New Solid Forms of Nitrofurantoin and 4-Aminopyridine Salt: Influence of Salt Hydration Level on Crystal Packing and Physicochemical Properties

The crystallization of the poorly soluble drug nitrofurantoin (NFT) with 4-aminopyridine (4AmPy) resulted in three multicomponent solid forms with different hydration levels: anhydrous salt [NFT+4AmPy] (1:1), salt monohydrate [NFT+4AmPy+H(2)O] (1:1:1), and salt tetrahydrate [NFT+4AmPy+H(2)O] (1:1:4). Each salt was selectively prepared by liquid-assisted grinding in the presence of acetonitrile or ethanol/water mixture at a specific composition. The NFT hydrated salts were characterized using single crystal X-ray diffraction. The [NFT+4AmPy+H(2)O] salt (1:1:1) crystallized as an isolated site hydrate, while the [NFT+4AmPy+H(2)O] salt (1:1:4) crystallized as a channel hydrate. The dehydration processes of the NFT salt hydrates were investigated using differential scanning calorimetry and thermogravimetric analysis. A powder dissolution experiment was carried out for all NFT multicomponent solid forms in pH 7.4 phosphate buffer solution at 37 °C.