Enantiotropy

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... 

ENANTIOTROPY. The property possessed by a substance of existing in two crystal forms, one stable below, and the other stable above, a certain temperature called the transition point. 

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. 

Knowing the relationship between the thermodynamic quantities H (enthalpy), G (free energy), S (entropy), and T (temperature), it is often simple to represent equilibrium states by plotting the free energy G as a function of the temperature for each form. If the two curves intersect before the melting point, there is reversibility, i.e., enantiotropy, and if the reverse is true, there is monotropy. 

Fig. 6 Energy diagrams showing plots of enthalpy H and Gibbs free energy G, against temperature T, for the solid and liquid phases of a single compound, showing (A) enantiotropy and (B) monotropy.

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. 

In the case of enantiotropy (Fig. 7A), only the form A should be encountered below the transition point and the behavior upon heating is illustrated by the DSC scan 1, the endothermic transition A B... 

Very often some substances have two melting points separated by an exotherm. Such a DSC scan can correspond to a monotropy or to an enantiotropy. The sample may be a pure form or a mixture. Using different heating rates and tempering in DSC, one... 

Enantiotropy combined with Monotropy.—N t-"ORiy oari. 4 ly-morghk exhihit enantiotropy Of ixtQUOtropy, but, if the sub-... 

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. 

In the case of enantiotropy, stability ranking changes at a certain temperature, the so-called transition temperature Tf One form is thermodynamically stable and less soluble below this temperature the other form is stable at temperatures above T. ... 

---