Improved solubility and permeability of both nifedipine and ketoconazole based on coamorphous formation with simultaneous dissolution behavior

Abstract Coamorphous formation between the hydrophobic drugs nifedipine (NIF) and ketoconazole (KTZ) was investigated with the expectation of improving the solubility and permeability of the two compounds. NIF and KTZ spray-dried particles (SDPs) were prepared in a range of NIF/KTZ molar ratios (3/1-1/3). All NIF/KTZ SDPs were in an amorphous state with a single glass transition temperature (Tg). The Tg value of NIF/KTZ (1/1) SDPs showed the largest positive deviation from the theoretical Tg values calculated by the Gordon–Taylor equation, resulting in NIF/KTZ (1/1) SDPs having the highest physical stability at 40°C and 75% relative humidity. The Fourier transform infrared spectroscopy spectra of NIF/KTZ SDPs suggested hydrogen bonding between the NH group of NIF and the tertiary amine group of KTZ. These findings suggest a coamorphous formation between NIF and KTZ at a molar ratio of 1/1 through hydrogen bonding in the solid state. The investigation of the dissolution profiles of NIF and KTZ from NIF/KTZ SDPs showed that NIF/KTZ (1/1) SDPs exhibited supersaturation and had the highest improved solubility of both drugs. NIF/KTZ (1/1) SDPs showed simultaneous dissolution and precipitation of NIF and KTZ, whereas NIF/KTZ (2/1) and NIF/KTZ (1/2) SDPs had different dissolution profiles, suggesting that hydrogen bonding between NIF and KTZ can be maintained in an aqueous solution. Furthermore, the improved permeabilities of both drugs through coamorphous formation were observed in a permeation study using the Caco-2 cell line. The permeated amounts of NIF and KTZ from NIF/KTZ (1/1) SDPs were 2.3- and 3.6-fold higher than those of the individual drug crystals, respectively. This study revealed that coamorphous formation between hydrophobic drugs has a high potential to enhance solubility and improve the membrane permeability of both drugs.