Traditional amorphous phase, glass transition

Sometimes, the traditional methods (such as salt formation) used for increasing the dissolution rate and thereby the bioavailability of the drug in the body may not be feasible. This was the case for 2-[4-(4-chloro-2-fluorophenoxy)-phenyl]pyrimidine-4-carboxamide, a sodium channel blocker. It was a weak base with very low solubility of 0.1 pg mL in water, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The extremely low pATa of —0.7, made it non-amenable to salt formation, even with strong acids such as hydrochloric acid, sulfuric acid and phosphoric acid. Also, its glass transition temperature (Jg) at 43 °C, was close to that at room temperature, which limited the formation of the amorphous phase reproducibly. It should also be noted that the amorphous phase, which might be an option in some cases, was not desirable either. This is because it could lead to the formation of a metastable state that could limit its shelf life. As a result, co-crystal formation was attempted in order to manipulate its physicochemical and pharmacokinetic properties. 

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