Thermodynamics concomitant polymorphs

Two-component (i.e. two molecules) systems also exhibit concomitant polymorphism, implying a balance for the equilibrium situations governing the formation of the isomeric complexes as well as the kinetic and thermodynamic factors associated with the crystallization processes. The often serendipitous nature of the discovery of concomitant polymorphs is also illustrated by an example of a hydrogen-bonded two-component system, pyromellitic acid 3-XIV and 2,4,6-trimethylpyridine 3-XV (Biradha and Zaworotko 1998). The first polymorph (A) was obtained by reacting 3-XIV with four equivalents of 3-XV in a methanolic solution. Using 3-XV as the solvent yielded a second polymorph (B) in 15 min. Modification A was found to have crystallized as well in the same reaction vessel after about 24 h. These two polymorphs are not readily distinguishable by their morphology. However, the authors point out that the experimental evidence indicates that Form B is the kinefically controlled one, while Form A is the thermodynamically preferred one. 

To this point this account of instances of concomitant polymorphs has been phenomenological. We have discussed the thermodynamic and kinetic crystallization of polymorphs. There is still the question if any insight concerning controlling the polymorph obtained can be gained from the study of the crystal structure of concomitantly crystallized polymorphs. A qualitative attempt was made to see if details of the... 

The phenomenon of polymorphism demonstrates that metastable erystal struetures are observed, and it is not always obvious that sueh crystal structures are metastable. The energy differences between different polymorphs crystallized out of different solvent are small, and those between concomitant polymorphs presumably are very small. Kinetics must play a major role in determining which of the approximately equi-energetic hypothetical crystal structures are actually observed. How do the kinetics of nucleation and growth, and the variations with crystallization conditions, affect which thermodynamically feasible crystal structures are actually seen How can this be incorporated in the crystal structure prediction model to produce a polymorph prediction model ... 

By making use of Volmer s equations some attempts have been made by Becker and Doring (1935), Stranski and Totomanov (1933), and Davey (1993) to explain the Rule in kinetic terms. In doing this, it becomes apparent that the situation is by no means as clear cut as Ostwald might have us believe. Figure 2.11 shows the three possible simultaneous solutions of the nucleation equations which indicate that by careful control of the occurrence domain there may be conditions in which the nucleation rates of two polymorphic forms are equal, and hence their appearance probabilities are nearly equal. Under such conditions we might expect the polymorphs to crystallize concomitantly (see Section 3.3). In other cases, there is a clearer distinction between kinetic and thermodynamic crystallization conditions, and that distinction may be utilized to selectively obtain or prevent the crystallization of a particular polymorph. 

Figure 3-11. DSC of forms 1-3 of sulfonamide 7 polymorphs. Form 1 crystallizes concomitantly with a minor amount of thermodynamic form 3. Form 2 undergoes phase transition to form 3 at ca. 140°C. Form 3 exhibits a sharp melting endotherm at 159°C as the only phase transition...

Recently, Lee et al investigated the concomitant crystallization of glycine polymorphs on patterned self assembled monolayers (Lee, l.S. et al, 2008). Six distinct polymorphic forms of glycine are known in the Hterature three of them - a, p and y - are formed at ambient environment. At room temperature, yglycine is the thermodynamically most stable form. However, in neutral aqueous solution, the a-form is normally obtained. The y-form is typically obtained from acidic and basic solutions. P-glycine is the least stable of the three forms. It can be obtained from ethanol-water mixtures, but readily converts to a-glycine in the presence of water or upon heating. 

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