Enantiotropic transition

Most solid materials produce isotropic liquids directly upon melting. However, in some cases one or more intermediate phases are formed (called mesophases), where the material retains some ordered structure but already shows the mobility characteristic of a liquid. These materials are liquid crystal (LCs)(or mesogens) of the thermotropic type, and can display several transitions between phases at different temperatures crystal-crystal transition (between solid phases), melting point (solid to first mesophase transition), mesophase-mesophase transition (when several mesophases exist), and clearing point (last mesophase to isotropic liquid transition) [1]. Often the transitions are observed both upon heating and on cooling (enantiotropic transitions), but sometimes they appear only upon cooling (monotropic transitions). 

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. 

In another example, an antiarrhythmic under development (McCauley etal. 1993) was shown to exist in two anhydrous polymorphs, two dihydrated enantiotropic polymorphs, a monohydrate, and the solvates of several organic solvents. Following characterization of all of these modifications it was desired to selectively obtain one of the dihydrates, termed modification A, which is thermodynamically less stable at room temperature than another dihydrate, D, in contact with aqueous solutions, but A is more stable over a wider range of relative humidities. The enantiotropic transition point between these two crystal modifications is 37 °C. Procedures were developed for obtaining A preferentially. Above the transition point a thermodynamic crystallization is carried out at 50 °C, using type A seeds as an added precaution to force the crystallization to type A. The desired type A can also be obtained under kinetic conditions by spontaneous crystallization below the transition point followed by rapid filtration and removal of excess water. The latter procedure prevents a transformation from the A state (metastable below the transition temperature) to the D form in the crystallization medium. Similar considerations were applied to develop procedures for the selective crystallization of the a and /3 modifications of glutamic acid (Kitamura 1989). 

The brown low-temperature form of Mn (05115)2 shows a sharp transition point at 158-159°K and undergoes an enantiotropic transition into a pale pink modification. There thus takes place a sudden transition to five unpaired electrons, see Fig. 3 (corresponding to a moment of 5.9 Bohr magnetons for = 0) and these are also observed to be present from the melting point at 170-172° to 530°K. We interpret this as being a gradual transition of a penetration complex in which relaxation occurs... 

These curves illustrate the complex transitions that may occur when heating or cooling polymorphs. Therefore, combined techniques are very useful for complete interpretation of observations given by DSC as emphazised in Ref. Fig. 8 illustrates a reversible enantiotropic transition followed by DSC and by temperature-resolved X-ray diffraction of a purine derivative. For this substance six crystalline forms were found. The Burger s rule as well as the study of the supersaturated solutions and the use of combined techniques allowed us to find out that the form of Fig. 8 was the stable form below the transition point. All other forms were monotrops to this form. ... 

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. 

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. 

In the enantiotropic transition (Fig. 11), when the stable a form is heated, only one peak, the melting point, is observed in the thermogram. After cooling (rapid but noncontrolled cooling rate), the same heating curve is obtained. 

A further interesting aspect of diindenoperylene is the solid-to-solid phase transition which occurs at around 403 K [56, 57]. Figure 25.9 shows the characteristics of this enantiotropic transition measured by X-ray diffraction in Bragg-Brentano geometry along the [001] direction. The transition comprises... 

In contrast, compound 53 exhibits only one enantiotropic transition by DSC, which occurs between a chiral nematic phase and the isotropic liquid, in... 

Solid-Phase Transitions. A heating curve usually shows the existence of solid solid or enantiotropic transitions. When melting occurs before the solid - solid transition is completed, the melting curve will obviously be unreliable. Smit (31) recommended that the sample be stored for a period of time at a temperature above the transition temperature before determination of the melting curve. 

It should be assumed, however, that by analogy with the behavior of low-molecular-weight liquid crystals, there must be a temperature at which, in a pure polymer containing no solvent, transition from the liquid-crystalline to the isotropic state takes place. This transition must occur above the fusion temperature of the cyrstalline polymer (enantiotropic transition). Therefore, curves of compositions must, in principle, extrapolate... 

Some mesogens are polymorphic, exhibiting more than one type of fiquid-crystalline phase as the temperature is changed. When the transitions are reversible, they are called enantiotropic transitions. Enantiotropic polymorphism is observed for bis(/ -heptyloxyphenyl) terephthalate (1) with = 6. The transition temperatures (°C) and changes in enthalpy (kJmol ) experimentally observed for 1 are indicated on the transition map shown below the molecular formula. Mesogen 1 exhibits two smectics and a nematic phase the more ordered Sc phase occurs at... 

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. 

Focusing attention on PTEB, it has been found that, similar to the case of PDTMB, the mesophase experiences a very slow transformation into the crystal. Thus, only the isotropization is observed in a sample freshly cooled from the melt [27]. However, after a long time at room temperature, the transformation mesophase-crystal is produced, owing to a glass transition temperature of about 14°C. Moreover, several endotherms were obtained before the final isotropization for a sample of PTEB annealed at 85°C for 12 days, i.e., PTEB shows enantiotropic behavior. The different endotherms may arise from polymorphism or melting-recrystallization phenomena [30]. 

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]. 

Liquid crystals based on aliphatic isocyanides and aromatic alkynyls (compounds 16) show enantiotropic nematic phases between 110 and 160 °C. Important reductions in the transition temperatures, mainly in clearing points (<100 °C), areobtained when a branched octyl isocyanide is used. The nematic phase stability is also reduced and the complexes are thermally more stable than derivatives of aliphatic alkynes. Other structural variations such as the introduction of a lateral chlorine atom on one ring of the phenyl benzoate moiety or the use of a branched terminal alkyl chain produce a decrease of the transition temperatures enhancing the formation of enantiotropic nematic phases without decomposition. 

If a modification is unstable at every temperature and every pressure, then its conversion into another modification is irreversible such phase transitions are called monotropic. Enantiotropic phase transitions are reversible they proceed under equilibrium conditions (AG = 0). The following considerations are valid for enantiotropic phase transitions that are induced by a variation of temperature or pressure. 

The importance of temperature-controlled scanning calorimetry for measurements of heat capacity and of scanning transitiometry for simultaneous caloric and pVT analysis has been demonstrated for polymorphic systems [9]. This approach was used to study an enantiotropic system characterized by multiphase (and hindered) transitions, the role of heat capacity as a means to understand homogeneous nucleation, and the creation of (p, T) phase diagrams. The methodology was shown to possess distinct advantages over the more commonly used combination of characterization techniques. 

An enantiotropically related pair of polymorphs was obtained for p-aminoben-zoic acid, with the system being characterized by a transition temperature of 25 °C [31]. The a-form was obtained as fibrous needles, while the /M orm was obtained in the form of prisms. The solubilities of the two forms are almost the same, indicating the existence of comparable values for AG, which in turn explained the slow transformation of the a-form into the [>-form. Nucleation of the a-form was found to be favored, which is reasonable considering that the structural motif of the a-form consists of carboxylic acid dimmers that would be expected to be stable association species in solution. 

The structures of two polymorphs of pleconaril, enantiotropically related with a transition temperature of 35.7°C, have been reported [36], Form I was described as consisting of a network of dimers, while Form III was described as a three-dimensional network of monomers. The two forms contradicted the density rule, and the solid solid transition could occur only through a destructive-reconstructive mechanism. A quantitative differential scanning calorimetry method was also described that enabled the quantitative determination of Form I in bulk Form III to be made at levels as low as 0.1%. 

On heating from a crystalline phase, DOBAMBC melts to form a SmC phase, which exists as the thermodynamic minimum structure between 76 and 95°C. At 95°C a thermotropic transition to the SmA phase occurs. Finally, the system clears to the isotropic liquid phase at 117°C. On cooling, the SmC phase supercools into the temperature range where the crystalline solid is more stable (a common occurrence). In fact, at 63°C a new smectic phase (the SmF) appears. This phase is metastable with respect to the crystalline solid such phases are termed monotropic, while thermodynamically stable phases are termed enantiotropic. The kinetic stability of monotropic LC phases is dependent upon purity of the sample and other conditions such as the cooling rate. However, the appearance of monotropic phases is typically reproducible and is often reported in the phase sequence on cooling. It is assumed that phases appearing on heating a sample are enantiotropic. 

Enantioseparation, 14 180 Enantiotropic phase transitions, 15 101 Enargite, 3 263t Enbrel, 2 824... 

In its heyday, DTA analysis was very useful for the study of compound polymorphism and in the characterization of solvate species of drug compounds. It was used to deduce the ability of polymorphs to undergo thermal interconversion, providing information that could be used to deduce whether the system in question was monotropic or enantiotropic in nature. For instance, the enthalpies of fusion and transition were measured for different polymorphs of sulfathiazole and methylprednisolone [24]. The DTA thermograms shown in Fig. 4.5 demonstrate that Form-I is metastable with respect to Form-II, even... 

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. 

An example of monotropic behavior consists of the system formed by anhydrous ibuprofen lysinate [41,42], Figure 4.12 shows the DSC thermogram of this compound over the temperature range of 20-200°C, where two different endothermic transitions were noted for the substance (one at 63.7°C and the other at 180.1°C). A second cyclical DSC scan from 25 to 75°C demonstrated that the 64°C endotherm, generated on heating, had a complementary 62°C exotherm, formed on cooling (see Fig. 4.13). The superimposable character of the traces in the thermograms demonstrates that both these processes were reversible, and indicates that the observed transition is associated with an enantiotropic phase interconversion [41]. X-ray powder (XRPD) diffraction patterns acquired at room temperature, 70°C, and... 

MDSC is particularly useful for the study of reversible (related to the heat capacity) thermal reactions, and is less useful for non-reversing (kinetically controlled) reactions. Examples of reversible thermal events include glass transitions, heat capacity, melting, and enantiotropic phase transitions. Examples of non-reversible events include vaporization,... 

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. 

Enantiotropic behaviour may constrain the temperature envelope over which a crystallization process could operate. Transition temperatures can be predicted with DSC derived AHm and Tm values together with Eq. 2. Sluny experiments on either side of the transition temperature can then be used to validate the calculations. 

A plot of the ideal solubility curves can be used to identify the transition temperatures for the enantiotropic relationships. Form C is the most stable polymorph at high temperature, with a transition to Form B at 20 °C. The Form C to A transition occurs at 11 °C. 

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