We have designed a novel formulation of pyrazinamide (PZA), an antitubercular drug within large porous particles intended for deep lung delivery. By simply spray-drying PZA, we have obtained crystalline particles of the δ polymorph of PZA that were unstable and not adapted for lung administration. Several excipients were added to the formulation to obtain stable large porous particles with a median size above 5 μm and a low tap density. Although a combination of leucine and ammonium bicarbonate (AB) allowed to reduce tap density and to increase particle size, these excipients were not sufficient to prevent crystallization and promote stability. The addition of hyaluronic acid (HA) in combination with dipalmitoylphosphatidylcholine (DPPC) allowed to obtain stable partially crystalline spherical particles adapted for deep lung delivery. The optimized formulation obtained by spray-drying 0.9 g/L PZA, 0.6g/L leucine, 0.2g/L HA, 0.3g/L DPPC and 2g/L AB in a mixture of ethanol-water (70/30, v/v) possesses a median size of 5.8 ± 0.1 μm and a tap density around 0.09 ± 0.01 g/cm(3). The estimated aerodynamic diameter is around 1.75 μm and the powder is stable for more than 4 weeks of storage.