CHF-6523

The development of inhalation formulations for CHF-6523, a selective PI3Kδ inhibitor, presents significant hurdles due to atropisomerism and a strong tendency to form amorphous solids, complicating the access to a suitable crystalline form of the pharmaceutically active isomer. NMR experiments and DFT calculations revealed a near-equilibrium distribution of two atropisomers (R_aS and S_aS, ≈55:45 in ethanol-d6/D₂O), and their low interconversion energy barriers of 86.5 and 87.1 kJ/mol. After a comprehensive salt screening, CHF-6523 monomaleate was the only crystalline solid obtained as a single diastereoisomer (R_aS). Concerns regarding the suitability of the maleate counterion for pulmonary administration prompted the exploration of amorphous solid dispersions (ASDs) using CHF-6523 xinafoate, identified as the most promising amorphous salt candidate. Three manufacturing techniques - blending, spray-drying and freeze-drying - were evaluated to preserve the amorphous phase, improve powder handling and ensure dissolution and aerosolization performance. Spray-dried powder provided the most favorable physicochemical profile, yielding particles with dv90 below 5 µm, a residual moisture of ∼ 6%, with water uptake below 1% and superior resistance to physical and chemical changes over 180 days. In vitro dissolution studies in simulated lung fluid showed that spray-dried and freeze-dried ASDs reached concentrations above 950 µg/mL within the first hour, outperforming the crystalline monomaleate and the free base (∼700-800 µg/mL at 4 h). Preliminary aerosol characterization confirmed the superior respirable fraction of the spray-dried ASD (∼73%), compared to blend (∼66%) and freeze-dried formulations (∼37%). This work demonstrates how atropisomer-related conformational dynamics can hinder crystalline form identification while guiding the development of stable amorphous formulations for inhalation therapies.