Abstract: A method of characterizing and monitoring a fermentation process includes acquiring online Raman spectra of a fermentation process within a fermenter vessel at different times during the fermentation process to generate a training data set; acquiring physical samples from fermentation process near in time to the acquired Raman spectra; performing offline measurements of the target analyte properties and/or compositions using an assay measurement technique; generating a correlative model of the target analyte such that spectral changes in the training data set correlate with the offline measurements of the target analyte properties and/or compositions; acquiring online Raman spectra of a subsequent run of the fermentation process within the fermenter vessel at different times during the run to generate a process data set; and applying the correlative model to the process data set to qualitatively and/or quantitatively predict a value of a property and/or composition of the target analyte.

Abstract: The effective coherence length of a single-frequency, solid-state laser is limited to reduce spurious, secondary holograms in conjunction with a holographic recording. The wavelength of the laser is varied or ‘scanned’ with high precision over a very small wavelength range. In an embodiment, the temperature of the laser's resonant cavity optical bench is altered, causing the dimension of the cavity to change and the emission wavelength to move in a controlled manner. The changing wavelength is monitored at high resolution, and a feedback control loop updates the temperature set-point to keep the monitored laser wavelength moving at a desired rate of change through a desired range. As the wavelength of the laser is scanned, the phase of the holographic interference pattern is locked at a position of maximum coherence/contrast within the holographic film aperture.

Abstract: An improved method of sealing a window into an aperture in a body uses a lubricant comprising polytetrafluoroethylene (PTFE) particles suspended in a volatile, low viscosity, low surface tension carrier fluid. The carrier fluid is applied to one or both of the sidewalls of the window and aperture, and the window is pressed into the aperture such that the carrier fluid evaporates, leaving the PTFE particles to fill interstitial surface voids, while enabling the sidewall of the window to make intimate mechanical contact with the sidewall of the aperture. While having broader application, the present disclosure finds particular utility in optical characterization techniques based upon the Raman effect and fluorescence probes used in process monitoring and control.

Abstract: The present disclosure includes discloses a method for analyzing a multi-component gas sample using spectroscopy in combination with the measurement of extrinsic or intrinsic properties of the gas sample. The results of the spectroscopic analysis and the measurement are combined to quantify a gas component unseen by the spectroscopic analysis.

Abstract: A radiation shield for near-infrared detectors of the type used in Raman spectroscopic systems comprises a chamber enclosing the detector and a cooling device in thermal contact with the chamber and the detector to reduce the level of unwanted radiation to which the detector would otherwise be exposed. The chamber may include a window in optical alignment with the detector, and the window may include one or more coatings to pass wavelengths in a range of interest or block radiation at wavelengths outside of this range. The shield may be enclosed in an evacuated dewar having a window which may also include one or more coatings to favor the wavelength range.

Abstract: A Raman spectroscopic measurement system for measuring the material composition of a mixed phase fluid having a gas phase dispersed in a liquid phase or vice versa is disclosed, which includes an insert to be inserted into a process. The insert includes a measurement chamber partially defined by a phase separating membrane that enables the gas phase to diffuse into and out of the measurement chamber and facilitates coalescing of the liquid phase which into a collector. A first probe of the measurement system is configured to transmit excitation light into the measurement chamber and to receive a Raman signal emanating from the gas phase therein, and a second probe is configured to transmit excitation light into the drain and to receive a Raman signal emanating from the liquid phase therein. The measurement system further includes a spectrometer to determine the material composition of the fluid from the Raman signals.

Abstract: An improved method for integrating curve peaks as compared to techniques such as the trapezoidal rule wherein integration parameters are at fixed x-axis positions. Integration parameters are instead specified relative to a peak center, which allows the peak to shift over time due to hardware changes, temperature fluctuation, pressure changes, etc., while maintaining integration parameters at optimal locations for that peak. As such, the present disclosure finds particular utility in spectroscopy wherein, in the case of Raman spectroscopy, for example, specific wavenumber shift locations may drift over time, leading to inaccurate results based upon absolute integration parameters.

Abstract: In one aspect of the present disclosure, improved end optics are disclosed that maximize the numerical aperture focused at a sample point while minimizing unwanted artifacts such as vignetting. The configurations also maintain centering of the excitation/collection beam on the objective if the probe tilts or bends. The disclosed configurations are particularly suited to probes wherein the excitation and/or collection paths between the probe and the laser/analyzer are coupled through multimode fibers, such as in Raman and other forms of laser spectroscopy. The disclosure includes the insertion of one or more additional lenses between the probe head and the focusing objective at the probe tip.

Abstract: Pharmaceutical tablet properties, including surface roughness, gloss and temperature, are determined in real-time using Raman spectroscopy. A plurality of coated pharmaceutical tablets are provided having a distribution of known values of a surface property to be modeled. The Raman spectrum of each coated tablet is acquired to generate a distribution of Raman spectra. A correlative model is then developed based upon the distribution of the acquired Raman spectra relative to the distribution of the known values of the measured property. The Raman spectrum of a pharmaceutical tablet is then acquired during and/or after a coating process, and the value of the surface property of the tablet is determined using the correlative model. The steps associated with model development are carried out off-line, whereas the step or steps associated with acquiring the Raman spectra of the pharmaceutical tablet during (preferable) or after online coating process(es) are carried out on-line using a remote, fiber-coupled probe.

Abstract: Systems and methods are used to couple an optical sampling probe to a port in a single-use bioreactor bag for in-process monitoring. A combination of re-useable and disposable components maintain precision while reducing costs. A disposable barb with an integral window, received by the port of the reaction vessel, is coupled to a re-useable optic component with a focusing lens. A separate focus alignment tool is used to set the lens position to a precise focal point before placement of the optic component into the barb. The fixture includes a window to simulate the window in a barb component, a target with a known spectral signature, and a probe head coupled to a spectral analyzer. The axial position of the lens is adjusted with respect to the spacer component to maximize the spectral signature from a sample target, whereupon the spacer component is bonded to the lens mount.

Abstract: Methods and systems for spectrometer dark correction are described which achieve more stable baselines, especially towards the edges where intensity correction magnifies any non-zero results of dark subtraction, and changes in dark current due to changes in temperature of the camera window frame are typically more pronounced. The resulting induced curvature of the baseline makes quantitation difficult in these regions. Use of the invention may provide metrics for the identification of system failure states such as loss of camera vacuum seal, drift in the temperature stabilization, and light leaks. In system aspects of the invention, a processor receives signals from a light detector in the spectrometer and executes software programs to calculate spectral responses, sum or average results, and perform other operations necessary to carry out the disclosed methods. In most preferred embodiments, the light signals received from a sample are used for Raman analysis.

Abstract: The present disclosure relates to assistive mechanisms and methods that aid an operator of a spectrometer to make spectral measurements of a sample, the measurements having a desired quality. The method enables quality spectral measurements quickly and simply, without a prior understanding of a sample's spectrum or of the details as to how the spectrum is measured. Data quality is improved, and the time required to collect the data is reduced. While a specific example of sample optic focus is disclosed in detail, the optimization of numerous other parameters is possible.

Abstract: The present disclosure is directed to a method of particle size determination for particles suspended within a light-transmissive medium. The method includes directing a monochromatic light source into the medium and collecting from the medium a Raman-scattered light spectrum. The method includes analyzing the Raman spectrum to determine an amount of Tyndall scattering of the Raman spectrum caused by particles within the medium, and thus determine the size and the number of particles mediating the Tyndall scattering.

Abstract: Methods and systems for spectrometer dark correction are described which achieve more stable baselines, especially towards the edges where intensity correction magnifies any non-zero results of dark subtraction, and changes in dark current due to changes in temperature of the camera window frame are typically more pronounced. The resulting induced curvature of the baseline makes quantitation difficult in these regions. Use of the invention may provide metrics for the identification of system failure states such as loss of camera vacuum seal, drift in the temperature stabilization, and light leaks. In system aspects of the invention, a processor receives signals from a light detector in the spectrometer and executes software programs to calculate spectral responses, sum or average results, and perform other operations necessary to carry out the disclosed methods. In most preferred embodiments, the light signals received from a sample are used for Raman analysis.

Abstract: A monolithic optical element and system is used for collimating or focusing laser light from or to optical fibers. The optical fiber terminates in a tip that directly abuts against the first surface of the optical element. The optical element may provide a collimation or focusing function depending upon whether the abutting fiber delivers light for collimation or receives focused light from a collimated beam. The optical element may be a standard or modified barrel or drum lens, with the first and second surfaces being convex curved surfaces having the same or different radii of curvature. The end of the optical element to which the fiber abuts may have a diameter to match the inner diameter of a ferrule for positioning the fiber. A pair of the elements may be used for collimation and focusing in a Raman probehead or other optical detection system.

Abstract: A monolithic optical element and system is used for collimating or focusing laser light from or to optical fibers. The optical fiber terminates in a tip that directly abuts against the first surface of the optical element. The optical element may provide a collimation or focusing function depending upon whether the abutting fiber delivers light for collimation or receives focused light from a collimated beam. The optical element may be a standard or modified barrel or drum lens, with the first and second surfaces being convex curved surfaces having the same or different radii of curvature. The end of the optical element to which the fiber abuts may have a diameter to match the inner diameter of a ferrule for positioning the fiber. A pair of the elements may be used for collimation and focusing in a Raman probehead or other optical detection system.

Abstract: Raw data inputs are treated as independent signal sources to reduce computational lag without adversely affecting signal-to-noise ratio (SNR). Applications include spectroscopy, multiple linear regression, mass balance quantitation and the calculation of physical properties. The input-specific averaging has been applied to Raman spectroscopy, where the inputs are averaged spectra from which peak heights or areas are obtained from integration. Alternatively, peak areas or heights can be obtained from unaveraged spectra and are then averaged before use in further calculations as inputs to produce a desired output. The output(s) are linear or nonlinear combinations of the peak heights or areas, coupled with weighting factors which relate the raw inputs to a quantitative output such as concentration of a chemical species. Each specific input can use a different type of averaging. The overall goal may be optimization for best precision, and/or optimization for minimum lag time.

Abstract: Methods and apparatus facilitate dynamic range balancing for multi-component peaks of widely varying magnitude in an optical spectrometer. In a specific embodiment, filters attenuate the C—H stretch region to produce a better fit of a multi-component hydrocarbon Raman spectrum to the dynamic range of a CCD detector. The filter may be translated into and out of the collimated collection beam to achieve a varying degree of attenuation. In certain applications, the filter is insertable into a collimated collection beam within a fiber-optic probe head to collect Raman spectra. The invention may include optical elements to create the collimated collection beam if not already present or not suitable for insertion of the filter. A second filter, an “opaque” or neutral density filter, may be insertable into the collimated collection beam to attenuate a broad spectral response within and outside the spectral range.

Abstract: Raman signal amplification apparatus comprises an ellipsoidal reflector providing a first real focus f1, and second real or virtual focus f2, both foci being situated within a sample volume. When an input laser excitation beam having an initial numerical aperture (NA) is focused onto one of the foci, the beam is reflected by the reflector and refocused onto alternating foci, such that the NA of the reflected optical path progressively increases for higher efficiency collection of Raman emissions from the multiple foci. The ellipsoidal reflector may be a half section providing a single real focus f1, with a flat reflector producing a mirror image of the ellipsoidal reflector, such that f2 is a virtual focus occupying the same point as f1. Alternatively, the ellipsoidal reflector may have a first half section with a first real focus f1 and a second half section with a second real focus f2.

Abstract: A compact Raman analysis system combines a near-infrared (NIR) laser source, a 2D array collecting anti-Stokes Raman spectra, and a probe configured to measure complex solid samples, including pharmaceutical tablets and other large-area targets with reduced background fluorescence at relatively low cost. The system collects spectra from an area of 1-mm or greater, preferably 3-12 mm or more, facilitating the collection of statistically useful data from inhomogeneous and laser-sensitive samples, among other applications. Potential pharmaceutical applications include tablet dosage level measurements, as well as online and at-line quality-control (QC) monitoring opportunities. Other applications include tablet identification as a forensic tool to identify counterfeit pharmaceutical products; granulation and blend uniformity for improved formulation via better process understanding.