Why investigate polymorphism?

Since the middle of the last century, it has been widely recognized that many organic compounds can be obtained in more than one crystal structure, a phenomenon known as polymorphism [1-3]. It also became apparent that the adopted crystal structure often exerts a significant effect in the solid-state properties of the compounds, so that, in fact, each polymorph should be regarded as a different material. Hence, the control of polymorphism provides a means to tune the properties of a product in view of an application, without changing the molecule involved. The achievement of this goal currently has a strong impact in the production, shelf life, and patenting of organic conductors, pigments, or pharmaceuticals [1-3]. From a more fundamental point of view, polymorphism is also an important phenomenon to probe the mechanisms of crystallization and the intermolecular interactions that determine the molecular arrangements in the crystal structures [4].

Alternative strategies of tuning a product in view of an application are the production of solvates [1-3] or, more recently, the preparation of the so-called co-crystals [5]. Solvates are formed when solvent molecules co-crystallize with the solute. The term co-crystals is normally used to designate crystalline solids composed of the molecule of interest and one or more different molecules that are not from the solvent [5]. The inclusion of solvent or other molecules in the crystal lattice is expected to induce significant changes in the structure, physical properties, and dissolution rate of a material, when compared with the corresponding pure forms.

Three major issues normally arise after new solid forms are isolated and structurally characterized: the evaluation of (i) their stability domains and (ii) kinetic barriers for possible transformation, and (iii) the development of systematic methodologies for their selective and reproducible preparation.

Indeed two or more polymorphs can often be prepared and stored at normal ambient temperature and pressure but, in the absence of kinetic barriers, all metastable forms will tend to evolve over time into the thermodynamically most stable modification [1-3]. Consequently, once polymorphism is identified it is very important to define a stability hierarchy among different forms. For most applications the compounds are used at ambient temperature and pressure. Typical ambient pressure changes (even when the samples are subject to vacuum-drying operations) are usually not sufficient to induce phase transitions. The same is not true, however, for ambient temperature, which can undergo significant variations between winter and summer, in various zones of the globe. Therefore, it is normally desirable to establish the stability domains of the various forms at ambient pressure (or below) and in a range as large as possible around 298 K. To this end one is frequently interested in three questions: (i) are the polymorphs monotropically (i.e. one is more stable than the other at any temperature before fusion) or enantiotropically related (i.e. there is a transition temperature, before fusion at which the stability order is reversed)? (ii) For an enantiotropic system, what is the transition temperature, Ttrs, relating the two forms? (iii) What are the pressure vs. temperature or Gibbs energy vs. temperature diagrams that define the location of the phase boundaries for the substance under examination?