Polymorphism suspended transformation

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. 

The concepts of metastable equilibrium and suspended transformations are extremely important in any practical understanding of polymorphism. Metastable equilibrium can be defined as a state which will exist for some time period without change, even though a more stable state does exist (Findlay et al. 1951 Zemike 1955). This is distinct from unstable equilibrium that results in spontaneous and instantaneous change. A suspended transformation is one that should occur on the basis of the thermodynamic considerations but does not occur because of kinetic factors. Suspended transformations must and do result in metastable states. Without metastable equilibrium and suspended transformations, polymorphism would not be as significant an issue as it is. 

Closely allied with the concepts of metastable equilibrium and suspended transformations is Ostwald s rule (Ostwald s step rule or law of successive reactions). Essentially Ostwald s rule states that in all processes it is not the most stable state with the least amount of free energy that is initially obtained but the least stable state lying nearest to the original state in free energy (Ostwald 1897). It is easy to see how this rule and the concept of suspended transformations can explain the production of a metastable polymorph through crystallization from a melt or solution. 

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). 

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. 

C. Equilibrium between Solid and Liquid Phases only. I. The Components are Completely Miscible in the Liquid State. a) The pure components only occur as solid phases. Polymorphism of components. Determination of the equilibrium curve. Example, b) Compounds are formed with a congruent meltings point. The indifferent point. Determination of the composition of a compound by thermal analysis. Examples, (c) Compounds are formed with an %ncongruent melting-point. Determination of the composition of the coinpound by thermal analysis. Example. (d) Solid solutions or " mixed crystals are formed, i) The two components can form an unbroken series of solid solutions. Examples. Melting-point curve. Example. Fractional crystallisation of solid solutions, h) The two components do not form a continuous series of solid solutions. Examples. Changes in solid solutions with the temperature. II. The Components are not Completely Miscible in the Liquid State. Suspended transformation. 

Suspended phase transformations are those phase conversions that are predicted to take place at a defined Sj-S2-V triple point but do not, owing to some nonideality in the system. One can immediately see that only through the occurrence of a suspended transformation could a metastable polymorph be obtained in the first place. In the case of two solids, slow conversion kinetics can permit the transition point to be exceeded when moving in either direction along the 8,-82 transition curve, permitting the isolation of the otherwise unobtainable metastable phase. 

One of the best known examples of suspended transformation is found with the polymorphs formed by quartz [23]. The three principal polymorphic forms are quartz, tridymite, and cristobalite, which are enantiotropically related to each other. The ordinary transition point for the quartz/tridymite transition is 870°C, while the ordinary transition point for the tridymite/cristobalite transition is 1470°C. The melting point of cristobalite is at 1705°C, which exceeds all of the solid phase transition points. However, the phase transformations of these forms are extremely sluggish, and consequently each mineral form can be found in nature existing in a metastable form. 

It Is known that many carboxyl acid crystals have polymorphs (3) and that the crystals suspended In saturated solution sometimes display a solid-transformation (2). If a-form crystal or 3-form crystal In saturated solution changes Into other crystal form within experimental time scale, solubilities for a-form crystal or 3-form crystal do not have substantial meaning. So stability of a-form crystal or 3-form crystal suspended In the saturated solution was Investigated. 

Photochemical stability of the solid compound is an important aspect when the drug is formulated as a suspension. Photochemical stability of a drug in the solid state can depend on the polymorphic/pseudo polymorphic form of the compound, which is demonstrated for chloroquine, mefloquine, and furosemide (Nord et al., 1997b Tpnnesen et al., 1997 De Villiers et al., 1992). The crystal structure, molecular conformations, and surface of the particles can thus influence photoreactivity of a suspended drug. When formulated as a suspension, the drug should be in the form of the stable polymorph. Transformation can occur between different crystal forms in the presence of a liquid, often accompanied by caking of the crystals (Martin, 1993). Photochemical stability of solids is further discussed in Chapter 16. 

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