Thermodynamic vs kinetic crystallization conditions

Physical organic chemists have long been accustomed to making the distinction between thermodynamic and kinetic conditions when referring to reactions and reaction mechanisms. In chemical parlance, thermodynamic conditions essentially means those conditions under which thermodynamic equilibrium is maintained or very nearly maintained. Kinetic conditions refer to situations that are far from equilibrium (van Hook 1961). 

Berman et al. (1968) noted that mannitol is unusual among carbohydrates in that exists in several polymorphic forms , indicating that a number of these are often obtained simultaneously. They describe the preparation of a number of these modifications. The a form is obtained by slow crystallization from 96 per cent ethanol, the a form by evaporation from 100 per cent ethanol and the p form from aqueous ethanolic solutions, all apparently under thermodynamic conditions. On the other hand the y form is obtained kinetically by rapid cooling of a 1 1 water-ethanol solution. An additional k form was obtained (unexpectedly) upon evaporation of a boric acid/methanol solution (Kim et al. 1968). 

Bock has studied a number of systems in which different polymorphs were obtained under thermodynamic and kinetic conditions. (2-pyridyl)(2-pyrimidyl)amine 3-II is dimorphic. Modification I is readily crystallized thermodynamically from any solvent (toluene was actually used) while modification II is obtained kinetically by fast evaporation of an ethereal solution or by resolidification of the melt (Bock et al. 1997). 

8-tetramethoxythianthrene 3-III, the less stable (lower in both density and absolute value of lattice energy) monoclinic modification is obtained under kinetic conditions rapid crystallization from polar diisopropyl ether, whereas the more stable (higher density and lattice energy) orthorhombic modification is thermodynamically obtained from a non-polar hydrocarbon solvent. 

In pharmaceutical applications the choice of polymorphic modification for formulation depends very much on the robustness of the crystallization process as well as the properties and characteristics of the preferred modification. Hence, considerable effort is expended in gaining control over the polymorphic form obtained under various conditions. As noted above, up to four polymorphic modifications and three monohydrates have been reported for cimetidine (SmithKline Beecham s Tagamet ) (Bavin et flZ.1979 Prodic-Kojic et al. 1979 Shibata etal. 1983 Hegedus and Gorog 1985). In experiments to selectively crystallize the A form in preference to the more stable B congener it was found that with isopropanol as a solvent, A crystallizes exclusively at high supersaturation, in the presence or absence of seeds (Sudo et al. 1991). 

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