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The use of nonlinear optical Stokes ellipsometric (NOSE) microscopy for rapid discrimination of two polymorphic forms of the small molecule D-mannitol is presented. Fast (8 MHz) polarization modulated beamscanning microscopy and a recently developed iterative, nonlinear least-squares fitting algorithm were combined to allow discrimination of orthorhombic and monoclinic crystal structures of i>mannitol with data acquisition times of <7 s per field of view with a signal-to-noise ratio (SNR) of ~300. Discrimination between polymorphic forms within the 99.99% confidence interval was achieved by standard statistical tests of the recovered probability density functions for the measured observables following two class linear discriminant analysis. These measurements target bottlenecks in small-volume, high-throughput solid form screening experiments for polymorph discovery in the development of emerging active pharmaceutical ingredients. [ABSTRACT FROM AUTHOR]

Here we demonstrate the use of second harmonic generation (SHG) microscopy-guided synchrotron powder X-ray diffraction (PXRD) for the detection of trace crystalline active pharmaceutical ingredients in a common polymer blend. The combined instrument is capable of detecting 100 ppm crystalline ritonavir in an amorphous hydroxypropyl methylcellulose matrix with a high signal-to-noise ratio (>5000). The high spatial resolution afforded by SHG microscopy allows for the use of a minibeam collimator to reduce the total volume of material probed by synchrotron PXRD. The reduction in probed volume results in reduced background from amorphous material. The ability to detect low crystalline loading has the potential to improve measurements in the formulation pipeline for pharmaceutical solid dispersions, for which even trace quantities of crystalline active ingredients can negatively impact the stability and bioavailability of the final drug product. [ABSTRACT FROM AUTHOR]

A digital filter derived from linear discriminant analysis (LDA) is developed for recovering impulse responses in photon counting from a high speed photodetector (rise time of ~1 ns) and applied to remove ringing distortions from impedance mismatch in multiphoton fluorescence microscopy. Training of the digital filter was achieved by defining temporally coincident and noncoincident transients and identifying the projection within filter-space that best separated the two classes. Once trained, data analysis by digital filtering can be performed quickly. Assessment of the reliability of the approach was performed through comparisons of simulated voltage transients, in which the ground truth results were known a priori. The LDA filter was also found to recover deconvolved impulses for single photon counting from highly distorted ringing waveforms from an impedance mismatched photomultiplier tube. The LDA filter was successful in removing these ringing distortions from two-photon excited fluorescence micrographs and through data simulations was found to extend the dynamic range of photon counting by approximately 3 orders of magnitude through minimization of detector paralysis. [ABSTRACT FROM AUTHOR]

Tuning ion energies in plasma-enhanced atomic layer deposition (PEALD) processes enables fine control over the material properties of functional coatings. The growth, structural, mechanical, and optical properties of HfO 2 thin films are presented in detail toward photonic applications. The influence of the film thickness and bias value on the properties of HfO 2 thin films deposited at 100 °C using tetrakis(dimethylamino)hafnium (TDMAH) and oxygen plasma using substrate biasing is systematically analyzed. The HfO 2 films deposited without a substrate bias show an amorphous microstructure with a low density, low refractive index, high incorporation of residual hydroxyl (OH) content, and high residual tensile stress. The material properties of HfO 2 films significantly improved at a low bias voltage due to the interaction with oxygen ions accelerated to the film. Such HfO 2 films have a higher density, higher refractive index, and lower residual OH incorporation than films without bias. The mechanical stress becomes compressive depending on the bias values. Further increasing the ion energies by applying a larger substrate bias results in a decrease of the film density, refractive index, and a higher residual OH incorporation as well as crystalline inclusions. The comparable material properties of the HfO 2 films have been reported using tris(dimethylamino)cyclopentadienyl hafnium (TDMACpH) in a different apparatus, indicating that this approach can be transferred to various systems and is highly versatile. Finally, the substrate biasing technique has been introduced to deposit stress-compensated, crack- and delamination-free high-reflective (HR) mirrors at 355 and 532 nm wavelengths using HfO 2 and SiO 2 as high and low refractive index materials, respectively. Such mirrors could not be obtained without the substrate biasing during the deposition because of the high tensile stress of HfO 2 , leading to cracks in thick multilayer systems. An HR mirror for 532 nm wavelength shows a high reflectance of 99.93%, a residual transmittance of ∼530 ppm, and a low absorption of ∼11 ppm, as well as low scattering losses of ∼4 ppm, high laser-induced damage threshold, low mechanical stress, and high environmental stability.

The past decade has seen an increase in the use of nonlinear optical (NLO) techniques such as second harmonic generation, coherent antistokes Raman scattering, stimulated Raman scattering, and two-photon fluorescence for the solid-state characterization of pharmaceutical materials. These combined techniques offer several advantages (e.g., speed, selectivity, quantitation) of potential interest to the pharmaceutical community, as decreased characterization times in formulation development and testing could help decrease the time required to bring new, higher quality drugs to market. The large body of literature recently published in this field merits a review. Literature will be discussed in order of drug development, starting with applications in initial therapeutic molecule crystallization and polymorphic analysis, followed by final dosage form characterization, and ending with drug product performance testing.

Second harmonic generation (SHG) microscopy was used to rapidly identify regions of interest for localized confocal Raman spectroscopy measurements in order to quantify crystallinity within lyophilized Abraxane powder (protein bound paclitaxel for injectable suspension). Water insoluble noncentrosymmetric crystalline particles ranging from ∼1 to 120 μm were identified by SHG, with wide variability in crystal size and frequency observed between several batches of Abraxane. By targeting the Raman analysis to these localized regions identified by SHG, the required measurement time was decreased over 2 orders of magnitude, from 8 h to 2 s. Experimental Raman spectra of SHG active domains in Abraxane were in good agreement with experimental spectra of pure crystalline paclitaxel. These collective results are consistent with up to 30% of the active ingredient being present as poorly soluble crystalline particulates in some batches of Abraxane.