Why the Lung Is Worth the Complexity
The lungs offer a drug delivery surface area of roughly 70 to 100 square metres, a thin alveolar membrane, rich vasculature, and, for respiratory conditions, direct access to the target tissue. For drugs targeting the lung, inhalation delivers drug precisely where it is needed, at doses a fraction of what would be required orally. For systemic delivery, the pulmonary route bypasses first-pass metabolism and produces rapid onset of action.
The price of those advantages is formulation complexity. The aerosol must be generated in a particle size range that reaches the target region of the lung: too large and it deposits in the throat; too small and it is exhaled. The formulation must be stable in the device, the drug must not irritate the airways, and the device and the formulation must work together as an integrated system. None of that is straightforward.
The Three Primary Inhaled Delivery Systems
Dry Powder Inhalers (DPIs)
DPIs deliver a dry powder formulation that is aerosolised by the patient’s inspiratory effort. The powder is typically a blend of micronised API and a carrier (most commonly lactose), where the carrier particles are large enough to be retained in the throat while the drug particles detach and penetrate into the lung.
The critical particle size range for deep lung deposition is 1 to 5 micrometres. Achieving this requires micronisation of the API, usually by jet milling, to a consistent and controlled particle size distribution. The surface properties of the micronised particles, which affect their tendency to agglomerate and their detachment from the carrier under airflow, are as important as the particle size itself.
Metered Dose Inhalers (MDIs)
MDIs deliver a metered dose of drug dissolved or suspended in a liquefied propellant, typically HFA 134a or HFA 227ea following the phase-out of CFCs. When the canister is actuated, the propellant evaporates rapidly after the valve opens, atomising the drug into an aerosol.
Formulation challenges for MDIs include drug solubility or suspension stability in the propellant, co-solvents and surfactants to assist solubilisation, and protection of the formulation against valve and canister interactions over the product shelf life. Suspension MDIs require controlled particle size in the formulation to ensure dose uniformity and appropriate aerosol performance.
Nebulisers
Nebulisers convert a liquid drug solution or suspension into an aerosol using jet, ultrasonic, or vibrating mesh technology. They are predominantly used in hospital settings or for patients unable to use DPIs or MDIs, including infants and severely compromised patients.
The formulation requirements for nebuliser use are primarily those of a sterile or microbiologically controlled solution: appropriate pH, tonicity, and absence of irritants. The nebuliser device drives the aerosol characteristics rather than the formulation, which simplifies the formulation challenge but introduces a device variable that affects clinical performance.
Key Characterisation Parameters for Inhaled Products
| Parameter | Why It Matters | Measurement Method |
| Aerodynamic particle size distribution (APSD) | Determines lung deposition pattern; particles must be 1-5 micrometres for deep lung delivery | Next Generation Impactor (NGI) or Andersen Cascade Impactor (ACI); required for all inhaled product registration |
| Fine Particle Fraction (FPF) | Proportion of dose in respirable size range; key efficacy indicator | Derived from APSD data; particles below 5 micrometres as fraction of total emitted dose |
| Mass median aerodynamic diameter (MMAD) | Central tendency of aerodynamic particle size distribution | Derived from APSD data; should be 1-3 micrometres for peripheral lung targeting |
| Emitted dose and dose uniformity | Total dose leaving the device; must be consistent across the life of the product | Dose uniformity testing by actuation throughout container life; USP/Ph. Eur. specifications |
| Moisture content (DPI) | Affects powder flowability, aerosolisation efficiency, and drug stability | Karl Fischer titration or gravimetric analysis; critical for DPI performance and stability |
Regulatory Considerations for Inhaled Products
Inhaled drug products are subject to specific regulatory guidance that goes beyond standard pharmaceutical development requirements. In the US, the FDA’s guidance on MDIs and DPIs describes the CMC and bioequivalence study requirements in detail. In Europe, the EMA’s guidelines on oral inhalation and nasal drug products set similar expectations. A key feature of both sets of guidance is that the device and the formulation are assessed as an integrated combination product, not separately.
Inhaled Formulation Development at Ardena
Ardena’s formulation and analytical teams have experience developing inhaled drug products including DPI powder blends and nebuliser solutions. The team provides particle size characterisation, APSD measurement using cascade impaction, and stability testing designed to meet ICH and product-specific regulatory requirements. For programmes combining inhaled formulation with HPAPI handling requirements, the site capabilities at Pamplona are available for contained processing of potent inhaled APIs.
