Enantiotropic changes

The DTA curve of sulfur, as recorded by Chiu i 2k is shown in Figure 7.22. The enantiotropic change from the rhombic to the monoclinic form is indicated by the 113CC peak, while melting was observed during the 124°C peak. Further transformations in liquid sulfur were observed at 179°C, and finally the boiling peak at 446°C. 

Ammonium nitrate (melting point 169.6 °C) exhibits five polymorphs and four enantiotropic changes between —18 and 125 °C, as shown below ... 

The positional order of the molecules within the smectic layers disappears when the smectic B phase is heated to the smectic A phase. Likewise, the one-dimensional positional order of the smectic M phase is lost in the transition to the nematic phase. AH of the transitions given in this example are reversible upon heating and cooling they are therefore enantiotropic. When a given Hquid crystal phase can only be obtained by changing the temperature in one direction (ie, the mesophase occurs below the soHd to isotropic Hquid transition due to supercooling), then it is monotropic. An example of this is the smectic A phase of cholesteryl nonanoate [1182-66-7] (4), which occurs only if the chiral nematic phase is cooled (21). The transitions are aH reversible as long as crystals of the soHd phase do not form. 

The presence of three oxyethylene units in the spacer of PTEB slows down the crystallization from the meso-phase, which is a very rapid process in the analogous polybibenzoate with an all-methylene spacer, P8MB [13]. Other effects of the presence of ether groups in the spacer are the change from a monotropic behavior in P8MB to an enantiotropic one in PTEB, as well as the reduction in the glass transition temperature. This rather interesting behavior led us to perform a detailed study of the dynamic mechanical properties of copolymers of these two poly bibenzoates [41]. 

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. 

In the enantiotropic case the relative solubility and stability changes at a specific transition temperature where the two solubility curves cross. A given polymorph may be more soluble (less stable) above the transition point, but less soluble below and vice versa, Figure 4. An example of this relationship is the Form C and A or B relationships for Cimetidine in the case study. 

Ammonium nitrate exists in four different forms, all of which are enantiotropic the change of white phosphorus into the red (or violet) variety is monotropic. Mercuric iodide exhibits a striking example of an enantiotropic transition. Above 126.3°, it is obtained in yellow rhombic crystals while below that temperature, a scarlet tetragonal modification appears. 

The change is enantiotropic, but the reverse transformation is much slower than the direct decomposition. 

Most interesting are the effects of salt complexation on the mesomorphic behavior of liquid crystalline crown ethers and liquid crystalline crown ether polymers. Sodium triflate was added to poly(17) [34] and poly(25) (Scheme 14) [39]. The enantiotropic nematic and smectic phases of poly(17) were changed dramatically [40]. With increasing amounts of salt, the clearing temperatures are shifted to higher values while the melting transition increases only slightly. 

If an endothermic phase change is observed at a particular temperature, the transition point hes below that temperature, and the two polymorphs are enantiotropically related. If an exothermic transition is observed, then there is no thermodynamic transition point below that transition temperature. This can occur when the two modifications are monotropicaUy related or when they are enantiotropically related and the thermodynamic transition point is higher than the measured transition temperature. 

Whereas hot stage microscopy can be used to obtain qualitative information on polymorphic behaviour, thermal analysis provides quantitative information about the relative stability of polymorphic modifications, the energies involved in phase changes between them and the monotropic or enantiotropic nature of those transitions. The two techniques are best used in conjunction. 

In some cases, new phases that may not be detectable by other methods may be detected optically (Chang et al. 1995). Solid state conversions and their monotropic (Burger et al. 1997) or enantiotropic nature (Henck et al. 2000), or the products of desolvations may be easily recognized (Schinzer et al. 1997). Intimate processes of polymorphic behaviour, such as nucleation, crystal growth, habit transformation, sublimation and properties of the melt (e.g. degradation) may be readily observed and video recorded (de Wet et al. 1998). 

Table 5 deals with the example of a benzisoquino-line hydrochloride for which both forms presented a melting that was followed by decomposition. No change was observed by slow heating rate. Since the melting enthalpies differed only by 10%, the proper interpretation needed the verification of the hypothesis enantiotropic transition. The analysis of the insoluble solid in the equilibration of both forms in alcohols (solvent mediated transition) showed that form A is always obtained, what confirmed the observation of the Burger s rule. 

Originally the only variable in studies of polymorphism was the temperature, and substances are described as enantiotropic if the polymorphic change takes place... 

When the solvent-isolated losartan was subjected to DSC characterization, the DSC curve (Fig. 3-5, curve A) showed a minor endotherm at an extrapolation onset temperature of about 229°C (10°C/min) and a major melting endotherm at an extrapolation onset temperature of about 273°C (10°C/min). When a sample of Form I was heated to 255°C and then cooled back to room temperature, the subsequent DSC curve showed only the high-temperature endotherm (Fig. 3-5, curve B). Chemical analysis (HPLC) and solution NMR showed no change in the material heated to 255°C and cooled back to room temperature. However, XRPD indicated a change in the crystal structure. Therefore, it was concluded that the minor endotherm corresponded to a kinetically irreversible enantiotropic polymorphic transition and that the losartan system was not under complete thermodynamic control. Form I is the low-temperature stable form, up to the transition point, and the high-temperature stable form was... 

The solubility measurements of the two losartan forms (Form II prepared by heating) in isopropanol and ethyl acetate at 25 C and with overnight equilibration resulted in the conversion of Form U to Form I and no change in the initial Form I. The observed solubilities were 35 to 0.3 mg/g, respectively. However, in isopropyl acetate, no conversion of either form was observed after overnight equilibration at 25°C. The resulting solubihties were 18 and 41 mcg/gm for Forms I and II, respectively. More extensive solubility data, in methyl ethyl ketone at temperatures ranging from 25 to 65 C with shorter equilibration times that did not result in any conversions, showed Form I, once again, to have the lower measured values (Crocker and McCauley 1997). Extrapolation (Fig. 3-6) of the methyl ethyl ketone data indicated that the two solubility-temperature curves cross at a temperature of about 192 C, which is consistent with the enantiotropic transition seen in the DSC curves for Form I. The solubility data confirm that Form I is the more thermodynamically stable form at room temperature. 

The thermodynamic activity of each crystalline form, represented by its solubility, may change quite differently as a function of temperature. Monotropic systems are dehned as systems where a single form is always more stable regardless of the temperature. Enantiotropic systems are dehned as systems where the relative stability of the two forms inverts at some transition temperature (Bym et al., 1999). 

---