Characterization of Pharmaceutical Polymorphs by Isothermal Calorimetry

Abstract

A great number of pharmaceutical substances exist in crystalline solid-state. Because of the complexity of their chemical structure many different polymorphs of a given substance can exist. Polymorphic forms of solid pharmaceuticals influence not only their dissolution behavior, i.e. bioavailability but also their solid-state stability. It is well known that only one polymorphic form is thermodynamically stable and all other metastable forms will convert, eventually, to the more stable form. Hence it is essential to choose the most suitable polymorphic form in the early stage of pharmaceutical development. The following article reviews the recent applications of solution calorimetry that allows characterization of pharmaceutical polymorphs through accurate determination of enthalpy of solution. Each crystalline form possesses a defined enthalpy of solution, therefore solution calorimetry is used for the quantitative analysis of the desired polymorphic form and determination of enthalpy of transition corresponding to the difference in enthalpies of solution for a polymorphic pair. More recently this technique has been applied to the estimation of thermodynamic transition temperature, which is useful for the evaluation of thermodynamic stability relationships between polymorphs. This article will also describe the kinetics and thermodynamics of polymorphic transitions, from a metastable form to the thermodynamically stable form, through studies using ampoule-based isothermal microcalorimetry. Such studies are particularly useful when metastable forms are to be selected in order to enhance bioavailability. If the metastable form, or the pharmaceutical product containing it, can be shown to be sufficiently stable, it could then be used in a formulation where its therapeutic effects could be exploited.