Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline

Abstract

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir-theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature-composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

Keywords: SARS-CoV-2; antiviral cocrystal; cocrystal screening; drug-drug cocrystal; improved pharmaceutical properties; inhalable cocrystal; quality-by-design; reformulation.

Figure 1

Thermal ellipsoid plot of the asymmetric unit of THP:FAV 1:1 showing the numbering scheme for the single crystal structure.

Figure 2

PXRD patterns of the FAV-THP cocrystal system. New characterization peaks of the cocrystal are marked with *.

Figure 3

Overlaid DSC thermograms of the FAV-THP cocrystal system.

Figure 4

FTIR spectra of the FAV-THP cocrystal systems.

Figure 5

The crystal packing of THP:FAV showing (a) centrosymmetric hydrogen bonding ring motifs generating chains of THP and FAV viewed down the b-axis; (b) ring-stacking interleaving THP (blue) and FAV (red) chains (viewed down the b-axis) cross-linked by short contacts between THP:FAV imidazole-amide (>N…HN) and methyl-phenol (CH…OH), and by THP-THP carbonyl-imidazole (CO…HC) which propagate the structure parallel to c-axis; (c) the stacked interleaved chains of THP (blue) and FAV (red) chains viewed down the c-axis ‘crossing’ through the action of the 2₁-screw axis parallel to b.

Figure 6

NGI deposition patterns of spray-dried FAV-THP formulations with the corresponding upper aerodynamic cutoff diameter specified. MOC: the micro-orifice collector in the NGI.

Figure 7

In vitro aerosolization performance of the spray-dried F1 at different inspiratory flow rates.

Figure 8

Pareto charts illustrate the standardized effect of the independent variables (A: Solid concentration, B: Feed pump rate, C: Atomizing gas flow) and their interactions on MMAD (a), FPF (b), EF (c), and CI (d) of the inhalable cocrystal formulation. The factors that cross the vertical red reference line indicate that their effects are statistically significant. Normal probability plots (e–h) are used to determine the magnitude, direction and the importance of the effects of the independent variables and their interactions on MMAD (e), FPF (f), EF (g), and CI (h). Effects further from 0 are more statistically significant. The Pareto charts and normal probability plots both indicate that the feed pump rate is a significant parameter affecting the MMAD; the solid concentration and feed pump rate are the significant parameters affecting the FPF and EF; and the CI is not significantly affected by any of the studied processing parameters.

Figure 8

Pareto charts illustrate the standardized effect of the independent variables (A: Solid concentration, B: Feed pump rate, C: Atomizing gas flow) and their interactions on MMAD (a), FPF (b), EF (c), and CI (d) of the inhalable cocrystal formulation. The factors that cross the vertical red reference line indicate that their effects are statistically significant. Normal probability plots (e–h) are used to determine the magnitude, direction and the importance of the effects of the independent variables and their interactions on MMAD (e), FPF (f), EF (g), and CI (h). Effects further from 0 are more statistically significant. The Pareto charts and normal probability plots both indicate that the feed pump rate is a significant parameter affecting the MMAD; the solid concentration and feed pump rate are the significant parameters affecting the FPF and EF; and the CI is not significantly affected by any of the studied processing parameters.

Figure 8

Pareto charts illustrate the standardized effect of the independent variables (A: Solid concentration, B: Feed pump rate, C: Atomizing gas flow) and their interactions on MMAD (a), FPF (b), EF (c), and CI (d) of the inhalable cocrystal formulation. The factors that cross the vertical red reference line indicate that their effects are statistically significant. Normal probability plots (e–h) are used to determine the magnitude, direction and the importance of the effects of the independent variables and their interactions on MMAD (e), FPF (f), EF (g), and CI (h). Effects further from 0 are more statistically significant. The Pareto charts and normal probability plots both indicate that the feed pump rate is a significant parameter affecting the MMAD; the solid concentration and feed pump rate are the significant parameters affecting the FPF and EF; and the CI is not significantly affected by any of the studied processing parameters.

Figure 9

Scanning electron micrographs of raw cocrystal formers, spray-dried cocrystal formers, and spray-dried FAV-THP cocrystal powders (F1 vs. F8 formulations) at 500× magnification (Panel A) and 5000× magnification (Panel B).

Figure 9

Scanning electron micrographs of raw cocrystal formers, spray-dried cocrystal formers, and spray-dried FAV-THP cocrystal powders (F1 vs. F8 formulations) at 500× magnification (Panel A) and 5000× magnification (Panel B).

Figure 10

In vitro dissolution profile of FAV and THP in the optimized spray-dried cocrystal formulation F1 with aerodynamic diameters <5 μm (n = 3).

Figure 11

Cell viability of the raw drugs, the physical mixture and the spray-dried F1 at concentrations from 1.6 to 1000 µM.