Dissolution testing is a crucial part of pharmaceutical dosage form investigations and is generally performed by analyzing the concentration of the released drug in a defined volume of flowing dissolution medium. As solid-state properties of the components affect dissolution behavior to a large and sometimes even unpredictable extent there is a strong need for monitoring and especially visualizing solid-state properties during dissolution testing. In this study coherent anti-Stokes Raman scattering (CARS) microscopy was used to visualize the solid-state properties of lipid-based oral dosage forms containing the model drug theophylline anhydrate during dissolution in real time. The drug release from the dosage form matrix was monitored with a spatial resolution of about 1.5 microm. In addition, as theophylline anhydrate tends to form the less soluble monohydrate during dissolution, CARS microscopy allowed the solid-state transformation of the drug to be spatially visualized. The results obtained by CARS microscopy revealed that the method used to combine lipid and active ingredient into a sustained release dosage form can influence the physicochemical behavior of the drug during dissolution. In this case, formation of theophylline monohydrate on the surface was visualized during dissolution with tablets compressed from powdered mixtures but not with solid lipid extrudates.

Abstract:In this article we show that heterodyne CARS, based on a controlled and stable phase-preserving chain, can be used to measure amplitude and phase information of molecular vibration modes. The technique is validated by a comparison of the imaginary part of the heterodyne CARS spectrum to the spontaneous Raman spectrum of polyethylene. The detection of the phase allows for rejection of the non-resonant background from the data. The resulting improvement of the signal to noise ratio is shown by measurements on a sample containing lipid.

In biological samples the resonant coherent anti-Stokes Raman scattering signal of less abundant constituents can be overwhelmed by the nonresonant background, preventing detection of those molecules. We demonstrate a method to obtain the phase of the oscillators in the focal volume that allows discrimination of those hidden molecules. The phase is measured with respect to the local excitation fields using a cascaded phase-preserving chain. It is measured point-by-point and takes into account refractive index changes in the sample, phase curvature over the field-of-view, and interferometric instabilities. The detection of the phase of the vibrational motion can be regarded as a vibrational extension of the linear (refractive index) phase contrast microscopy introduced by Zernike around 1933.

Abstract:We investigated the influence of thermal initiation pathway on the irradiance threshold for laser induced breakdown in transparent, absorbing and scattering phantoms. We observed a transition from laserinduced optical breakdown to laser-induced thermal breakdown as the absorption coefficient of the medium is increased. We found that the irradiance threshold after correction for the path length dependent absorption and scattering losses in the medium is lower due to the thermal pathway for the generation of seed electrons compared to the laser-induced optical breakdown. Furthermore, irradiance threshold gradually decreases with the increase in the absorption properties of the medium. Creating breakdown with lower irradiance threshold that is specific at the target chromophore can provide intrinsic target selectivity and improve safety and efficacy of skin treatment methods that use laser induced breakdown. Phys. 64(4), 1549-1554 (1976). 11. P. K. Kennedy, "A first-order model for computation of laser-induced breakdown thresholds in ocular and aqueous media. I. Theory," IEEE J. Quantum Electron. 31(12), 2241-2249 (1995). 12. D. X. Hammer, R. J. Thomas, G. D. Noojin, B. A. Rockwell, P. P. Kennedy, and W. P. Roach, "Experimental investigation of ultrashort pulse laser-induced breakdown thresholds in aqueous media," IEEE J. Quantum Electron. 32(4), 670-678 (1996). calculation of thresholds, absorption coefficients, and energy density," IEEE J. Quantum Electron. 35(8), 1156-1167 (1999

Abstract:We demonstrate heterodyne detection of CARS signals using a cascaded phase-preserving chain to generate the CARS input wavelengths and a coherent local oscillator. The heterodyne amplification by the local oscillator reveals a window for shot noise limited detection before the signal-to-noise is limited by amplitude fluctuations. We demonstrate an improvement in sensitivity by more than 3 orders of magnitude for detection using a photodiode. This will enable CARS microscopy to reveal concentrations below the current mMolar range.

In coherent anti-Stokes Raman scattering (CARS), the emitted signal carries both amplitude and phase information of the molecules in the focal volume. Most CARS experiments ignore the phase component, but its detection allows for two advantages over intensity-only CARS. First, the pure resonant response can be determined, and the nonresonant background rejected, by extracting the imaginary component of the complex response, enhancing the sensitivity of CARS measurements. Second, selectivity is increased via determination of the phase and amplitude, allowing separation of individual molecular components of a sample even when their vibrational bands overlap. Here, using vibrational phase contrast CARS (VPC-CARS), we demonstrate enhanced sensitivity in quantitative measurements of ethanol/methanol mixtures and increased selectivity in a heterogeneous mixture of plastics and water. This powerful technique opens a wide range of possibilities for studies of complicated systems where overlapping resonances limit standard methodologies.

An efficient, widely tunable, narrow-bandwidth, green-pumped, noncritical phase-matched lithium triborate based optical parametric oscillator (OPO) is applied to coherent anti-Stokes Raman scattering (CARS) spectroscopy and microscopy. The tunable signal beam (740–930nm) of the OPO is combined with the fundamental of a Nd:YVO4 pump laser (1064nm, 15ps) to obtain high resolution vibrational spectra of molecules around the CH vibrational stretch (2700–3100cm−1). The straightforward and convenient tunability of the OPO is demonstrated by CARS microscopy for the identification of different polymer microparticles on the same substrate.

The identification of large molecules in complex environments requires probing of multiple vibrational resonances rather than a single resonance. Phase-shaping the excitation pulses allows the coherent mixing of several resonances so that the presence of molecules can be inferred directly from the integrated output pulse energy. This avoids the need for the collection of spectra or multiple measurements. This article describes a particular implementation for coherent anti-Stokes Raman scattering microscopy that uses a broadband pump and probe field in combination with a narrowband Stokes field. We numerically study the possibilities of optimizing selectivity, specificity, and sensitivity by precalculating pulse shapes using an evolutionary algorithm.