Microparticles in drug development and delivery
Microparticles, synthetic structures made from polymers, lipids, or inorganic materials, have the potential to increase therapeutic efficacy due to their ability to control drug release and to perform targeted drug delivery. To guarantee steady and predictable release, these formulations depend on precise control of microstructures, including drug dispersion, polymer matrices, and porosity.
Microparticle-based drug-delivery systems must be developed and marketed in accordance with stringent regulatory requirements to ensure quality, efficacy, and safety. Regulatory bodies such as the US FDA and the European Medicines Agency require detailed documentation and rigorous testing of drug-loaded microparticle, including pre-clinical trials, stability assessments, manufacturing process validation, along with extensive clinical trials. The reproducibility of particle parameters between batches is pivotal for regulatory compliance and the realization of consistent therapeutic effects.
Microparticle characterization
Particle size, morphology, aggregation, surface charge, drug loading efficiency, release kinetics, stability, and degradation behavior are some of the most important and commonly analyzed critical quality attributes (CQAs). While several different techniques can be used to determine individual CQAs, advanced scanning electron microscopy (SEM) and focused ion beam-SEM (FIB-SEM) are capable of analyzing multiple CQAs within a single workflow, greatly enhancing microparticle characterization.

Advanced scanning electron microscopy for the characterization of microparticles
Scanning electron microscopy is a powerful technique that can provide micro- to nano-scale information on microparticle drug formulations. SEM instruments can even perform elemental analysis with the addition of an energy-dispersive X-ray spectroscopy (EDS) detector. Overall, the ability of SEM to measure multiple CQAs makes it a vital tool for failure analysis, development, and quality control in drug formulation.
As an example, a study utilized SEM to visualize the surface characteristics of poly(lactic-co-glycolic acid) (PLGA) microspheres, including particle diameter, pore diameter, and porosity fraction.1 This provided crucial insight into how factors such as solvent type, along with polymer type, viscosity, and synthesis, affect microsphere porosity and morphology.

Testing the drug release profiles of porous and non-porous microspheres of similar mean size revealed significantly different release rates, indicating a positive correlation between porosity and higher drug release rate. This information is useful for the future design of microparticle drug formulations with desired drug release profiles.
FIB-SEM enables 3D characterization of microparticles
Drug release kinetics in microspheres are directly influenced by their interior microstructure, including pore networks and the distribution of polymers and active pharmaceutical ingredients (APIs). Current methods, like mercury intrusion porosimetry, optical microscopy, and computed tomography, lack the resolution and depth required for comprehensive 3D characterization, limiting insights into subsurface features.
FIB milling effectively addresses these challenges by using a highly focused beam of ions to precisely remove material from a surface without unintended mechanical damage to the sample. When combined with SEM imaging, this approach can provide insights into the internal microstructure of microspheres, quantifying drug particle and pore size distributions within the polymer matrix.

In a recent study, researchers used this approach to investigate the delayed drug release of risperidone, producing a PLGA–lipid hybrid microparticles that offered faster and more consistent release than drugs currently on the market.2 FIB-SEM and nano-computed tomography (nano-CT) were used to unravel the internal architecture of the risperidone-loaded PLGA–lipid hybrid microparticles. Precise milling and high-resolution imaging of cross-sections with FIB-SEM showed well-dispersed, spherical structures approximately 2 micrometers in diameter embedded within the PLGA matrix.

The FIB-SEM findings helped to reveal how multicore microdomain structural arrangement influences drug release behavior, directly linking microstructure to function. These insights helped validate the design strategy for improved and tunable release kinetics, making FIB-SEM a critical component in the formulation’s structural characterization.
In another study, FIB-SEM was used to investigate the effect of ageing on risperidone-loaded PLGA microspheres.3 Cross-sections of drug-loaded microparticles within (fresh) and beyond (aged) their shelf life were obtained by FIB milling. High-resolution SEM images of the particles then provided comparative characterization, revealing significant changes in morphology as the particles aged, including an increase in porosity and a decrease in polymer density. EDS analysis of the cross sections helped identify the API, polymer matrix, and pore distribution within the microspheres. Microstructural alterations could be directly linked to changes in drug release behavior, highlighting the importance of structural integrity for consistent therapeutic performance. These insights underscore the value of FIB-SEM in the assessment of drug stability and efficacy over time.

Implications for drug development
SEM and FIB-SEM are transformative tools for drug development, particularly in the design and optimization of microparticle-based advanced drug delivery systems. SEM provides high-resolution surface analysis, enabling precise assessment of particle size, shape, porosity, and surface integrity. FIB-SEM takes this a step further with 3D imaging, revealing internal microstructures that directly influence drug release kinetics and formulation performance. Together, these techniques enable the design of more effective, stable, and predictable drug delivery systems, ensuring compliance with stringent regulatory requirements and facilitating the successful transition from lab to clinic.
References
- Amoyav B and Benny O. Microfluidic based fabrication and characterization of highly porous polymeric microspheres. Polymers 11:3 (2019). doi: 10.3390/polym11030419
- Janich C, et al. Risperidone-loaded PLGA–lipid particles with improved release kinetics: Manufacturing and detailed characterization by electron microscopy and nano-CT. Pharmaceutics 11:12 (2019). doi: 10.3390/pharmaceutics11120665
- Clark AG, et al. Aging-induced microstructural evolution in risperidone loaded PLGA microspheres.Int J Pharm 675 (2025). doi: 10.1016/j.ijpharm.2025.125512
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