Synthesis of the first remdesivir cocrystal: design, characterization, and therapeutic potential for pulmonary delivery

• Published in: International journal of pharmaceutics 2023-06, Vol.640, p.122983-122983, Article 122983
• Main Authors: Wong, Si Nga, Low, Kam-Hung, Poon, Yi Lam, Zhang, Xinyue, Chan, Ho Wan, Chow, Shing Fung
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Chemistry, Pharmaceutical - methods; Cocrystal; COVID-19; COVID-19 Drug Treatment; Dry powder inhaler; Dry Powder Inhalers; Humans; Lung; Particle Size; Powders - chemistry; Pulmonary drug delivery; Remdesivir; Spray drying
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2023.122983

[Display omitted] While cocrystal engineering is an emerging formulation strategy to overcome drug delivery challenges, its therapeutic potential in non-oral applications remains not thoroughly explored. We herein report for the first time the successful synthesis of a cocrystal for remdesivir (RDV), an antiviral drug with broad-spectrum activities against RNA viruses. The RDV cocrystal was prepared with salicylic acid (SA) via combined liquid-assisted grinding (LAG) and thermal annealing. Formation of RDV-SA was found to be a thermally activated process, where annealing at high temperature after grinding was a prerequisite to facilitate the cocrystal growth from an amorphous intermediate, rendering it elusive under ambient preparing conditions. Through powder X-ray analysis with Rietveld refinement, the three-dimensional molecular structure of RDV-SA was resolved. The thermally annealed RDV-SA produced by LAG crystalized in a non-centrosymmetric monoclinic space group P21 with a unit cell volume of 1826.53(17) Å3, accommodating one pair of RDV and SA molecules in the asymmetric unit. The cocrystal formation was also characterized by differential scanning calorimetry, solid-state nuclear magnetic resonance, and Fourier-transform infrared spectroscopy. RDV-SA was further developed as inhaled dry powders by spray drying for potential COVID-19 therapy. The optimized RDV-SA dry powders exhibited a mass median aerodynamic diameter of 4.33 ± 0.2 μm and fine particle fraction of 41.39 ± 4.25 %, indicating the suitability for pulmonary delivery. Compared with the raw RDV, RDV-SA displayed a 15.43-fold higher fraction of release in simulated lung fluid at 120 min (p = 0.0003). RDV-SA was safe in A549 cells without any in vitro cytotoxicity observed in the RDV concentration from 0.05 to 10 µM.