ATR/Raman and fractal characterization of HPBCD/progesterone complex solid particles

PURPOSE: Characterization of hydroxypropyl-beta-cyclodextrin/progesterone (HPBCD/P) complex solid particles obtained from an aqueous solution, by three different technological processes, with the aim of preparing ready-to-dissolve powders for injectable as well as solid oral formulations in progestinic therapy. METHODS: HPBCD/P complex in the 2:1 molar ratio was prepared in aqueous solution and obtained as dry solid particles by freeze-drying, by spray-drying and by fluid-bed evaporation of the solvent. The particles were characterized by mu-FT-IR, mu-Raman and X-ray spectroscopy, by thermal analysis (differential scanning calorimetry-DSC and thermogravimetry-TGA), by Karl Fischer (KF) titration, by image and fractal analysis and by BET specific surface area analysis. The structure of the complex was also defined by comparison of FT-IR and Raman spectra of progesterone with those of pregnenolone and testosterone, structurally related. Dissolution tests were also performed. RESULTS: Powders of the complex obtained by the three different methods are different in size and shape. Particles obtained by freeze-drying are flat and angular, irregularly shaped without any relation to known geometrical solid figures. Particles obtained by spray-drying are spherically shaped and display a very small size (5-10 microm), with evident deformations and depression of the external surface, due to the rapid evaporation of the solvent. Particles obtained by fluid bed technique have intermediate sizes, display a tri-dimensional structure and irregular surface, with small and rounded protuberances. Fractal dimension of the particle contour was found close to one unit for the microspheres obtained by spray-drying. FT-IR and Raman spectra confirm the occurrence of the complexation by the shift of representative bands of the two carbonyl groups in positions 3 and 20 of the complexed progesterone. X-ray diffractograms indicate the amorphous nature of all the types of particles, also suggested by the absence of any melting peak of the drug in DSC thermograms. The samples contain different amounts of humidity: particles obtained by fluid-bed method demonstrated non-porous in BET analysis. Dissolution of different types of particles is complete after 3 min and only negligible differences could be appreciated among the three powders. CONCLUSIONS: - mu-FT-IR, mu-Raman and X-ray spectroscopy, and the dissolution test did not reveal defined differences among the three different types of particles, confirming occurrence of the complex in the solid state. The spherical shape, the very small size and the low value of the contour fractal dimension allows better technological performance of the particles obtained by spray-drying: this drying process appears the most promising one to prepare dry particles of the HPBCD/P complex, in view of its formulation in the fast preparation of extemporaneous injectable solutions and solid oral formulations intended for sublingual delivery.