Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs.

The multi-stage cascade impactor (CI) is the mainstay method for the determination of the aerodynamic particle size distribution (APSD) of aerosols emitted from orally inhaled products (OIPs). CIs are designed to operate at a constant flow rate throughout the measurement process. However, it is necessary to mimic an inhalation maneuver to disperse the powder into an aerosol when testing passive dry powder inhalers (DPIs), which constitute a significant portion of available products in this inhaler class. Methods in the pharmacopeial compendia intended for product quality assurance initiate sampling by applying a vacuum to the measurement apparatus using a timer-operated solenoid valve located downstream of the CI, resulting in a period when the flow rate through the impactor rapidly increases from zero towards the target flow rate. This article provides recommendations for achieving consistent APSD measurements, including selection of the CI, pre-separator, and flow control equipment, as well as reviewing considerations that relate to the shape of the flow rate-sampling time profile. Evidence from comparisons of different DPIs delivering the same active pharmaceutical ingredients (APIs) is indicative that the compendial method for APSD measurement is insensitive as a predictor of pharmacokinetic outcomes. Although inappropriate for product quality testing, guidance is therefore provided towards adopting a more clinically realistic methodology, including the use of an anatomically appropriate inlet and mimicking patient inhalation at the DPI while operating the CI at constant flow rate. Many of these recommendations are applicable to the testing of other OIP classes.

The Influence of Electrostatic Controls on MDI Size Distribution Measurements.

Cascade impactor testing is widely used to characterize the aerodynamic particle-size distribution of metered dose inhaler aerosols. Charge is often imparted to MDI aerosols by triboelectrification as formulation rapidly travels through the valve stem and actuator during atomization. The presence of charge on MDI aerosols can impact the accuracy and reproducibility of APSD measurements made using cascade impactors. The aerodynamic particle size distribution of three different experimental MDI formulations were evaluated using the Next Generation Impactor with and without incorporating static controls during testing. The static controls included grounding the analyst and the equipment, using an ionizing air blower and anti-static gun, rinsing and allowing the actuator to air dry prior to testing, and having the analyst not wear gloves or touch the USP throat during testing. For all three formulations, tests that used static controls had lower actuator and throat deposition and correspondingly higher deposition on the impactor stages. While static controls influenced the amount of drug entering into the impactor during testing, the static controls did not otherwise change the aerodynamic particle size distribution of these particles. Static controls had the greatest impact on the ethanol-free HFA-227 formulation. For this formulation, there was a 15% difference in throat deposition for the tests that did or did not incorporate static controls. These results demonstrated that electrostatic effects can lead to meaningful variability in cascade impactor test results. Static controls should be considered when developing cascade impactor test methods for MDI products in order to eliminate variability in test results.

Impact of droplet evaporation rate on resulting in vitro performance parameters of pressurized metered dose inhalers.

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of pulmonary diseases. The overall efficiency of pMDI drug delivery may be defined by in vitro parameters such as the amount of drug that deposits on the model throat and the proportion of the emitted dose that has particles that are sufficiently small to deposit in the lung (i.e., fine particle fraction, FPF). The study presented examines product performance of ten solution pMDI formulations containing a variety of cosolvents with diverse chemical characteristics by cascade impaction with three inlets (USP induction port, Alberta Idealized Throat, and a large volume chamber). Through the data generated in support of this study, it was demonstrated that throat deposition, cascade impactor deposition, FPF, and mass median aerodynamic diameter of solution pMDIs depend on the concentration and vapor pressure of the cosolvent, and the selection of model throat. Theoretical droplet lifetimes were calculated for each formulation using a discrete two-stage evaporation process model and it was determined that the droplet lifetime is highly correlated to throat deposition and FPF indicating that evaporation kinetics significantly influences pMDI drug delivery.

The History of Therapeutic Aerosols: A Chronological Review.

In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the future. We hope that you will find this chronological summary intriguing and informative.

Modeling and Understanding Combination pMDI Formulations with Both Dissolved and Suspended Drugs.

A simulation model has been established to predict the residual aerodynamic particle size distribution (APSD) of dual-component pressurized metered dose inhalers (pMDIs). More specifically, this model estimates the APSD of pMDI formulations containing dissolved and suspended compounds for various formulations, and has been verified experimentally. Simulated and experimental data illustrate that APSDs of the dissolved and suspended components of the pMDI are influenced by concentrations of the dissolved and micronized suspended drugs, along with suspended drug size. Atomized droplets from such combination formulations may contain varying number of suspended drug particles and a representative concentration of dissolved drug. These sub-populations of atomized droplets may explain the residual APSDs. The suspended drug follows a monomodal, lognormal distribution and is more greatly impacted by the size and concentration of the suspended drug in comparison to the concentration of dissolved drug. On the other hand, dissolved drug illustrates a bimodal, lognormal residual particle size distribution both theoretically and experimentally. The smaller mode consists of residual particles made of dissolved drug only, while the larger mode consists of residual particles that contain both dissolved and suspended drugs. The model effectively predicted the size distributions of both the dissolved and suspended components of combination formulations (r(2) value of 0.914 for the comparison of simulated versus experimental MMAD values for the formulations examined). The results demonstrate that this model is a useful tool that may be able to expedite the development of combination pMDI formulation.

Factors influencing aerodynamic particle size distribution of suspension pressurized metered dose inhalers.

Pressurized metered dose inhalers (pMDIs) are frequently used for the treatment of asthma and chronic obstructive pulmonary disease. The aerodynamic particle size distribution (APSD) of the residual particles delivered from a pMDI plays a key role in determining the amount and region of drug deposition in the lung and thereby the efficacy of the inhaler. In this study, a simulation model that predicts the APSD of residual particles from suspension pMDIs was utilized to identify the primary determinants for APSD. These findings were then applied to better understand the effect of changing drug concentration and micronized drug size on experimentally observed APSDs determined through Andersen Cascade Impactor testing. The experimental formulations evaluated had micronized drug mass median aerodynamic diameters (MMAD) between 1.2 and 2.6 µm and drug concentrations ranging from 0.01 to 1% (w/w) with 8.5% (w/w) ethanol in 1,1,1,2-tetrafluoroethane (HFA-134a). It was determined that the drug concentration, micronized drug size, and initially atomized droplet distribution have a significant impact in modulating the proportion of atomized droplets that contain multiple suspended drug particles, which in turn increases the residual APSD. These factors were found to be predictive of the residual particle MMAD for experimental suspension HFA-134a formulations containing ethanol. The empirical algebraic model allows predicting the residual particle size for a variety of suspension formulations with an average error of 0.096 µm (standard deviation of 0.1 µm).

Advances in metered dose inhaler technology: formulation development.

Pressurized metered dose inhalers (MDIs) are a long-standing method to treat diseases of the lung, such as asthma and chronic obstructive pulmonary disease. MDIs rely on the driving force of the propellant, which comprises the bulk of the MDI formulation, to atomize droplets containing drug and excipients, which ideally should deposit in the lungs. During the phase out of chlorofluorocarbon propellants and the introduction of more environmentally friendly hydrofluoroalkane propellants, many improvements were made to the methods of formulating for MDI drug delivery along with a greater understanding of formulation variables on product performance. This review presents a survey of challenges associated with formulating MDIs as solution or suspension products with one or more drugs, while considering the physicochemical properties of various excipients and how the addition of these excipients may impact overall product performance of the MDI. Propellants, volatile and nonvolatile cosolvents, surfactants, polymers, suspension stabilizers, and bulking agents are among the variety of excipients discussed in this review article. Furthermore, other formulation approaches, such as engineered excipient and drug-excipient particles, to deliver multiple drugs from a single MDI are also evaluated.

Advances in metered dose inhaler technology: hardware development.

Pressurized metered dose inhalers (MDIs) were first introduced in the 1950s and they are currently widely prescribed as portable systems to treat pulmonary conditions. MDIs consist of a formulation containing dissolved or suspended drug and hardware needed to contain the formulation and enable efficient and consistent dose delivery to the patient. The device hardware includes a canister that is appropriately sized to contain sufficient formulation for the required number of doses, a metering valve capable of delivering a consistent amount of drug with each dose delivered, an actuator mouthpiece that atomizes the formulation and serves as a conduit to deliver the aerosol to the patient, and often an indicating mechanism that provides information to the patient on the number of doses remaining. This review focuses on the current state-of-the-art of MDI hardware and includes discussion of enhancements made to the device's core subsystems. In addition, technologies that aid the correct use of MDIs will be discussed. These include spacers, valved holding chambers, and breath-actuated devices. Many of the improvements discussed in this article increase the ability of MDI systems to meet regulatory specifications. Innovations that enhance the functionality of MDIs continue to be balanced by the fact that a key advantage of MDI systems is their low cost per dose. The expansion of the health care market in developing countries and the increased focus on health care costs in many developed countries will ensure that MDIs remain a cost-effective crucial delivery system for treating pulmonary conditions for many years to come.

The influence of initial atomized droplet size on residual particle size from pressurized metered dose inhalers.

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of diseases of the lung, including asthma and chronic obstructive pulmonary disease. The mass median aerodynamic diameter of the residual particles (MMADR) delivered from a pMDI plays a key role in determining the amount and location of drug deposition in the lung and thereby the efficacy of the inhaler. The mass median diameter of the initial droplets (MMDI), upon atomization of a formulation, is a significant factor influencing the final particle size. The purpose of this study was to evaluate the extent that MMDI and initial droplet geometric standard deviation (GSD) influence the residual aerodynamic particle size distribution (APSDR) of solution and suspension formulations. From 48 solution pMDI configurations with varying ethanol concentrations, valve sizes and actuator orifice diameters, it was experimentally found that the effective MMDI ranged from 7.8 to 13.3 µm. Subsequently, computational methods were utilized to determine the influence of MMDI on MMADR, by modulating the MMDI for solution and suspension pMDIs. For solution HFA-134a formulations of 0.5% drug in 10% ethanol, varying the MMDI from 7.5 to 13.5 µm increased the MMADR from 1.4 to 2.5 µm. For a suspension formulation with a representative particle size distribution of micronized drug (MMAD=2.5 µm, GSD=1.8), the same increase in MMDI resulted in an increase in the MMADR from 2.7 to only 3.3 µm. Hence, the same increase in MMDI resulted in a 79% increase in MMADR for the solution formulation compared to only a 22% increase for the suspension formulation. Similar trends were obtained for a range of drug concentrations and input micronized drug sizes. Thus, APSDR is more sensitive to changes in MMDI for solution formulations than suspension formulations; however, there are situations in which hypothetically small micronized drug in suspension (e.g. 500 nm MMAD) could resemble trends observed for solution formulations. Furthermore, the relationship between APSDR and drug concentration and MMDI is predictable for solution pMDIs, but this is not as straightforward for suspension formulations. In addition, the MMADR was relatively insensitive to changes in initial droplet GSD (from 1.6 to 2.0) and the solution and suspension pMDI residual particle GSDs were essentially identical to the initial droplet GSDs.

A model for predicting size distributions delivered from pMDIs with suspended drug.

A new model has been developed for predicting size distributions delivered from pressurized metered dose inhalers (pMDIs) that contain suspended drug particles. This model enables the residual particle size distribution to be predicted for a broad range of formulations. It expands on previous models by allowing for polydisperse micronized input drug, multiple suspended drugs, dissolved drug, and dissolved or suspended excipient to be included in the formulation. The model indicates that for most pMDI configurations, the majority of droplets contain no drug or a single drug particle and the residual particle size distribution delivered from the pMDI is essentially equivalent to the size distribution of the micronized drug used in the formulation. However, for pMDIs with a high drug concentration or that use small micronized drug particles, there can be a substantial fraction of the droplets that contain multiple drug particles. The residual particle size distribution obtained from these pMDIs can be substantially larger than the size distribution of the micronized drug. Excellent agreement was observed between size distributions predicted using this model and those obtained from experimental cascade impactor measurements (r(2)=0.97), thus demonstrating the ability of the model to accurately predict the size distributions obtained from suspension pMDIs.

Estimating the number of droplets and drug particles emitted from MDIs.

The objective of this paper is to assess the number of drug particles or droplets contained in metered dose inhaler (MDI) aerosols. Equations were developed to estimate this. The number of drug particles was estimated to be as high as about 300 million for QVAR solution MDIs and as low as 670,000 for Beclovent MDIs. The number of particles in MDI aerosols was shown to be highly dependent on the mass median aerodynamic diameter (MMAD) and geometric standard deviation, and to a lesser extent the total mass of the aerosol. It was demonstrated that when the number of particles are calculated assuming that the aerosol is monodisperse and using the MMAD as the particle size, the number of particles are significantly underestimated. The number of droplets atomized from HFA-134a MDIs was estimated to range from about 220 million to about 1.1 billion droplets per actuation. For solution MDIs, each of the atomized droplets contains drug and thus the number of drug particles is the same as the number of atomized droplets. However, for suspension MDI formulations many of the droplets do not contain any micronized drug particles and the number of drug particles is much lower than the number of atomized droplets.

Aiming for a moving target: challenges with impactor measurements of MDI aerosols.

Experiments were conducted to illustrate some of the challenges associated with measuring dynamic MDI aerosols. Experimental HFA-134a solution MDIs containing 8 or 20% ethanol were measured using the Andersen cascade impactor using three different inlets. It was demonstrated that the size distribution of MDI aerosols changes substantially during the measurement process. The measured size distribution was shown to be dependent on the degree of evaporation that has occurred prior to size measurement. Additionally, the degree of evaporation prior to measurement also influences the number of modes present in the measured size distribution. While MDI aerosols appeared to have a separate large particle mode when measured using the U.S. Pharmacopeial induction port ("USP inlet"; [U.S. Pharmacopeia, 1996. Physical tests and determinations <601> aerosols, metered dose inhalers, and dry powders. Pharmacopeial Forum 22, pp. 3065-3095]), the aerosols were shown to be monomodal when measured using a large volume inlet. The apparent large particle mode observed with the USP inlet seem rather to be droplets from the same monomodal distribution that have not fully evaporated. The complex interaction of the MDI plume and inlet configuration was described. Inlet design was shown to influence inlet deposition, measured particle size, and even deposition in the actuator mouthpiece. Inlet deposition was shown to be highly size-dependent with large droplets being collected more efficiently than smaller droplets.

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.

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.

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 µm. It has been determined that the previous cut-point used in the Model 3306 was nominally closer to 4.14 µm, 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.

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.

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.

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.

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.