Enantiotropic polymorphism

Based on the reversibility of their phase transformation behavior, polymorphs can easily be classified as being either enantiotropic (interchange reversibly with temperature) or monotropic (irreversible phase transformation). Enantiotropic polymorphs are each characterized by phase stability over well-defined temperature ranges. In the monotropic system, one polymorph will be stable at all temperatures, and the other is only metastable. Ostwald formulated the rule of successive reactions, which states that the phase that will crystallize out of a melt will be the state that can be reached with the minimum loss of free... 

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. 

Y. Hu, H. Wikstrom, S.R. Bym and L.S. Taylor, Estimation of the transition temperature for an enantiotropic polymorphic system from the transformation kinetics monitored using Raman spectroscopy, J. Pharm. Biomed. Anal, 45, 546-551 (2007). 

Moraglio, G., Polizzotti, G. and Danusso, F. Enantiotropic polymorphism of transtactic poly-1,3-butadiene, Europ. Polymer J. 1, 183 (1965)... 

Enantiotropic polymorphs exhibit this transition temperature below their melting temperature (Figure 19.5), which means that the stable modiLcation depends on the temperature of reference This temperature represents the point of equal solubility for the two polymorphs, and one will have greater solubility above this temperature, and one below it. These transitions are often reversible, but may be kinetically limited or outside the temperature range studied. Haleblian and McCrone (1969) have cautioned that an enantiotropic relationship cannot be discounted because of the lack of an observed transition point. The transition can be examined microscopically if the crystal habits differ, or by solubility-temperature curves if the metastable form solubility can be measured before transformation. 

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). 

Figure 2-14 Solubility curves of monotropic and enantiotropic polymorphs. For monotropic polymorphs, there is no crossing-over of solubihties of two forms. For enantiotropic polymorphs, there is a crosssing-over.

In the real world, the transition or equilibrium point between two enantiotropic polymorphs is often not directly observed because of suspended transformations in connection with metastable equilibrium. Measurement of various physical properties at different temperatures can be related to the relative free energy of the polymorphs, and the forms, can be classified as enantiotropic or monotropic. 

It is clear from the DTA curves that Form I is the more stable polymorph in the high-temperature range. However, based upon solubility and rate of dissolution measurements (Tables 3-2 and 3-3 and Fig. 3-4), the reverse situation applies at lower temperatures. Form II is more stable near room temperature. The extrapolation of the solubility and dissolution rate date indicate a transition point at about 165°C for Form II to Form I. This transition is not observed in the DTA curve for Form II, as it should be if the situation were thermodynamically ideal. The lack of transition in the DTA curve corresponds to a case of suspended transformation. Forms I and II of sulindac are enantiotropic polymorphs, with Form II being more stable at room temperature (McCauley 1991). 

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... 

Anhydrous ibuprofen lysinate, an analgesic agent, provides another example of enantiotropic polymorphs. Figure 3-9 exhibits a representative DSC curve for anhydrous ibuprofen lysinate. The curve has features that are similar to those of the DSC curve for Form I of finasteride. However, the XRPD pattern after heating to a temperature above that of the minor endotherm for anhydrous ibuprofen lysinate and cooling back to room temperature remains unchanged, in contrast to the finasteride... 

The DSC curve for Form II (Fig. 3-16) also showed a minor endotherm, but at a lower Tons (53°C) than seen starting with Form I. The solid phase observed above 53°C was different from any of the previously seen solid structures and was designated Form IV (Fig. 3-17). Form IV, once formed and cooled below 53°C, spontaneously converted to Form II. Forms II and IV were a second pair of enantiotropic polymorphs. The solid state NMR spectra of Forms III and IV were also unique (Fig. 3-18). 

As for monotropic polymorphism, the common L V curve will normally intersect the Si V and -S n-F curves below their intersection (Figure 3) (4). There is no region of stability for the second polymorph (-S ), and the melting point of the metastable An polymorph will invariably be lower than that of the stable form (Ai). Unlike enantiotropic polymorphism, the triple point is always higher than the melting point of the stable 5i phase. Only one of the polymorphs remains stable up to the melting point upon heating, and the other polymorph can exist only as a metastable phase, irrespective of... 

Employing the same SEDS crystallization technique and keeping the pressure at 200 bar, two enantiotropic polymorphs (I and II) of salmeterol xinafoate have been separately produced in pure forms simply by varying the vessel temperature (6). The vessel temperature can be tightly controlled to within 2°C. Form I is obtained at 40 to 65°C, while form II is generated at 70 to 90 °C. Thus, the transition temperature between the two polymorphs should lie somewhere between 65 and 70°C at 200 bar. 

If a drug has two enantiotropic polymorphic forms, either may be stable depending on the temperature at a given pressure, whereas for monotropic polymorphism only one form is stable irrespective of temperature. The study of polymorphism is further complicated by the fact that both thermodynamic and kinetic factors must be considered, as some metastable forms are sufficiently kinetically stable as to render them extremely difficult to differentiate from thermodynamically stable configurations. Clearly, however, the more detailed the knowledge of the thermodynamic and kinetic behavior of the different forms, the greater the ability to predict the likely behavior on storage. 

The difference between enantiotropic and monotropic forms may be visualized in terms of differences in the temperature-dependent free energy relationship between the respective forms. For enantiotropic polymorphs, there exists a unique temperature (7 0) below the melting point of either form at which the free energy of the two is the same. Consequently, above or below this temperature, either one or the other form will be thermodynamically stable. For monotropic polymorphs,... 

Summary of Means of Differentiating between Monotropic and Enantiotropic Polymorphism, with... 

McMahon et al. (40) have studied carbamazepine, which may be present as two enantiotropic polymorphs and as a dihydrate. The authors compared the properties of dihydrates produced from Form 1 and Form 111 carbamazepine in order to investigate the influence of the choice of the anhydrous polymorphic form used to produce the dihydrate (by suspension in distilled water). The authors reported that holding the sample at 25°C in a TGA resulted in the generation of anhydrous form 1, irrespective of the source of the dihydrate. DSC studies, however, indicated... 

Polymorphism. Polymorphic literally means multiform, but the term does not refer to variation in external shape. It indicates that crystals of the same molecules have different unit cells, be it of the same or of a different crystal system. The phenomenon is quite common. There are two types of polymorphism. Enantiotropic polymorphs each are stable within a certain range of temperature and pressure. Consequently, a phase diagram of the various polymorphs can be made. The prime example is ice (Section 15.3.1). If monotropic polymorphs exist, all but one of these are unstable. There is no phase diagram and, given time, only the most stable form will remain. The prime examples are compounds with long paraffinic chains, including most lipids (especially acylglycerols), where three main polymorphs exist (a, (F, and (3). 

We conclude our discussion of polymorphism with some brief general remarks. The physical factors most commonly involved in bringing about an enantiotropic polymorphic transformation are changes... 

Solution phase transformation experiments at different temperatures can provide a good estimate of the phase transition temperature for enantiotropic polymorphs. The process is somewhat tedious and time-consuming but can yield a highly accurate value for the transition temperature. The experiment is conducted at successively higher temperatures until the stability relationship reverses as indicated by the growth of the other polymorph. It then is necessary to bracket the transition temperature by repeated experiments. As the transition temperature is approached the experiments generally require more time. It is... 

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