Material & particle analysis - the microscopical path
Scott Aldrich, President of Ultramikro LLC, Particulate Matter Control Consulting, outlined a very logical approach to particle characterization techniques useful for the pharmaceutical scientist. Scott draws on 38 years of working experience with companies such as UpJohn and Pfizer, following both QA and R & D disciplines. His approach begins with keeping it simple, then expanding the analytical techniques once the initial properties of the particle have been established. Detect-Isolate-Categorize-Characterize-Identify are the basic steps taken along the path of particle analysis. The assets for this approach are that it is simple, direct, and practical, but the drawbacks include a long (never ending?) learning curve, a limited sample size, tedious work, and the need for reference materials. A good database of known materials is very important for the identification of unknown particulate matter.
Detection of particulate matter, whether intrinsic or extrinsic, remains a topic of debate among both analysist and manufacturer. About 70% of all particles detected are 150 micrometers or larger, wheras particles smaller than this fall into the "visible gray zone". Good eyesight and particle contrast assist immensely during the detection process, so understandably there can exist disagreements concerning the mere existence of a foreign particle. However, once the particle has been detected, a series of steps need to be taken to assure efficient characterization.
Observations include appearance, context, and nature of the particle; color, luster, transparency, homogeneity, association, habit (flake, rod, acicular, equant, tablet/plate, fiber, lath), size, interior and exterior content. Needless to say, it is critical to keep in mind the magnification at which you are studying the particle. First tests performed include physical assessments, such as pressing the particle to see if it is rubbery and oozing, or hard and brittle. Further tests involve heating the particle and noting behavior, being careful to keep any residue for further testing.
The next set of tests ascertain the solubility of the particle and the result of exposure to solvents, as well as humidification chamber exposure. This, in turn may be followed by a battery of selected microchemical and functional group tests based on the works of McCrone, Chamot, Winchell, and Feigl, to name a few.
Analytical electron microscopy (form, association, elemental info.), spectroscopy (infrared and Raman), mass spectrometry, and chromatography are the finishing touch techniques that hopefully finalize the characterization and identification of the particulate matter. It is the observations across all microscopies that keeps your eye on the prize...as Scott describes the particle chase... "Know it and pursue it."
Scott was generous enough to share some "Tricks of the Trade" in his presentation. Tiny particles can be difficult to work with, and one false move can result in the loss of the entire sample. Therefore, his first piece of advice is to maintain visual connection with the particle as much as possible while manipulating it. He also suggests changing the views often while studying the particle in the light microscope. Use not only transmitted light, but oblique and darkfield lighting as well. Other tips include waving a magnet near the particle for its reaction, and to try drawing the particle rather than just taking a micrograph, claiming that you learn more about the particle if you draw it.
Other tricks were revealed when Scott described a few of his particle isolation techniques. The use of a cat's whisker and Post-it notes mentioned as dry, direct removal methods caught my attention, and the remark "...anything by Anna Teetzov" will surely have me Googling her name as soon as I get the chance!