Developing a dissolution testing technique for inhalable formulations
In 2003, Feddah and Davies introduced a dissolution testing technique for inhalable formulations based on a flow through apparatus.7 This technique involves the use of an Andersen cascade impactor (ACI) to capture the emitted dose from the DPI. A glass
fibre filter mounted at the base of a USP induction port, of the type routinely used with multistage cascade impactors, captures
the dose during otherwise standard operation of the ACI. Once captured, the dose is held in a dissolution cell through which
solvent is pumped at a known flow rate.
This method was used to differentiate the solubility of glucocorticoids employed in the treatment of pulmonary disease, but
it has a number of disadvantages. Firstly, although an ACI was used to capture the dose for testing, the size fractionation
capabilities of the impactor were not exploited — the entire emitted dose was captured. Therefore, the recorded dissolution
behaviour does not relate to just those particles fine enough to deposit in the lung. An additional problem is the amount
of solvent used in flow through testing, which is significant; no attempt is made to simulate the sparing presence of lung
surfactant in vivo. Furthermore, recorded solubility is dependent on the flow rate of solvent selected, making it too easy to achieve noncomparable
results for "zero order" drug solubility.
To address these issues and improve test sensitivity, researchers at the University of Texas have developed a dissolution
test for OIP formulations based on the standard "Paddle over Disc" method described in US Pharmacopeia Method 5 and European
Pharmacopoeia 22.214.171.124,9 A modified version of this solution is now commercially available (Figure 1). To ensure analysis only of the portion of interest in the emitted dose, the apparatus enables preseparation and sample
collection using a Next Generation Impactor (NGI), one of the systems of choice for routine aerodynamic particle size distribution
Figure 1: NGI dissolution cup and membrane holder (Copley Scientific, UK).
Multistage cascade impactors, such as the NGI and ACI, separate the emitted dose from an OIP into fractions on the basis of
aerodynamic particle size. Using the NGI, these fractions are captured in collection cups. The NGI dissolution cup (Copley
Scientific, UK) is almost identical to a standard NGI cup except that it has a 50 mm removable insert in the impaction area
where separated sample collects. It fits directly into positions 2 through 7 in a standard NGI cup tray.
To collect a dose for dissolution testing the NGI is operated exactly as for routine APSD measurement, but with the dissolution
cup installed at the stage of interest to allow capture of only the size fraction of interest rather than the entire emitted
dose. Once collection is complete, the insert is simply removed from the cup and covered with a pre-punched 55 mm diameter
polycarbonate membrane. Securing this in place with the supplied membrane holder forms a sealed disc or sandwich that can
be placed in a vessel of a conventional dissolution tester (Figure 2). Dissolution testing can then be conducted in an exactly analogous way as for other solid dosage forms, using appropriate
Figure 2: NGI membrane holder in position in the vessel of a standard USP Method 2 test apparatus.
Selection of an appropriate diffusion barrier for testing was crucial to the success of this solution. Although relatively
thin (approximately 6 µm), the polycarbonate membrane is robust with properties superior to those of a cellulose acetate alternative
used in prototype studies. The chosen membrane neither swells nor creates air bubbles, and has non-tortuous cylindrical pores
of well-defined size. These allow free diffusion of both the dissolved drug and dissolution media, enabling dissolution testing
under relevant hydrodynamic conditions.