Monotropic polymorphs

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. 

It is worth noting that a monotropic polymorphic system offers the potential of annealing the substance to achieve the preferred form of the thermodynamically stable phase. The use of the most stable form is ordinarily preferred to avoid the inexorable tendency of a metastable system to move toward the thermodynamic form. This is especially important especially if someone elects to use a metastable phase of an excipient as part of a tablet coating, since physical changes in the properties of the coating can take place after it has been made. Use of the most stable form avoids any solid-solid transition that could... 

Like most multi-component fats, milk fat exhibits monotropic polymorphism. Only one polymorph is stable (Bailey, 1951). Molecular rearrangements result in polymorphic transformations from the less to the more thermodynamically stable forms (Hagemann, 1988). Figure 7.5 shows the polymorphic transformations that occur in edible fats. 

Figure 12-5. Intersecting solubility curves (dependence of the logarithm of the saturation concentration on the inverse temperature) indicate an enantiotropic nature of the polymorps, while parallel curves are indicative for monotropic polymorphs. The intercept for enantiotrops corresponds to the transition temperature.

Figure 3. Monotropic polymorphism of lipids where (Tmh. temperatures of the a, p, and p polymorphs, respectively.

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.

Polymorphism can be classified into two types, enantiotropic and monotropic polymorphism. Each type involves two polymorphic forms or a polymorphic pair, whose interconversion is defined by a characteristic transition temperature. The temperature-dependent solid phase transformation is best understood by referring to the respective energy-temperature diagrams at constant pressure, as depicted in Figure 1 (3). 

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... 

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,... 

FIGURE 3.1 The relationship between Gibbs free energy (G) and temperature for (a) enan-tiotropic and (b) monotropic polymorphic forms (1 and 11). The solid lines indicate thermodynamically stable forms and the dashed line metastable the long-dashed line represents the free energy of the melt. (Based on Giron, D., Thermochim. Acta, 248, 1, 1995.)... 

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). 

Monotropic polymorphism involves one or more unstable forms and a stable one this occurs in fats. Compound crystals contain two or more different substances. They may be solute and solvent, usually water as in NaCl 2H20, or a range of very similar molecules. 

For monotropic polymorphs Figure 6.42a) only one form is thermodynamically stable at all temperatures in the range considered. All other forms are metastable and potentially capable of transforming into the stable form. For... 

Monoamine derivatives of fatty acids, 320 Monoclinic chain packing, 323 Monoclonal theory of smooth muscle proliferation, 539 Monoene acids and esters, 3, 273 see also individual compounds Monogalactosyldiacylglycerol, 35,314,491, 492, 515, 516, 523,384 Monoglucosyldiacylglycerol, 35 Monolayers, 338-41, 356, 380 Monolaurin, 362-64 Monomeric acids, 174 Monomyristin, 340 Mono-olein, 328, 364,382,384 Monoperoxymaleic add, 460 Monoperoxyphthalic acid, 460 Monoperoxysuccinic acid, 460 Monophytanylglycerol, 27 Monostearin, 333 Montanic acid, 1 Monotropic polymorphism, 325 MONSAVON process, 241 Mormon cricket, 145 Morphine, 80 see also Poppy seed oil Mouse, 144 Mowrah butter, 72 MS-API, 434 MS applications, 436 Mwcor lipids, 152,153, 478... 

Schematic E-T diagrams for enantiotropic and monotropic polymorphs are shown in Figure 8.

The E-T diagram for monotropic polymorphs is represented in Figure 8(b). In this case, there is no transition point below the melting points of the two polymorphs, and the free energy cmves do not intersect. This means that one form (Form I) is always stable below the melting point of both polymorphs. It is also apparent from the diagram that Form II can undergo a spontaneous exothermic transformation into Form I, and this is thermodynamically feasible at any temperamre, because G < Gn at all temperatures. 

Most TAGs exhibit monotropic polymorphism [25] i.e., below the stability domain of the liquid, there is a single stable phase throughout the temperature range. Other polymorphic forms are not stable, so they never form. 

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