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

Abstract

<p>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 <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/remdesivir" title="Learn more about remdesivir from ScienceDirect's AI-generated Topic Pages">remdesivir</a> (RDV), an antiviral drug with broad-spectrum activities against <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/rna-virus" title="Learn more about RNA viruses from ScienceDirect's AI-generated Topic Pages">RNA viruses</a>. The RDV cocrystal was prepared with <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/salicylic-acid" title="Learn more about salicylic acid from ScienceDirect's AI-generated Topic Pages">salicylic acid</a> (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 <em>P</em>2₁ with a unit cell volume of 1826.53(17) ų, accommodating one pair of RDV and SA molecules in the asymmetric unit. The cocrystal formation was also characterized by <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/differential-scanning-calorimetry" title="Learn more about differential scanning calorimetry from ScienceDirect's AI-generated Topic Pages">differential scanning calorimetry</a>, 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 (<em>p</em> = 0.0003). RDV-SA was safe in A549 cells without any <em>in vitro</em> cytotoxicity observed in the RDV concentration from 0.05 to 10 µM.<br></p>