Introduction: The efficacy of inhaled products is affected by the degree, and potentially the site, of drug particle deposition in the lungs. Lung deposition correlates with the fine particle fraction (FPF; the proportion of dose containing particles \5 lm in aerodynamic diameter). This in vitro study (defining fluticasone propionate/ formoterol particulate size [DIFFUSE]) examined the effects of inhalation flow rate on the FPF of the fluticasone propionate/ formoterol (FP/FORM) pMDI aerosol compared with three other inhaled corticosteroids/longacting b 2-agonist (ICS/LABA) combination therapies administered by either DPI or pMDI [fluticasone propionate/salmeterol (FP/SAL), budesonide/formoterol (BUD/FORM) and beclometasone dipropionate/formoterol (BDP/ FORM)]. Methods: Aerodynamic particle size distribution was determined for each product using an 8-stage Andersen Cascade Impactor at two inhalation flow rates: 28.3 and 60.0 L/min. Fine particle dose (mass of dose \5.0 lm) and FPF were calculated as a percentage of the labeled dose for the LABA and ICS of each product at both flow rates. Results: FP/FORM suspension aerosol provided a high and consistent FPF of approximately 40% for the ICS and LABA components at both flow rates. At 28.3 L/min, the FPF of each component of FP/FORM (41.2% and 39.2%) was greater than that of FP/SAL DPI (12.5% and 11.3%), BUD/FORM DPI (8.2% and 6.6%) and BDP/ FORM pMDI (28.5% and 26.0%). At 60.0 L/min, the FPFs of the FP/FORM components (43.7% and 42.1%) were greater than those of FP/SAL

Different halocyclopropanes prepared by cycloaddition of halocarbenes to olefins by phase-transfer reactions have been analyzed by gas chromatography/mass spectrometry (GUMS). Starting from CCI,-adducts, the investigations have been extended to bromine-and fluorine-containing cyclopropanes. As reaction partners, a group of olefins, containing different alkyl substituents, have been selected. Thereby, special attention has been paid to smooth reaction conditions, high reaction yield and simple handling. The suitability for mass spectral analysis is discussed. Fragmentation pathways and diagnostic potential are evaluated. Best results have been obtained by addition of bromofluorocarbene to double bonds. The resulting bromofluorocyclopropanes are considered to be the most promising derivatives for mass spectral localization of double bonds.

Abstract. Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPD PIM were made by each organization using either the full-resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPD AIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPD AIM varied from 4.4 to 5.0 μm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPD PIM was fixed at 5 μm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPD AIM /FPD PIM ], expressed as a percentage, was contained in the predetermined 85-118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques.

We would like to clarify some points about the DIFFUSE (Defining fluticasone propionate/ formoterol particulate size) study (December 2013, p 39) [1] in light of the recent review by De Maria and colleagues [2]. Our in vitro study assessed the effects of inhalation flow rate on the aerodynamic particle size distribution Hence, the flow rate dependency of inhalers is of interest to physicians as well as regulators. Including a faster flow rate of 60 L/min in our study was therefore appropriate, and is relevant to the real-life use of these inhalers.All inhalers were tested across pre-defined parameters, using the same apparatus and the same ambient conditions, to ensure a fair and appropriate comparison. The review questions the use of an Andersen Cascade Impactor (ACI):an ACI is arguably the most widely used tool for testing inhalers, and is routinely used at flow rates of 30, 60 L/min, and above [9][10][11][12][13][14]. Indeed, the authors of the review have themselves used