Enantiotropic polymorphs drug polymorphism

If a drug has two enantiotropic polymorphic forms, either may be stable depending on the temperature at a given pressure, whereas for monotropic polymorphism only one form is stable irrespective of temperature. The study of polymorphism is further complicated by the fact that both thermodynamic and kinetic factors must be considered, as some metastable forms are sufficiently kinetically stable as to render them extremely difficult to differentiate from thermodynamically stable configurations. Clearly, however, the more detailed the knowledge of the thermodynamic and kinetic behavior of the different forms, the greater the ability to predict the likely behavior on storage. 

Differential thermal analysis proved to be a powerful tool in the study of compound polymorphism, and in the characterization of solvate species of drug compounds. In addition, it can be used to deduce the ability of polymorphs to thermally interconvert, thus establishing the system to be monotropic or enantiotropic in nature. For instance, form I of chloroquine diphosphate melts at 216°C, while form II melts at 196°C [18]. The DTA thermogram of form I consists of a simple endotherm, while the thermogram of form II is complicated (see Fig. 4). The first endotherm at 196°C is associated with the melting of form II, but this is immediately followed by an exotherm corresponding to the crystallization of form I. This species is then observed to melt at 216°C, establishing it as the thermodynamically more stable form at the elevated temperature. 

Polymorphism is a common phenomenon in the chemical and pharmaceutical industries. Figure 2-15 illustrates the solubility of Forms 1 and 111 polymorphs of a reverse transcriptase inhibitor drug candidate which exhibit enantiotropic behavior. Figure 2-16... 

These curves are essential to design the process because they provide information about how much the drug has to be diluted and whether cooling can be used to generate supersaturation and result in adequate yield. Complex solubility curves are a strong indicator of polymorphs with enantiotropic behavior or solvates. 

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