A case study where pharmaceutical salts were used to address the issue of low in vivo exposure

Abstract

The present active pharmaceutical ingredient (API) is a lipophilic compound with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The aim of the presented studies was to investigate whether three novel salts of a new selected candidate in the cardiovascular therapy area could be applied to improve intestinal absorption and the subsequent in vivo exposure. Three salts (chloride, hydrogen sulfate, and hemi-1.5-naphtalenedisulphonate) of the compound were manufactured and investigated regarding solubility, dissolution rate, and in vivo exposure in rats. The chemical and physical stability of the salt forms (and the crystalline parent compound) were followed in solid state, when dissolved and when formulated as microsuspensions. All salts showed improved solubility in investigated media, increased dissolution rate, and elevated in vivo exposures compared to a nanocrystal formulation (top-down) of the parent free base of the compound. The chloride- and the hydrogen sulfate salts of the API showed similar patterns regarding the chemical stability in solid state as the crystalline free base, while the salt formed of the hemi-1.5-naphtalenedisulphonic acid showed significantly improved stability. In conclusion, this study showed that three salts of a new selected candidate drug could be used to improve solubility, increase dissolution rate, and enhance oral absorption compared with a more commonly used nanocrystal formulation of the API. However, the identity of the counter ion appeared to be of less importance. On the other hand, only the salt of the hemi-1.5-naphtalenedisulphonic acid seemed to improve chemical stability compared with the API.