Preparation Of Ultra-Fine Budesonide By Anti-Solvent Recrystallization And Its Application In Dpi Formulations

Budesonide (BUD) is the first high-selectivity inhaled glucocorticosteroid (IGCS) drug, and its market sales are ranking first in the pharmaceuticals for the treatment of asthma. For IGCS, the particle size and corresponding size distribution are the key factors, which determine if drug particles can reach the site of action. Drug particles with smaller diameter are easier to enter the respiratory tract and reach the alveoli. Therefore, the particle size reduction is a very effective method to improve the efficiency of pulmonary drug delivery.In this study, ultra-fine BUD particles were successfully prepared by anti-solvent recrystallization method. The following parts were systematically investigated:(1) the effects of experimental parameters on particle size and morphology, such as the solvent and anti-solvent, the volume ratio of solution to anti-solvent, temperature, concentration of BUD solution and stirring speed, etc.,(2) the effects of surfactants in the crystallization process,(3) the crystallization process of BUD particles in micro-reactor and inside circulation rotating packed bed (RPB). Furthermore, the properties of as-prepared BUD powders were assessed by multi-stage liquid impinger (MSLI), in a new formulation, dry powder inhaler (DPI).When solvent-1and/or solvent-2used as the solvent, ultra-fine BUD particles with flake-like could be prepared and their particle size could be well-controlled under the following conditions:the volume ratio of solution to anti-solvent1/(7～10), crystallization temperature5℃, BUD solution concentration0.025～0.03g/ml, stirring speed at5000rpm, stirring time5min and oven drying at60℃. The mean major axis size and thickness of the particles were1～5μm and lower than300nm respectively, with narrow particle size distribution. There was not apparently difference in particle size between the powders prepared in solvent-1and solvent-2. In the presence of surfactant-1(0.16%, g·mL-1), mono-dispersed particles with ellipsoidal shape could be prepared by anti-solvent recrystallization method. The mean diameter of the particles in major axis was1～5μm. Additionally, by studying the preparation process in micro-reactor and RPB, it was proved that there existed a transformation from amorphism to crystallinity in the particle growth. Stable crystalline particles could be obtained by controlling the stirring conditions and/or adding some surfactants.The Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) analysis indicated that no chemical decomposition took place during the process, and no crystal structure of the drug occurred. In deposition experiment, the fine partial fraction (FPFemitted) of BUD drug powder was68.57%, almost ten times than that of raw material. The as-prepared powders could be used for inhalation directly and be good for improving drugs bioavailability.