Pirfenidone microcrystals for pulmonary delivery: Regulation of the precipitation behavior in the supercooled droplet

Pirfenidone (PFD) is one of the first-line drugs for treating idiopathic pulmonary fibrosis, while directly delivering PFD to lung showed better efficiency. However, PFD is a non-glass former and easily precipitates into larger-sized crystals that are undesirable for pulmonary delivery. Hence, the fabrication of PFD particles with pulmonary delivery efficiency remains challenging. Herein, a series of particles were prepared by spray freeze drying a PFD and leucine mixed solution. The sub-ambient behavior of the mixed solution was evaluated via a differential scanning calorimeter. The effects of the PFD/leucine mass ratio and freezing temperature on the particle morphology, size, crystal polymorphism, molecular structure and in vitro aerosol performance were investigated. Shortening the lifetime of the droplet and adding proper amounts of leucine are the keys to decreasing the PFD crystal size and improving its dispersity. The optimal sample is SF_-80D-P₉₅L₅-2, with high FPF and eFPF values of ∼ 65.97 % and ∼ 27.86 %, and owing to its high drug loading (95 %), the FPD and eFPD are extremely high at ∼ 6.27 mg and ∼ 2.65 mg, respectively, equivalent to ∼ 6.27 mg and ∼ 2.65 mg PFD deposited in the lungs and alveoli, respectively, when 10 mg dry powder is inhaled. This work provides a potential strategy for tuning the precipitation behavior of PFD microcrystals with high pulmonary drug delivery efficiency.