and their individual signal intensities proportional to their mole fractions were observed using X-ray powder diffraction and Fourier transform infrared spectrometry at standard temperature. The endothermic signals of the α-form, with a melting point of 426 K, and that of the γ-form, with a melting point of 433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an exothermic DSC peak of the α/γ-phase transition at approximately 428 K was obtained. As we computed the melting entropy of the α-form and that of its transformation, the frequency of the transition was quantitatively determined, which indicated the maximum of the α/γ-phase transition at an α-form proportion of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol-1, respectively, which are in agreement with the quantitative contribution predicted by the product of the temperature and melting entropy. The contribution of melting entropy was conserved in different dissolution processes with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, +82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, and +22.7, respectively. We conclude that the dissolution ability of the solid state and solubilizers indicate their additivity independently.

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.

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.