Effect of particle size reduction and crystalline form on dissolution behaviour of nimesulide

The objective of this study was to develop and examine innovative and very simple and easily scalable techniques able to improve solubility and/or dissolution rate and thus oral bioavailability of nimesulide. Three different nimesulide batches were obtained by three different laboratory-scale methods: Method A (Batch A) used crystallization by solvent evaporation in a nanospray dryer, Method B (Batches G and GLN) involved cryo-milling, and Method C (Batch Neu) dispersed nimesulide in Neusilin(A (R)) UFL2. All the nimesulide batches were fully characterized for chemical stability, thermal behaviour, physicochemical and micromeritics properties, and intrinsic dissolution and particle dissolution rates. Batch A not only showed a good reduction in particle size but also exhibited a reduced degree of crystallinity by both differential scanning calorimetry and X-ray powder diffractometry, which could explain the increase in intrinsic dissolution rate (IDR) and particle dissolution. Batch GLN showed an acceptable increase in IDR, probably caused by a slight decrease in the degree of crystallinity, and good improvement in dissolution rate due to a certain decrease in particle size. Batches G and native crystals exhibited very close IDRs, while G showed somewhat higher particle dissolution, probably attributed to the particle size reduction. The dispersion of nimesulide in Neusilin UFL2 in a 1:6 drug-polymer ratio made it possible to recover anamorphous powder, as proven by thermal analysis and X-ray powder diffractometry, characterized by pronounced particle size reduction to nanometric dimensions. Both amorphous character and nanometric dimensions could account for the fastest particle dissolution during the first 10 min of the experiment. The stability study conducted according to the International Conference on Harmonization (ICH) confirmed the good chemical and physicochemical stability of all the batches.