Using SEM/EDX for Particle Characterization in the Drug Manufacturing Process

Drug manufacturing processes―especially production of drugs delivered through inhalation―must have strict control over contaminate particles. Numerous methodologies allow companies to monitor these particles, the challenge is gathering the information quickly enough in order to be able to detect manufacturing problems. Furthermore, the information provided by standard particle classification instruments typically includes only size and shape. While process control can be maintained with just this information, the ability to determine the chemistry of composition for each of these particles would be a benefit to the researcher or production engineer.

Scanning electron microscopy (SEM) with energy dispersive x-ray spectrometry (EDX) for particle characterization using an automated electron beam can be used to monitor the production process. Electron microscopy provides not just visual information about the organic and inorganic sub-micron particles (size, shape, and morphology), but also chemical identification based on the X-ray energy lines. By automating this process, users can characterize thousands of particles within minutes.

Typically a traditional SEM/EDX will image particles much like a camera. A traditional SEM/EDX analysis requires three separate scans of the same particle: one to locate the particle, one to identify the particle size and shape, and the third to collect the particle chemistry. Unfortunately, while all of this is occurring, the electron beam could shift, causing the second or third scans of the particle to provide incorrect information―resulting in “false positives” for size or chemical characterization.

The automated electron beam used on ASPEX SEM/EDX systems collects all of this data simultaneously. Instead of imaging each field and processing that image, an automated electron beam subdivides the stage fields into smaller magnification fields that can be individually defined by deflecting the beam. The beam is then moved across these fields in fairly coarse steps while monitoring the brightness of the backscatter electron detector (BSED) signal. If a particle is detected, a sizing sequence is initiated using several different algorithms to determine the size and shape of the particle. Once the algorithm completes the particle measurements, the beam is automatically moved back to the center of the particle and an X-ray spectrum of the particle is collected. This happens in less than one second(0.2 seconds)once the edge of the particle is detected via the change in brightness of the BSED. Because of the automated nature of the electron beam, particle data collection can be performed in minutes for one sample where it would take up to five hours on a traditional SEM/EDX.

The sample preparation can be completed within minutes. Active solid powders can be dispersed on an adhesive surface and analyzed nondestructively. Active particulate material and precipitates in diluent samples are recovered using standard filtration methods. Specifically, polycarbonate filter membranes with varying pore sizes are used to collect all particles and air dried prior to the automated analysis (Figure 1). The ASPEX SEM/EDX has a variable pressure (low vacuum) setting that allows analysis of non-conductive filter membranes containing the particles of interest just minutes after the sample has been prepared.

In the pharmaceutical industry, electron microscopy testing is conducted regularly not only to investigate the nature of foreign particles, but also to determine the design and efficacy of powder products. For example, the shape, diameter, and asperity of particles provide insight in the inhalation properties of dry powder inhalers with carrier particles. The size, morphology, and surface properties are modified during the development phase to optimize dispersion and overcome problems associated with agglomeration. These changes in production can occur real-time if this technology is applied to the manufacturing process. Thanks to the speed of the particle characterization, changes can be made to production that result in cost savings for drugmakers.

About the authors
Sue Benes conducts research and development of applications around ASPEX’s product portfolio, while monitoring the needs of the customers and incorporating those into the applications. Marie Vicéns, PhD directly supervises all daily laboratory functions, develops analytical services business, and supports the ASPEX sales team.