Crystallization and Crystallinity of Fluticasone Propionate

Abstract

Solubilization of fluticasone propionate (FP) was effected using aqueous solutions of (i) different grades of poly(ethylene glycol) (PEG), (ii) methanol, and (iii) acetone to enable antisolvent crystallization by the addition of water. The solubility of FP in acetone was significantly higher than in PEG 400 or PEG 6000, and FP solubility was observed to be nonideal in either cosolvent. Crystallization of FP was instantaneous upon addition of water as antisolvent, with nucleation occurring during the mixing phase. The smallest crystals were produced in all cases from PEG solvents, which was attributed to a greater degree of nucleation and microcrystals of a size-range were produced. Crystals produced from PEG solvents also displayed a resistance to agglomeration and Ostwald ripening, which was observed to affect the morphology of FP crystallized from either methanol or acetone by the addition of water. In spite of the very rapid kinetics of solid formation, FP crystallized as the stable Form I polymorph from PEG 400 and PEG 6000. Conversely, mechanical milling of highly crystalline particles resulted in the generation of disorder in the crystals, which was apparent from surface dynamic vapor sorption analysis. The generation of FP microcrystals with a small size range from environmentally benign PEG solvents as the stable crystalline form represents an improvement over current crystallization and micronization techniques for the production of inhalable FP

Investigations into the Formulation of Metered Dose Inhalers of Salmeterol Xinafoate and Fluticasone Propionate Microcrystals

“…The differences identified between the density values and the reproducibility of density determinations by pycnometry for all SX microparticle batches as well as FP PEG 400, FP PEG 6000 and mFP batches, were within ranges identified in previous studies of micronized particles (24). The value for FP PEG 400B were significantly different to the other FP microparticles, however, it was confirmed that the material was of an identical polymorph to all other batches (25).…”

Engineering of Crystalline Combination Inhalation Particles of a Long-Acting β2-agonist and a Corticosteroid

“…4 show sharp diffraction peaks associated with micronised FP, micronised SX and combination drug particles of FP/SX, which suggest that the materials were predominately crystalline. The XRPD diffractograms of micronised FP and SX are similar to those reported previously (23,26). The XRPD diffractogram of combination drug particles of FP/SX possessed similar peaks to micronized FP, which was to be expected as the combination drug particles of FP/SX contain a significantly greater amount of FP than SX.…”

Micronization of Fluticasone Propionate using Supercritical Antisolvent (SAS) Process

“…7b) and c). After comparison with literature evidence, metastable form II particles were obtained after the SAS process, while the original particles were analyzed as stable form I [26,39]. The SAS process favored the production of metastable polymorph owing to higher supersaturation and fast nucleation.…”