Particle size distribution (PSD) is a critical quality attribute in pharmaceutical manufacturing, directly influencing powder flowability, compressibility, content uniformity, and dissolution behavior. During wet fluidized bed granulation, particles continuously evolve through nucleation, agglomeration, densification, and drying mechanisms, causing PSD to change throughout the process. Because these changes occur in a complex and nonlinear manner, manufacturers increasingly rely on Process Analytical Technology (PAT) tools to gain real-time insight into granule growth and support improved process control.
Wet fluidized bed granulation remains one of the most widely used particle engineering processes in pharmaceutical production. However, determining the optimal process endpoint can be difficult because particle growth dynamics vary throughout a batch. Traditional offline sampling approaches provide only limited snapshots of the process and may not capture critical changes as they occur.
Real-time laser diffraction (RT-LD) has emerged as a valuable technique for continuous particle size measurement because it can accurately characterize a wide range of particle sizes, including fine particles below 50 μm. Conventional online monitoring systems typically use Closed-Loop Circulation (CLC), where powder is continuously transported from the granulator through a measurement cell and returned to the process. While effective, this approach can introduce challenges related to sample residence time, wall deposition, continuous powder transport, and system installation requirements.
Recent developments in sampling technology have introduced the Micro Sampling Shutter (MSS) probe as an alternative approach for real-time particle size analysis. Rather than continuously circulating material, the MSS probe performs intermittent sampling by mechanically opening and closing a shutter to capture a small amount of powder only when measurements are required.
This design helps minimise particle residence time within the sampling system while maintaining purge airflow to reduce powder accumulation and carryover. By decreasing the likelihood of measurement artefacts associated with prolonged transport and deposition, intermittent sampling offers a potentially more representative view of the material inside the granulator.
The full application note examines the use of real-time laser diffraction combined with MSS technology during wet fluidized bed granulation. Comparative studies were performed using a model pharmaceutical formulation, with particle size distributions monitored using both conventional CLC sampling and MSS-based sampling approaches.
Key PSD metrics, including Dv10, Dv50, and Dv90, were tracked throughout the granulation process to evaluate how effectively each method captured particle growth behaviour. These volume-based percentile measurements provide insight into changes across the entire particle size distribution and are widely used in pharmaceutical process development and manufacturing.
The complete application note provides a detailed examination of:
As pharmaceutical manufacturers continue to adopt Quality by Design (QbD) principles and data-driven manufacturing strategies, access to accurate real-time process information becomes increasingly important. Reliable online PSD measurement can support enhanced process understanding, improved batch consistency, more informed decision-making, and stronger PAT implementation.
Innovations in sampling technology are helping overcome practical barriers associated with traditional monitoring systems while maintaining the analytical benefits of laser diffraction particle sizing. Understanding the capabilities and limitations of different sampling approaches is becoming increasingly relevant for organisations seeking to optimise granulation operations and strengthen process control strategies.
Register to access the complete application note and explore the experimental setup, sampling system design, comparative particle size measurements, and detailed discussion of real-time PSD monitoring using Micro Sampling Shutter technology. Learn how advanced particle sizing methods can support pharmaceutical process development, PAT initiatives, and improved granulation process understanding.
Particle Size Distribution (PSD) is one of the critical quality attributes (CQAs) that directly affects flowability, compressibility, content uniformity, and dissolution behavior. In wet fluidized bed granulation, which is fundamentally a batch process, PSD changes over time in a nonlinear manner as nucleation, agglomeration, and densification progress, making endpoint determination and process control challenging. Consequently, real-time PSD monitoring during fluidized bed granulation has attracted attention as a promising process monitoring approach.
Among the available techniques, online particle size analyzers based on laser diffraction, such as Insitec®, are a viable option because they can adequately sample fine particles down to sizes below 50 μm. However, several challenges remain in their implementation.
Traditionally, online PSD monitoring in such processes has been performed using a combination of Closed-Loop Circulation (CLC), in which powder is pneumatically conveyed using compressed air, and Real-Time Laser Diffraction (RT-LD). Although the CLC approach enables continuous measurement with high temporal resolution, excessive drying caused by continuous powder transport may affect the granulation process, depending on scale. In pharmaceutical manufacturing, contamination risks associated with the introduction of external air are also a concern.
Recently, a Micro Sampling Shutter (MSS) probe was developed, enabling an intermittent-sampling RT-LD approach #reference-1[1]. This application note reports a comparative evaluation of the measurement performance of the MSS and conventional CLC methods.
In the conventional CLC approach, powder is continuously aspirated under negative pressure, passed through the measurement cell, and returned to the process. Consequently, samples circulate through the transport line and may be influenced by residence time and wall deposition.
In contrast, the MSS approach uses a mechanical shutter to intermittently open and close the sampling port, collecting a small amount of sample only when required. By maintaining purge air even when the shutter is closed, powder accumulation and carryover are minimized, reducing measurement bias associated with sample residence time (Fig. 1).
![[AN260731-figure1.png] AN260731-figure1.png](/assets/AN260731-figure1_54-112889.png)
The actual system configuration and installation setup are shown in Figs. 2 and 3. In addition, whereas the CLC approach requires dedicated piping for each unit operation, the MSS approach employs a quick-connect design and can be operated as a portable unit, allowing it to be shared among multiple systems (Fig. 3).
![[AN260731-figure2.png] AN260731-figure2.png](/assets/AN260731-figure2_54-112890.png)
![[AN260731-figure3.png] AN260731-figure3.png](/assets/AN260731-figure3_54-112891.png)
Model wet fluidized bed granulation was performed using a placebo formulation manufactured at a collaborator’s facility. Two independent batches were prepared: one was evaluated using the CLC approach and the other using the MSS approach. Particle size measurements were conducted using the Insitec® system. For the MSS approach, samples were collected intermittently at predefined time intervals, and the PSD was determined by averaging data acquired over short measurement periods. The results are presented in Fig. 4.
![[AN260731-figure4.png] AN260731-figure4.png](/assets/AN260731-figure4_54-112892.png)
Dv10, Dv50, and Dv90 showed consistent increases with granulation time for both the MSS and CLC approaches. In this application note, the analysis focused on the stabilization period from 20 to 80 minutes. The measurement results obtained using the MSS and CLC methods showed good overall agreement. In particular, the differences between the two methods were minimal for Dv50 and Dv90. Although relatively large variations were observed for Dv10, the particle size change trends were consistently captured by both methods.
These results confirm that the MSS approach provides PSD tracking performance comparable to that of the continuous-sampling approach. In addition, maintaining purge air reduced sample residence time, which tended to suppress measurement bias arising from wall deposition and re-agglomeration.
Furthermore, because the MSS approach does not require continuous piping infrastructure and allows a single system to be shared among multiple units, it has the potential to substantially reduce capital investment costs. The shorter sample residence time associated with intermittent sampling also enables particle size measurements with reduced susceptibility to measurement artifacts under wet conditions.
Intermittent-sampling RT-LD using the MSS probe demonstrated PSD tracking performance comparable to that of the conventional CLC approach during wet fluidized bed granulation. In addition, reduced sample residence time and improved portability indicate its suitability as a flexible process analytical technology (PAT).
This application note is based on the results of a collaborative study with Towa Pharmaceutical Co., Ltd. For details, please refer to the cited reference.
[1] Sasakura, D., Sato, F., Horie, K., & Nakayama, K. (2026). A Flexible and Cost-Effective Real-Time Particle Size Monitoring Approach Using a Portable Micro-Sampling Probe in Fluidized Bed Granulation. Journal of Pharmaceutical Innovation, 21, 275. https://doi.org/10.1007/s12247-026-10553-7