Analytical Methods for Stability Assessment of Nitrate Esters-Based Propellants.

Nitrate esters-based propellant (NEBP) belongs to the main classes of energetic materials being used in civilian and military applications. These NEBPs are not highly stable, and during aging, some of their functional characteristics may change, what can lead to serious safety problems. A thorough analytical characterization of NEBP is of fundamental importance to provide an adequate support for their stability and safe life assessment. Moreover, in order to safely store and fully exploit these energetic materials, accurate analytical techniques and strategies are indispensable to efficiently judge their properties during aging. Although various methodologies have been developed worldwide to evaluate the aging behavior of NEBP, the characterization is not a simple task and often involves the combination of several techniques, whose results have to be evaluated together. This review sought to evaluate existing analytical techniques which can be utilized for a suitable analysis of NEBP stability and aging, evidencing their respective advantages and shortcomings. The employment of each examined technique is described and discussed by relevant examples from the literature.

The application of "in-flight" laser diffraction to the particle size characterization of a model suspension metered dose inhaler.

Laser diffraction (LD) has been used to measure the particle size of pharmaceutical aerosols. In this study, the application of LD for measuring the particle size of a model suspension metered dose inhaler (MDI) containing a hydrofluorocarbon propellant was investigated using a Sympatec LD apparatus with an automatic spray device. In order to obtain meaningful results, test parameters such as spray distance and temperature needed to be optimized for this model formulation and then well-controlled during testing. Using a suitable LD test methodology, it was found that particle size variations as a function of nonvolatile excipient levels as well as changes to the suspended drug substance could be observed and, in some cases, correlated to cascade impaction results. Based on these studies, it is believed that the methodology is a valuable rapid screening tool for investigating variations in or permutations to suspension MDI formulations. Nonetheless, the trends in the LD droplet size are complicated by the presence of drug-free droplets. Consequently, the results are not always consistent with other particle sizing techniques such as cascade impaction in which the droplets associated with drug are evaluated. Therefore, for suspension MDIs, the "in-flight" LD method would probably best be utilized as a complementary sizing technique during formulation development.

Characterisation of polycyclic aromatic hydrocarbons in atmospheric aerosols by gas chromatography-mass spectrometry.

An accurate and reliable method for determining polycyclic aromatic hydrocarbons (PAHs) in atmospheric aerosols is described. This optimised gas chromatography-mass spectrometry (GC-MS) method permits a wide range of concentrations to be analysed without the influence of interferences. Pre-treatment comparison of four kinds of aerosol collector filters determined that quartz and glass fibre filters were the most suitable. Solvents like cyclohexane, toluene, acetonitrile and dichloromethane were evaluated for their PAH-extraction capacity. Ultrasonic extraction using CH2Cl2 was selected because it is rapid and easy; moreover, this solvent increases the sample-throughput capacity. PAH compounds were quantitatively collected and ultrasonically extracted twice using 15 mL of CH2Cl2 for 15 min for each replicate. Rotavapor concentration, fractionation and dissolution were also optimised. A certified standard mixture (16 EPA PAHs), a deuterated compound and precision recovery assays were used for validating the proposed methodology. Adequate analytical parameters were obtained. Detection limits were (1.6-26.3) x 10(-5) ng and quantification limits were (5.2-87.6) x 10(-5) ng. Analysis of the environmental samples detected 4-10 EPA list PAH compounds. In addition, 2-11 tentative compounds were found, and their molecular structures were described for the first time. Our study of both Youden method and the standard addition method has shown that the proposed determination of PAHs in environmental samples is free of systematic errors. In conclusion, this unbiased methodology improves the identification and quantification of PAH compounds. High sensitivity as well as acceptable detection and quantification limits were obtained for the environmental applications.

The importance of nonelectrostatic materials in holding chambers for delivery of hydrofluoroalkane albuterol.

INTRODUCTION: Electrostatic attraction of aerosolized particles to the inner walls of an aerosol holding chamber (HC) made from a nonconducting material can reduce medication delivery, particularly if there is a delay between actuation and inhalation. OBJECTIVE: Compare total emitted mass and fine-particle mass (mass of particles < 4.7 microm) of hydrofluoroalkane-propelled albuterol from similar-sized HCs manufactured from conductive material (Vortex), charge-dissipative material (AeroChamber Max), and nonconductive material (OptiChamber Advantage, ProChamber, Breathrite, PocketChamber, and ACE), with and without wash/rinse pretreatment of the HC interior with ionic detergent, and with 2-s and 5-s delays between actuation and inhalation. METHODS: All the HCs were evaluated (1) directly from their packaging (with no wash/rinse pretreatment) and (2) after washing with ionic detergent and rinsing and drip-drying. We used an apparatus that interfaced between the HC mouthpiece and the induction port of an 8-stage Andersen cascade impactor to simulate a poorly coordinated patient, with delays of 2 s and 5 s between actuation and inhalation/sampling, at 28.3 L/min. RESULTS: With the 2-s delay, the delivered fine-particle mass per actuation, before and after (respectively) wash/rinse pretreatment was: AeroChamber Max: 23.8 +/- 4.8 microg, 21.5 +/- 3.2 microg; Vortex: 16.2 +/- 1.7 microg, 15.5 +/- 2.0 microg; OptiChamber Advantage: 2.6 +/- 1.2 microg, 6.7 +/- 2.3 microg; ProChamber: 1.6 +/- 0.4 microg, 5.1 +/- 2.5 microg; Breathrite: 2.0 +/- 0.9 microg, 3.2 +/- 1.8 microg; PocketChamber: 3.4 +/- 1.6 microg, 1.7 +/- 1.6 microg; ACE: 4.5 +/- 0.9 microg, 5.4 +/- 2.9 microg. Similar trends, but greater reduction in aerosol delivery, were observed with the 5-s delay. Significantly greater fine-particle mass was delivered from HCs made from conducting or charge-dissipative materials than from those made from nonconductive polymers, even after wash/rinse pretreatment (p < 0.01). The fine-particle mass was also significantly greater from the AeroChamber Max than from the Vortex, irrespective of wash/rinse pretreatment or delay interval (p < 0.01). CONCLUSION: HCs made from electrically conductive materials emit significantly greater fine-particle mass, with either a 2-s or 5-s delay, than do HCs made from nonconducting materials, even with wash/rinse pretreatment.

Levalbuterol aerosol delivery with a nonelectrostatic versus a nonconducting valved holding chamber.

BACKGROUND: Hydrofluoroalkane-propelled levalbuterol (Xopenex) aerosol is a recently approved formulation for delivery via metered-dose inhaler for the treatment or prevention of bronchospasm in adults, adolescents, and children > or = 4 years of age who have reversible obstructive airway disease. Valved holding chambers (VHCs) made from conventional polymers are susceptible to accumulation of electrostatic charge, which can be minimized by prewashing with ionic detergent, but it may be desirable to be able to use the product straight from the package, without pretreatment, especially during an exacerbation. METHODS: We studied the performance of the AeroChamber Plus and AeroChamber Max VHCs in delivering hydrofluoroalkane-propelled levalbuterol. Both VHCs were prewashed, rinsed, and drip-dried before testing. The AeroChamber Max is manufactured from charge-dissipative material and was therefore also evaluated without prewashing. Aerosol samples were collected at 28.3 L/min with an Andersen 8-stage cascade impactor, per the procedure specified in Chapter 601 of the United States Pharmacopeia. RESULTS: The mean +/- SD fine-particle mass (mass of aerosol particles < 4.7 microm aerodynamic diameter) values were 33.5 +/- 1.4 microg and 36.3 +/- 1.1 microg with the AeroChamber Max, without and with wash/rinse pretreatment, respectively, and 28.5 +/- 2.4 microg with the prewashed AeroChamber Plus. CONCLUSIONS: We think the small differences we observed are unlikely to be of clinical importance, given the inter-patient variability seen with inhaled drug delivery. The performance of the AeroChamber Max was substantially comparable whether or not it was prewashed.

High-pressure aerosol suspensions--a novel laser diffraction particle sizing system for hydrofluoroalkane pressurised metered dose inhalers.

In this study, a novel laser diffraction particle size analysis dispersion system, capable of sizing particles in situ within suspension hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs), was developed and tested. The technique was compared to four indirect particle sizing methods commonly used to determine the size of particles suspended in HFA pMDIs. The median volume diameter obtained using laser diffraction of both the salbutamol sulphate and fluticasone propionate suspended either in 2H, 3H-decafluoropentane or perfluoropentane (employed as surrogate propellants) was over one-order of magnitude larger than the particle sizes of the drugs suspended in HFA 134a. In contrast, the "in-flight" particle size using the Sympatec inhaler 2000 laser diffraction equipment undersized the particles, predicting higher delivery efficacy compared to the other sizing methods. However, the size of particles suspended in HFAs derived using the novel pressurised dispersion system, showed a linear correlation with the impaction results, r2=0.8894 (n=10). The novel pressure cell sizing technique proved to be simple to use, has the ability to be automated and was accurate, suggesting it could be an essential tool in the development of new suspension-based pMDI formulations.

A comparison of two methods to determine the solubility of compounds in aerosol propellants.

A new on-line reverse phase HPLC method for determining the solubility of compounds in propellant based metered dose inhaler (MDI) formulations was compared with a conventional method. The new method employs a direct injection from a MDI vial into the needle injector port of a manual injector. To evaluate the two methods, beclomethasone dipropionate (BDP), 5,5-diphenyl hydantoin and 3,3'-diindolylmethane, were used as model compounds in propellant HFA-134a. Comparison was performed by analyzing known and unknown concentrations of BDP in various combinations of HFA-134a and ethanol. In addition, the solubility of 5,5-diphenyl hydantoin and 3,3'-diindolylmethane were determined in HFA-134a using both the new and the conventional methods. The two methods were found to be in good agreement with each other, with the new direct injection technique offering enhanced precision and accuracy along with considerable reduction in analysis time.

R-134a emissions from vehicles.

We report the first study of R-134a (also known as HFC-134a and CF3CFH2) refrigerant leakage from air conditioning (AC) systems of modern vehicles. Twenty-eight light duty vehicles from five manufacturers (Ford, Toyota, Daimler Chrysler, General Motors, and Honda) were tested according to the USEPA (Federal) extended diurnal test procedure using the Sealed Housing for Evaporative Determination (SHED) apparatus. All tests were conducted using stationary vehicles with the motor and air conditioning system turned off. R-134a was measured using gas chromatography (GC) with a flame ionization detector (FID). All vehicles exhibited measurable R-134a leakage over the 2-day diurnal test. Leak rates of R-134a ranged from 0.01 to 0.36 g/day with an average of 0.07+/-0.07 g/day. When combined with leakage associated with vehicle operation, servicing, and disposal we estimate that the lifetime average R-134a emission rate from an AC equipped vehicle is 0.41+/-0.27 g/day (the majority of emissions are associated with vehicle servicing and disposal). Assuming that the average vehicle travels 10 000 miles per year we estimate that the global warming impact of R-134a leakage from an AC equipped vehicle is approximately 4-5% of that of the CO2 emitted by the vehicle. The results are discussed with respect to the contribution of vehicle emissions to global climate change.

Bedside tracer gas technique accurately predicts outcome in aspiration of spontaneous pneumothorax.

BACKGROUND: There is no technique in general use that reliably predicts the outcome of manual aspiration of spontaneous pneumothorax. We have hypothesised that the absence of a pleural leak at the time of aspiration will identify a group of patients in whom immediate discharge is unlikely to be complicated by early lung re-collapse and have tested this hypothesis by using a simple bedside tracer gas technique. METHODS: Eighty four episodes of primary spontaneous pneumothorax and 35 episodes of secondary spontaneous pneumothorax were studied prospectively. Patients breathed air containing a tracer (propellant gas from a pressurised metered dose inhaler) while the pneumothorax was aspirated percutaneously. Tracer gas in the aspirate was detected at the bedside using a portable flame ioniser and episodes were categorised as tracer gas positive (>1 part per million of tracer gas) or negative. The presence of tracer gas was taken to imply a persistent pleural leak. Failure of manual aspiration and the need for a further intervention was based on chest radiographic appearances showing either failure of the lung to re-expand or re-collapse following initial re-expansion. RESULTS: A negative tracer gas test alone implied that manual aspiration would be successful in the treatment of 93% of episodes of primary spontaneous pneumothorax (p<0.001) and in 86% of episodes of secondary spontaneous pneumothorax (p=0.01). A positive test implied that manual aspiration would either fail to re-expand the lung or that early re-collapse would occur despite initial re-expansion in 66% of episodes of primary spontaneous pneumothorax and 71% of episodes of secondary spontaneous pneumothorax. Lung re-inflation on the chest radiograph taken immediately after aspiration was a poor predictor of successful aspiration, with lung re-collapse occurring in 34% of episodes by the following day such that a further intervention was required. CONCLUSIONS: National guidelines currently recommend immediate discharge of patients with primary spontaneous pneumothorax based primarily on the outcome of the post-aspiration chest radiograph which we have shown to be a poor predictor of early lung re-collapse. Using a simple bedside test in combination with the post-aspiration chest radiograph, we can predict with high accuracy the success of aspiration in achieving sustained lung re-inflation, thereby identifying patients with primary spontaneous pneumothorax who can be safely and immediately discharged home and those who should be observed overnight because of a significant risk of re-collapse, with an estimated re-admission rate of 1%.

Spray-induced frostbite in a child: a new hazard with novel aerosol propellants.

A case of deep frostbite occurred in an 8.5-year-old child. The lesion was due to the improper use of a toilet air freshener and was severe enough to require a skin graft. The propellants contained in the spray were propane and butane. We measured the temperature of this aerosol during spraying (-40 degrees) in comparison with an ethyl chloride spray (-3 degrees) widely used for local skin anesthesia. This difference is mainly due to the much lower evaporation temperature of propane (-42.2 degrees) and butane (-0.6 degrees) compared with ethyl chloride (12.5 degrees). This child aimed the spray directly toward his skin, thus producing a deep frostbite. We wish to draw the attention of clinicians to this potential hazard with new propellants, since they should soon replace chlorohydrofluorocarbons throughout the world for ecologic reasons.

The detection of aerosol propellants in body fluids and tissue by gas chromatography-mass spectrometry.

The increased incidence of aerosol abuse in recent years has led to the development of a method for the detection of halogenated hydrocarbons in body fluids and tissue compatible with other routine methods. The use of the method in two background studies and a case investigation is described.

Aerosol propellant interference with clinical mass spectrometers.

Metered dose inhalers containing halogenated propellants may interfere with mass spectrometer quantitation of halogenated inhalation anesthetics. We identify the propellant(s) in a commercially available metered dose inhaler that caused erroneous mass spectrometer readings. In addition, we identify the causes of different types of interference in different mass spectrometers.

The effects of bronchodilator-inhaler aerosol propellants on respiratory gas monitors.

Spurious readings from a mass spectrometer have been reported following the administration of aerosol bronchodilators. We quantified the response of various respiratory gas analyzers to the aerosol propellant of albuterol inhalant (Proventil). The mass spectrometer systems tested, two Advantage systems, a SARA system, and a Model 6000 Ohmeda system, all displayed artifactual readings in response to the albuterol propellant. Each metered dose of the Proventil brand of albuterol contains 4 ml of Freon 11 (trichloromonofluoromethane) and 11 ml of Freon 12 (dichlorodifluoromethane). The concentration of propellant was expressed in doses/L, where each liter of gas contains 0.4 vol % of Freon 11 and 1.1 vol % of Freon 12 per dose. In proportion to the concentration of albuterol propellant, the two Advantage systems showed substantial readings of isoflurane (%) when no isoflurane was present (13% and 16% per dose/L) and reduced readings of enflurane (-8% and -10% per dose/L) and carbon dioxide (CO2) (-3 and +5 mm Hg per dose/L). The SARA system showed substantial CO2 readings when no CO2 was present (5 mm Hg per dose/L) and displayed small enflurane readings (0.1% per dose/L) when no enflurane was present. The Model 6000 unit showed CO2 readings when no CO2 was present (5 mm Hg per dose/L). Neither the Raman spectrometer, the infrared spectrometers, nor the piezoadsorptive analyzer we tested showed an artifactual effect of albuterol propellant on any of its readings. Simulation and clinical tests demonstrated that a single dose of albuterol propellant into a breathing circuit at the onset of inspiration resulted in concentrations of 0.8 and 0.3 dose/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Methodological aspects of the determination of the acute inhalation toxicity of spray-can ingredients.

Spray-can ingredients, if liberated in confined spaces, are potential health hazards for man. Thus, appropriate inhalation toxicity studies have to be performed in accordance with internationally recognized guidelines, e.g. the US Environmental Protection Agency: Federal Insecticide, Fungicide and Rodenticide Act (FIFRA no. 81-3) or OECD no. 403. One of the essential requirements of such guidelines is that test animals (preferably rats) be exposed to a steady-state concentration in a dynamic inhalation chamber for at least 4 hours. This is not easy to achieve with vapours released from a pressurized spray-can. The method described here makes it possible to expose experimental animals in an inhalation chamber to a steady-state concentration of intermittently released spray jets of constant doses per jet. Animal experiments and theoretical considerations (computer simulations) have shown that the method presented allows an up-to-date determination of the acute inhalation toxicity of spray-can ingredients.

Physiological response to aerosol propellants.

Acute exposures to isobutane, propane, F-12, and F-11 in concentrations of 250, 500, or 1000 ppm for periods of 1 min to 8 hr did not produce any untoward physiological effects as determined by the methods employed which included serial EKG's and continuous monitoring of modified V5 by telemetry during exposure. Repetitive exposures to these four propellants were also without measurable untoward physiological effect with the exception of the eight male subjects repetitively exposed to 1000 ppm, F-11, who did show minor decrements in several of the cognitive tests. Of particular importance is the observation that none of the subjects showed any decrement in pulmonary function or alteration in cardiac rhythm as the result of exposure to concentrations of the gases or vapors far greater than encountered in the normal use of aerosol products in the home.