Multi-Participant Blinded Investigation into Internal Losses of Medication in Commercially Available Mixing Inlets:...

Area of Science:

• Pharmaceutical Sciences
• Aerosol Science and Technology
• Drug Delivery Systems

Background:

• The Miller mixing inlet (MI) allows cascade impactors to maintain constant flow rates during aerosolized product testing at varying user inhalation flow rates.
• This design controls airflow via a side-arm, facilitating consistent evaluation of orally inhaled products.

Purpose of the Study:

• To experimentally determine internal losses of various inhaler-generated aerosolized medications within commercially available MIs.
• To assess the suitability of MIs for pharmacopeial methods in product testing, focusing on active pharmaceutical ingredient (API) mass and aerodynamic particle size distribution (APSD).
• To investigate the impact of different airflow rates on MI performance across multiple organizations and device types.

Main Methods:

• Cross-industry investigation involving five organizations evaluating solution and suspension formulations from pressurized metered dose inhalers (pMDIs), passive dry powder inhalers (DPIs), and nebulizers (jet and mesh).
• Evaluations conducted using four different apparatuses at varying constant airflow rates to the MI side-arm.
• Nebulizers tested with a variable adult flow profile generated by a breathing simulator.

Main Results:

• Generally, MI losses were less than 5% of the delivered API mass ex-inhaler, often within pharmacopeial allowances for emitted mass.
• Blister-based DPIs exhibited average losses between 2.8% and 5.2% of the API mass presented to the MI.
• APSD measures were largely unaffected by airflow up to 60 L/min, except for solution pMDIs where higher flow reduced mass median aerodynamic diameter and increased geometric standard deviation due to ethanol evaporation.

Conclusions:

• MI losses are typically minimal (<5%) and generally acceptable for pharmacopeial aerodynamic particle size distribution (APSD) determination.
• MI loss evaluation is crucial during method development to minimize internal aerosol losses.
• Specific formulations, like solution pMDIs with ethanol, may show flow-rate dependencies requiring careful method optimization.