Tablets

Contamination on tablets is well addressed by microscopical techniques.  Some surface contaminants are actually a clump of ingredient that is not properly dispersed.  Gray or black spots may be caused by a number of tiny metal particles (wear or corrosion particles) that are mixed with tablet material causing a dark particle.  Tan or brown particles on or in tablets are frequently found to be thermally degraded (charred) excipient material. 

click image to enlarge (147K) FIGURE 14 Raman spectrum of a reflective flake from a pharmaceutical product compared to a Raman spectrum of graphite.

Using Raman microscopy, surface defects may be analyzed directly with no sample preparation needed.  One example involved a tablet that supported a number of silver reflective particles on the surface that initially appeared to be metallic.  EDS analysis indicated only carbon and oxygen were present.  Light microscopical analysis at high magnification showed that the reflective particles had a platy morphology that was consistent with graphite.  In situ Raman analysis confirmed the presence of graphite (Figure 14).  Graphite can be easily distinguished from other phases of carbon by the strong, sharp band that occurs around 1590 cm^-1.   

Defects that are caused by processing agents, such as lubricants on tablets, are sometimes difficult to identify.  The lubricant is intermixed with the tablet material and an infrared spectrum of the defect material contains bands due to the tablet excipients in addition to the contaminant.  The bands due to the contaminant frequently are masked by those of the tablet material.  Lubricant oils may be isolated from tablets using microextraction techniques.  The tan discoloration on the surface of a tablet (Figure 15a) was extracted using a glass capillary micropipette and solvent.  The FTIR spectrum of the extracted material is shown in Figure 15b.  The primary bands are characteristic of hydrocarbon oils. 

click image to enlarge (43K)     FIGURE 15a FTIR spectrum of oily residue extracted from a tan defect on a pharmaceutical tablet.

click image to enlarge (48K) FIGURE 15b The spectrum is consistent with hydrocarbon oil.

Yellow stains on tablets are somewhat common, but are usually problematic to identify.  The discoloration can vary from a faint tan to orange yellow.  The cause of the discoloration is frequently difficult to detect analytically.  In a few cases, evidence of an active ingredient other than that found in the tablet has been detected.  One particular tablet supported a yellow stain over almost the entire white coating.  Initial FTIR analysis of the yellow stain indicated only components that could be attributable to the coating.  A second stereoscopic examination of the tablet indicated that there were some orange spots scattered on the surface.  The FTIR spectrum of an orange spot within the yellow coating was consistent with that of sulfasalazine.  There is a published report (5) of orange stains on Daypro^® tablets that were identified as sulfasalazine.   This active ingredient was not present in the manufacturing facility where the tablet was produced.  It was deduced that the tablets were contaminated with sulfasalazine dust in a dispensing tray at a pharmacy.  The article (5) may be consulted for further information concerning the Daypro investigation.

Summary

Successful microscopical analysis of particulate contamination begins with good communication between analyst and client.  The optical examination, using a stereomicroscope and a polarizing light microscope, enables the analyst to characterize the contaminant and chose the appropriate sample isolation technique.  Analytical methods that are optimized for small particle analysis, such as FTIR microspectrometry, Raman microspectrometry and SEM/EDS permit chemical identification of particles that are too small for conventional chemical analysis.  The results of the optical examination, coupled with the chemical data, usually enable the client to identify the source of the contamination.

References

1. Teetsov, Anna S. (1995) Unique Preparation Techniques for Nanogram Samples, in Practical Guide to Infrared Microspectroscopy (H. Humecki, ed.), Marcel Dekker, Inc., New York, 417-443.

2. Teetsov, Anna, Preparation and Use of Needles and Micropipets for Handling Very Small Particles, The Microscope, 1999, 47, 63-70.

3. Teetsov, Anna, An Organized Approach to Isolating and Mounting Small Particles for Polarized Light Microscopy; The Microscope, 2002, 50, 159-168.

4. McCrone, W. C. and J. G. Delly, The Particle Atlas, Ed. 2, Vol. 1, 1973, 228-229.

5. Schmann, Steven C., Investigation of Product Complaints About a Prescription Drug: Implications for Pharmacy Practice and Development Pharmaceutics; Journal of the American Pharmaceutical Association, 2000, 40, 89-92.

Acknowledgements

The author gratefully acknowledges Joe Barabe, John Delly and Bonnie Betty for their assistance in preparing this paper.  The author also thanks Dr. Kenneth Smith and Barbara Blaum for their contributions to the manuscript.