Canister valve and actuator deposition in metered dose inhalers formulated with low-GWP propellants.

A challenge in pressurised metered-dose inhaler (pMDI) formulation design is management of adhesion of the drug to the canister wall, valve and actuator internal components and surfaces. Wall-material interactions differ between transparent vials used for visual inspection and metal canister pMDI systems. This is of particular concern for low greenhouse warming potential (GWP) formulations where propellant chemistry and solubility with many drugs are not well understood. In this study, we demonstrate a novel application of X-ray fluorescence spectroscopy using synchrotron radiation to assay the contents of surrogate solution and suspension pMDI formulations of potassium iodide and barium sulphate in propellants HFA134a, HFA152a and HFO1234ze(E) using aluminium canisters and standard components. Preliminary results indicate that through unit life drug distribution in the canister valve closure region and actuator can vary significantly with new propellants. For solution formulations HFO1234ze(E) propellant shows the greatest increase in local deposition inside the canister valve closure region as compared to HFA134a and HFA152a, with correspondingly reduced actuator deposition. This is likely driven by chemistry changes. For suspension formulations HFA152a shows the greatest differences, due to its low specific gravity. These changes must be taken into consideration in the development of products utilising low-GWP propellants.

Metered dose inhalers in the transition to low GWP propellants: what we know and what is missing to make it happen.

INTRODUCTION: The urgency to replace the propellants currently in use with the new sustainable ones has given rise to the need for investigation and reformulation of pMDIs. AREAS COVERED: The reformulation requires in-depth knowledge of the physico-chemical characteristics of the new propellants, which impact the atomization capacity and the plume geometry. Among the investigated propellants, HFA 152a, due to its lower vapor pressure and higher surface tension compared to HFA 134a, deliver larger particles and has a higher solvent capacity toward lipophilic drugs. On the other hand, HFO 1234ze has properties more similar to HFA 134a, but showed lower reproducibility of the generated spray, indicating a possible high susceptibility to variation in the consistency of the dose delivered. In addition, the device components currently in use are compatible with the new propellants. This allowed promising preliminary results in the re-formulation of pMDIs by academia and pharma companies. However, there is little information about the clinical studies required to allow the marketing of these new products. EXPERT OPINION: Overall, studies conducted so far show that the transition is technically possible, and the main obstacle will be represented by the investment required to put the product on the market.

Pharmacokinetic Study of Epinephrine Hydrofluoroalkane (Primatene MIST) Metered-Dose Inhaler.

Background: Primatene® MIST CFC, an epinephrine metered-dose inhaler (MDI), was discontinued from the market owing to environmental concerns from its use of chlorofluorocarbon (CFC) propellant. As a result, a new epinephrine MDI was developed using hydrofluoroalkane (HFA) propellant. This article reports the pharmacokinetic (PK) profile of the newly Food and Drug Administration-approved epinephrine HFA MDI. Methods: A randomized, evaluator-blinded, active-controlled, single-dose, two-arm crossover study was conducted to evaluate the PK profile of epinephrine HFA (Primatene® MIST) and epinephrine CFC (Primatene® MIST CFC) in 23 healthy volunteers to characterize the epinephrine absorption extent and rate. The study was performed at a high dose of five times the normal dose to obtain measurable plasma epinephrine levels. Plasma epinephrine levels were measured and safety was assessed by adverse events (AEs), vital signs, clinical laboratory tests, and physical examinations. Results: Epinephrine HFA demonstrated a greater systemic drug exposure (greater area under the curve) than that of epinephrine CFC (∼37% higher). The Cmax occurred at ∼2 minutes and was significantly higher in the epinephrine HFA group (0.18 ng/mL) compared with the CFC version (0.046 ng/mL) at normal dose. Within 20 minutes, both groups demonstrated comparable plasma epinephrine levels. No clinically significant adverse effects were found to be associated with epinephrine HFA, even after an ultrahigh dose (i.e., 10 inhalations). Conclusions: The systemic exposure of epinephrine HFA was found to be higher for the first 20 minutes, and then comparable with epinephrine CFC. Minimal AEs were found in this study despite the very high 1250-2200 µg inhaled doses (i.e., 10 inhalations) used for PK characterization.

A Dose-Ranging Study of Epinephrine Hydrofluroalkane Metered-Dose Inhaler (Primatene® MIST) in Subjects with Intermittent or Mild-to-Moderate Persistent Asthma.

Background: Two sequential single-dose crossover dose-ranging studies were performed to evaluate the clinical efficacy and safety profile of epinephrine hydrofluroalkane (HFA) metered-dose inhaler (MDI) formulation at various doses in subjects with asthma. Methods: In these multicenter, multiarm, double-blinded, or evaluator-blinded studies, subjects were randomized to receive the epinephrine HFA (Primatene® MIST HFA) MDI medication at doses ranging from 90 to 440 µg/dose, as well as to a placebo (PLA) control and an active control of epinephrine CFC (chlorofluorocarbon) MDI (Primatene® MIST CFC) at 220 µg/inhalation. Results: Spirometry testing for FEV1 (Forced Expiratory Volume in one second) demonstrated statistically significant improvements over PLA for epinephrine HFA MDI at all doses above 125 µg, as the amount out of the actuator (i.e., mouthpiece). The efficacy results for epinephrine HFA MDI in the dose range of 125-250 µg were also comparable to epinephrine CFC MDI (220 µg/inh). Safety assessments demonstrated minimal safety concerns for all treatment groups. No notable safety differences were observed between the studied doses of epinephrine HFA MDI and the active control formulation of epinephrine CFC MDI. Conclusion: The findings indicate that epinephrine HFA MDI provided clinically significant bronchodilator efficacy with minimal safety concerns in a dose range of 125-250 µg. These findings confirmed the optimal treatment doses of 125-250 µg that were appropriate for use in longer term 12 and 26 week chronic dosing studies of epinephrine HFA MDI for patients with intermittent or mild to moderate persistent asthma. Clinical trials registration number: NCT01025648.

Drug distribution transients in solution and suspension-based pressurised metered dose inhaler sprays.

This paper presents in situ time-resolved drug mass fraction measurements in pressurised metered dose inhaler (PMDI) sprays, using a novel combination of synchrotron X-ray fluorescence and scattering. Equivalent suspension and solution formulations of ipratropium bromide in HFA-134a propellant were considered. Measurements were made both inside the expansion chamber behind the nozzle orifice, and in the first few millimeters of the spray where droplet and particle formation occur. We observed a consistent spike in drug mass fraction at the beginning of the spray when the first fluid exits the nozzle orifice. Approximately 20% of the total delivered dose exits the nozzle in the first 0.1 s of the spray. The drug mass fraction in the droplets immediately upon exiting the nozzle peaked at approximately 50% of the canister mass fraction, asymptoting to approximately 20% of the canister concentration. The effect is due to a change in the drug mass fraction inside the droplets, rather than changes in droplet size or distribution. The transient was found to originate inside the expansion chamber. We propose that this effect may be a major contributor to low delivery efficiency in PMDIs, and have important implications for oropharyngeal deposition and inhalation technique. This highlights the importance of expansion chamber and nozzle design on the structure of PMDI sprays, and indicates areas of focus that may lead to improvement in drug delivery outcomes.

Particle Surface Roughness Improves Colloidal Stability of Pressurized Pharmaceutical Suspensions.

PURPOSE: The effects of particle size and particle surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were investigated using monodisperse spray-dried particles. METHODS: The colloidal stability of multiple suspensions in the propellant HFA227ea was characterized using a shadowgraphic imaging technique and quantitatively compared using an instability index. Model suspensions of monodisperse spray-dried trehalose particles of narrow distributions (GSD < 1.2) and different sizes (MMAD = 5.98 µm, 10.1 µm, 15.5 µm) were measured first to study the dependence of colloidal stability on particle size. Particles with different surface rugosity were then designed by adding different fractions of trileucine, a shell former, and their suspension stability measured to further study the effects of surface roughness on the colloidal stability of pressurized suspensions. RESULTS: The colloidal stability significantly improved (p < 0.001) from the suspension with 15.5 µm-particles to the suspension with 5.98 µm-particles as quantified by the decreased instability index from 0.63 ± 0.04 to 0.07 ± 0.01, demonstrating a strongly size-dependent colloidal stability. No significant improvement of suspension stability (p > 0.1) was observed at low trileucine fraction at 0.4 % where particles remained relatively smooth until the surface rugosity of the particles was improved by the higher trileucine fractions at 1.0 % and 5.0 %, which was indicated by the substantially decreased instability index from 0.27 ± 0.02 for the suspensions with trehalose model particles to 0.18 ± 0.01 (p < 0.01) and 0.03 ± 0.01 (p < 0.002) respectively. CONCLUSIONS: Surface modification of particles by adding shell formers like trileucine to the feed solutions of spray drying was demonstrated to be a promising method of improving the colloidal stability of pharmaceutical suspensions in pressurized metered dose inhalers.

Characterization of the suspension stability of pharmaceuticals using a shadowgraphic imaging method.

A new shadowgraphic imaging method and an associated instrument for analyzing the physical stability of pharmaceutical suspensions are introduced in this paper. The new suspension tester consists mainly of a high-resolution camera that takes sequential shadowgraphic images of emulsions or suspensions and a 2D collimated LED for simultaneous whole-sample illumination in bright field. A built-in ultrasonic bath provides controlled initial agitation to the samples of interest. Sequential images acquired by the experimental setup were used to derive normalized transmission profiles from which an instability index was developed for quantitative stability comparison between samples. Instrument performance was verified by measuring the stability of a series of oil-in-water emulsions prepared with surfactant mixtures of different ratios. The new instrument correctly determined the required hydrophilic-lipophilic balance for sunflower oil to be 7.0. The stability of a pressurized suspension of spray dried lipid (DSPC) particles was monitored for 5 days after propellant filling. Although stable for the first 24 h, the lipid suspension was found to decrease in stability from day 1 to day 4. Morphological and spectroscopic analysis revealed that the suspended DSPC particles had reformed into large thin sheets of lipid, thereby causing the gradual stability decrease during the aging study. The effects of initial agitation on the stability of suspensions were demonstrated by agitating a suspension of micronized fluticasone propionate in propellant using a wrist action shaker and an ultrasonic bath respectively. A significant improvement of suspension stability was achieved by replacing the wrist action shaker method with ultrasonic agitation. Simultaneous illumination of the complete suspension, a high image acquisition rate, and controlled initial agitation are features that make this new suspension tester a suitable and more reliable instrument for investigating the stability of pressurized pharmaceutical suspensions.

Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography.

PURPOSE: Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques. METHODS: We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays. RESULTS: Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 µm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow. CONCLUSIONS: Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.

Effects of Emulsion Composition on Pulmonary Tobramycin Delivery During Antibacterial Perfluorocarbon Ventilation.

BACKGROUND: The effectiveness of inhaled aerosolized antibiotics is limited by poor ventilation of infected airways. Pulmonary delivery of antibiotics emulsified within liquid perfluorocarbon [antibacterial perfluorocarbon ventilation (APV)] may solve this problem through better airway penetration and improved spatial uniformity. However, little work has been done to explore emulsion formulation and the corresponding effects on drug delivery during APV. This study investigated the effects of emulsion formulation on emulsion stability and the pharmacokinetics of antibiotic delivery via APV. METHODS: Gravity-driven phase separation was examined in vitro by measuring emulsion tobramycin concentrations at varying heights within a column of emulsion over 4 hours for varying values of fluorosurfactant concentration (Cfs = 5-48 mg/mL H2O). Serum and pulmonary tobramycin concentrations in rats were then evaluated following pulmonary tobramycin delivery via aerosol or APV utilizing sufficiently stable emulsions of varying aqueous volume percentage (Vaq = 1%-5%), aqueous tobramycin concentration (Ct = 20-100 mg/mL), and Cfs (15 and 48 mg/mL H2O). RESULTS: In vitro assessment showed sufficient spatial and temporal uniformity of tobramycin dispersion within emulsion for Cfs ≥15 mg/mL H2O, while lower Cfs values showed insufficient emulsification even immediately following preparation. APV with stable emulsion formulations resulted in 5-22 times greater pulmonary tobramycin concentrations at 4 hours post-delivery relative to aerosolized delivery. Concentrations increased with emulsion formulations utilizing increased Vaq (with decreased Ct) and, to a lesser extent, increased Cfs. CONCLUSIONS: The emulsion stability necessary for effective delivery is retained at Cfs values as low as 15 mg/mL H2O. Additionally, the pulmonary retention of antibiotic delivered via APV is significantly greater than that of aerosolized delivery and can be most effectively increased by increasing Vaq and decreasing Ct. APV has been further proven as an effective means of pulmonary drug delivery with the potential to significantly improve antibiotic therapy for lung disease patients.

Temporally and Spatially Resolved x-ray Fluorescence Measurements of in-situ Drug Concentration in Metered-Dose Inhaler Sprays.

PURPOSE: Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution. METHODS: In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 [Formula: see text] / [Formula: see text] IPBr. RESULTS: Instantaneous concentration measurements were obtained with 1 ms temporal resolution and 5 [Formula: see text] spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo. CONCLUSIONS: Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.

Respiratory Tract Deposition of HFA-Beclomethasone and HFA-Fluticasone in Asthmatic Patients.

BACKGROUND: The asthmatic patient's respiratory tract deposition of HFA fluticasone (Flovent HFA(™)) has not been established. There is a known large particle size difference with another commercial inhaled HFA steroid (QVAR(™)). This study compared the 2D and 3D respiratory tract deposition of each inhaled steroid. METHODS: This study was an open label, crossover study in eight patients diagnosed with asthma. The regional respiratory and oropharyngeal deposition of the two steroids were compared and contrasted using planar and SPECT imaging following delivery of the (99m)Tc-radiolabeled drug in each product. The SPECT images were merged with computed tomography images to quantify regional deposition within the patients. RESULTS: Two-dimensional (2D) planar images indicated that 24% of the Flovent HFA dose and 55% of the QVAR dose deposited in the lungs. 2D oropharyngeal deposition indicated that 75% of the Flovent HFA dose was deposited in the oropharynx, while 42% of the QVAR dose deposited in the oropharynx. Three-dimensional (3D) SPECT data indicated that 22% of the Flovent HFA dose and 53% of the QVAR dose deposited in the lungs. 3D oropharyngeal and gut deposition indicated 78% of the Flovent HFA dose was deposited in the oropharynx, while 47% of the QVAR dose deposited in the oropharynx. The increased lung deposition and decreased oropharynx deposition for both 2D and 3D image data of QVAR were statistically different from Flovent HFA. CONCLUSIONS: QVAR exhibited a significant increase in lung delivery compared to Flovent HFA. Conversely, QVAR delivered a significantly lower dose to the oropharynx than Flovent HFA. The findings were presumed to be driven by the smaller particle size of QVAR (0.7 microns MMAD) compared with Flovent HFA (2.0 microns MMAD).

A Review of Methods for Evaluating Particle Stability in Suspension Based Pressurized Metered Dose Inhalers.

Advances in particle engineering techniques, such as spray drying, freeze drying and supercritical fluid precipitation, have greatly enhanced the ability to control the structure, morphology, and solid state phase of inhalable sized particles (1 - 5 µm) for formulation in pressurized metered dose inhalers (pMDI). To optimize the properties of these engineered particles for formulation in hydrofluoroalkane propellants (HFA 134a / 227) it is necessary to measure both bulk and individual particle properties before, after, and during formulation. This review examines established and recently developed methods for evaluating a variety of particle properties including but not limited to size, surface and internal morphology, chemical composition, and solid state phase. Novel methods for evaluating particle physical and chemical stability directly in propellant or similar environments are also discussed.

Quantification of Aerosol Hydrofluoroalkane HFA-134a Elimination in the Exhaled Human Breath Following Inhaled Corticosteroids Administration.

Inhaled corticosteroids (ICS) and ß2-agonists are the primary pharmacotherapies of asthma management. However, suboptimal medication compliance is common in asthmatics and is associated with increased morbidity. We hypothesized that exhaled breath measurements of the aerosol used in the inhaled medications might prove useful as surrogate marker for asthma medication compliance. To explore this, 10 healthy controls were recruited and randomly assigned to ICS (Flovent HFA) or short acting bronchodilators (Proventil HFA). Both inhalers contain HFA-134a as aerosol propellant. Exhaled breath sampling and pulmonary function tests were performed prior to the inhaler medication dispersion, immediately after inhalation, then at 2, 4, 6, 8, 24, and 48 hours postadministration. At baseline, mean (SD) levels of HFA-134a in the breath were 252 (156) pptv. Immediately after inhalation, HFA-134a breath levels increased to 300 × 10(6) pptv and were still well above ambient levels 24 hours postadministration. The calculated ratio of forced expiratory volume in 1 second over forced vital capacity did not change over time following inhaler administration. This study demonstrates, for the first time, that breath HFA-134a levels can be used to assess inhaler medication compliance. It may also be used to evaluate how effectively the medicine is delivered.

Plume Characteristics of Two HFA-Driven Inhaled Corticosteroid/Long-Acting Beta2-Agonist Combination Pressurized Metered-Dose Inhalers.

INTRODUCTION: New inhalers propelled by hydrofluoroalkanes (HFAs) have improved plume characteristics: higher fine particle fraction, and warmer plumes with reduced force and velocity. Together, this may avoid reflex interruption of inhalation and improve lung deposition of the inhaled drugs. However, even with HFA-propelled pressurized metered-dose inhalers (pMDIs), there are notable differences in device properties. Here we compared the duration, velocity, force, and temperature of two inhaled corticosteroid/long-acting ß2-agonist combination therapies, administered via HFA pMDIs: fluticasone propionate/formoterol 125/5 µg (FP/FORM; flutiform(®)) and fluticasone propionate/salmeterol 125/25 µg (FP/SAL; Seretide(®) Evohaler(®)). METHODS: Inhalers were fired into ambient air. Plume duration and velocity were recorded with a high-speed camera and a pulsed laser light source. A copper disc attached to a sensitive load cell measured the plume force at various distances from the device. A thermal imaging video camera recorded impaction temperature in line with the device. RESULTS: The average plume duration for FP/FORM was longer than that of FP/SAL: 168.3 vs. 114.0 ms, respectively. The mean maximum plume velocities observed at 95 mm (the approximate distance between mouthpiece and throat) was consistently slower for FP/FORM (10.08 m/s) compared to FP/SAL (15.55 m/s). FP/FORM had a slower velocity at the outset, remaining relatively constant before declining steadily over the plume duration. The force of the FP/SAL plume was greater than that of FP/FORM at all distances: maximum force for FP/FORM was 138.2 vs. 278.9 mN for FP/SAL. The minimum impaction temperature was +5.9 °C for FP/FORM and -37.8 °C for FP/SAL; this difference became less pronounced over distance. CONCLUSION: There were substantial differences between the plumes of the two pMDIs. FP/FORM was warmer, less forceful, had a longer plume duration and slower maximal velocity. These plume characteristics of FP/FORM may lead to improved lung deposition. FUNDING: Mundipharma Research Limited, Cambridge, UK.

The formulation of a pressurized metered dose inhaler containing theophylline for inhalation.

BACKGROUND: Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use. This study aims to improve COPD treatment by creating a low-dose pressurized metered dose inhaler (pMDI) inhalable formulation of TP. METHODS: Aerosol performance was assessed using Andersen Cascade Impaction (ACI). Solubility of TP in HFA 134/ethanol mixture was measured and morphology of the particles analyzed with a scanning electron microscope (SEM). Calu-3 cell viability, epithelial cell transport and inflammatory-response assays were conducted to study the impact of the formulation on lung epithelial cells. RESULTS: The mass deposition profile of the formulation showed an emitted dose of 250.04±14.48µg per 5 actuations, achieving the designed nominal dose (50µg/dose). SEM showed that the emitted particles were hollow with spherical morphology. Approximately 98% of TP was transported across Calu-3 epithelial cells and the concentration of interleukin-8 secreted from Calu-3 cells following stimulation with tissue necrosis factor-α (TNF-α) resulted in significantly lower level of interleukin-8 released from the cells pre-treated with TP (1.92±0.77ng·ml(-1) TP treated vs. 8.83±2.05ng·ml(-1) TNF-α stimulated, respectively). CONCLUSIONS: The solution pMDI formulation of TP developed in present study was shown to be suitable for inhalation and demonstrated anti-inflammatory effects at low doses in Calu-3 cell model.

Pervaporation performance of PPO membranes in dehydration of highly hazardous mmh and udmh liquid propellants.

Polyphenylene oxide (PPO) membranes synthesized from 2,6-dimethyl phenol monomer were subjected to pervaporation-based dehydration of the highly hazardous and hypergolic monomethyl hydrazine (MMH) and unsymmetrical dimethyl hydrazine (UDMH) liquid propellants. Membranes were characterized by TGA, DSC and SEM to study the effect of temperature besides morphologies of surface and cross-section of the films, respectively. Molecular dynamics (MD) simulation was used to study the diffusion behavior of solutions within the membrane. CFD method was employed to solve the governing mass transfer equations by considering the flux coupling. The modeling results were highlighted by the experimental data and were in good agreement. High separation factors (35-70) and reasonable water fluxes (0.1-0.2 kg/m(2)h) were observed for separation of the aqueous azeotropes of MMH (35 wt%) and UDMH (20 wt%) and their further enrichment to >90% purity. Effect of feed composition, membrane thickness and permeate pressure on separation performance of PPO membranes were investigated to determine optimum operating conditions.

The effect of actuator nozzle designs on the electrostatic charge generated in pressurised metered dose inhaler aerosols.

PURPOSE: To investigate the influence of different actuator nozzle designs on aerosol electrostatic charges and aerosol performances for pressurised metered dose inhalers (pMDIs). METHODS: Four actuator nozzle designs (flat, curved flat, cone and curved cone) were manufactured using insulating thermoplastics (PET and PTFE) and conducting metal (aluminium) materials. Aerosol electrostatic profiles of solution pMDI formulations containing propellant HFA 134a with different ethanol concentration and/or model drug beclomethasone dipropionate (BDP) were studied using a modified electrical low-pressure impactor (ELPI) for all actuator designs and materials. The mass of the deposited drug was analysed using high performance liquid chromatography (HPLC). RESULTS: Both curved nozzle designs for insulating PET and PTFE actuators significantly influenced aerosol electrostatics and aerosol performance compared with conducting aluminium actuator, where reversed charge polarity and higher throat deposition were observed with pMDI formulation containing BDP. Results are likely due to the changes in plume geometry caused by the curved edge nozzle designs and the bipolar charging nature of insulating materials. CONCLUSIONS: This study demonstrated that actuator nozzle designs could significantly influence the electrostatic charges profiles and aerosol drug deposition pattern of pMDI aerosols, especially when using insulating thermoplastic materials where bipolar charging is more dominant.

Developing an in vitro understanding of patient experience with hydrofluoroalkane-metered dose inhalers.

As a result of the Montreal Protocol on Substances that Deplete the Ozone Layer, manufacturers of metered dose inhalers began reformulating their products to use hydrofluoroalkanes (HFAs) as propellants in place of chlorofluorocarbons (CFCs). Although the new products are considered safe and efficacious by the US Food and Drug Administration (FDA), a large number of complaints have been registered via the FDA's Adverse Events Reporting System (FAERS)-more than 7000 as of May 2013. To develop a better understanding of the measurable parameters that may, in part, determine in vitro performance and thus patient compliance, we compared several CFC- and HFA-based products with respect to their aerodynamic performance in response to changes in actuator cleaning interval and interactuation delay interval. Comparison metrics examined in this study were: total drug delivered ex-actuator, fine particle dose (<5 µm), mass median aerodynamic diameter, plume width, plume temperature, plume impaction force, and actuator orifice diameter. Overall, no single metric or test condition distinguishes HFA products from CFC products, but, for individual products tested, there were a combination of metrics that differentiated one from another.

Predicting physical stability in pressurized metered dose inhalers via dwell and instantaneous force colloidal probe microscopy.

Colloidal probe microscopy (CPM) is a quantitative predictive tool, which can offer insight into particle behavior in suspension pressurized metered dose inhalers (pMDIs). Although CPM instantaneous force measurements, which involve immediate retraction of the probe upon sample contact, can provide information on inter-particle attractive forces, they lack the ability to appropriately imitate all critical particle pMDI interactions (e.g., particle re-dispersion after prolonged pMDI storage). In this paper, two novel dwell force techniques - indentation and deflection dwell - were employed to mimic long-term particle interactions present in pMDIs, using particles of various internal structures and a model liquid propellant (2H,3H perfluoropentane) as a model system. Dwell measurements involve particle contact for an extended period of time. In deflection dwell mode the probe is held at a specific position, while in indentation dwell mode the probe is forced into the sample with a constant force for the entirety of the contact time. To evaluate the applicability of CPM to predict actual pMDI physical stability, inter-particle force measurements were compared with qualitative and quantitative bulk pMDI measurement techniques (visual quality and light scattering). Measured instantaneous attractive (snap-in) and adhesive (max-pull) forces decreased as a function of increasing surface area, while adhesive forces measured by indentation dwell decreased as a function of dwell contact time for particles containing voids. Instantaneous force measurements provided information on the likelihood of floccule formation, which was predictive of partitioning rates, while indentation dwell force measurements were predictive of formulation re-dispersibility after prolonged storage. Dwell force measurements provide additional information on particle behavior within a pMDI not obtainable via instantaneous measurements.