ABSTRACT
OBJECTIVE: To optimize air-jet milling conditions of ibuprofen (IBU) using design of experiment (DoE) method, and to test the generalizability of the optimized conditions for the processing of another non-steroidal anti-inflammatory drug (NSAID). METHODS: Bulk IBU was micronized using an Aljet mill according to a circumscribed central composite (CCC) design with grinding and pushing nozzle pressures (GrindP, PushP) varying from 20 to 110 psi. Output variables included yield and particle diameters at the 50th and 90th percentile (D50, D90). Following data analysis, the optimized conditions were identified and tested to produce IBU particles with a minimum size and an acceptable yield. Finally, indomethacin (IND) was milled using the optimized conditions as well as the control. RESULTS: CCC design included eight successful runs for milling IBU from the ten total runs due to powder "blowback" from the feed hopper. DoE analysis allowed the optimization of the GrindP and PushP at 75 and 65 psi. In subsequent validation experiments using the optimized conditions, the experimental D50 and D90 values (1.9 and 3.6 µm) corresponded closely with the DoE modeling predicted values. Additionally, the optimized conditions were superior over the control conditions for the micronization of IND where smaller D50 and D90 values (1.2 and 2.7 µm vs. 1.8 and 4.4 µm) were produced. CONCLUSION: The optimization of a single-step air-jet milling of IBU using the DoE approach elucidated the optimal milling conditions, which were used to micronize IND using the optimized milling conditions.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Ibuprofen/chemical synthesis , Technology, Pharmaceutical/methods , Particle Size , Research DesignABSTRACT
OBJECTIVE: To investigate influences of capsule fill weight, batch size, and storage conditions on in vitro aerodynamic performance of jet-milled ibuprofen (IBU) carrier-free, dry powder inhaler formulations. MATERIALS AND METHODS: Milled and unmilled IBU samples were characterized thermally and spectroscopically. Physicochemical characterization was performed by quantifying specific surface area, density, and angle of repose. Performance testing was conducted on IBU formulations in combination with a high resistance Monodose RS01 using Next Generation Impactor. RESULTS AND DISCUSSION: There were no detectable differences between IBU samples thermally and spectroscopically. The milled IBU sample exhibited improved powder flow in comparison with the unmilled sample. The milled IBU powders possessed surprisingly high in vitro aerodynamic performance with a fine particle fraction percentage between 67 and 85%, and a minimum respirable fraction percentage of 49%. The capsule fill weights, from 10 to 50mg, and milling batch sizes did not significantly influence performance. The importance of powder conditioning following milling was illustrated as the storage duration and temperature negatively affected performance. CONCLUSION: In vitro aerodynamic performance of IBU is independent of capsule fill weight and batch size; however, some period of powder conditioning is recommended to reduce variability in formulation performance.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Chemical Phenomena , Chemistry, Pharmaceutical/methods , Dry Powder Inhalers/methods , Ibuprofen/chemistry , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Dosage Forms , Ibuprofen/administration & dosage , Particle Size , X-Ray DiffractionABSTRACT
OBJECTIVE: To crystallize diclofenac (DF) from diclofenac sodium (DFNa), to micronize DF and DFNa, and to evaluate in vitro aerodynamic performance of the jet-milled formulations MATERIALS AND METHODS: From the acidic titration of aqueous DFNa, DF crystals were formed and were identified using thermal analysis, spectroscopy, and X-ray powder diffraction. Following the micronization of the DF and DFNa powders, the recovered samples were imaged, and their particle size distributions were evaluated. Samples before and after jet millings were characterized, and in vitro aerodynamic performance testing was performed on the DF sample before jet milling and the DF and DFNa samples following jet milling. RESULTS AND DISCUSSION: Hollow needles of DF were precipitated. With similar particle size distributions, the jet-milled DFNa sample from the collection bag, and the DF sample from the cyclone were used for further characterization. Despite different deposition patterns in the Next Generation Impactor, the DF hollow needles had a comparable respirable fraction percentage to the jet-milled DF and DFNa particles. However, the jet-milled DF formulation had the best in vitro aerodynamic performance. CONCLUSIONS: Hollow, crystalline needles of DF were formed and possessed promising aerosol performance in comparison with the jet-milled powders.
Subject(s)
Diclofenac/chemistry , Drug Delivery Systems , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Calorimetry, Differential Scanning , Crystallization , Dry Powder Inhalers , Microscopy, Electron, Scanning , Particle Size , Powder Diffraction , Powders , Spectroscopy, Fourier Transform Infrared , Technology, Pharmaceutical , X-Ray DiffractionABSTRACT
BACKGROUND: Delivery of pharmacologically active compounds to the lung for systemic effects is well known and recently has entered a new era with several products achieving regulatory approval. This review focuses on the barriers to pulmonary delivery of biologics. METHODS: Lessons learned from the development of recently approved products will be reviewed to shed light on the current challenges that are faced when developing biological products for inhaled delivery. RESULTS: The text and tables presented herein consolidate the current data and ongoing research regarding biological, inhaled products. CONCLUSION: With this basis, we also review the future prospects for pulmonary delivery of biologics for systemic delivery and how the biological and physical barriers may be overcome.
