THE INFLUENCE OF IMPURITIES AND SOLVENTS ON CRYSTALLIZATION

As a starting point for considering the effect of impurity and solvent on crystallization, the growth and interaction process is examined in the framework of the fundamental solid-state, interfacial, and liquid phase (solute-solvent-impurity) chemistry. The solid-state chemistry is specific to a given crystalline material and the nature of the bonds (e.g., ionic, covalent, van der Waals, etc.) that hold the crystal structure together. A complete description of the solid-state aspects of crystal growth is beyond the scope of this 

Lastly, the mass transport processes at the crystal-liquid interface play a central role in crystallization. The influence of solvent and impurities on the structure and growth rates of faces is considered in this chapter along with its effect on the incorporation of impurities. The solvent solute-impurities interactions in solution will also be shown to interact in subtle, but important, ways with the interface during the crystallization process. With appropriate thermodynamic analysis it is shown how these interactions ultimately affect crystallization as a purification process. 

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Bundgaard, H. Influence of an acetylsalicylic anhydride impurity on the rate of dissolution of acetylsalicylic acid. J. Pharm. Pharmacol. 1974, 26, 535-540. Klug, D.L. The influence of impurities and solvents on crystallization. In Handbook of Industrial Crystallization Myerson, A.S. Ed. Butterworth-Heinemann Boston, 1993 65-87. 

Under most conditions, the shape (i.e., the habit) of a crystal is determined by kinetics rather than thermodynamics and the resulting habit is termed the growth, as opposed to the equilibrium, habit. The kinetics of each crystal face can be influenced by such external factors as supersaturation, temperature, and mixing. However, the complexity of crystallization operations arises from the fact that the mass transfer processes at the crystal interface, as opposed to the bulk, are often rate-determining. Thus, without consideration of the role of the interface during crystallization it is impossible to predict the influence of impurities or solvents on crystallization, or explain such diverse processes as secondary nucleation and inclusion formation. 

Typically, crystal habits predicted based on crystal chemistry alone are best compared with crystals grown from sublimation processes, or to solution-based systems where the solvent/impurity interactions are negligible. In fact, significant deviations from structure-based predictions are often best explained by such solvent and impurity interactions (Davey et al. 1992 Winn et al. 2000). There are significant efforts underway to understand such phenomena at the molecular level and to consequently predict the influences of solvent and impurities on crystal growth rates. This will be further highlighted in subsequent sections. 

As shown in this chapter, the solvent can influence crystal product quality through its effect on crystallization kinetics, solution thermodynamics, and crystal interface structure. However, in many instances, the presence of impurities, reaction by-products, or corrosion products in the commercial system can override the solvent-induced behavior, yielding results different from those obtained in pure solvent. The strong influence of impurities at the parts per million level stems from the unique ability of certain impurities to adsorb at key growth sites on the crystal growth surface, as discussed in detail in Section 3.6. 

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