The use of microfluidics for production of particles in dry powder inhalation systemsSaboti, Denis (Avtor) Planinšek, Odon (Mentor) Chan, Hak-Kim (Komentor) farmacevtska tehnologijapljučne boleznizdravljenjeinhalatorjiinhalatorji s suhim prahomzdravilne učinkovinenosilni delcipripravaizolacijamikrofluidni reaktorjisušenje z razprševanjembudezonidbeklometazon dipropionatdisertacijeRespiratory devices such as metered dose inhalers (MDI), nebulizers and dry powder inhalers (DPI) have been used to administer active pharmaceutical ingredients to treat lung diseases. Inhalable drug particles for DPI formulation are conventionally produced by a top down approach through crystallization followed by milling. This approach tends to generate partially amorphous materials that require post-processing to improve the formulations’ stability. Other methods involve homogenization or precipitation and often require the use of stabilizers, mostly surfactants. The purpose of our work was therefore to develop a novel method for preparation of fine drug particles using a microfluidic reactor and to find an appropriate particle isolation method, in this case ultrasonic spray freeze drying, hence avoiding the need of additional homogenization step or use of a stabilizer. Different active pharmaceutical ingredients and excipients were tested for compatibility with budesonide and beclomethasone dipropionate found to be the most appropriate for further characterization. In the final developed method, a commercial T-junction microfluidic reactor was employed to produce the particle suspension (using an ethanol–water, methanol-water and an acetone–water systems), which was directly fed into an ultrasonic atomization probe, followed by direct feeding to liquid nitrogen. Freeze drying was the final step in the process. The result were fine crystalline budesonide and beclomethasone dipropionate powders that were characterized by the following analytical techniques: optical microscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), dynamic light scattering (DLS), dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), X-ray powder diffraction (XRD) and aerosol performance with Next Generation Impactor (NGI). When blended with lactose and dispersed using an Aerolizer at 100 L/min air flow rate, budesonide generated fine particle fraction in the range 47.6±2.8% to 54.9±1.8%, thus exhibiting a good aerosol performance. Drug product formulations were compared to commercially available products and showed comparable aerosol performance. Subsequent sample analysis confirmed the suitability of the developed method to produce inhalable drug particles without additional homogenization or stabilizers. The developed method provides a general viable solution for particle isolation from microfluidic reactor.[D. Saboti]20172023-01-12 11:02:25Doktorska disertacija143798sl