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. 2018 Apr 3;90(7):4832-4839.
doi: 10.1021/acs.analchem.8b00298. Epub 2018 Mar 19.

Time-Gated Raman Spectroscopy for Quantitative Determination of Solid-State Forms of Fluorescent Pharmaceuticals

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Free PMC article

Time-Gated Raman Spectroscopy for Quantitative Determination of Solid-State Forms of Fluorescent Pharmaceuticals

Tiina Lipiäinen et al. Anal Chem. .
Free PMC article

Abstract

Raman spectroscopy is widely used for quantitative pharmaceutical analysis, but a common obstacle to its use is sample fluorescence masking the Raman signal. Time-gating provides an instrument-based method for rejecting fluorescence through temporal resolution of the spectral signal and allows Raman spectra of fluorescent materials to be obtained. An additional practical advantage is that analysis is possible in ambient lighting. This study assesses the efficacy of time-gated Raman spectroscopy for the quantitative measurement of fluorescent pharmaceuticals. Time-gated Raman spectroscopy with a 128 × (2) × 4 CMOS SPAD detector was applied for quantitative analysis of ternary mixtures of solid-state forms of the model drug, piroxicam (PRX). Partial least-squares (PLS) regression allowed quantification, with Raman-active time domain selection (based on visual inspection) improving performance. Model performance was further improved by using kernel-based regularized least-squares (RLS) regression with greedy feature selection in which the data use in both the Raman shift and time dimensions was statistically optimized. Overall, time-gated Raman spectroscopy, especially with optimized data analysis in both the spectral and time dimensions, shows potential for sensitive and relatively routine quantitative analysis of photoluminescent pharmaceuticals during drug development and manufacturing.

Conflict of interest statement

The authors declare the following competing financial interest(s): Lauri Kurki and Mari Tenhunen are affiliated with the company that commercialized the CMOS SPAD detector technology used in this research.

Figures

Figure 1
Figure 1
Relative lifetimes (not to scale) of Raman and photoluminescence (including fluorescence) signals (adapted from ref (25)).
Figure 2
Figure 2
Mixture design employed in the experiments.
Figure 3
Figure 3
(a) Schematic of the time-gated Raman instrument used for obtaining the Raman spectra and performing fluorescence rejection and (b) basis for bin 3 selection. The four bins collect the scattered photons with different delays and the intensity of the obtained signal varies. Bin 3 provided the strongest signal at the optimal time frame for detection of Raman scattered photons for PRX.
Figure 4
Figure 4
Raman spectra obtained with (a) the CW Raman setup, (b) the time-gated Raman instrument, presented as sum spectra from 0 to 5.5 ns, and (c) the time-gated Raman instrument, presented as spectra after fluorescence rejection. The Raman intensity scale is the same for each solid-state form but different for each of the three columns for clarity.
Figure 5
Figure 5
3D spectra obtained with time-gated Raman of (a) raw spectrum (form β), (b) baseline spectrum (form β), (c) Raman spectrum (form β), (d) raw spectrum (form α2), (e) baseline spectrum (form α2), (f) Raman spectrum (form α2), (g) raw spectrum (MH), (h) baseline spectrum (MH), and (i) Raman spectrum (MH).
Figure 6
Figure 6
Leave-one-out cross-validation mean squared error (LOOCV-MSE) results from one round of the inner-loop of the kernel-based RLS model, where the model tries to find optimal parameters (time-interval, σ2, λ) based on the LOOCV-MSE. The X-axis represents the number of different time intervals tested during each round of the model construction to find the optimal time interval along with the other optimal model parameters. The time interval corresponding to the lowest LOOCV-MSE was 0.25–0.6 ns in this example.

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