Microstructural Characterization of Dry Powder Inhaler Formulations Using Orthogonal Analytical Techniques.

PURPOSE: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device. METHODS: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies. RESULTS: APSD testing alone might not be able to explain differences reported elsewhere in in vivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products. CONCLUSIONS: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing in vitro tools that are able to provide a bridge between material attributes or process parameters and in vivo performance.

Highly sensitive spectrofluorimetric method for rapid determination of orciprenaline in biological fluids and pharmaceuticals.

Orciprenaline sulphate (ORP) is a direct-acting sympathomimetic with mainly beta-adrenoceptor stimulant activity. It is used as a bronchodilator in the management of reversible airway obstruction. For the first time, a rapid highly sensitive spectrofluorimetric method is described that is relied on measuring the fluorescence spectra of ORP at acidic pH and without addition of any chemical reagents. The relative fluorescence intensity was measured at 310 nm and after excitation at 224 nm. ORP native fluorescence was calibrated in both water and acetonitrile as diluting solvents. The method was designed to estimate the drug in miscellaneous matrices with high accuracy and precision. Linear ranges of calibration curves were 30.0-400.0 ng/ml and 10.0-240.0 ng/ml in water and acetonitrile, respectively. The detection limits were calculated and reached as low as 3.3 and 3.1 ng/ml, respectively, representing the ultra-sensitivity of the proposed method. This result permitted application of this method for spiked human plasma and urine and was used as a preliminary investigation with good percentage recovery (89.4-106.8%). The application was further extended to analyse ORP in its pharmaceutical formulations. The method was validated in compliance with International Council of Harmonization (ICH) Guidelines.

RP-HPLC-UV method development and validation for simultaneous determination of terbutaline sulphate, ambroxol HCl and guaifenesin in pure and dosage forms.

OBJECTIVE: The objective of the present work was to develop and validate a simple, sensitive, rapid and stable reverse-phase high performance liquid chromatography (RP-HPLC) method for a combination of Terbutaline sulphate (TSL), Ambroxol hydrochloride (AML) and Guaifenesin (GFN). METHOD: The combination of these drugs was analyzed by using Shimadzu LC 2010 CHT high performance liquid chromatography (HPLC). Successful separation was achieved by isocratic elution on a reverse-phase C18 column (sun fire) (250mm, 4.6mm, 5µ), using a mobile phase consisting of buffer: acetonitrile in the ratio 80: 20 (buffer - 0.1% v/v triethyleamine pH-3.0) followed by 1.0mL/min flow rate. The wavelength of detection was at 220nm. RESULT: The chromatographic retention times were consistent at 3.0, 10.5 and 13.8minutes for TSL, AML and GFN respectively. For these three compounds, the lower limit of detection was 1.0, 1.25, and 1.5µg/mL and lower limit of quantification was 3.3, 4.1 and 5.0µg/mL respectively. The linearity concentrations established for TSL, AML and GFN were 1.0-7.0, 1.5-7.5 and 4.0-14.0µg/mL respectively. The correlation coefficients for all the drugs were found to be greater than 0.999. The relative standard deviation of inter- and intra-day were less than 2.0%. CONCLUSION: This method provides a necessary tool for quantification of the selected drugs for their assay. The proposed method is simple, accurate, reproducible and applied successfully to analyze three compounds in pure as well dosage form.

Hair analysis to monitor adherence to prescribed chronic inhaler drug therapy in patients with asthma or COPD.

BACKGROUND: Poor adherence to inhaled drug therapy in individuals with asthma and/or chronic obstructive pulmonary disease (COPD) may be associated with suboptimal therapeutic outcomes. Measurement of drug residues in hair samples has been employed to assess oral medication use over time. Here, we test the feasibility of analyzing hair samples from patients with asthma and/or COPD for assessing adherence to prescribed inhaled medication. METHODS: In total, 200 male and female subjects, ≥ 18 years of age, with stable asthma and/or COPD who were receiving an acceptable standard of care daily inhaled product consistently, were recruited. Head hair samples were taken during a single visit to the clinical site and grouped by hair color according to the Fischer-Saller scale. Drug residues were extracted from milled hair samples using solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Inhaled drugs were detected in hair for 72% of subjects from whom it was possible to analyze hair samples (n = 157/200). Most hair samples obtained from subjects receiving formoterol or vilanterol had amounts of drug present that allowed determination of a quantifiable concentration, and demonstrated a dose response. Drugs were detected in all hair colors, with higher concentrations of formoterol observed in dark-haired versus light-haired individuals. CONCLUSIONS: This is the first study to demonstrate that inhaled medication can be measured in hair samples from subjects with asthma and/or COPD. The results show that hair drug concentration data could potentially provide a record of historical adherence to inhaled therapeutics.

Carboxymethyl ß-cyclodextrin as chiral selector in capillary electrophoresis: Enantioseparation of 16 basic chiral drugs and its chiral recognition mechanism associated with drugs' structural features.

Herein we present the enantioseparation of 10 cardiovascular agents and six bronchiectasis drugs including propranolol, carteolol, metoprolol, atenolol, pindolol, esmolol, bisoprolol, bevantolol, arotinolol, sotalol, clenbuterol, procaterol, bambuterol, tranterol, salbutamol and terbutaline sulfate using carboxymethyl-ß-cyclodextrin (CM-ß-CD) as chiral selector. To our knowledge, there is no literature about using CM-ß-CD for separating carteolol, esmolol, bisoprolol, bevantolol, arotinolol, procaterol, bambuterol and tranterol. During the course of work, changes in pH, CM-ß-CD concentration, buffer type and concentration were studied in relation to chiral resolution. Excellent enantiomeric separations were obtained for all 16 compounds, especially for procaterol. An impressive resolution value, up to 17.10, was obtained. In particular, most of them achieved rapid separations within 20 min. Given the fact that enantioseparation results rely on analytes' structural characters, the possible separation mechanisms were discussed. In addition, in order to obtain faster separation for propranolol enantiomers in practical application, the effective length of capillary was innovatively shortened from 45 to 30 cm. After the validation, the method was successfully applied to the enantiomeric purity determination of propranolol in the formulation of drug substances.

Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol.

This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.

Probing the Distribution of Water in a Multi-Component System by Solid-State NMR Spectroscopy.

PURPOSE: To characterize the distribution of water among various components in a powder blend using solid-state NMR spectroscopy. METHODS: Water sorption behavior of theophylline anhydrate and excipients was determined by dynamic vapor sorption (DVS) and Karl Fischer Titration (KFT) after storing them in humidity chambers for 1 week at room temperature (RT) and calibration curves were generated for water content vs. (1)H T 1 relaxation times. Powder blends (either with microcrystalline cellulose or lactose as diluent) were stored at different relative humidity (RH) conditions and analyzed periodically using solid-state NMR, powder X-ray diffraction, and KFT. RESULTS: Anhydrous theophylline converted to the hydrate at ≥ 84% RH. Based on the calibration curves of water content vs. relaxation times, the distribution of water in the powder blends was estimated. The total water content calculated using ssNMR was in good agreement with values measured using KFT. In blends stored at 90% RH, theophylline anhydrate-to-hydrate conversion did not occur in 1 week. CONCLUSIONS: The distribution of water in multi-component powder blends was successfully determined using correlation between (1)H T 1 relaxation times and total water content. Excipient water sorption inhibited hydrate formation in theophylline at 90% RH. Water distribution was affected by excipient type. The extent of water sorbed by excipients in blends was found to be different than their standalone equilibrium water content.

Study of doxofylline and its degradation products in bulk drug by a newly developed stability-indicating HPLC method.

The purpose of this work was to study the stability behavior of doxofylline under different stress conditions and to develop a sensitive stability-indicating HPLC assay method. The stress conditions applied included heat, moisture, acid-base hydrolysis, oxidation, and UV light. The drug was particularly labile under oxidative and thermal stress conditions, with 58.40 and 53.90% degradation, respectively. Good resolution of drug from degradation products formed under stress conditions was achieved on a C18 column using 10 mM KH2PO4 buffer solution (pH 6) methanol (40 + 60, v/v) as the mobile phase (pH 7.2). The flow rate was 1 mLlmin, and the detection wavelength was 273 nm. The method was validated for linearity, range, precision, accuracy, LOD, and LOQ. The RSD was found to be <2%. Since the method effectively separates the drug from its degradation products, it can be used as a stability-indicating method.

Production of extended release mini-tablets using directly compressible grades of HPMC.

CONTEXT: Hypromellose (HPMC) has been previously used to control drug release from mini-tablets. However, owing to poor flow, production of mini-tablets containing high HPMC levels is challenging. Directly compressible (DC) HPMC grades have been developed by Dow Chemical Company. OBJECTIVE: To compare the properties of HPMC DC (METHOCEL™ K4M and K100M) with regular (REG) HPMC grades. METHOD: Particle size distribution and flowability of HPMC REG and DC were evaluated. 3 mm mini-tablets, containing hydrocortisone or theophylline as model drugs and 40% w/w HPMC DC or REG were produced. Mini-tablets containing HPMC DC grades were manufactured using a rotary press simulator at forces between 2-4 kN and speeds of 5, 10, 15 or 20 rpm. Mini-tablets containing HPMC REG were produced manually. RESULTS AND DISCUSSION: The improved flowability of HPMC DC grades, which have a narrower particle size distribution and larger particle sizes, meant that simulated large scale production of mini-tablets with good weight uniformity (CV 1.79-4.65%) was feasible. It was not possible to automatically manufacture mini-tablets containing HPMC REG due to the poor flowability of the formulations. Drug release from mini-tablets comprising HPMC DC and REG were comparable. Mini-tablets containing HPMC DC illustrated a higher tensile strength compared to mini-tablets made with HPMC REG. Mini-tablets produced with HPMC DC at different compression speeds had similar drug release profiles. CONCLUSIONS: Production of extended release mini-tablets was successfully achieved when HPMC DC was used. Drug release rate was not influenced by the different HPMC DC grades (K4M or K100M) or production speed.

Factors affecting the stability and performance of ipratropium bromide; fenoterol hydrobromide pressurized-metered dose inhalers.

The aim of the study was to investigate the factors affecting the stability and performance of ipratropium bromide and fenoterol hydrobromide in a pressurized-metered dose inhaler (pMDI). A factorial design was applied to investigate the effects of three parameters (propellant, water, and ethanol) on the performance of 27 designed formulations of a solution-based pMDI. The formulations that contained a hydrofluoroalkane (HFA) propellant lower than 72% v/v and an ethanol concentration higher than 27% v/v remained as clear solutions. Nine formulations that contained the HFA propellant higher than 74% v/v precipitated. The results indicated that it was not only the HFA propellant content of the formulations that was related to the formulation instability but also ethanol content. Only six formulations from the 18 formulations, that did not precipitate, produced drug contents that were within the acceptable range (80-120%). These six formulations generated aerosols with mass median aerodynamic diameters (MMAD) of approximately 2 µm with a fine particle fraction (FPF; particle size, <6.4 µm) between 45% and 52%. The MMAD and FPF did not change significantly after 6 months of storage (P > 0.05).

Stability and compatibility of doxofylline with phentolamine mesilate in 0.9% sodium chloride or 5% dextrose injection for intravenous infusion.

WHAT IS KNOWN AND OBJECTIVE: The use of extemporaneously prepared admixtures of drugs must be supported by documentation of their chemical stability. The objective was to assess the physical compatibility and the chemical stability of doxofylline with phentolamine mesilate in 0.9% sodium chloride or 5% dextrose injection for intravenous infusion. METHODS: Total volumes of 20 and 1 mL of doxofylline solution and phentolamine mesilate solution, respectively, were added to 250 mL polyolefin bags containing 5% dextrose injection or 0.9% sodium chloride injection. Bags were stored for 24 h at 20-25 °C. Chemical compatibility was measures with high-performance liquid chromatography, and physical compatibility was determined visually. RESULTS: The samples were clear and colourless when viewed in normal fluorescent room light. The pH value and particulate content of the admixtures exhibited little change. The retentions of the initial concentration of doxofylline and phentolamine mesilate in the admixtures were within 97-105%. Doxofylline and phentolamine mesilate were stable in 5% dextrose injection or in 0.9% sodium chloride for up to 24 h at 20-25 °C. WHAT IS NEW AND CONCLUSION: Doxofylline and phentolamine mesilate mixed in both 5% dextrose injection and 0.9% sodium chloride injection in 250 mL multilayer polyolefin bags at concentrations of 0.74 mg/mL and 36.9 µg/mL, respectively, were stable for up to 24 h at 20-25 °C.

Development and validation of a stability-indicating high-performance liquid chromatography method for the simultaneous determination of albuterol, budesonide, and ipratropium bromide in compounded nebulizer solutions.

In recent years, there has been a large increase in the use of pharmaceutical compounding to prepare medications that are not commercially available. The treatment of asthma typically includes the use of albuterol (ALB), ipratropium bromide (IPB), and/or budesonide (BUD) nebulizer solutions. There is currently no commercially available nebulizer solution containing all three of these compounds, and patients must rely on often-unregulated compounding. There is a distinct need for methodologies that can be used to analyze compounded formulations to ensure patient safety. We report an HPLC-UV method to separate and quantitate ALB, IPB, and BUD in nebulizer solutions. The method used a gradient elution to achieve separation via an RP C18 column. The method was validated, showed good selectivity, and was linear over several orders of magnitude. The method was applied to the analysis of nebulizer solutions and determination of their storage stability. Significant ALB-dependent degradation occurred within 5 h in solutions formulated with the free base of ALB, while those containing the sulfate salt of ALB produced no degradation. Alkali solutions can cause base-catalyzed hydrolysis of IPB and degradation of BUD. Compounded formulations containing ALB need to include an acid to control pH and prevent degradation.

An in vitro investigation into the release of fugitive medical aerosols into the environment during manual ventilation.

BACKGROUND: During manual resuscitation, nebulizer therapy may be used to deliver therapeutics to patients in respiratory distress. However, the devices used to generate and deliver these medical aerosols have the potential to release these therapeutics into the local environment and expose caregivers to unwanted medical aerosols. AIM: To quantify the levels of fugitive medical aerosol released into the environment during aerosol drug delivery using a manual resuscitation bag with and without filtration. METHODS: Time-varying fugitive aerosol concentrations were measured using an aerodynamic particle sizer placed at a position designed to mimic a caregiver. Two nebulizer types were assessed, a vibrating mesh nebulizer and a jet nebulizer. The aerosol dose delivered to the simulated patient lung was also quantified. FINDINGS: Filtration of the exhalation port of the manual resuscitation bag was seen to reduce fugitive medical aerosols to ambient levels for both nebulizer types. The vibrating mesh nebulizer delivered the greatest quantity of aerosol to the simulated adult patient (18.44 ± 1.03% versus 3.64 ± 0.26% with a jet nebulizer). CONCLUSIONS: The results highlight the potential for exposure to fugitive medical aerosols released during the delivery of aerosol therapy with a manual resuscitation bag and also the potential for significant variation in patient lung dose depending on nebulizer type.

Deposition of albuterol aerosol generated by pneumatic nebulizer in the Sophia Anatomical Infant Nose-Throat (SAINT) model.

PURPOSE: To quantify distribution of albuterol aerosol generated by a pneumatic nebulizer within the nose and lungs of a model of a 9-month-old child (SAINT) and aerosol loss to the environment, during simulated breathing at increasing tidal volumes (TVs). METHODS: (99m)technetium-labeled albuterol aerosol was generated by an IPI nebulizer with face-mask. Deposition was quantified as a percentage of emitted dose using gamma scintigraphy. RESULTS: Lung deposition was similar for all TVs, averaging 7.17 +/- 0.01%, 9.34 +/- 0.01% and 9.41 +/- 0.02% at 50, 100 and 200 mL TV, respectively. In contrast, nose deposition increased significantly with TV, averaging 4.40 +/- 0.02%, 11.39 +/- 0.02% and 22.12 +/- 0.02% at 50 mL, 100 mL and 200 mL TV, respectively (all p < 0.0167). Aerosol loss to the environment was significantly lower at 200 mL TV (53.81 +/- 0.04%), compared to 50 mL (71.99 +/- 0.02%) (p < 0.0167). CONCLUSIONS: Our results suggest that nasal deposition of albuterol aerosol generated by a pneumatic nebulizer in 9-month-old infants may be significantly affected by changes in TV, ranging between 50 to 200 mL, whereas total lung deposition may not be affected. These results also predict that environmental losses would be highest when administering to a child breathing at 50 mL TV. These data should be useful to companies who are working to improve aerosol delivery systems to treat infants.

Pharmacological basis for the medicinal use of Zanthoxylum armatum in gut, airways and cardiovascular disorders.

This study describes the gut, airways and cardiovascular modulatory activities of Zanthoxylum armatum DC. (Rutaceae) to rationalize some of its medicinal uses. The crude extract of Zanthoxylum armatum (Za.Cr) caused concentration-dependent relaxation of spontaneous and high K(+) (80 mM)-induced contractions in isolated rabbit jejunum, being more effective against K(+) and suggestive of Ca(++) antagonist effect, which was confirmed when pretreatment of the tissues with Za.Cr shifted Ca(++) concentration-response curves to the right, like that caused by verapamil. Za.Cr inhibited the castor-oil-induced diarrhea in mice at 300-1000 mg/kg. In rabbit tracheal preparations, Za.Cr relaxed the carbachol (1 microM) and high K(+)-induced contractions, in a pattern similar to that of verapamil. In isolated rabbit aortic rings, Za.Cr exhibited vasodilator effect against phenylephrine (1 microM) and K(+)-induced contractions. When tested in guinea pig atria, Za.Cr caused inhibition of both atrial force and rate of spontaneous contractions, like that caused by verapamil. These results indicate that Zanthoxylum armatum exhibits spasmolytic effects, mediated possibly through Ca(++) antagonist mechanism, which provides pharmacological base for its medicinal use in the gastrointestinal, respiratory and cardiovascular disorders.

Carbomer-modified spray-dried respirable powders for pulmonary delivery of salbutamol sulphate.

The present study investigates the feasibility of using two types of carbomer (971 and 974) to prepare inhalable dry powders that exhibit modified drug release properties. Powders were prepared by spray-drying formulations containing salbutamol sulphate, 20-50% w/w carbomer as a drug release modifier and leucine as an aerosolization enhancer. Following physical characterization of the powders, the aerosolization and dissolution properties of the powders were investigated using a Multi-Stage Liquid Impinger and a modified USP II dissolution apparatus, respectively. All carbomer 974-modified powders and the 20% carbomer 971 powder demonstrated high dispersibility, with emitted doses of at least 80% and fine particle fractions of approximately 40%. The release data indicated that all carbomer-modified powders displayed a sustained release profile, with carbomer 971-modified powders obeying first order kinetics, whereas carbomer 974-modified powders obeyed the Higuchi root time kinetic model; increasing the amount of carbomer 971 in the formulation did not extend the duration of drug release, whereas this was observed for the carbomer 974-modified powders. These powders would be anticipated to deposit predominately in the lower regions of the lung following inhalation and then undergo delayed rather than instantaneous drug release, offering the potential to reduce dosing frequency and improve patient compliance.

Bilinear and trilinear algorithms utilizing full and selected variables for resolution and quantitation of four components with overlapped spectral signals in bulk and syrup dosage form.

Spectrophotometric-assisted chemometric techniques are beneficial for resolving spectral overlapping and are considered comparable to traditional chromatographic methods. In this work, different chemometric approaches were applied for simultaneous determination of Bromhexine HCl (BRHX), Guaifenesin (GUA) and Salbutamol sulphate (SALB) in the presence of Guaiacol (GUAIA), without any prior separation. Two-way and three-way techniques were applied. The resolving power of genetic algorithm (GA-PLS), trilinear partial least square (N-PLS) and multivariate curve resolution (MCR-ALS) were investigated. A set of 17 synthetic samples in the concentration range 10.0-30.0 µg/mL of BRHX, GUA and SALB and 6.0-10.0 µg/mL of GUAIA were used in the construction of the calibration models. Commercially available syrup dosage form was successfully analyzed by the developed methods without interference from formulation additives. The developed models were evaluated through calculation of root mean squared error of prediction (RMSEP), the obtained values were 0.263, 0.419 and 0.342 for BRHX, 0.254, 0.318 and 0.503 for GUA and 0.298, 0.268 and 0.302 for SALB using N-PLS, MCR-ALS and GA-PLS, respectively. The resolving power of the developed models was emphasized through comparison with a reported HPLC method, where no significant difference was found regarding both accuracy and precision.

Albuterol Delivery Efficiency in a Pediatric Model of Noninvasive Ventilation With a Single-Limb Circuit.

BACKGROUND: Pediatric patients treated with noninvasive ventilation (NIV) are frequently given aerosol therapy. Limited pediatric data are available on the efficiency of aerosol delivery efficiency. We evaluated the effect of different nebulizers, positions in the single-limb ventilator circuit, and ventilator settings on the efficiency of aerosol delivery in a model of pediatric NIV. We hypothesized that using a vibrating mesh nebulizer, placing the nebulizer after the circuit leak, and not using the highest inspiratory positive airway pressure would increase aerosol delivery efficiency. METHODS: We connected a breathing simulator in series to a low-dead-space filter holder (lung dose) and to an anatomically correct face/airway model of a 5-y-old child. A mask with an entrainment elbow was connected to a ventilator operated in a NIV bi-level mode and assembled with a single-limb heated-wired circuit. Inspiratory/expiratory pressures of either 15/5 or 20/5 cm H2O were used. We studied 3 different jet nebulizers and 2 vibrating mesh nebulizers loaded with albuterol solution (2.5 mg/3 mL). Albuterol was measured with spectrophotometry. The outcome measure was the efficiency of aerosol delivery (ie, lung dose expressed as percentage of the nominal dose). RESULTS: Vibrating mesh nebulizers placed after the exhalation port of the circuit had the highest delivery efficiency, even compared with a vibrating mesh nebulizer integrated into the mask. Placing the nebulizer after the exhalation port of the circuit increased efficiency for all nebulizers. Vibrating mesh nebulizers were more efficient than jet nebulizers, regardless of their position in the circuit. Increasing the inspiratory pressure resulted in a variable effect on aerosol-delivery efficiency. CONCLUSIONS: In a model of pediatric NIV using a single-limb circuit, aerosol delivery devices were more efficient when placed after the exhalation port of the ventilator circuit. Vibrating mesh nebulizers were more efficient than jet nebulizers.