Developments in Scanning Electron Microscopy for Tablet and Granule Characterization

May 1, 2008
Pharmaceutical Technology

Volume 2008 Supplement, Issue 2

Recent advances in SEM, particularly the incorporation of automation and software, have made simpler, lower-end SEM instruments easy to operate and have improved the capabilities of larger, sophisticated instruments.

Scanning electron microscopy (SEM) provides a qualitative assessment of size, shape, morphology, porosity, size distribution, crystal form, and consistency of powders or compressed dosage forms (see Figure 1). This information can be correlated to assess dissolution behavior, bioavailability, and crystalline structure. SEM images also help analysts determine whether particles are maintaining desired physical characteristics during processing, including after compaction or direct compression (see Figures 2, 3).


As an analytical tool, electron microscopy in general has changed extensively, especially with the incorporation of automation and software. An SEM instrument in the 1940s, for example, had a resolving power of about 50 nm and a magnification of 8000×. Today, SEM devices have resolving power of 1 nm and a magnification as high as 400,000× (1). Simple, low-end SEM instruments now have touchscreen user interfaces and provide a fast visual inspection of samples. On the very high end, transmission electron microscopes have recently demonstrated the capability to identify individual atoms (2).


"Commonly called the laboratory 'workhorse,' microscopes have come a long way to the present day in terms of advancements in automation, higher precision, and better resolution," says Sharon Mathews, a research associate for Technical Insights at Frost & Sullivan. "With digital imaging gaining momentum in the recent years, microscope manufactures are now designing microscopes with image analysis at the forefront" (see sidebar, "Microscopy advances").

Microscopy advances

Mathews attributes the following factors as primary drivers to increasing use of microscopy:

  • Innovations in digital imaging: "Digital imaging offers numerous capabilities to the microscopy market opportunities in terms of enhanced features to extract information or modify the images captured. The convergence of digital imaging and information technology is enabling microscope manufacturers in tailoring their product offerings to suit the specific requirements."

  • Cost effectiveness and ease of operation: "With the diversity of the end-user and lower cost, the microscopy market is steadily growing. Simple automated systems are now increasing the usage of microscopes."

  • Novel applications: "The clinical market, namely, pathology, cytology, and hematology have greatly relied on microscopy over the years. Owing to new imaging applications and research funding, the pharmaceutical, academic, and government laboratories are now propelling the microscopy market. Live cell imaging, molecular imaging enabling identification of events at molecular level and specific applications such as dynamic behavior of cells ... has been responsible for the rapid progress of the microscopy market" (3).



Simple SEM. Traditional SEM analysis required trained operators who knew how to find and sharpen images using various controls on the instrument. "A lot of these labs are spending thousands of dollars looking at samples; and the lead time and preparation time needed to take these samples to contract labs is likely quite time consuming," says Joe Fillion, FEI (Hillsboro, OR). In 2007, FEI launched "Phenom," a tabletop point-and-shoot version of a traditional SEM. "We redesigned the entire user interface to be very intuitive. Operators simply touch the area you want to look at and you click a picture. Whereas a traditional method you may be turning dials for many minutes or hours in some cases. We're finding that pharmaceutical companies are using this in place of outsourcing their SEM work to analytical laboratories," says Fillion.


Traditional optical microscopes are incapable of capturing an image of the ever-smaller particles the industry is currently producing. "You can go to about 1000×, but it's very featureless and very flat," says Fillion. "Most of our customers want to see particles in the 3000–8000× range, where most of our customers use it. As these grain sizes get smaller, we're seeing a lot more interest in SEM. I've been told on a number of occasions that, as these particles get smaller and smaller, scientists want to be able to see the samples they are evaluating. They can do laser scattering to determine the distribution, but a picture is a powerful thing to see."

SEM–software combination. Sophisticated SEM instruments generate images uses low-energy secondary electrons "pulled" from the sample surface after impact with the electron as well as electron back scattering (elastic scattering from the high-energy electron beam) to generate an image. Trained operators use this combination to obtain detailed images and elemental information (see Figures 4, 5). Gaining clear definition of particle edges allows measurement of various parameters characterizing particle size, including the diameter and particle shape measurements encouraged in USP ‹776› "Microscopy."


Resent advances in high-end SEM instruments include the coupling of SEM visualization with statistical software. The software automatically provides direct measurements for several characterization parameters ("Quanta Morphologi," FEI Company and Malvern Instruments). The data for each particle can be stored with the image in a database and viewed at a later time.


To provide the resolution necessary to generate images that can be statistically analyzed, FEI had to modify its detectors. "The high energy primary electron beam causes low energy (secondary) electrons to emerge from the specimen and are then accelerate (pulled) toward the detector," says Ben Lich, strategic marketing manager of SEM and DualBeam at FEI. Using a standard secondary electron detector the particles in the image appear to be illuminated from one side only, resulting in a dark and a bright side. The company engineers created a special symmetrical secondary electron detector that eliminates this effect. "But when you do that, normally you will get a dark side of the object and a bright side of the object, with the bright side being the side facing," says Lich. "For particle detection this is not desired because you want a good impression of the outer area of the particle so you can do a precise measurement." Engineers then made a special detector that collects a secondary electron symmetrically around the column and around the primary beam, thereby providing uniform illumination of the entire specimen surface and a good definition of the edge around the entire particle.

The advances in SEM instrumentation are making it easier for tablet manufacturers looking into adding SEM instrumentation to their quality laboratories. "With a low-entry type of tool, people get exposed to electron microscopy and may then follow with a higher-end instrument," says Lich. "They find that it is not as hard as some people think it is."


1. All You Wanted to Know about Electron Microscopy (FEI Company, Hillsboro, OR).

2. D.A. Muller et al., "Atomic-Scale Chemical Imaging of Composition and Bonding by Aberration-Corrected Microscopy," Science 319 (5866), 1073–1076 (2008).

3. Advances in Optical Imaging (D0D2) and Emerging Technologies in Microscopy (D353) (Frost & Sullivan,