(W0930-08-53) Assessment of Laser Directed Infrared Imaging for In Vitro Characterization of Pharmaceutical Tablets

Purpose: Vibrational spectroscopic imaging techniques allow for visual assessment and chemical identification of compounds within a wide variety of sample types and dosage forms. Non-destructive high resolution spectroscopic images can be collected by Raman mapping which can be a lengthy process for data collection with sufficient resolution. Near infrared (NIR) microscopy can improve the data collection times to minutes however has very low spatial resolution in comparison to Raman mapping. Conventional IR microscopy can provide high resolution but suffers from very long acquisition times. Quantum cascade laser (QCL) is a new advance in laser technology that emit all their output power in a single narrow range of wavenumbers with tunability of the laser. QCLs coupled with IR microscopy have resulted in an emerging technology known as laser direct infrared spectroscopy (LDIR) imaging that overcomes these challenges (resolution of image and data acquisition time) and allows for collection of spectroscopic images in minutes with high spatial resolution without losing critical physicochemical information such as chemical identity, particle size and shape, and distribution of components over large surface areas. LDIR could be an ideal technique for the characterization of complex generic drugs. However, commercially available LDIR technology is still in its infancy and thus this work will focus on evaluating LDIR imaging and comparing it to more conventional spectroscopic imaging approaches such as Raman mapping for in-house and over-the-counter (OTC) pharmaceutical tablets.

Methods: An LDIR imaging method was prepared with the library spectra of the active pharmaceutical ingredients (API) and excipients. Method was confirmed from point spectra and compared to the representative library. Midodrine HCl, prepared in-house as tablets with different proportion of API and two excipients (microcrystalline cellulose (MCC) and corn starch (CS)) were evaluated and assessed with LDIR spectroscopic imaging (Agilent 8700 LDIR chemical imaging system) and Raman mapping (Renishaw InVia Raman Microscope). Additionally, an OTC product (Excedrin^®) consisting of three different APIs was imaged and evaluated by both techniques. ImageJ analyses were executed to obtain the representation of components in a sample, feret diameter of particles (domain), and percent area coverages of the components.

Results: LDIR images of in-house midodrine HCl tablet is shown in Figure 1 demonstrating good agreement with the Raman mapping for the morphology, and percent area coverage (~ 1.33% in figure 1), though, LDIR reducing data collection time from 70 hours to 2 minutes. Feret diameter of specific particles in figure 1 and mean feret diameter in figure 1 (42 vs 50 µm) were smaller for LDIR images than Raman and number of individual particles (235 vs 185 in figure 1) was higher for LDIR images than Raman. Comparative LDIR and Raman images of OTC Excedrin tablet is shown in figure 2 and there were no significant differences in surface morphologies observed between both images, however, LDIR took 5 minutes and Raman took 5 days for data acquisition. ImageJ analyses were executed for both images. LDIR was able to detect a greater number of particles than Raman for caffeine and aspirin (see table 1). Mean feret diameter of the 3 APIs were smaller in LDIR images than Raman images which is consistent with in-house midodrine HCl tablet results. Percent area coverages were found close for all three APIs from LDIR and Raman imaging.

Conclusion: LDIR provided high resolution images comparable to Raman imaging, but with collection times on the order of minutes rather than the hours or days needed for Raman collection. LDIR imaging can detect both API and excipients in pharmaceutical products. Feret diameter of specific particles and mean feret diameter of particles found smaller in LDIR images than Raman. Percent area coverage by the API was found comparable by both method for in-house and over the counter (OTC) tablets. LDIR has potential as a rapid and non-destructive spectroscopic imaging technology for pharmaceutical analysis.

Acknowledgements: This project was supported in part by the FDA-CDER Critical Path Intramural Grants Program and by the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

Disclaimer: The findings and conclusions in this presentation reflects the views of the author and should not be construed to represent FDA’s views or policies.

Figure 1. LDIR (left) and Raman (right) chemical images of the same in-house prepared Midodrine HCl Tablet.

Figure 2. Comparative LDIR and Raman images of OTC Excedrin® tablet

Table 1. ImageJ analysis of Excedrin® OTC tablet for three APIs.