Comparison of the Determination of a Low-Concentration Active Ingredient in Pharmaceutical Tablets by Backscatter and Transmission Raman Spectrometry

Abstract

A total of 383 tablets of a pharmaceutical product were analyzed by backscatter and transmission Raman spectrometry to determine the concentration of an active pharmaceutical ingredient (API), chlorpheniramine maleate, at the 2% m/m (4 mg) level. As the exact composition of the tablets was unknown, external calibration samples were prepared from chlorpheniramine maleate and microcrystalline cellulose (Avicel) of different particle size. The API peak at 1594 cm(-1) in the second derivative Raman spectra was used to generate linear calibration models. The API concentration predicted using backscatter Raman measurements was relatively insensitive to the particle size of Avicel. With transmission, however, particle size effects were greater and accurate prediction of the API content was only possible when the photon propagation properties of the calibration and sample tablets were matched. Good agreement was obtained with HPLC analysis when matched calibration tablets were used for both modes. When the calibration and sample tablets are not chemically matched, spectral normalization based on calculation of relative intensities cannot be used to reduce the effects of differences in physical properties. The main conclusion is that although better for whole tablet analysis, transmission Raman is more sensitive to differences in the photon propagation properties of the calibration and sample tablets.

Matrix Effects in Quantitative Assessment of Pharmaceutical Tablets Using Transmission Raman and Near-Infrared (NIR) Spectroscopy

“…38 Their results contradict the later findings of Townshend et al, that quantitative assessment with transmission Raman spectroscopy was more sensitive to a mismatch in particle size of the filler between the calibration and test sets than was Raman spectroscopy in backscatter geometry. 34 The present study confirms that transmission Raman spectroscopy is indeed sensitive to variations in the particle size of the drug substance and of the filler, as well as of other matrix effects, such as tablet hardness (here expressed as compression force). We believe that in backscatter mode, the effect of sampling volume is a statistical phenomenon related to the number of particles of the drug substance.…”

“…Investigations of the influence of particle size in the literature have shown a varying degree of sensitivity to variation in particle size, although it has been suggested that transmission Raman is more sensitive than backscatter Raman owing to the significantly longer optical path length. 34 Their suggestion, however, is not in agreement with the findings of Hu et al, 38 who concluded that if the sampling volume is much larger than the particle size, the Raman signal intensity should not be affected by particle size. A proposed method for handling sensitivity to particle size in quantitative Raman analysis is simply to make sure that calibrations are made on a size range relevant to the actual samples.…”

“…We here report large matrix effects also on transmission Raman spectra, in accordance with similar effects reported. 30,32,–36…”

“…The influence of pharmaceutical material properties on optical spectroscopy techniques has been studied and shown to be of great importance. 28,–37 Dry pharmaceutical powders and powder blends are highly turbid media with significant elastic scattering and, in most wavelength bands, low absorption, resulting in potentially large effects on spectra and quantitative calibrations. Investigations of the influence of particle size in the literature have shown a varying degree of sensitivity to variation in particle size, although it has been suggested that transmission Raman is more sensitive than backscatter Raman owing to the significantly longer optical path length.…”

“…A proposed method for handling sensitivity to particle size in quantitative Raman analysis is simply to make sure that calibrations are made on a size range relevant to the actual samples. 34,38…”