Biomedical subjects

Stephen W Stein

Publications and source records attributed to Stephen W Stein.

6 recordsLinked to original sources

PubMed2006

Evaluation of the TSI aerosol impactor 3306/3321 system using a redesigned impactor stage with solution and suspension metered-dose inhalers.

The purpose of this research was to evaluate a redesigned impactor stage for the TSI Model 3306 Impactor Inlet with nozzles adjusted to obtain a target cut-point of 4.7 microm. It has been determined that the previous cut-point used in the Model 3306 was nominally closer to 4.14 microm, thus potentially impacting the characterization of aerosol mass. The reassessment of the Model 3306 was performed on 4 solution and 2 suspension metered-dose inhaler (MDI) formulations. The redesigned impactor stage resulted in a 5% to 6% increase in aerosol mass when compared with the previous impactor stage for the products Ventolin-HFA, Proventil-HFA, and 2 cyclosporin solution formulations with high ethanol concentrations (15% wt/wt). For the formulations with low ethanol concentrations (3% wt/wt), minimal differences were observed between the 2 cut-points. In addition, this study reevaluated the requirement of a vertical inlet extension length when using the TSI 3306/3321 system with the redesigned cut-point. It was shown that the use of a 20-cm extension provides mass and aerosol size distributions that are comparable to the Andersen 8-stage Cascade Impactor, for both solution and suspension MDIs. This work indicates that the TSI 3306/3321 system is suitable for preformulation studies of both suspension and solution MDI systems.

Aerosols↗

PubMed2006

Application of heated inlet extensions to the TSI 3306/3321 system: comparison with the Andersen cascade impactor and next generation impactor.

Pharmaceutical aerosol size distribution analysis based on multi-stage inertial impaction is well accepted, though laborious. The TSI 3306 Impactor Inlet/3321 time-of-flight (TOF) Aerodynamic Particle Size Analyzer (APS) has been evaluated for its ease of use and potential for time savings during product development. However, instrument inlet modifications may be necessary for increased correlation with equivalent measurements obtained by inertial impaction following pharmacopeial methods. A heated inlet extension tube was located between the USP/Ph.Eur. throat and the Single-Stage Impactor (SSI) to promote evaporation of residual ethanol from aerosol droplets, generated from two formulations containing ethanol as semi-volatile solubilizer (8 and 20% w/w) for the active pharmaceutical ingredient. As temperature and extension length increased, the SSI-measured fine particle fraction (aerosol < 4.7 microm aerodynamic diameter) also increased, for the aerosols used in this study. These values correlated quite closely with equivalent measures made by multi-stage cascade impactor equipped with the same throat. Particle size distribution profiles measured with the APS for either formulation did not significantly change utilizing the heated extensions, suggesting that ethanol evaporation was largely complete at any condition by the time the aerosol entered the measurement zone of the TOF analyzer. The addition of a heated inlet extension may be useful to facilitate evaporation of residual semi-volatile species, especially when an agreement of APS-derived particle size mass distribution data from the SSI with multi-stage cascade impactors is desired. However, complete evaporation of the semi-volatile species may not be necessary for SSI-generated mass distribution to match conventionally used cascade impactors.

Administration, Inhalation↗

PubMed2004

A theoretical and experimental analysis of formulation and device parameters affecting solution MDI size distributions.

The influence of formulation and device configurations on the initial droplet and residual particle size distribution from solution MDIs was theoretically and experimentally examined. Aerodynamic size distribution tests were conducted to characterize the size distribution of the residual particles formed when a solution MDI is actuated. The measured size distributions were approximately log-normally distributed, and did not show evidence of a secondary large particle mode. Theoretical relationships were developed to relate the residual particle size distribution to the initial size distribution of the atomized droplets. The residual particle size distribution was shown to be proportional to the nonvolatile concentration to the one-third power. Ethanol concentration, propellant type, valve size, and actuator orifice diameter were all shown to affect the initial droplet size distribution. Deposition of drug in the mouthpiece and USP inlet affect the measured size distribution during aerodynamic particle size measurements. Although there is a significant increase in the size of initial droplets as ethanol concentration increases, there is only a minor increase in the size of the residual particles measured when the USP Inlet is used due to size dependent deposition in the USP inlet and actuator mouthpiece. Vapor pressure was shown to explain only part of the differences in the size of the atomized droplets for various formulations. Theoretical and empirical equations were developed that make it possible to predict the residual particle size distribution for solution MDIs.

Chemistry, Pharmaceutical↗

PubMed2004

Comparison of the TSI Model 3306 Impactor Inlet with the Andersen Cascade Impactor: solution metered dose inhalers.

The product performance of a series of solution Metered Dose Inhalers (MDIs) were evaluated using the TSI Model 3306 Impactor Inlet and the Andersen Cascade Impactor (ACI). The goal of the study was to test whether the fine particle and coarse particle depositions obtained using the Model 3306 were comparable to those results obtained by ACI testing. The analysis using the Model 3306 was performed as supplied by the manufacturer as well as with 20 cm and 40 cm vertical extensions that were inserted between the Model 3306 and the USP Inlet. Nine different solution formulations were evaluated. The drug concentrations ranged from 0.08 to 0.8% w/w and the ethanol cosolvent concentration varied between 5 and 20% w/w. In general, it was found that good correlations between the two instruments were obtained. However, for formulations containing 10-20% w/w ethanol it is shown that an extension fitted to the Model 3306 yielded an improved correlation to those obtained from the ACI.

Beclomethasone↗

PubMed2003

Evaluation of a new Aerodynamic Particle Sizer Spectrometer for size distribution measurements of solution metered dose inhalers.

The ability of the Model 3320 and newer Model 3321 Aerodynamic Particle Sizer Spectrometer (APS) to make accurate mass-weighted size distribution measurements of solution metered dose inhalers (MDIs) was evaluated. Measurements of experimental HFA-134a beclomethasone dipropionate MDIs were made with both the APS 3320 and APS 3321 and compared to the Andersen Cascade Impactor (ACI). The mass-weighted size distribution measurements from the ACI and APS 3321 agreed well but were very different than the APS 3320 measurements. Evaluation of the APS 3320 size distribution measurements indicated that the presence of a few erroneous particle measurements caused a gross overestimation of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). When a previously described technique was used to eliminate erroneous particle size measurements from the size distribution calculation, the MMAD and GSD from the APS 3320 agreed well with those from the ACI and APS 3321. The GSD from the APS 3321 and the APS 3320 after a mask was applied were slightly larger than from the ACI. It is believed that both APS instruments slightly underestimate the GSD while the ACI slightly overestimates the GSD. Further experiments were conducted using the APS 3321 to examine the influence of drug concentration and cosolvent level on the size distribution of solution formulation MDIs. The MMAD was shown experimentally and theoretically to be proportional to drug concentration to the one-third power. Cosolvent concentration had minimal influence on MMAD over the range examined. The measurements reported in this paper demonstrate that it is possible to obtain accurate mass-weighted size distribution measurements with the APS 3320 and APS 3321. These instruments allow for accurate size distribution measurements to be made in minutes as opposed to the hours required to conduct and analyze size distribution measurements from cascade impactors.

Aerosols↗

PubMed2003

Balancing ethanol cosolvent concentration with product performance in 134a-based pressurized metered dose inhalers.

The effects of formulation parameters on the product performance characteristics of solution metered dose inhalers (MDIs) were determined using ethanol as the cosolvent and HFA 134a as the propellant. Solubility of beclomethasone dipropionate (BDP) was determined in various blends of 134a and ethanol and was shown to increase with ethanol concentration. Product performance was assessed using the APS Model 3306 Impactor Inlet in conjunction with APS Model 3320 Aerodynamic Particle Sizer (APS). Nine solution formulations containing various BDP and ethanol concentrations were studied. Chemical analysis of the Impactor Inlet was performed in order to determine the "respirable" deposition of the MDI system. With increased ethanol concentration, the throat deposition and plate deposition increased and the respirable deposition decreased. The mass median aerodynamic diameter (MMAD) increased with the increasing drug concentration, but did not show a significant increase with an increase in ethanol concentration. This indicates that the efficiency of solution MDIs decreases with increased ethanol concentration. A Maximum Respirable Mass (MRM) was calculated based on the drug solubility at a particular ethanol concentration and the respirable deposition for a 50mcl valve and QVAR actuator for that ethanol concentration. The MRM represents the maximum amount of a given drug that can be delivered to the lungs theoretically and is very sensitive to the solubility profile of the drug. The MRM increased with the increasing ethanol concentration in the formulation until a plateau was reached at an ethanol concentration of 10-15% w/w. The MRM initially increases with increase in ethanol concentration due to the increase in drug solubility. However, at higher ethanol concentrations the increase in drug solubility was negated by a decrease in the respirable deposition. This study illustrates the importance of considering both formulation properties and product performance characteristics when optimizing a metered dose inhaler drug delivery system.

Administration, Inhalation↗