Confocal Raman Microscopy in Forensic Pharmaceutical Investigations

Feb 01, 2012
By Spectroscopy Editors
Volume 27, Issue 2

Scanning electron microscopy with energy dispersive X-ray spectrometry (SEM-EDS) and Fourier-transform infrared microspectrophotometry (micro-FT-IR) have been widely demonstrated as complementary analytical tools for the identification of complex mixtures and unknown materials. However, there is a gap between the information provided by these two techniques. Even though elemental and morphological information is obtained on small single particles with SEM-EDS technology, no molecular or structural information is available. Likewise, although chemical information can be acquired using FT-IR, analysis of small single particles is significantly limited. We applied confocal Raman microscopy (CRM) in our laboratory to bridge the gap between FT-IR and SEM, and it provided chemical and vibrational information on a scale approaching the resolution of an SEM. In one application, monomer solutions used during a contact lens manufacturing process exhibited haze that was related to particulate contamination. The particles were isolated and analyzed by CRM, SEM, and micro-FT-IR. The particle size range was about 1–500 µm. Particles <50 µm were analyzed and identified by Raman spectroscopy and SEM. Particles >50 µm were analyzed and identified by micro-FT-IR and SEM. Numerous materials associated with the manufacturing process of the monomer were identified, as well as foreign materials. The identification of the particulate materials causing the haze of the monomer assisted the manufacturer in determining the sources of the contamination and improving the quality of the product.

Raman spectroscopy is an ideal technique for analyzing product contaminants. Many materials can be identified by their Raman spectra, including minerals, dyes and pigments, polymers, and drugs. Raman microscopy has high spatial resolution, excellent sensitivity, and can quickly obtain spectral data. The technique often requires little-to-no sample preparation, and it is possible to collect spectra of materials through glass, plastics, and aqueous solutions. The ability to acquire spectral data without sample preparation limits accidental contamination and loss of the particle or material of interest (1). The technique is nondestructive in most applications. Confocal Raman microscopy (CRM) is especially useful for obtaining depth profiles (xz scans) without conventional cross-sectioning of the samples (2–4). The ability to obtain vibrational spectra of small particles (<1–50 µm) complements the data obtained by the more traditional techniques of micro Fourier-transform infrared (micro-FT-IR) and scanning electron microscopy with energy dispersive X-ray spectrometry (SEM-EDS) (5–7). Raman spectroscopy is a particularly useful method for applications in the pharmaceutical, biomedical device, and consumer health products industries.

Janet Woodcock's article "The Concept of Pharmaceutical Quality" describes the Food and Drug Administration's (FDA) perspective on the quality of pharmaceuticals and highlights the efforts and financial resources invested to protect the health and safety of consumers (8). Forensic investigations in the pharmaceutical industry began with examinations of counterfeit and adulterated drug products (9,10). This area now extends to quality-related issues in manufacturing processes, including consumer health products, drug tablets and capsules, implantable medical devices, surgical equipment and supplies, and ophthalmic lenses.

Monomer solutions are used in a variety of applications, including hard and soft contact lenses; a novel application reported in the literature is the use of contact lenses for delivery of controlled release drugs directly to the eye (11). Contamination of the monomer may reduce biocompatibility and permeability of the lens. Not only is the biocompatibility of the polymer important, it also must be produced in such a way that any residual monomer or solution does not pose a health risk (12). In general, high quality, inclusion-free polymers are equally important to all industries where a transparent polymer is required. Depending on the application, inclusions may result in reduced visibility and unintentional reflection or refraction of light.

In a recent case, inspection of monomers intended for use in the production of lenses revealed hazy solutions. These monomers did not meet the standard criteria for the final product manufacture, which requires a colorless, transparent polymer lens. MVA Scientific Consultants (Duluth, Georgia) was asked to investigate the nature of the haze in the monomer and intermediate product solutions and determine the source of the problem. The monomer is a proprietary formula consisting of multiple components, including but not limited to, silicone, fluoropolymer, organotin, acrylic, and isocyanate compounds.

This article describes the use of confocal Raman microscopy for the identification of particles in the 5–50 µm range and illustrates how it bridges the gap between micro-FT-IR and SEM-EDS analyses. The use of these complementary techniques in the pharmaceutical and allied industries is widely reported in the literature, especially for analyses and identification of small particles (6,7,10,13–16).

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