Formulation of metered-dose inhalers containing beclomethasone dipropionate using quality by design approach

Metered-dose inhalers (MDIs) containing corticosteroids are widely prescribed for the treatment of asthma and chronic obstructive pulmonary disease, but the high cost of brand-name products limits access in developing countries. A quality by design (QbD) approach offers a systematic framework for developing cost-effective generic alternatives while ensuring consistent product quality.

Our findings demonstrate that a QbD framework can accelerate formulation optimization, enhance product reliability, and support patient access to affordable, high-quality corticosteroid inhalers.

Beclomethasone dipropionate (BDP) MDI formulation was developed and optimized using QbD principles, focusing on establishing critical quality attributes (CQAs) and defining the design space for key formulation parameters. CQAs were identified through risk assessment.

A mixture/I-optimal design was employed to optimize ethanol (5-15%), oleic acid (0.05-2%), and HFA-134a propellant (82.8-94.75%). Statistical modeling in Design-Expert (Stat-Ease Inc., Minneapolis, MN) defined the control space and an optimized formulation region for these components. Formulations within this space consistently met target specifications, including a mass median aerodynamic diameter (MMAD) of 3.26 ± 0.17 μm (target < 5 μm), fine particle fraction (FPF) of 60.4 ± 2% (target ≥ 55%), and delivered dose uniformity (DDU) of 99.7 ± 1.5% (target: 75-125%). The model showed high predictability, with R² values of 0.98, 0.88, and 0.93 for MMAD, FPF, and DDU, respectively.

QbD approach enabled the development of a robust design space for a generic BDP MDI. The optimized formulation demonstrated comparable performance to the reference product, supporting the development of more affordable inhaled corticosteroid therapies.