Label-Free Autofluorescence-Detected Mid-Infrared Photothermal Microscopy of Pharmaceutical Materials.

Label-free autofluorescence-detected photothermal mid-IR (AF-PTIR) microscopy is demonstrated experimentally and applied to test the distribution of active pharmaceutical ingredients (APIs) in a mixture containing representative pharmaceutical excipients. Two-photon excited UV-fluorescence (TPE-UVF) supports autofluorescence of native aromatic moieties using visible-light optics. Thermal modulation of the fluorescence quantum yield serves to report on infrared absorption, enabling infrared spectroscopy in the fingerprint region with a spatial resolution dictated by fluorescence. AF-PTIR provides high selectivity and sensitivity in image contrast for aromatic APIs, complementing broadly applicable optical photothermal IR (O-PTIR) microscopy based on photothermal modulation of refractive index/scattering. Mapping the API distribution is critical in designing processes for powdered dosage form manufacturing, with high spatial variance potentially producing variability in both delivered dosage and product efficacy. The ubiquity of aromatic moieties within API candidates suggests the viability of AF-PTIR in combination with O-PTIR to improve the confidence of chemical classification in spatially heterogeneous dosage forms.

Fluorescence-Detected Mid-Infrared Photothermal Microscopy.

We demonstrate instrumentation and methods to enable fluorescence-detected photothermal infrared (F-PTIR) microscopy and then demonstrate the utility of F-PTIR to characterize the composition within phase-separated domains of model amorphous solid dispersions (ASDs) induced by water sorption. In F-PTIR, temperature-dependent changes in fluorescence quantum efficiency are shown to sensitively report on highly localized absorption of mid-infrared radiation. The spatial resolution with which infrared spectroscopy can be performed is dictated by fluorescence microscopy, rather than the infrared wavelength. Intrinsic ultraviolet autofluorescence of tryptophan and protein microparticles enabled label-free F-PTIR microscopy. Following proof of concept F-PTIR demonstration on model systems of polyethylene glycol (PEG) and silica gel, F-PTIR enabled the characterization of chemical composition within inhomogeneous ritonavir/polyvinylpyrrolidone-vinyl acetate (PVPVA) amorphous dispersions. Phase separation is implicated in the observation of critical behaviors in ASD dissolution kinetics, with the results of F-PTIR supporting the formation of phase-separated drug-rich domains upon water sorption in spin-cast films.

Portable broadband photoacoustic spectroscopy for trace gas detection by quantum cascade laser arrays.

We report a portable broadband photoacoustic spectroscopic system for trace gas detection using distributed feedback quantum cascade laser arrays. By sequentially firing 128 lasers, our system acquires a photoacoustic spectrum covering 565cm-1 (935-1500cm-1) with a normalized-noise-equivalent-absorption coefficient of 2.5×10-9cm-1WHz-1/2. The firing sequence that determines when and which laser to activate is programmable, which enables frequency-multiplexing excitation. For demonstration, 12 lasers are modulated simultaneously at distinct frequencies, and a photoacoustic spectrum is acquired within 13 ms. The compactness (28cm×17cm×13cm, 3.5 kg) and low power consumption enable convenient installation for on-site monitoring.

Broadband detection of methane and nitrous oxide using a distributed-feedback quantum cascade laser array and quartz-enhanced photoacoustic sensing.

Here we report on the broadband detection of nitrous oxide (N2O) and methane (CH4) mixtures in dry nitrogen by using a quartz-enhanced photoacoustic (QEPAS) sensor exploiting an array of 32 distributed-feedback quantum cascade lasers, within a spectral emission range of 1190-1340 cm-1 as the excitation source. Methane detection down to a minimum detection limit of 200 ppb at 10 s lock-in integration time was achieved. The sensor demonstrated a linear response in the range of 200-1000 ppm. Three different mixtures of N2O and CH4 in nitrogen at atmospheric pressure have been analyzed. The capability of the developed QEPAS sensor to selectively determine the N2O and CH4 concentrations was demonstrated, in spite of significant overlap in their respective absorption spectra in the investigated spectral range.

Portable standoff spectrometer for hazard identification using integrated quantum cascade laser arrays from 6.5 to 11 µm.

This article presents new spectroscopic results in standoff chemical detection that are enabled by monolithic arrays of Distributed Feedback (DFB) Quantum Cascade Lasers (QCLs), with each array element at a slightly different wavelength than its neighbor. The standoff analysis of analyte/substrate pairs requires a laser source with characteristics offered uniquely by a QCL Array. This is particularly true for time-evolving liquid chemical warfare agent (CWA) analysis. In addition to describing the QCL array source developed for long wave infrared coverage, a description of an integrated prototype standoff detection system is provided. Experimental standoff detection results using the man-portable system for droplet examination from 1.3 meters are presented using the CWAs VX and T-mustard as test cases. Finally, we consider three significant challenges to working with droplets and liquid films in standoff spectroscopy: substrate uptake of the analyte, time-dependent droplet spread of the analyte, and variable substrate contributions to retrieved signals.

High tuning stability of sampled grating quantum cascade lasers.

Predictable tuning behavior and stable laser operation are both crucial for laser spectroscopy measurements. We report a sampled grating quantum cascade laser (QCL) with high spectral tuning stability over the entire tuning range. We have determined the minimum loss margin required to suppress undesired lasing modes in order to ensure predictable tuning behavior. We have quantified power fluctuations and drift of our devices by measuring the Allan deviation. To demonstrate the feasibility of sampled grating QCLs for high-precision molecular spectroscopy, we have built a simple transmission spectroscopy setup. Our results prove that sampled grating QCLs are suitable light sources for highly sensitive spectroscopy measurements.

Dispersion-compensated wavelength beam combining of quantum-cascade-laser arrays.

A multiwavelength array of distributed feedback (DFB) quantum cascade lasers (QCLs) that spans λ = 8.28 to 9.62 µm is wavelength beam combined (WBC) using both single-grating and dual-grating designs. WBC with a single grating results in a pointing error of 3-times the beam divergence for a single laser and arises from the nonlinear dispersion of the grating. By adding a second grating to compensate for the nonlinear dispersion, the pointing error is reduced to only 13% of the beam divergence for a single laser. A transceiver based on the dual-grating-WBC QCL was used to measure the transmittance of a polymer sheet placed between itself and a retroreflector over a round-trip distance of 70 meters.