Particle Size Control: Balancing Solubility, Safety and Regulatory Compliance

Developing oral solid dosage (OSD) forms continues to be a priority for the pharmaceutical industry. While biopharmaceuticals often receive more attention, recent FDA approvals reveal that OSD products remain a very viable dosage form. In 2024, the Center for Drug Evaluation and Research (CDER) approved a total of 50 new drugs, of which 20 were OSD products — specifically, 14 tablets and six capsules — a strong showing for the OSD sector.

However, as increasingly potent and complex small molecules enter development pipelines, manufacturers face mounting challenges in formulating these compounds into effective oral medications. At the core of these challenges lies particle size control — a critical factor that directly impacts solubility, bioavailability, safety and regulatory compliance.

The Solubility Challenge in Modern Pharmaceuticals

The pharmaceutical industry is confronting a sobering reality: Over 90% of drug substances have bioavailability limitations, of which 70% are related to solubility challenges. This trend represents a fundamental shift in drug discovery outputs, as approximately 80% of candidates in development pipelines exhibit poor water solubility. This has created an urgent need for innovative approaches to overcome these limitations while maintaining the patient-centric advantages of oral administration.

The Biopharmaceutical Classification System (BCS) and, more recently, the Developability Classification System (DCS) categorize drugs based on their solubility and permeability characteristics. For molecules falling into DCS Class IIa, complete solubility is theoretically feasible, but formulation design must ensure the drug can freely disperse and dissolve. More challenging are DCS Class IIb and IV compounds, where oral absorption is fundamentally limited by solubility in the gastrointestinal tract — these molecules simply cannot fully dissolve during the three-hour transit time in the small intestine where most absorption occurs.

Particle Engineering Approaches for Enhanced Solubility

Particle size reduction is one of the most direct approaches to enhancing solubility. By decreasing particle dimensions, formulators can dramatically increase the surface area available for solvent interaction. Micronization, a relatively simple approach, reduces API particle size to increase surface area and improve dissolution rates.⁴ However, for more challenging compounds, more sophisticated particle engineering techniques are required.⁵

Nanomilling can reduce particles to precise and uniform sizes needed for controlled dissolution but requires specialized technologies and multiple process steps. This approach is particularly valuable for DCS Class IIa compounds where dissolution rate, rather than absolute solubility, is the limiting factor.

For crystalline APIs that exhibit particularly poor solubility, conversion to amorphous particle forms offers another solution pathway. Amorphous solid dispersions (ASDs) provide shaped particles with significantly greater surface area. The amorphous form, being thermodynamically less stable than crystalline forms, offers enhanced dissolution profiles and improved bioavailability. Studies indicate that more than 80% of amorphous dispersions deliver improved dissolution rates and bioavailability. However, this approach typically requires polymeric matrices to improve stability, adding formulation complexity.⁶

Advanced Analytical Methods for Particle Characterization

The evolution of particle characterization techniques has been instrumental in enabling sophisticated particle engineering approaches.⁵ Laser diffraction has emerged as the gold standard for particle size analysis across the pharmaceutical industry.7 This technique measures particle size distributions by analyzing the angular variation in light intensity scattered as a laser beam passes through a dispersed sample. Large particles scatter light at small angles relative to the beam, while small particles scatter at larger angles.⁸

The popularity of laser diffraction stems from several advantages: it provides rapid results (typically under one minute), offers excellent reproducibility, and can analyze both wet and dry samples.⁹ The technique can typically measure particles from approximately 0.02 micrometers up to 3500 micrometers, providing exceptional range for pharmaceutical applications.¹⁰ Laser diffraction is recognized by numerous standards organizations including ISO, ASTM, USP, EP and JP, making it ideal for regulatory submissions.¹⁰

For more complex formulations, particularly protein based therapeutics, newer technologies like flow imaging microscopy (FIM) provide enhanced capabilities.¹¹ FIM captures high-resolution images of individual particles in formulations, allowing for accurate particle count and size measurements across a wide range, including critical subvisible particles between 2 and 1000 μm.¹¹ This visual data is particularly valuable for identifying foreign particles or aggregates that may impact product safety.¹¹

Regulatory Considerations and Specifications

From a regulatory perspective, particle size control represents both a critical quality attribute and a compliance requirement.⁷ FDA guidance emphasizes several key principles for particle size analysis in pharmaceutical manufacturing. First and foremost, manufacturers should not compare particle sizes measured by different techniques, as each method may yield fundamentally different results even for the same material.⁷ Instead, they must select the appropriate analytical method for their specific application and consistently apply it throughout development and manufacturing.⁷

For formulations with broad particle size distributions, regulators emphasize controlling the entire distribution rather than simply the mean size.⁷ This is because two powders with identical mean particle sizes but different distributions can exhibit dramatically different performance characteristics.⁵ The D-values derived from particle size analysis (D10, D50 and D90, representing the sizes below which 10%, 50% and 90% of the particles fall) are commonly used to establish control strategies.⁵

When establishing acceptance criteria for particle size specifications, the FDA recommends that the acceptance range should correspond directly to the performance or manufacturability of the drug product. Typically, a one sided limit is not acceptable without adequate scientific justification. These specifications are determined through design of experiment (DoE) studies or by leveraging prior process knowledge.⁵

Real-Time Monitoring and Process Control

The implementation of Process Analytical Technology (PAT) for particle size monitoring represents a significant advancement in pharmaceutical manufacturing. In-process particle size analysis provides real-time information that enables continuous process monitoring and control, facilitating Quality by Design (QbD) approaches. This is particularly critical at key process stages where particle properties directly impact product quality.⁷

For OSD manufacturing, in-process particle size analysis is valuable at multiple points in the manufacturing process: after milling operations, during wet granulation endpoint determination, after drying processes, and prior to tablet compression.⁷ Real-time feedback at these points allows manufacturers to adjust process parameters to maintain particle size specifications, preventing downstream issues like poor flow properties, content uniformity problems, or inconsistent dissolution profiles.⁷ The industry transition toward continuous manufacturing makes real-time particle monitoring even more essential, as it enables closed-loop control systems that can automatically adjust process parameters to maintain target particle attributes. This approach not only improves product consistency but also enhances manufacturing efficiency and reduces waste.⁷

Balancing Bioavailability with Manufacturing Scalability

The ultimate challenge for pharmaceutical manufacturers is balancing the theoretical benefits of particle size optimization with the practical realities of large-scale production. While nanoscale particles may offer superior dissolution properties in laboratory settings, their production at commercial scale presents numerous challenges. Fine particles often exhibit poor flowability, increased electrostatic properties, and greater susceptibility to agglomeration — all of which can compromise manufacturing efficiency and product uniformity.⁶

Formulation scientists must carefully consider the entire manufacturing process when selecting particle engineering approaches.³ For molecules falling into DCS class IIa, complete solubility is feasible with appropriate particle size control, making techniques like micronization and controlled crystallization potentially cost-effective options.³ However, for more challenging DCS class IIb compounds, more advanced technologies like amorphous solid dispersions may be necessary despite their greater manufacturing complexity.³

The Future of Particle Engineering in Pharmaceuticals

As the pharmaceutical industry continues to develop increasingly complex molecules with solubility challenges, particle size control will remain a cornerstone of effective OSD formulation. The integration of advanced analytical methods, real-time monitoring capabilities, and innovative formulation technologies provides manufacturers with the tools needed to overcome these challenges while meeting regulatory requirements.⁵

The future of particle engineering in pharmaceuticals will likely see further refinement of existing technologies alongside the development of novel approaches. By embracing these innovations while maintaining a focus on manufacturing practicality, the industry can continue to deliver effective oral medications that maximize patient benefit while ensuring consistent quality and regulatory compliance.⁵

References

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3. Savla, R., Tindal, S. (2017). Particle Engineering for Improved Bioavailability in Oral Solid Dose Medications. American Pharmaceutical Review.
4. Patil, V. (2020). Dissolving Bioavailability & Solubility Challenges in Formulation & Development. Drug Development & Delivery.
5. How to Establish a Particle Size Specification for OSD Control. (2023). Innopharma Technology.
6. Lilitorp, K. (2024, Oct). Why does Particle Size Matter for Pharmaceuticals? Particle Analytical.
7. Sun, Z. (2011). In-Process Particle Size Analysis: Regulatory Perspective. PQRI Workshop. FDA. [Presentation].
8. Rastogi, S. What is Oral Solid Dosage? Vici Health Sciences. 
9. Light Scattering/Laser Diffraction. Malvern Panalytical. [accessed May 2025].
10. Laser Diffraction Particle Size Analysis. (2016, Dec). Pharmaceutical Networking.
11. Laser Diffraction. (2023). Particle Technology Labs. [accessed May 2025].
12. Daniels, A. (2025). How Flow Imaging Microscopy Helps QA in Drug Formulation Development. Fluid Imaging Technologies. Yokogawa