Improving Inhaled Product Testing: Methods for Obtaining Better In vitro-In vivo Relationships

Even in an industry in which all product development is complicated by the intricacies of human biology, orally inhaled products (OIP) stand out as singularly demanding.
Feb 02, 2013
Volume 37, Issue 2

The technique of cascade impaction is used to measure the aerodynamic particle size distribution (APSD) of all orally inhaled products (OIPs). The resulting data are broadly indicative of likely deposition behavior in the respiratory tract and support development of a target drug-delivery efficiency. Cascade impaction is widely acknowledged as being unable to completely replicate the complex aerodynamics and deposition behaviors taking place in the throat and lungs. The lungs operate under high humidity conditions, and within them volumetric flow rate decelerates with each bifurcation, establishing complex velocity profiles across the lung structure. The resulting mechanisms of particle deposition, which include sedimentation and diffusion as well as impaction, are difficult to comprehensively simulate. Improving the relationship between in vitro test data and in vivo behavior, however, is becoming increasingly important for a number of reasons, including the successful implementation of quality by design (QbD), the need to reduce the costs of OIP development, and the desire to achieve in vitro bioequivalence for generic products.

Steps to modify cascade impaction to secure better in vitro-in vivo relationships (IVIVRs) range from the use of new testing equipment, such as the Alberta Idealized Throat (AIT) and state-of-the-art breathing simulators, to the adoption of more efficient information-gathering techniques, including Abbreviated Impactor Measurement (AIM).

Multistage cascade impaction

Multistage impactors consist of a series of stages each made up of a nozzle plate, with a specific nozzle arrangement, and a collection surface. Sample-laden air is drawn into the impactor, at a constant volumetric flow rate, and passes sequentially through the stages. Because nozzle size and total nozzle area decrease with stage number, the particles are progressively accelerated. At each stage, particles with sufficient inertia break free of the prevailing air flow and impact on the collection surface, thus producing a series of mass fractions that can be analyzed to determine how the active is distributed with respect to size.

Figure 1: A typical cascade impactor test setup for dry-powder inhaler (DPI) testing.
Figure 1 shows a typical pharmacopeial cascade impactor setup for dry-powder inhaler (DPI) testing that includes a number of essential ancillaries. The device is interfaced to the cascade impactor using an appropriate mouthpiece adapter and an induction port. Flow rate through the cascade impactor is controlled by the critical flow controller/flow meter, and a vacuum pump draws air through the whole system.

It is possible to draw a loose connection between the different elements of this setup and the real-life scenario that it aims to reflect. The induction port represents the mouth and throat, and the cascade impactor sizes those particles most likely to deposit in the lungs. The flow controller/flow meter ensures application of a stable and suitably representative flow rate during testing.

lorem ipsum