Craig A. Dunbar

EVALUATION OF PROBABILITY DENSITY FUNCTIONS TO APPROXIMATE PARTICLE SIZE DISTRIBUTIONS OF REPRESENTATIVE PHARMACEUTICAL AEROSOLS

The purpose of this work was to evaluate the application of probability density functions (PDFs) and curve-fitting methods to approximate particle size distributions emitted from four pharmaceutical aerosol systems characterized using standard methods. The aerosols were produced by a nebulizer, pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI) and nasal spray. PDFs selected for analysis were (i) log-normal, (ii) upper-limit, (iii) Nukiyama-Tanasawa (iv) Rosin-Rammler and (v) modified Rosin-Rammler. Two curve-fitting methods were used to estimate the adjustable parameters of the PDFs: linear least-squares fit of the cumulative distribution function ( Method A) and non-linear least-squares fit of the probability density function (Method B). Large truncation of the pMDI and DPI particle size distributions obtained by cascade impaction resulted in poor fits of the PDFs. The nebulizer and nasal spray were not affected by truncation and were well represented by the Rosin-Rammler and log-normal PDFs, respectively (Method B only). Probability distribution functions (Method B) were fitted without bias from linear coordinate transformation and produced significantly better fits than Method A for each aerosol system (p < 0.05). Considerable caution must be used when estimating representative parameters from cumulative or probability distributions.

Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3: Final report on a statistical procedure for determining equivalence

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test’s limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.

Evaluation of atomizer performance in production of respirable spray-dried particles

The purpose of this study was to analyze atomizer performance in the production of respirable spray-dried particles. An ultrasonic nebulizer and a plain-jet airblast atomizer were evaluated in an open cycle, cocurrent spray-drying tower using a 0.5% w/v disodium fluorescein solution. The plain-jet airblast atomizer produced smaller initial droplet sizes (D32 = 4.5-4.8 microns) relative to the ultrasonic nebulizer (D32 = 20-48 microns) over a range of atomizer operating conditions. The airblast atomizer was selected for further analysis in two spray-drying tower configurations: grounded and electrostatically charged. The spray-dried particles produced by the airblast atomizer were of a size range (mass median aerodynamic diameter [MMAD] < 1.6 microns) suitable for inhalation. Significant differences were observed for the grounded and electrostatically charged tower configurations, the latter producing the smaller median particle size at the expense of decreased collection efficiency. The electrostatically charged tower was size selective because of diffusion charging, retaining particles with an aerodynamic diameter (Dae) in the range 1 < Dae < 2 microns. The particle size was reduced with decreasing ambient relative humidity, although a controlled study of this parameter would be required to explicitly define its effects.

Selected parameters affecting characterization of nebulized aqueous solutions by inertial impaction and comparison with phase-Doppler analysis.

The objective of this study was to evaluate selected parameters affecting the characterization of air-jet nebulized aqueous solutions by inertial impaction. Parameters affecting characterization of the droplet size distribution by inertial impaction were considered to be nebulizer T-piece connecting tube length, solute concentration, droplet charge accumulation, sample time and marker concentration. Parametric effects on nebulizer output characteristics were evaluated using a fractional factorial design. Response factors were defined as mass median aerodynamic diameter (MMAD), relative span factor (Delta), fine particle mass and delivery rate of solute. Connecting tube length, grounding the impaction stages and marker concentration did not significantly affect the response factors (0.05). Mass median aerodynamic diameter (MMAD) and delivery rate of solute were significantly affected by solute concentration (p<0.05). Fine particle mass was significantly affected by the interaction between solute concentration and sampling time. Droplets attained an equilibrium size with an MMAD=1.0 microm, Delta=2.12 (0.9% solute) and MMAD=1.7 microm, Delta=2.00 (9. 0% solute) before the exit of the nebulizer T-piece. The droplet size distributions obtained by inertial impaction were compared with data obtained by phase-Doppler analysis.

Generation of Gelatin Aerosol Particles from Nebulized Solutions as Model Drug Carrier Systems

Purpose. Aerodynamically stable, nebulized aerosols are desirable to achieve optimum asthma therapy. Stabilizing droplet size using gel-forming polymers may assist in achieving this goal. Semisolid particles may be generated through aerosolization of a polymer solution. Gelatin was employed as a model polymer in a process optimization study using the marker, disodium fluorescein, and the drug, budesonide delivered from two commercially available air-jet nebulizers. Methods. The aerosol delivery system consisted of either of the air-jet nebulizers attached to a 30 cm drying column. The nebulizers employed were the Aerotech II and Salter SL8900. Two gelatin solutions (0.1 and 0.7%w/v) were evaluated following initial density and viscosity measurements. Particle characterization was conducted by scanning electron microscopy, eight-stage cascade impaction (CI), and phase-Doppler analysis. Disodium fluorescein (NaF, 5 and 7%w/v) and budesonide (B, 0.05%w/v) were added to the gelatin solutions in a 24-factorial design study and the follow-up drug formulation study, respectively. The factorial design experiment evaluated the influence of device, operating pressure, marker, and gelatin concentrations on mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF). Spectrophotometry of the CI samples was performed at wavelengths of 486 (NaF) and 254 (B) nm. Results. The factorial design experiment utilizing NaF showed that MMADs were not influenced significantly by the device, operating pressure, marker, or gelatin concentrations (p>0.05). However, FPFs were significantly influenced by marker concentration and device (p<0.05). In the presence of budesonide, the MMADs and FPFs for Aerotech and Salter, respectively, were: MMAD=1.39±0.30 μm and 1.75±0.63 μm, FPF=93.5±4% and 68.5±5%, (n=3). These values were consistent with those predicted in the designed experiment. Conclusions. A range of semisolid particle sizes were produced (1.3