Characterisation of jet-milled and spray dried isoniazid for pulmonary administration

The aim of this study was to develop a dry powder isoniazid formulation with no or a limited amount of excipients for pulmonary administration. Milled isoniazid showed an excellent particle size distribution for inhalation, however dispersion was poor. In 78% of the dispersion measurements the inhaler blocked, retaining most of its dose. Pure spray dried isoniazid yielded particles too large for pulmonary delivery, but the addition of 5% of L-leucine resulted in spray dried particles of inhalable size. DSC data showed complete crystallinity for all samples, while TGA analysis showed that isoniazid sublimates around 100°C. SEM imaging showed that pure jet milled and spray dried isoniazid particles fused together. Isoniazid spray dried with L-leucine resulted in spherical particles with no fusion visible. The most likely explanation for particle fusion is that isoniazid crystalizes, resulting in solid bridge formation. L-leucine however, forms a coating around isoniazid particles, thereby preventing this phenomenon. Further experiments are needed to show why isoniazid fuses together in the jet mill. A possible explanation is that some isoniazid sublimates due to heat generation during particle collisions, and causes solid bridge formation between particles when it ripens. Further experiments have to show whether isoniazid co-spray dried with L-leucine disperses efficiently and is stable over time.