Search

The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs.

HFA 134a (1,1,1,2-tetrafluoroethane) is a ‘non-ozone depleting’ candidate for use as a drug propellant in multi-dose inhalers (MDIs). A means for assuring the safety of such a compound for human use is to check mat there is no excessive or unexpected accumulation in the body and selected regions. HFA 134a has been labelled with fluorine-18 and used with a highly sensitive whole-body γ-counting technique to measure the whole-body and regional absorption, distribution and retention of HFA 134a after administration in humans by single breath inhalation. In 7 healthy subjects, radiolabeled HFA 134a was mainly eliminated by ventilation during the first few minutes, with on average 7.2% of the radioactivity retained in the body at 10 min. This radioactivity cleared with an apparent terminal half-life of 1.5-4.2 h. At 5.5 h an average of < 1% of the administered dose (< 750 μg, ca 0.2 μCi) was retained in the body. The disposition of radioactivity was independent of the position of radiolabel. Hence, there was no evidence of degradative metabolism. Inhaled HFA 134a first distributed to all regions of the body and then cleared without evident accumulation in any specific region. The study supports the proposal that HFA 134a is a safe substitute for current propellants in MDIs.