The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR–TER cocrystal formation was ball milling. The stoichiometry of the ITR–TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR–TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR–oxalic acid > ITR–succinic acid > ITR–TER. Additionally, the ITR–TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.

The search for new solid forms of an active pharmaceutical ingredient (API) is an important step in drug development. Often, an API has a low water solubility, which then leads to low oral bioavailability. For basic or acidic APIs, the rational solution is the preparation of salts. For neutral, poorly ionizable, compounds, the cocrystallization is often the only choice. Agomelatine, a poorly soluble “nonionizable” amide acting as a melatonergic antidepressant is a typical representative of such class of compounds. Until recently, the only multicomponent forms of agomelatine were cocrystals. In this work, we report the preparation of three salts of agomelatine (hydrogensulfate, mesylate, and besylate) and their solvated forms, along with their crystallographic characterization. Interestingly, the crystal structures of the solvated and nonsolvated hydrogensulfates were determined from the same crystal via a topotactic transformation. In all of the structures, the agomelatine molecule was positively charged with the amide oxygen being protonated. The salt formation was also confirmed by solid state nuclear magnetic resonance measurements and density functional theory calculations. By sulfonate salt formation, up to ∼200-times faster dissolution of agomelatine was achieved, which proves that salts might be an attractive alternative even for the poorly ionizable compounds.

No abstract

No abstract

No abstract