Advanced Applications of Infrared and Raman Spectroscopy in Pharmaceutical Characterization

Infrared and Raman spectroscopy-based methods have served the pharmaceutical industry as routine chemical characterization tools for decades. Recently, implementation of tunable and coherent light sources such as quantum cascade lasers (QCL) instead of thermal light sources for infrared spectroscopy and use of narrowband optical filters, various excitation wavelengths and detection modalities in Raman spectroscopy have led to development of variant techniques designed to address specific challenges in pharmaceutical characterization. In this presentation, various distinct applications are demonstrated, each focusing on a certain analytical challenge and providing alternative or unique approaches for pharmaceutical products ranging from over-the-counter (OTC) products to complex formulations.

The first example in this presentation is development of a quantitative, through-container screening method for rapid and non-destructive screening of hand sanitizers. During the COVID-19 pandemic a large number of hand sanitizer products were allowed to enter the market. Some of these products were later found to be out of specification in terms of potency as well as contamination or substitution. Using spatially offset Raman spectroscopy (SORS) and support vector regression (SVR), active ingredients of 170 commercial and in-house products in various types of containers were identified and quantified and substandard samples were identified.

The second illustration of this presentation is development of an alternative solid state characterization method using low frequency Raman (LFR) spectroscopy. Ritonavir is a well-known drug product by analytical scientists due to its history of polymorphism, which is currently formulated as an amorphous solid dispersion (ASD) via hot-melt-extrusion (HME). Stability of ritonavir was initially evaluated using X-ray powder diffraction (XRPD) based validated methods after storage under accelerated conditions. The LFR-based quantitative method developed in this study was found to be as sensitive as the XRPD method yet highly practical, requiring only a 10 seconds per measurement compared with 66 minutes for XRPD.

In-line or at-line non-destructive characterization of coatings in pharmaceutical products such as tablets and capsules. This example demonstrates use of confocal Raman with single measurements to evaluate the coating thickness distributions of a dosage form comprised of small, functionally-coated pellets in capsules. Resulting distributions from the confocal Raman analysis correlate with dissolution profiles for enterically coated pellets, highlighting the power of the method as a process analytical tool to assure the quality of small enteric coated dosage forms.

Chemical imaging using infrared, and Raman based methods are powerful tools that allow structural, physical, and chemical visualization of pharmaceutical products and allow assessment of API distribution, particle size solid state analysis in steady-state conditions as well as in time-lapse or dissolution/drug release studies. Final examples in this presentation will focus on evaluation of chemical imaging techniques and development of methods to address analytical challenges in pharmaceutical characterization. First, Raman mapping of transdermal delivery systems in a time lapse study will be demonstrated, where recrystallization due to off-label modifications were identified and characterized. Second, an atomic force microscope (AFM) and QCL-based ultrahigh resolution chemical imaging method for visualization of API and excipient distribution in a complex nanomaterial containing product will be presented.