Optimising a dissolution test method for inhalation formulations
Through a series of experiments, factors associated with each step of the test process — from dose collection through to solution
sampling method — were investigated to develop an optimal test procedure for use with this new apparatus.10 The following discussion tracks the experiment path taken and its outcome.
Tests to establish optimal conditions were carried out using budesonide (BD) and albuterol sulphate (AS), which are routinely
used to treat asthma. BD and AS were fired into the NGI with a Pulmicort Flexhale DPI (AstraZeneca) and Ventolin HFA MDI (GlaxoSmithKline),
respectively. Multiple actuations ensured the presence of sufficient sample on the collection surface in initial tests; however,
the actuation number was one of the variables investigated as part of the experimental programme.
The test flow rate through the NGI was set at 30 L/min for the Ventolin HFA and 60 L/min for the Pulmicort Flexhaler. These
air flow rates were established with reference to pharmacopeial monographs for the testing of MDIs and DPIs.11,12 The monographs stipulate that the flow rate should be set to 30 L/min when testing an MDI (using the NGI) and at a flow
rate to give a pressure drop across the device of 4 kPa when testing a DPI. Calibration data for the NGI allows the accurate
determination of stage cutoff diameters at both of these flow rates.13
Following size fractionation of the sample in the NGI, the removable impaction surface from the dissolution cup was covered
with a polycarbonate membrane (pre-soaked in dissolution fluid) and secured in the membrane holder. This entire assembly was
then placed at the bottom of a vessel of a standard USP Method 2 apparatus containing 300 mL of dissolution fluid.
During dissolution testing, 3 mL samples were periodically withdrawn from the vessel for analysis using a validated HPLC method.
A corresponding volume of fresh dissolution medium was added after each extraction. With the BD, sample testing took place
over a period of 2 h, while 1 h proved sufficient for AS. At the end of the experiment, the residual material on the membrane
was recovered and quantified.
Selecting an optimal collection surface for dose collection
Using the dissolution cup it is possible to select one fraction with which to compare one drug to another, or to assess the
influence of particle size on dissolution rate by testing different fractions of the dose. With the Pulmicort Flexhaler (BD)
stage 4 consistently displayed the maximum deposition while for the Ventolin HFA (AS) it was stage 5. These stages were therefore
selected for dose collection for subsequent tests. Stage 4 has a cutoff diameter of 1.66 µm at 60 L/min, while stage 5 has
a cut-off diameter of 1.36 µm at an air flow rate of 30 L/min.
For the BD, dissolution profiles were determined as a function of particle size by collecting samples on stage 2 through 5
(Figure 3). Eighty percent of the samples collected on stages 2, 3 and 4 dissolved after 15 min, but there were differences in initial
dissolution rates. Statistical analysis shows similarity factors* of 52.5 and 59.7 for stages 2 and 3 compared with stage
4 (the reference stage), but the dissolution profile for stage 5 is significantly different (a similarity factor of 40.6).
The smaller particles on this stage, which has a cut-off diameter of 0.94 µm, have a large surface area to volume ratio and,
therefore, might be expected to exhibit a faster dissolution rate in accordance with the standard NoyesWhitney model.
Figure 3: Exploring the influence of particle size on dissolution profile for budesonide.