Title:Solid-solid Phase Transitions between Crystalline Polymorphs of Organic
Materials
Volume: 29
Issue: 6
Author(s): Ivo B. Rietveld*
Affiliation:
- Laboratoire SMS - UR 3233, Université Rouen Normandie, Mont Saint Aignan, F 76821, France
- Faculté de Pharmacie, Université
Paris Cité, 4 avenue de l’observatoire, Paris 75006, France
Keywords:
Pharmaceutical ingredient, crystalline materials, crystal, phase behavior, phase diagram, transition mechanism.
Abstract: In this review, the analysis of solid-solid phase transitions between crystalline polymorphs of organic
molecules is discussed. Although active pharmaceutical ingredients (APIs) are the scope of the review,
whether an organic molecule has a biological activity or not does not particularly define its interactions in the
crystalline state. Therefore, other small organic molecules have been included in this analysis and in certain cases,
polymers have been discussed too. The focus of the review is on experimental analysis; however, a section
on computational and theoretical methods has been added because these methods are becoming important and
are obviously helpful in understanding for example transition mechanisms because the results can be easily visualized.
The following aspects of solid-solid phase transitions between crystalline structures are presented in this
review. The thermodynamics of phase transitions between polymorphs involving thermodynamic equilibrium
and the variables temperature and pressure closely linked to the Gibbs free energy are discussed. The two main
transition mechanisms in the organic crystalline solid, displacive and concerted, are discussed. Experimental
methods that are used to understand the mechanisms and thermodynamic equilibrium between different polymorphs
of an API are reviewed. The switching of polymorph properties is discussed, and heat storage and release
are reviewed as it is one of the main applications of solid-state phase transitions. Of interest for the control
of drug products, constraining phase transitions has been reviewed, as it may help increase the bioavailability
of an API by using metastable phases. Finally, second order phase transitions of organic materials, which appear
to be rare, are discussed. It can be concluded that although the general theory of polymorphism and phase
transitions is well understood, how it works out for a specific molecule remains difficult to predict.