Step-by-Step Guide to Conducting Particle Size Analysis for Granules Used in Tablets

What is Particle Size Analysis and Why is it Important?

Particle size analysis determines the distribution of particle sizes within a granulated batch used for tablet production. It is critical because particle size affects flowability, compressibility, dissolution, and uniformity of the final product. Accurate particle size analysis ensures batch consistency, improves tablet quality, and prevents manufacturing defects like weight variation and segregation.

This guide outlines the steps to conduct particle size analysis effectively.

Step 1: Select the Appropriate Analysis Method

Choosing the right method depends on the granule properties and desired accuracy. Common techniques include:

• Sieve Analysis: Suitable for large particles (50 µm to several millimeters) and provides size distribution through mechanical separation.
• Laser Diffraction: Ideal for a wide range of particle sizes (0.01–3000 µm) and provides rapid, high-resolution results.
• Dynamic Image Analysis: Captures real-time particle images to assess size and shape distributions.
• Microscopy: Used for small batches or specialized applications to measure particle dimensions manually.

Selecting the appropriate method ensures reliable and relevant results.

Step 2: Prepare the Granule Sample

Proper sample preparation ensures the results accurately reflect the batch. Steps include:

• Random Sampling: Collect a representative sample from different locations within the batch.
• Avoid Contamination: Use clean tools and containers to prevent introducing foreign particles.
• Drying: Ensure granules are free from excess moisture that may alter their size during analysis.

Well-prepared samples improve the accuracy and reliability of particle size analysis.

Step 3: Calibrate and Set Up the Equipment

Ensure the analysis equipment is calibrated for precise measurements. Recommendations include:

• Calibration Standards: Use certified reference materials with known particle sizes to verify equipment accuracy.
• Environmental Conditions: Perform the analysis in a controlled environment to prevent static or humidity interference.
• Settings Adjustment: Configure sieve apertures, laser parameters, or imaging software based on the granule size range.

Calibration ensures the equipment provides consistent and accurate measurements.

Step 4: Perform the Analysis

Conduct the particle size analysis using the selected method. Steps for each method include:

• Sieve Analysis:
  • Place the granule sample on a stack of sieves with decreasing aperture sizes.
  • Shake the sieves for a fixed time using a mechanical shaker.
  • Weigh the granules retained on each sieve to calculate size distribution.
• Laser Diffraction:
  • Dispense the granules into the laser diffraction analyzer.
  • Record the scattering patterns generated as the laser beam passes through the particles.
  • Use software to calculate the particle size distribution based on the scattering data.
• Dynamic Image Analysis:
  • Pass granules through the imaging chamber.
  • Capture real-time images of the particles.
  • Analyze the images using software to determine size and shape distribution.

Follow standardized protocols to ensure consistency and reproducibility.

Step 5: Analyze the Results

Evaluate the particle size distribution to ensure it meets process and product specifications. Key metrics include:

• D10, D50, D90: Report the particle sizes at 10%, 50%, and 90% cumulative distribution.
• Mean Particle Size: Calculate the average size to assess granule consistency.
• Shape Analysis: Identify irregular particles that may affect flow or compression.

Compare the results against predefined criteria to determine acceptability.

Step 6: Address Deviations in Particle Size

If the analysis reveals deviations, implement corrective actions. Common issues and solutions include:

• Excess Fines: Increase granulation time or reduce milling intensity to minimize fines.
• Oversized Particles: Adjust sieving or milling parameters to reduce large particles.
• Segregation: Re-blend the batch to achieve uniform particle distribution.

Proactive adjustments ensure batch quality and prevent downstream manufacturing issues.

Step 7: Document and Validate the Process

Thorough documentation and validation ensure compliance and reproducibility. Key steps include:

• Test Records: Maintain detailed records of the method, equipment settings, and results.
• Validation Studies: Validate the particle size analysis method to confirm its accuracy and reliability.
• Standard Operating Procedures (SOPs): Develop and implement SOPs to ensure consistency across batches.

Comprehensive documentation supports quality assurance and regulatory compliance.

Step 8: Integrate Particle Size Analysis into Process Control

Use particle size analysis results to optimize the manufacturing process. Recommendations include:

• Granulation Parameters: Adjust binder levels, mixing times, or drying conditions based on particle size data.
• Compression Efficiency: Ensure particle size supports uniform die filling and tablet strength.
• Dissolution Profile: Correlate particle size with drug release characteristics to achieve desired dissolution rates.

Integrating particle size analysis into process control improves product quality and consistency.

Conclusion

Conducting particle size analysis for granules used in tablets ensures batch uniformity and optimizes manufacturing processes. By selecting appropriate methods, calibrating equipment, and analyzing results effectively, manufacturers can prevent common issues like segregation and poor compressibility. Continuous monitoring and integration into process controls further enhance tablet quality and compliance with regulatory standards.