Monotropic 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. 

Three crystal forms (two polymorphs and one hydrate) of an oxazoli-done antimicrobial, RWJ-337813, were processed by means of the SEDS technique at different pressures (80-200 bar) and temperatures (36-120 °C) from dimethylformamide (containing 20 and 30 mg/mL of the drug) (27). For the preparation of the hydrate, water was added to the CO2 stream at up to 16% by volume. The two polymorphs of RWJ-337813 (forms A and B) generated are anhydrous and monotropic to each other, with A as the stable form. Form C is a hemihydrate generated at 200 bar and 40°C with modified CO2 flow. Form A was produced (as acicular particles) at 200 bar and 120°C, while form B was obtained (as small platelets) at lower pressure and temperature (80 bar and 36°C). 

For chiral drugs, it is usually necessary to apply several techniques to characterize both the enantiomer and the racemic species in order to interpret the origin of the polymorphism among the racemic species. For example, three monotropically related polymorphs of (R5)-nitrendipine were found [29]. Based on the melting phase diagram, IR spectra, and PXRD patterns, the thermodynamically stable form (I) of (R5)-nitrendipine was shown to be a racemic compound, while the other polymorphs, forms II and III, were both found to be conglomerates. Study of one of the pure... 

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