Powder Formulation and Primary Particle Size

To test the performance of the DAC-unit devices, a single batch of spray dried excipient enhanced growth (EEG) powder formulation was produced using the optimized approach developed by Son et al. (27). Albuterol sulfate (AS) was used as a readily quantifiable model drug and mannitol was implemented as the hygroscopic excipient. Based on the study of Son et al. (27), the final AS-EEG spray dried powder formulation consisted of drug, mannitol, L-leucine and Poloxamer 188 in a ratio of 30:48:20:2% w/w. The powder formulation was produced with a laboratory scale B-90 Buchi Nano Spray Dryer (Buchi Laboratory-Techniques, Flawil, Switzerland) with a drying temperature of 70 °C and gas flow rate of 120 L/min (LPM). Primary particles produced by the spray dryer were collected in an electrostatic precipitator and then stored in amber vials in an airtight glass desiccator.

As with all DPIs, the inline DAC-unit devices are intended to disperse a powder formulation into primary particles as efficiently as possible with the input energy that is available. However, powder formulation aggregates are formed during storage and it is typically not possible to break all particle-particle bonds and fully disperse the formulation to primary particles in the form of an aerosol. The powder formulation primary particle size is therefore a theoretical lower limit on the aerosol size that can be approached by a highly efficient inhaler or with a large amount of input energy.

The primary particle size of the EEG powder formulation was tested using a Sympatec HELOS (Sympatec GmbH, Clausthal-Zellerfeld, Germany) laser diffraction system with a ASPIROS/RODOS aerosol dispersion accessory, which uses a pressure drop of 400 kPa to disperse a milligram quantity of powder. Based on a preliminary analysis, the MMAD of the primary particles was calculated (using a theoretical particle density of 1.393 g/cm³) to be 1.18 μm. Fine particle fractions less than 5 μm (FPF_{<5 μm}) and less than 1 μm (FPF_{<1 μm}) were also calculated to further determine primary particle characteristics. The FPF_{<5 μm} value for this powder batch was determined to be 100% while the FPF_{<1 μm} was 38.2%.

The extreme high pressure used by the ASPIROS/RODOS aerosol dispersion accessory (400 kPa) is not intended to simulate DPI aerosolization, however it functions to almost completely deaggregate the powder formulation and provide an estimate of powder formulation primary particle size. For comparison, the operating pressure in the hand-operated syringe of the DAC-unit is approximately 55 kPa. Correct design of the DAC-unit flow pathway is sought in order to produce an aerosol that approaches the primary particle conditions with approximately seven-fold less actuation pressure and actuation air volumes of 10 ml.