Philippe Espeau

Polymorphism of progesterone: Relative stabilities of the orthorhombic phases I and II inferred from topological and experimental pressure‐temperature phase diagrams

Temperatures and melting enthalpies of orthorhombic Phases I and II of natural progesterone, together with the temperature dependence of their lattice parameters and the specific volume of the melt at ordinary pressure, have been determined. With these results, a topological pressure-temperature (P-T) phase diagram accounting for the thermodynamic relationships between these phases has been constructed by way of the Clapeyron equation. The dependence of the melting temperature on the pressure has also been determined for each phase by high-pressure differential thermal analysis. It was found that, upon increasing the pressure, the melting curves converge to the I-II-liquid triple point (T(I-II-liquid) = 459.4 K, P(I-II-liquid) = 149.0 MPa), in close agreement with its topological location. This entails that Phase II should exhibit a stable phase region at higher pressure.

Overall Monotropic Behavior of a Metastable Phase of Biclotymol, 2,2′-Methylenebis(4-Chloro-3-Methyl-Isopropylphenol), Inferred From Experimental and Topological Construction of the Related P-T State Diagram

The melt from the usual monoclinic phase (Phase I) of biclotymol (T(fusI) = 400.5 +/- 1.0 K, Delta(fus)H(I) = 36.6 +/- 0.9 kJ mol(-1)) recrystallizes into another phase, Phase II, that melts at T(fusII) = 373.8 +/- 0.2 K (Delta(fus)H(II) = 28.8 +/- 1.0 kJ mol(-1)). The transformation of Phase II into Phase I is found to be exothermic upon heating either as a direct process at 363 K or through a melting-recrystallization process (II --> liquid --> I). The melting curves, obtained from differential thermal analyses at various pressures ranging from 0 to 85 MPa, diverge as the pressure increases ((dP/dT)(fusI) = 2.54 +/- 0.07 MPa K(-1), (dP/dT)(fusII) = 5.14 +/- 0.85 MPa K(-1)). A topological P-T diagram with no stable phase region for Phase II, and similar to the 4th case of the P-T state diagrams formerly published by Bakhuis Roozeboom, is drawn, thus illustrating the overall monotropic behavior of Phase II.

Thermodynamic properties of n-alkanes inporous graphite

Differential scanning calorimetry on very thin layers of n-alkanes confined in the pores of delaminated graphite is reported. The thermodynamic behaviour of the strongly adsorbed component at the graphite surface and the apparently ‘bulk-phase’ component (from the point of view of X-ray diffraction) is analysed. The adsorbed phase is of the same crystalline form whatever the parity of the n-alkanes and has the same thermodynamic properties, as revealed by differential scanning calorimetry. A study of the solid–solid and solid–liquid transitions of the ‘bulk phase’ confined in the pores shows that the solid–solid transition is the most affected by the confinement in the pores and its temperature is decreased.

Lidocaine/L-menthol binary system: cocrystallization versus solid-state immiscibility.

We present the synthesis, structure determination, and thermodynamic properties of a never reported cocrystal prepared with lidocaine and L-menthol. The temperature-composition phase diagram of the lidocaine/L-menthol binary system was achieved using differential scanning calorimetry and X-ray diffraction experiments. The present study demonstrates that the only way to perform a phase equilibrium survey of the lidocaine/L-menthol system is to prepare the binary mixtures from the cocrystal, an equimolar stoichiometric compound of L-menthol and lidocaine. We describe a process that is crucial to elaborate pharmaceutical agents that remain in their thermodynamical stable state throughout their preparation, manufacture, and storage for effective use.

X-RAY DIFFRACTION FROM LAYERS OF N-ALKANES ADSORBED ON GRAPHITE

The structure of 1 to 80 layers of C 16 H 34 and C 17 H 36 n-alkanes adsorbed on graphite has been studied as a function of temperature using synchrotron X-ray radiation. The measurements confirm that a surface phase of two to four layers, distinct from the bulk adsorbed on the graphite, is formed at room temperature. The structure of the subsequent layers, for a particular hydrocarbon, is not appreciably affected by the number of layers. Warren-like peaks are observed for the adsorbed phase and can be indexed in a centred oblique two-dimensional lattice.

Topological and experimental approach to the pressure-temperature-composition phase diagram of the binary enantiomer system d- and l-camphor.

In 1981, Jacques, Collet, and Wilen already put forward the idea to use pressure to influence equilibria in binary enantiomer systems in analogy with temperature (Jacques et al. Enantiomers, Racemates and Resolutions; John Wiley & Sons: New York, 1981). Whereas temperature is used routinely to study phase equilibria, pressure is an all but forgotten parameter. This is therefore possibly the first paper on the influence of pressure on a binary enantiomer system: d- and l-camphor. The study consists of two parts, a topological approach, which uses data obtained from routine measurements (differential scanning calorimetry, X-ray diffraction), and the experimental determination of phase transitions as a function of pressure and temperature. This has resulted in two topological pressure-temperature phase diagrams of the pure enantiomer d-camphor and of the racemic mixture dl-camphor; both have been verified by the experiments as a function of pressure. In turn, these results have been used to construct part of the pressure-temperature-composition phase diagram of d- and l-camphor. A method to obtain the excess Gibbs energy from these binary phase diagrams as a function of pressure is proposed.

The role of stearic acid in ascorbic acid protection from degradation: a heterogeneous system for homogeneous thermodynamic data

A heterogeneous system between vitamin C and stearic acid was characterized by thermal and crystallographic analyses. The results showed that such a system prevents vitamin C from thermal decomposition. The evidence was provided by implementing a new protocol associating chromatic assays and thermal analyses in order to quantify the percentage of non-degraded vitamin C. The results collected with the vitamin C–stearic acid mixtures allowed deducing coherent interpretation of the results obtained with pure vitamin C at different heating scan rates. Vitamin C mainly degrades upon melting but also in the solid state for temperature close to the melting point when the heating rates are very low. Under these conditions, the temperature determined at the onset of the DSC graphs cannot be associated with the melting temperature but with a fusion-degradation phenomenon. At higher scan rates, the onset as well as the endothermic value of the signal increase to reach plateau values. These values have been identified as the temperature and enthalpy values of melting of vitamin C according to the results obtained from the heterogeneous system.

Liquid–liquid miscibility gaps and hydrate formation in drug–water binary systems: Pressure–temperature phase diagram of lidocaine and pressure–temperature–composition phase diagram of the lidocaine–water system

The pressure-temperature (P-T) melting curve of lidocaine was determined (dP/dT = 3.56 MPa K(-1)), and the lidocaine-water system was investigated as a function of temperature and pressure. The lidocaine-water system exhibits a monotectic equilibrium at 321 K (ordinary pressure) whose temperature increases as the pressure increases until the two liquids become miscible. A hydrate, unstable at ordinary pressure, was shown to form, on increasing the pressure, from about 70 MPa at low temperatures (200-300 K). The thermodynamic conditions of its stability were inferred from the location of the three-phase equilibria involving the hydrate in the lidocaine-water pressure-temperature-mole fraction (P-T-x) diagram.

Vitreous State Characterization of Pharmaceutical Compounds Degrading upon Melting by Using Fast Scanning Calorimetry.

Fast scanning calorimetry, a technique mainly devoted to polymer characterization, is applied here for the first time to low molecular mass organic compounds that degrade upon melting, such as ascorbic acid and prednisolone. Due to the fast scan rates upon heating and cooling, the substances can be obtained in the molten state without degradation and then quenched into the glassy state. The hydrated form and the polymorphic Form 1 of prednisolone were investigated. It is shown that once the sesquihydrate dehydrates, a molten product is obtained. Depending on the heating rate, this molten phase may recrystallize or not into Form 1.

Physicochemical stability of solid dispersions of enantiomeric or racemic ibuprofen in stearic acid

The aim of this study was to investigate the solid dispersion phase behavior of s- or rs-ibuprofen in stearic acid. By means of thermal analysis, we have demonstrated the total immiscibility, in solid state, of the corresponding binary mixtures. This indicates that no specific interactions exist between the chosen excipient and active pharmaceutical ingredient (API) that lead to eutectic systems. Furthermore, based on calorimetric and X-ray diffraction experiments, we have showed that upon cooling of the molten state, only stearic acid recrystallizes in the presence of s-ibuprofen, whereas a quaternary phase mixture is obtained for the racemic ibuprofen/stearic acid preparation. The solubility of stearic acid in s-ibuprofen liquid in all proportions was also determined. Overall, the results presented here offer an approach for the study of API/excipient interactions.