Impact of Dissolution Rate on Bioavailability

3 Case Studies Demonstrating the Relationship Between Dissolution Rate and Bioavailahility 

2-fold improvements in the mono-, di- and tri-salts, respectively, in comparison to piroxicam. 

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. 

Several commonly acceptable carboxylic acids were screened as co-crystal formers. Of these, the glutaric acid co-crystal was selected for development because of its lower melting point (64 °C lower than that of the free base) and almost 18-fold higher dissolution rate. Again, being a natural component of dietary foodstuffs and a metabolite product of fatty acids, tryptophan and lysine, glutaric acid was considered as a safe co-crystal former. 

In another example, Mutalik et at. demonstrated the use of natural polymers in preparing co-crystals that improve the pharmacokinetics and pharmacodynamics in animal models. The biocompatibility and the biodegradability of these polymers provide an added advantage as co-crystal formers. In the 

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