Thermo Fisher Scientific

Electron and cryo-electron microscopy stories and solutions about the advancement of cellular and structural biology

Accelerating ScienceLife in Atomic Resolution / Cryo-Electron Microscopy (Cryo-EM) / Drug Discovery / Analyzing Microparticles for Drug Delivery: the Critical Role of SEM and FIB-SEM Technology

Analyzing Microparticles for Drug Delivery: the Critical Role of SEM and FIB-SEM Technology

Written by Shrikant Harne, Manager, Vertical Marketing, Thermo Fisher Scientific | Published: 07.01.2025

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.

Table of analytical techniques and the critical quality attributes they reveal for drug development.
List of techniques and the critical quality attributes that they can provide. A correlative workflow consisting of Raman spectroscopy, Fourier-transform infrared spectroscopy (FTIR), and electron microscopy is indicated, and can be used to analyze the structure, composition, and properties of drug formulations.

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.

SEM imaging of microparticles with varying concentrations of PLGA.
SEM images of microspheres showing the effect of varying PLGA concentrations on particle porosity. An increase in PLGA concentration resulted in less porous particles. Figure adapted from Amoyav and Benny under CC BY 4.0.

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.

Schematic of microparticle FIB SEM milling.
Schematic representation of microparticle FIB milling and SEM imaging in a FIB-SEM.

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.

Microparticles loaded with isopropylmyristate, analyzed with FIB SEM.
SEM images of microcapsules loaded with isopropylmyristate (IPM), both intact (a, c) and FIB-milled (b, d). Particles exhibit spherical morphology with small crystals (red arrows) visible on their surface. Cross sections of the particles show multicore structures. Figure adapted from Janich et al. under CC BY 4.0.

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.

Risperidone-loaded PLGA microparticles analyzed with FIB SEM and EDS.
Characterization of risperidone-loaded PLGA microparticle with FIB-SEM and EDS. a) High-magnification SEM image of a cross-section. b) Close up view of the region within the blue box in (a) showing different phases (blue = risperidone crystals, red = pores, grey = PLGA). c,d) Cross sections of the fresh and aged microspheres with overlaid EDS segmentation. Figure adapted from Clark et al. under CC BY 4.0.

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

  1. Amoyav B and Benny O. Microfluidic based fabrication and characterization of highly porous polymeric microspheres. Polymers 11:3 (2019). doi: 10.3390/polym11030419
  2. 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
  3. 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

Learn how Thermo Scientific analytical tools support drug formulation and development >

A novel strategy for whole lung analysis with micro-optical sectioning tomography

A novel strategy for whole lung analysis with micro-optical sectioning tomography

Analysis of lung diseases Chronic obstructive pulmonary dise... by Rosa Pipitone / 06.20.2025

Read More

Cryo-TEM unlocks the potential of lipid nanoparticles for drug delivery

Lipid nanoparticles in drug development Lipid nanoparticles ... by Tilak Gupta / 05.21.2025

Read More
Fighting against antimicrobial resistance with next-generation antibiotics

Fighting against antimicrobial resistance with next-generation antibiotics

Bacterial pathogens, antimicrobial resistance, and antibioti... by Dominic Meusch / 02.04.2025

Read More
Finding new ways to treat pain with novel opioid receptor ligands

Finding new ways to treat pain with novel opioid receptor ligands

Analgesics, pain relief, and opioid addiction While pain man... by Alex Ilitchev / 10.28.2024

Read More

Shrikant Harne

Leave a Reply Cancel reply

Your email address will not be published. Required fields are marked *

Postmortem brain tissue imaging sheds light on cognitive function in life

Privacy StatementTerms & ConditionsLocationsSitemap

© 2025 Thermo Fisher Scientific. All Rights Reserved.

Talk to us

Notifications