Fluorescence-suppressed time-resolved Raman spectroscopy of pharmaceuticals using complementary metal-oxide semiconductor (CMOS) single-photon avalanche diode (SPAD) detector

Abstract

In this work, we utilize a short-wavelength, 532-nm picosecond pulsed laser coupled with a time-gated complementary metal-oxide semiconductor (CMOS) single-photon avalanche diode (SPAD) detector to acquire Raman spectra of several drugs of interest. With this approach, we are able to reveal previously unseen Raman features and suppress the fluorescence background of these drugs. Compared to traditional Raman setups, the present time-resolved technique has two major improvements. First, it is possible to overcome the strong fluorescence background that usually interferes with the much weaker Raman spectra. Second, using the high photon energy excitation light source, we are able to generate a stronger Raman signal compared to traditional instruments. In addition, observations in the time domain can be performed, thus enabling new capabilities in the field of Raman and fluorescence spectroscopy. With this system, we demonstrate for the first time the possibility of recording fluorescence-suppressed Raman spectra of solid, amorphous and crystalline, and non-photoluminescent and photoluminescent drugs such as caffeine, ranitidine hydrochloride, and indomethacin (amorphous and crystalline forms). The raw data acquired by utilizing only the picosecond pulsed laser and a CMOS SPAD detector could be used for identifying the compounds directly without any data processing. Moreover, to validate the accuracy of this time-resolved technique, we present density functional theory (DFT) calculations for a widely used gastric acid inhibitor, ranitidine hydrochloride. The obtained time-resolved Raman peaks were identified based on the calculations and existing literature. Raman spectra using non-time-resolved setups with continuous-wave 785- and 532-nm excitation lasers were used as reference data. Overall, this demonstration of time-resolved Raman and fluorescence measurements with a CMOS SPAD detector shows promise in diverse areas, including fundamental chemical research, the pharmaceutical setting, process analytical technology (PAT), and the life sciences.Graphical abstractTime-resolved Raman measurement of a pharmaceutical sample using the complementary metal-oxide semiconductor (CMOS) single photon avalanche diode (SPAD) detector technologyElectronic supplementary materialThe online version of this article (doi:10.1007/s00216-015-9156-6) contains supplementary material, which is available to authorized users.

SUPERTWIN: towards 100kpixel CMOS quantum image sensors for quantum optics applications

“…On top of this, a ring of two-rows and two columns of dead SPADs have been created at the boundary of each pixel to reduce crosstalk at the expense of lowering the FF. (2) is all the po ng the NW rosstalk eve efined as: ach of the th ransmitted anti-correlat entral anti-c l map of ph to the senso erently with r anti-corre e near field, pear as arti …”

“…Each pixel contains four time-gated SPADs and a Time-to-Digital Converter (TDC) that records the SPAD triggering time with 40ps resolution. The electronics fits in an area of 23.78×100µm 2 , achieving a 43.7% FF. In addition, the chip includes the circuitry to perform per-pixel Time-Correlated Single-Photon Counting (TCSPC) with 320ps binning and center of mass calculation.…”

“…For this reason, they represent a valid alternative to Electron-Multiplying CCDs (EMCCD). So far, CMOS SPAD technology has been applied (i) in biology for Fluorescence Lifetime Imaging Microscopy (FLIM) [1] and Raman Spectroscopy [2]; (ii) in the medical field for Positron Emission Tomography (PET) [3]; (iii) in the industrial/automotive/space domains for 3D Time-of-Flight (3D ToF) measurements [4,5,6]; and (iv) in cryptography for Quantum Random Number Generation (QRNG) [7]. Recently, CMOS SPAD consumer products entered the market as Light Detection And Ranging (LiDAR) devices for smartphone camera autofocusing [8].…”

Comparison of time‐gated surface‐enhanced raman spectroscopy (TG‐SERS) and classical SERS based monitoring of Escherichia coli cultivation samples

“…However, the broad application of Raman spectroscopy for the detection of compounds in the liquid phase upstream of microbial processes is mainly restricted to research purposes so far, although, in comparison to IR spectroscopic approaches, Raman bands of most analytes exhibit no interference with vibrations from water molecules . This is due to the basic drawback of Raman spectroscopy, i.e., data treatment and confidence limits are often not really optimized, and a high fluorescence background causes high threshold values for most analytes in biological samples, and thus a low sensitivity . In addition, the fluorescence background often dominates the Raman spectrum even when using common near‐infrared (NIR) laser excitation sources …”

“…While SERS reduces the fluorescence background by enhancing the Raman signal, time‐gating “gates out” not only the fluorescence, but also other disturbing signals like cosmic rays or room light . The TG‐Raman approach has reached the stage of a commercially available solution enabling routine process measurements.…”