(M1430-08-53) Process Analytical Technology for Inline Aerodynamic Particle Size Measurements during Spray Drying

Purpose: Particle engineering is critical for delivery of dry powder formulations to the lung by inhalation. For delivery to the deep lung, particles must be approximately 1-5µm in aerodynamic diameter. The objective of this study was to integrate an inline isokinetic sampling technique on a lab scale spray dryer to determine the accuracy, robustness and limitations for measuring aerodynamic particle size of inhalation sized particles (1-5µm). Monitoring aerodynamic particle size, a critical to quality attribute, would ensure product quality and could be used as feedback control for critical process parameters (CPP). In addition to large savings in experimental time and resources, this quality by design approach provides early understanding of the relationship of critical product attributes (CPA) to CPPs during process development and scale-up.

Methods: A sampling port with appropriate dimensions was fabricated to sample isokinetically (constant velocity) in line and parallel to the flow in the outlet ducting of a spray dryer such that representative distributions of powder could be sampled from the main stream without sample size bias and directly analyzed in real time via an aerodynamic particle sizer (APS, model 3321 TSI, Shoreview, MN, USA) [1]. A dilution module was used in conjunction with the APS to ensure the particle concentration was below the APS maximum threshold and accurate data was obtained. The inline isokinetic measurements were compared to the powder measured via the APS small-scale powder disperser unit (model 3433) post-manufacture for accuracy. A model inhalation-relevant formulation of Mannitol and Leucine was studied.

Results: Test conditions were selected to span a typical process space for pulmonary spray drying, including particle concentration, particle size, and drying gas flow rate, aimed at understanding the impacts of changes in aerodynamic properties on method accuracy. Figure 1 displays the median mass aerodynamic diameter (MMAD) for the conditions tested, comparing inline and post-manufacture, or offline, sizing methods. In general, the inline particle size measurements correspond nicely with the offline measurements. More particularly, even the low and high nitrogen (N2) drying gas flow rate conditions that deviate 20% from isokinetic conditions, appear to have no significant impact on the MMAD measurements. Furthermore, the aerodynamic particle size distributions for the experimental conditions match well, as depicted by Figure 2 which is representative of the other conditions’ distributions. In fact, the inline measurements are likely more representative of the powder in the process as the larger contributions to the distribution in the offline measurement (seen around 12 and 15 µm) are due to inadequate dispersion of the powder from the disperser unit.

Conclusion: Based on the agreement in MMAD and the aerodynamic particle size distributions the sampling technique appears both accurate and precise. Furthermore, it is robust in achieving accurate measurements when the sampling deviates slightly from isokinetic conditions.

References: [1] Ivey, James W. et al. “Isokinetic In-line Sampling Enables Rapid Characterization of Atomizers and Cyclones for Spray Drying Process Development.” (2018).

Median mass aerodynamic diameter (MMAD) summary for all conditions tested. Blue represents the inline measurement at the beginning of the spray, green near the end of the spray, and red the collected sample measured using the APS disperser unit.

Aerodynamic particle size distribution for the control sample, which is representative of the distributions of the other conditions.

Inline isokinetic sampling device setup