Polymorphism enantiotropy

Two polymorphs are reported (Benson et al., 2000) Indications of polymorphic enantiotropy were found primarily through solubility analysis and FTIR-ATR (Nordstom and Rasmuson, 2006). 

Thermodynamic and kinetic aspects of polymorphism enantiotropy and monotropy... 

Beside mid-IR, near-IR spectroscopy has been used to quantitate polymorphs at the bulk and dosage product level. For SC-25469 [34], two polymorphic forms were discovered (a and /3), and the /3-form was selected for use in the solid dosage form. Since the /3-form can be transformed to the a-form under pressure by enantiotropy, quantitation of the /3-form in the solid dosage formulation was necessary. Standard mixtures of both forms in the formulation matrix were prepared, and spectra were measured in the near-IR via diffuse reflectance. Utilizing a standard, near-IR multiple linear regression, statistical approach, the a- and /3-forms could be predicted to within 1% of theoretical. This extension of the diffuse reflectance IR technique shows that quantitation of polymorphic forms at the bulk and/or dosage product level can be performed. 

When a solid system undergoing a thermal change in phase exhibits a reversible transition point at some temperature below the melting points of either of the polymorphic forms of the solid, the system is described as exhibiting enantiotropic polymorphism, or enantiotropy. On the other hand, when a solid system undergoing thermal change is characterized by the existence of only one stable form over the entire temperature range, then the system is said to display monotropic polymorphism, or monotropy. 

Solubility measurements should be made for the desired polymorph in 5 or 6 representative solvents that cover the range of segment types in the NRTL-SAC method, and within the polymorphs stable temperature region where enantiotropy exists. Solubility should be measured in mol or mass fractions and... 

A number of empirical rules have been proposed to deduce the relative order of stability of polymorphs and the nature of the process that interconverts these (i.e., enantiotropy vs. monotropy). Among the better known are the Heat of Transition Rule, which states that if an endothermic transition is observed at some temperature, it may be assumed that there must be a transition point located at a lower temperature where the two forms bear an enantiotropic relationship. Conversely, if an exothermic transition is noted at some temperature, it may be assumed that there is no transition point located at a lower temperature. This in turn implies that either the two forms bear a monotropic relationship to each other or that the transition temperature is higher than the temperature of the exotherm. 

For each polymorph (single compound), there is a solid-liquid equilibrium curve and a solid-gas equilibrium curve. The solid-gas curves meet at a point. If the liquid-gas equilibrium curve meets the two solid-gas curves after this point of intersection, there will be a solid 1, solid 2 equilibrium curve and a reversible transition point 1 2 at a specific pressure. This is known as enantiotropy. At the transition point, the free energy of the two forms is the same. 

Fig. 7 illustrates the behavior of polymorphs A and B in case of enantiotropy (Fig. 7A) and monotropy (Fig. 7B) during heating. For all analysis where a temperature change is involved, kinetic factors have to be considered for proper interpretation of the results. The DSC scans will differ if the sample being analyzed is stable or metastable at ambient temperature. A is the stable form at ambient temperature in both cases. 

Univariant Systems.—Equilibrium between liquid and vapour. Vaporisation curve. Upper limit of vaporisation curve. Theorems of van t Hoff and of Le Chatelier. The Clausius-Clapeyron equation. Presence of complex molecules. Equilibrium between solid and vapour. Sublimation curve. Equilibrium between solid and liquid. Curve of fusion. Equilibrium between solid, liquid, and vapour. The triple point. Complexity of the solid state. Theory of allotropy. Bivariant systems. Changes at the triple point. Polymorphism. Triple point Sj—Sg— V. Transition point. Transition curve. Enantiotropy and monotropy. Enantiotropy combined with monotropy. Suspended transformation. Metastable equilibria. Pressure-temperature relations between stable and metastable forms. Velocity of transformation of metastable systems. Metastability in metals produced by mechanical stress. Law of successive reactions. 

The 8,-82-V triple point is one at which the reversible transformation of the crystalline polymorphs can take place. If both 8, and 82 are capable of existing in stable equilibrium with their vapor phase, then the relation is termed enantiotropy, and the two polymorphs are said to bear an enantiotropic relationship to each other. For such systems, the 8,-82-V triple point will be a stable and attainable value on the pressure-temperature phase diagram. A phase diagram of a hypothetical enantiotropic system is shown in Fig. 7. Each of the two polymorphs exhibits a 8-V sublimation curve, and they cross at the same temperature at which they meet the 8,-82 transition curve. The 82-V curve... 

Very complicated phase diagrams can arise when substances can exist in more than two crystalline polymorphs. In certain cases, some of the forms may be enantiotropic to each other, and monotropic to yet others. For instance, of the eight polymorphs of elemental sulfur, only the monoclinic and rhombic modifications exhibit enantiotropy and the possibility of reversible interconversion. All of the other forms are monotropic with respect to the monoclinic and rhombic forms and remain as metastable phases up to the melting point. 

Generally speaking, the concepts of monotropy and enantiotropy in phase theory appear to coincide with the structural concepts of unrelated and related lattices. Nevertheless, one must avoid equating the two, for it is certainly possible that one of two related lattices of the same substance is less stable than the other under all conditions of temperature and pressure. This would indicate the existenced of monotropy in spite of the existence of related lattices. This situation becomes especially important for polymorphic organic compounds, which form molecular lattices. 

As well, the real behavior in the liquid and solid phase has an influence on the SLE behavior. In some cases one or more solid compounds are formed. At the same time miscibility gaps can appear. Furthermore, many substances occur in more than one crystalline form. This phenomenon is called polymorphism for compounds and allotropy in the case of elements. If the transition curve lies within the region of stable states the phenomenon is called enantiotropy. In the metastable region it is called monotropy. 

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