Formation of drug–drug salt crystals and co-amorphous forms of levofloxacin and 4-aminosalicylic acid for pulmonary applications

Abstract

A dry powder inhaler is a viable formulation for pulmonary delivery; however, the co-delivery of multiple drugs requires a specially designed device. This study aimed to design multi-component crystal and amorphous forms for the co-delivery of levofloxacin (LVF) and 4-aminosalicylic acid (ASA). New multi-component crystals of LVF and ASA, crystal-I and crystal-II, were formed by solvent evaporation and slurry conversion. Thermal analysis revealed that crystal-I and crystal-II were the hydrate and anhydrate forms, respectively. Upon heating, each crystal was converted to different crystals. All polymorphs reverted to crystal-I during storage. The co-amorphous (CA) form was obtained by spray drying, which exhibited a relatively high glass transition temperature above 100 °C. Multi-component crystals and CA were estimated as salts by single crystal X-ray diffraction and infrared spectroscopy. An in vitro aerodynamic performance test was performed for LVF, ASA, physical mixture (PM), crystal-I, and CA. The fine particle fraction (FPF, %) of LVF/ASA was 0.9/13.3 for pure drugs and 0.4/14.1 for PM. However, the FPF (%) for crystal-I and CA significantly improved to 25.4/29.9 and 20.0/20.6, respectively, with the co-delivery of LVF and ASA. We conclude that the design of multi-component crystals and co-amorphous forms is an effective strategy for the simultaneous delivery of inhalation drugs.