Category: Formulation and Quality
Purpose: Aerosol performance characteristics such as the emitted dose and fine particle fraction are critical product attributes that are used in the development of novel aerosol formulation and inhaler combination products. For dry powder inhalers (DPI), it is important to characterize performance using realistic inhalation profiles that simulate patient use. This is challenging using cascade impaction (CI) methods that are designed to operate at constant flow. In this study, multiple batches of an albuterol sulfate (AS) spray dried excipient enhanced growth (EEG) formulation delivered by CC90-3D DPI are characterized using a CI constant flow technique and using a CI method adapted to actuate the DPI using a realistic inhalation profile. The CI performance testing results are compared with aerosol characterization using a rapid screening laser diffraction (LD) method performed with a realistic inhalation profile. The suitability of the LD method to assess aerosol performance is evaluated in comparison to the CI methods.
Methods: Four batches of a spray dried AS EEG formulation were produced containing AS, mannitol (hygroscopic growth excipient), L-leucine (dispersion enhancer), and poloxamer 188 in a ratio of 30:48:20:2. The AS EEG powders were spray dried using a Büchi Nano B-90 HP with a drying temperature of 120 °C and drying gas flow rate of 120 L/min. Primary particle size and powder dispersion properties were determined using the Sympatec HELOS with RODOS/M disperser operated at dispersion pressure of 1 and 4 bar. The median volume (Dv50) diameter was reported.
Aerosol performance testing of the spray dried batches using CI was performed using the Next Generation Impactor (NGI). 2mg of formulation was aerosolized using the CC90-3D inhaler which was attached directly to the impactor pre-separator and operated at constant flow rate of 45 L/min for 5.3 seconds generating a 4 kPa pressure drop. A number of modifications were required in order to measure the aerosol performance using the CI method with a realistic inhalation profile, including use of the Westech W7 Impactor plates and the Nephele Mixing Inlet. The realistic inhalation profile employed for the CC90-3D inhaler was characterized by an average flow rate of 45 L/min and a peak inspiratory flow rate of 65 L/min inhaled over 4 s. Emitted dose (ED), fine particle fraction less than 5 µm (FPF< 5µm) and mass median aerodynamic diameter (MMAD) were reported.
Aerosol characterization using LD was performed using the Spraytec® with inhalation cell for breath actuation of the CC90-3D inhaler containing 2 mg of spray dried formulation using the previously described inhalation profile. A PulmoGuard IITM filter was connected to the exit of the inhalation cell prior to the breath simulator to collect the emitted dose. Laser diffraction data was collected at 2500 Hz for 4 seconds and the particle size distribution of the emitted aerosol was presented as time averaged volumetric diameter (Dv) and %FPF< 5µm.
Results: The primary particle size of the four spray dried batches characterized by the mean (SD) Dv50 measured at both 1 and 4 bar was each 1.0 µm (0.0), respectively, indicating both the reproducibility of the batches and the dispersibility of the spray dried powders. Figure 1 presents the aerosol performance characterization using the CI and LD methods which shows a reproducible emitted dose ranging from 72 to 79 % across all AS EEG spray dried batches. The mean %FPF< 5µm was high ( >90%) and reproducible across batches of spray dried formulation (90 to 98 % of ED). Comparing the ED and FPF only Batch 2 showed a significant difference (P< 0.05, One-way ANOVA, Tukey) when the device was actuated using a constant flow rate compared to the realistic inhalation profile using the CI method. Table 1 shows the particle size characteristics of the emitted aerosols measured using CI and LD methods. Considering batch reproducibility, the aerosol size for the four batches showed that only one batch (#2) had a small (0.1 µm) but statistically significant difference (P< 0.05, One-way ANOVA, Tukey) when tested using the CI at constant flow although this difference was not observed with the LD method. Generation of the aerosol using the realistic inhalation profile did produce a significantly smaller MMAD (P< 0.05, One-way ANOVA, Tukey) for all batches compared to constant flow actuation using the CI method. The geometric particle size (Dv50) reported by the LD method with realistic inhalation were approximately 0.2 µm larger than the corresponding MMADs for each of the spray dried batches when comparing the realistic inhalation.
Conclusion: The batch reproducibility of the spray drying process in terms of primary particle size and aerosol performance revealed that micrometer sized particles were produced that were highly dispersible producing high emitted doses and fine particle fractions. Use of a realistic inhalation flow profile during CI and LD aerosol testing was observed to have only small effects on the measured aerosol performance.
Serena Bonasera– Richmond, Virginia
Serena Bonasera– Richmond, Virginia
Dale Farkas– Richmond, Virginia
Worth Longest– Professor, Virginia Commonwealth University, Richmond, Virginia
Michael Hindle– Professor, Virginia Commonwealth University, Richmond, Virginia