In vitro deposition properties of nebulized formoterol fumarate: effect of nebulization time, airflow, volume of fill and nebulizer type.

OBJECTIVE: The aim of this study was to investigate in vitro the delivery of a new long-acting beta2-agonist (LABA) drug formoterol fumarate inhalation solution (20 microg/2 mL) nebulized with and without ipratropium bromide (0.5 mg/2.5 mL) at different administration times (2.5-22.5 min), airflows (5-28.3 L/min), nebulizer fill volumes (2-6 mL),and nebulizer brands (Pari LC+, Ventstream and DeVilbiss). METHOD: Formoterol fumarate with and without ipratropium bromide was aerosolized at different administration times, airflows, nebulizer fill volumes, and nebulizer brands. The drug deposited on the throat, filter and stage plates was collected and analyzed by HPLC to determine the aerodynamic profiles of the nebulized drugs under each variable. RESULTS: In addition to altering the aerosol characteristics,increasing the nebulizer fill volume including the addition of ipratropium bromide produced a significant(p50.05) increase in the drug output. As expected, sputtering time was significantly longer at low airflows, and vice versa at higher airflows but with a significant loss of drug delivered presumably due to greater solvent evaporation at higher airflows. Airflows between 10 and 28.3 L/min and a nebulization time of approximately 10 min appear sufficient for producing aerosols within the respirable range (1-5 mm MMAD) with the nebulizer/compressor combination used.While the drug output varied significantly (p50.05) among the three brands of nebulizers tested, the LC+ nebulizer appears to produce aerosols (2.7 0.1 microm MMAD) capable of penetrating more deeply into the lung than the other nebulizers evaluated under the current test conditions. This study did not attempt to evaluate different nebulizer/compressor combinations. Also, the cascade impaction data may not necessarily reflect aerosol deposition in the airways in vivo, which may be different depending on the health status of the patient. CONCLUSION: The results demonstrated that administration of nebulized formoterol fumarate require proper selection of a delivery system/method for safe and effective therapy of the medication with and without ipratropium bromide.

Chiral HPLC analysis of formoterol stereoisomers and thermodynamic study of their interconversion in aqueous pharmaceutical formulations.

A chiral HPLC method was validated and successfully applied for the determination of formoterol stereoisomers and their inversion products in an aqueous matrix stored at 5-70 degrees C up to 3 weeks. Analysis was performed on a Chiral-AGP column (100 x 4-mm, 5-microm) using a variable mixture of mobile phase A (50-mM sodium phosphate buffer, pH 7.0) and B (10% v/v IPA) at a flow rate of 1.3 ml min(-1), and UV detection at 242 nm. All four formoterol stereoisomers were adequately resolved with acceptable detection and quantitation limits varying from 0.01-0.04 microg/ml and 0.04-0.1 microg/ml, respectively. The method showed acceptable accuracy (> or = 88%), precision (RSD < or = 8.5%) and good linearity (r(2) > or = 0.9999) over the concentration range investigated. While interconversion at 5+/-3 degrees C and 25+/-2 degrees C/60% RH +/-5% RH was too low to be determined accurately within the study period, chiral inversion of formoterol stereoisomers measured at high temperatures followed the first order rate kinetics and occurred at a single chiral center, resulting in the reversible formation of diastereoisomers, (R,R)<-->(S,R) and (S,S)<-->(R,S). No enantiomerization or diastereomerization occurred. There was no significant difference in inversion of the active components in racemic (R,R/S,S)-formoterol fumarate and the single isomer (R,R)-arformoterol tartrate drug formulations, and both drugs are expected to maintain their stereochemical integrity throughout the proposed shelf-life at the recommended storage condition (5+/-3 degrees C).

Compatibility and aerosol characteristics of formoterol fumarate mixed with other nebulizing solutions.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are often given admixtures of nebulizable drugs to minimize the time of administration in treatment regimens. OBJECTIVE: To evaluate the physicochemical compatibility and aerodynamic characteristics of formoterol fumarate 20 microg/2 mL when mixed or sequentially nebulized with budesonide inhalation suspension 0.5 mg/2 mL, ipratropium bromide 0.5 mg/2.5 mL, cromolyn sodium 20 mg/2 mL, or acetylcysteine 10% (100 mg/mL). METHODS: The admixtures were prepared in triplicate and analyzed for physicochemical compatibility at 0, 15, 30, and 60 minutes after mixing at room temperature. Physical compatibility was determined by visual examination and measurements of pH, osmolality, and turbidity. Chemical stability was evaluated using compendial or in-house-validated high-performance liquid chromatography (HPLC) assay methods. The aerodynamic characteristics of the admixtures or sequentially nebulized drugs were determined from aerosols generated from a Pari LC Plus nebulizer, using an 8-stage cascade impactor followed by HPLC analysis of the deposited drug. RESULTS: The admixtures remained clear, colorless solutions with no precipitation, except for cloudiness observed in the formoterol/budesonide combination due to budesonide suspension. The pH, osmolality, and turbidity for all admixtures were within the initial values (< or = 3%), and there were no significant changes (< or = 2%) in potency of the active components throughout the 1-hour study period. Due to increased drug volume or reconcentration in the nebulizer cup, the respirable fraction/delivered dose increased significantly (p < 0.05) for the mixed or sequentially nebulized drug. However, the fine particle fraction (FPF), mass median aerodynamic diameter, and geometric standard deviation generally remained unchanged for all admixtures, with the exception of FPF for the formoterol/budesonide combination. CONCLUSIONS: Our results indicate that admixtures of formoterol with budesonide, ipratropium, cromolyn, or acetylcysteine are physically and chemically compatible. However, admixing or sequential nebulization significantly increased the amount of drug delivered compared with single drug nebulization. The clinical implications of the in vitro data in patients with COPD have not been determined.