Thermodynamics of polymorphic molecular crystals

A Burger, R Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals. I. Theory of thermodynamic rules. Mikrochim Acta (Wein) 2 259-271, 1979. 

Polymorphism is an ability of the drug substance to form crystals with different molecular arrangements giving distinct crystal species with different physical properties such as solubility, hygroscopicity, compressibility, and others. This phenomenon is well known within pharmaceutical companies. The reader can find additional information in references 47 and 48. The determination of possible polymorphic transition and existence of thermodynamically unstable forms during preformulation stage of drug development is important. Typical methods used for solid-state characterization of polymorphism are DSC,... 

Polymorphic structures of molecular crystals are different phases of a particular molecular entity. To understand the formation of those phases and relationships between them we make use of the classic tools of the Phase Rule, and of thermodynamics and kinetics. In this chapter we will review the thermodynamics in the context of its relevance to polymorphism and explore a number of areas in which it has proved useful in understanding the relationship between polymorphs and polymorphic behaviour. This will be followed by a summary of the role of kinetic factors in detecting the growth of polymorphic forms. We will then provide some guidelines for presenting and comparing the structural aspects of different polymorphic structures, with particular emphasis on those that are dominated by hydrogen bonds. 

It is beyond the scope of this book to provide a comprehensive review of the thermodynamics of molecular crystals (Stall et al. 1969). The field was very adequately covered in the comprehensive chapter by Westrum and McCullough (1963), a work which has stood the test of time remarkably well, and can serve as an excellent resource on this general subject. An earlier useful reference is the chapter on polymorphism in the classic book by Tammann (1926). 

Solid Form Selection A drug can exist in multiple forms in the solid state. If the two forms have the same molecular structure but different crystal packing, then they are polymorphs. Pseudopolymorphs (or solvatomorphs) differ in the level of hydration/solvation between forms. Polymorphs and pseudopolymorphs in principle will have a different solubility, melting point, dissolution rate, etc. While less thermodynamically stable, polymorphs have higher solubilities they also have the potential to convert to the more thermodynamically stable form. This form conversion can lead to reduced solubility for the formulated product. One example is ritonavir, a protease inhibitor compound used to treat acquired immune deficiency syndrome (AIDS). Marketed by Abbott Labs as Norvir, this compound began production in a semisolid form and an oral liquid form. In July 1998, dissolution tests of several new batches of the product failed. The problem was traced to the appearance of a previously unknown polymorph (Form II) of the compound. This form is thermodynamically more stable than Form I and therefore is less soluble. In this case, the solubility is at least a factor of 2 below that of Form I.12 The discovery of this new polymorph ultimately led to a temporary withdrawal of the solid form of Norvir from the market and a search for a new formulation. 

The rate and mechanisms by which crystallization occurs are determined by numerous thermodynamic, kinetic, and molecular recognition factors. (Nyvlt et al., 1985 Sohnel and Garside, 1992 Mersmann, 1995 Mullin, 2001 Myerson, 2002) These factors are summarized in Figure 1. The solvent plays a key role in crystallization as many of the factors depend directly on the solvent (Davey, 1982). Therefore, the intricate balance between thermodynamic, kinetic, and molecular recognition must be considered when designing experiments for polymorph screening, selection, and isolation. 

In this chapter, the effects of these thermodynamic, kinetic, and molecular recognition phenomena on crystallization and the role of solvent in these processes will be described. The role of solvent on crystallization, polymorphic outcome, and phase transformations will also be discussed. Experimental approaches for polymorph screening will be presented with an emphasis on the important considerations and strategies for solvent selection. 

A Burger, R Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals. I. Theory of thermodynamic rules. Mikrochim Acta [Wien] 11 259— 271, 1979. A Burger, R Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals, n. Applicability of thermodynamic rules. Mikrochim Acta [Wien] 11 273-316, 1979. 

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