Time-resolved NIR spectroscopy for quantitative analysis of intact pharmaceutical tablets

Near-infrared (NIR) spectroscopy is a useful technique for quantitative measurements of intact tablets, but it suffers from limitations due to the fact that changes in the physical properties of a sample strongly affect the recorded spectrum. In this work, time-resolved transmission NIR spectroscopy was utilized to conduct quantitative measurements of intact tablets. The technique enables separation of the absorption properties of the sample from the scattering properties and can therefore handle changes of the physical parameters of the samples in a better way than conventional NIR transmission spectroscopy. The experiments were conducted using a pulsed Ti:sapphire laser coupled into a nonlinear photonic crystal fiber as light source. The light transmitted through the sample was measured by a time-resolving streak camera. A comparison of the results from the time-resolved technique with the results from conventional transmission NIR spectroscopy was made using tablets containing different concentrations of iron oxide and manufactured with different thicknesses. A PLS model made with data from the time-resolved technique predicted samples 5 times better than a PLS model made data from the conventional NIR transmission technique. Furthermore, an improvement to predict samples with physical properties outside those included in the calibration set was demonstrated.     

Least-squares support vector machines modelization for time-resolved spectroscopy

By use of time-resolved spectroscopy it is possible to separate light scattering effects from chemical absorption effects in samples. In the study of propagation of short light pulses in turbid samples the reduced scattering coefficient and the absorption coefficient are usually obtained by fitting diffusion or Monte Carlo models to the measured data by use of numerical optimization techniques. In this study we propose a prediction model obtained with a semiparametric modeling technique: the least-squares support vector machines. The main advantage of this technique is that it uses theoretical time dispersion curves during the calibration step. Predictions can then be performed by use of data measured on different kinds of sample, such as apples.     

MADSTRESS: a linear approach for evaluating scattering and absorption coefficients of samples measured using time-resolved spectroscopy in reflection

Time-resolved spectroscopy is a powerful technique permitting the separation of the scattering properties from the chemical absorption properties of a sample. The reduced scattering coefficient and the absorption coefficient are usually obtained by fitting diffusion or Monte Carlo models to the measured data using numerical optimization techniques. However, these methods do not take the spectral dimension of the data into account during the evaluation procedure, but evaluate each wavelength separately. A procedure involving multivariate methods may seem more appealing for people used to handling conventional near-infrared data. In this study we present a new method for processing TRS spectra in order to compute the absorption and reduced scattering coefficients. This approach, MADSTRESS, is based on linear regression and a two-dimensional (2D) interpolation procedure. The method has allowed us to calculate absorption and scattering coefficients of apples and fructose powder. The accuracy of the method was good enough to provide the identification of fructose absorption peaks in apple absorption spectra and the construction of a calibration model predicting the sugar content of apples.     

New methodology to obtain a calibration model for noninvasive near-infrared blood glucose monitoring

This paper reports new methodology to obtain a calibration model for noninvasive blood glucose monitoring using diffuse reflectance near-infrared (NIR) spectroscopy. Conventional studies of noninvasive blood glucose monitoring with NIR spectroscopy use a calibration model developed by in vivo experimental data sets. In order to create a calibration model, we have used a numerical simulation of light propagation in skin tissue to obtain simulated NIR diffuse reflectance spectra. The numerical simulation method enables us to design parameters affecting the prediction of blood glucose levels and their variation ranges for a data set to create a calibration model using multivariate analysis without any in vivo experiments in advance. By designing the parameters and their variation ranges appropriately, we can prevent a calibration model from chance temporal correlations that are often observed in conventional studies using NIR spectroscopy. The calibration model (regression coefficient vector) obtained by the numerical simulation has a characteristic positive peak at the wavelength around 1600 nm. This characteristic feature of the regression coefficient vector is very similar to those obtained by our previous in vitro and in vivo experimental studies. This positive peak at around 1600 nm also corresponds to the characteristic absorption band of glucose. The present study has reinforced that the characteristic absorbance of glucose at around 1600 nm is useful to predict the blood glucose level by diffuse reflectance NIR spectroscopy. We have validated this new calibration methodology using in vivo experiments. As a result, we obtained a coefficient of determination, r2, of 0.87 and a standard error of prediction (SEP) of 12.3 mg/dL between the predicted blood glucose levels and the reference blood glucose levels for all the experiments we have conducted. These results of in vivo experiments indicate that if the parameters and their vibration ranges are appropriately taken into account in a numerical simulation, the new calibration methodology provides us with a very good calibration model that can predict blood glucose levels with small errors without conducting any experiments in advance to create a calibration model for each individual patient. This new calibration methodology using numerical simulation has promising potential for NIR spectroscopy, especially for noninvasive blood glucose monitoring.     

Application of frequency domain photon migration to particle size analysis and monitoring of pharmaceutical powders

The frequency domain photon migration (FDPM) technique was employed to determine mean particle size of pharmaceutical powders. Results show that the FDPM-measured scattering coefficient increases linearly with reciprocal mean particle size of powdered samples. In contrast to near-infrared spectroscopy techniques, FDPM technique enables determination of scattering and absorption separately so that it does not require data pretreatment and chemometric calibration models. In addition, this unique advantage provides more detailed information about powder samples, which can be used as a potential tool for on-line monitoring of not only variation of active pharmaceutical ingredient concentrations from changes in the absorption coefficient but also variation of particle sizes from changes in the scattering coefficient.     

Quantifying ethanol content of beer using interpretive near-infrared spectroscopy

On the basis of absorption measurements in the near-infrared (NIR) spectral range, a new method for the quantification of the ethanol content of beer is presented. Instead of the multivariate calibration models most commonly employed in NIR spectroscopic works, we use interpretive difference spectroscopy: Two wavelengths are selected according to the assignment of the absorption bands of the main substances of content of beer in the NIR region, and the difference between the absorbances at these wavelengths is used for ethanol quantification. Absorption spectra of the dominating beer ingredients are discussed and the calibration procedure with ethanol/water mixtures is shown. Robustness against the carbohydrate content of beer samples was demonstrated by analyzing solutions of ethanol and maltose in water. Validation of the method was performed with various beer samples with an ethanol concentration range between 0.5 and 7.7 vol %. The pertinent advantage of the procedure developed in this work is the indication that the results are independent from seasonal variations of the ingredients, which is of high interest for products with natural ingredients such as beer.     

In vivo determination of local skin optical properties and photon path length by use of spatially resolved diffuse reflectance with applications in laser Doppler flowmetry

Methods for local photon path length and optical properties estimation, based on measured and simulated diffuse reflectance within 2 mm from the light source, are proposed and evaluated in vivo on Caucasian human skin. The accuracy of the methods was good (2%-7%) for path length and reduced scattering but poor for absorption estimation. Reduced scattering and absorption were systematically lower in the fingertip than in the forearm skin (633 nm). A maximum intrasite and interindividual variation of approximately 35% in an average photon path length was found. The methodology was applied in laser Doppler flowmetry, where path-length normalization of the estimated perfusion removed the optical property dependency.     

Real-time absorption and scattering characterization of slab-shaped turbid samples obtained by a combination of angular and spatially resolved measurements

We present a fast and accurate method for real-time determination of the absorption coefficient, the scattering coefficient, and the anisotropy factor of thin turbid samples by using simple continuous-wave noncoherent light sources. The three optical properties are extracted from recordings of angularly resolved transmittance in addition to spatially resolved diffuse reflectance and transmittance. The applied multivariate calibration and prediction techniques are based on multiple polynomial regression in combination with a Newton--Raphson algorithm. The numerical test results based on Monte Carlo simulations showed mean prediction errors of approximately 0.5% for all three optical properties within ranges typical for biological media. Preliminary experimental results are also presented yielding errors of approximately 5%. Thus the presented methods show a substantial potential for simultaneous absorption and scattering characterization of turbid media.     

Variations in predicted values from near-infrared spectra of samples in vials by using a calibration model developed from spectra of samples in vials: causes of the variations and compensation methods

The causes and compensation methods of variations in the predicted values from near-infrared (NIR) spectra of samples in vials by using a calibration model developed from spectra of samples in vials were studied. From the viewpoint of the path length and the peak height of spectra in the NIR region, vials with 1 mL volume (external diameter: 8 mm, inside diameter: about 6 mm, length: 40 mm) were selected as disposable vials for the samples. To investigate the causes of the variations in the predicted values, the optical path lengths and transmittance spectra of empty vials in five lots produced during the last four years were examined. The results showed that there were some differences in the path lengths of the vials and in the intensities of peaks near 7130 and 4515 cm-1, which were attributed to the hydroxyl groups in the spectra of the vials among the five lots. The calibration models for the concentration of isopropyl alcohol (IPA) in toluene contained in vials of the same lot were developed. To search the pretreatment methods for the best calibration model with small variations in the predictive values of the samples in the vials, six kinds of pretreatments (no pretreatment, baseline correction, first derivative, second derivative, multiplicative scattering correction (MSC), and standard normal variate (SNV)) were compared. The results indicated that MSC is a very effective method with small variation in the predicted values from the spectra of samples in vials. It was found that the variations in the predicted values are caused mainly by variations in the path lengths of vials. In real quality control, the NIR-chemometrics method is requested for long-term traceability and good reproducibility of the predictive value. Therefore, it is crucial to watch changes in the path length under a fixed path length as a reference. From this standpoint, modified MSC, which uses a particular spectrum as a reference instead of the average spectrum of a sample set, was proposed in the present study, and it was demonstrated that the variations due to the individual differences in the vials can not only be compensated, but the path lengths of vials could also be estimated by the modified MSC. Moreover, a calibration model for the toluene concentration in silicone oil was developed to confirm the effects of modified MSC by using another sample set. The results showed that the compensation of vial path lengths using the modified MSC is also useful for other samples, similar to the case of the sample of IPA in toluene.     

Characterization of the sources of variation affecting near-infrared spectroscopy using chemometric methods

A rapid assessment of product quality can often be made using a combination of near-infrared spectroscopy (NIR) and multivariate calibration. The robustness of such a method is determined by the sensitivity of the multivariate calibration model to variations in the spectral data. An approach is described that uses a combination of experimental design methodology and principal component analysis to identify the main sources of variation in the spectra and to estimate their influence on the quantitative predictions. This is accomplished by comparing variations in a set of measured, replicate spectra to spectra with simulated variations. The approach was applied to the hydroxyl number determination of polyols by NIR spectroscopy and partial least-squares calibration. The results indicated that the most significant sources of variation were due to a variable cell path length and a variable curved background. Correction for these errors resulted in a 58% reduction in the standard deviation of the hydroxyl number predictions, indicating that a substantial improvement in the method precision is possible.     

Near-infrared light propagation in an adult head model. I. Modeling of low-level scattering in the cerebrospinal fluid layer

Adequate modeling of light propagation in a human head is important for quantitative near-infrared spectroscopy and optical imaging. The presence of a nonscattering cerebrospinal fluid (CSF) that surrounds the brain has been previously shown to have a strong effect on light propagation in the head. However, in reality, a small amount of scattering is caused by the arachnoid trabeculae in the CSF layer. In this study, light propagation in an adult head model with discrete scatterers distributed within the CSF layer has been predicted by Monte Carlo simulation to investigate the effect of the small amount of scattering caused by the arachnoid trabeculae in the CSF layer. This low scattering in the CSF layer is found to have little effect on the mean optical path length, a parameter that can be directly measured by a time-resolved experiment. However, the partial optical path length in brain tissue that relates the sensitivity of the detected signal to absorption changes in the brain is strongly affected by the presence of scattering within the CSF layer. The sensitivity of the near-infrared signal to hemoglobin changes induced by brain activation is improved by the effect of a low-scattering CSF layer.     

Optical properties of normal and carcinomatous bronchial tissue

To understand better the optical characteristics and autofluorescence properties of normal and carcinomatous bronchial tissue, we measured the absorption coefficient, scattering coefficient, and anisotropy factor from 400 to 700 nm. We made the measurements by using an integrating sphere with a collimated white-light beam to measure total reflectance and transmittance of samples. The unscattered transmittance of the samples was measured through polarized on-axis light detection. The inverse adding-doubling solution was utilized to solve the equation of radiative transfer and to determine the absorption coefficient and reduced scattering coefficient. The scattering coefficient and anisotropy factor were derived from the unscattered transmittance of the sample and the reduced scattering coefficient. The measured parameters allow us to simulate photon propagation in normal bronchial and tumoral tissue by using Monte Carlo modeling.     

In vivo noninvasive measurement of blood glucose by near-infrared diffuse-reflectance spectroscopy

This paper reports in situ noninvasive blood glucose monitoring by use of near-infrared (NIR) diffuse-reflectance spectroscopy. The NIR spectra of the human forearm were measured in vivo by using a pair of source and detector optical fibers separated by a distance of 0.65 mm on the skin surface. This optical geometry enables the selective measurement of dermis tissue spectra due to the skin's optical properties and reduces the interference noise arising from the stratum corneum. Oral glucose intake experiments were performed with six subjects (including a single subject with type I diabetes) whose NIR skin spectra were measured at the forearm. Partial least-squares regression (PLSR) analysis was carried out and calibration equations were obtained with each subject individually. Without exception among the six subjects, the regression coefficient vectors of their calibration models were similar to each other and had a positive peak at around 1600 nm, corresponding to the characteristic absorption peak of glucose. This result indicates that there is every possibility of glucose detection in skin tissue using our measurement system. We also found that there was a good correlation between the optically predicted values and the directly measured values of blood samples with individual subjects. The potential of noninvasive blood glucose monitoring using our methodology was demonstrated by the present study.     

Determination of adsorbed protein concentration in aluminum hydroxide suspensions by near-infrared transmittance spectroscopy

Analysis of aluminum hydroxide based vaccines is difficult after antigen adsorption. Adsorbed protein is often assessed by measuring residual unadsorbed protein for quality control. A new method for the direct determination of adsorbed protein concentration in suspension using near-infrared (NIR) transmittance spectroscopy is proposed here. A simple adsorption system using albumin from bovine serum (BSA) and aluminum hydroxide as a model system is employed. The results show that the NIR absorbance at 700-1300 nm is correlated to the adsorbed BSA concentration, measured by the ultraviolet (UV) method, using the partial least square regression (PLSR) method to construct a calibration model. The linear concentration range of adsorbed BSA is from 0 to 1.75 mg/mL by using 10 mm path length cuvettes. The influence of the sedimentation in suspension, different buffers, and different aluminum hydroxide batches was investigated in this study. It shows that the batch variation is the main influence factor of this method, while the buffer variation has no influence. However, the pretreatment of spectral data by subtracting spectra of BSA blank control (aluminum hydroxide without BSA) can significantly reduce the batch influence, and the NIR predicted results show good agreement with the reference values. The NIR method might be the only direct method for the determination of adsorbed protein concentration in suspension so far. It is a nondestructive method, and it has great advantage for use in vaccine production as a method for quality control and quality assurance.     

Near-infrared spectra of Penicillium camemberti strains separated by extended multiplicative signal correction improved prediction of physical and chemical variations

Different methods for spectral preprocessing were compared in relation to the ability to distinguish between fungal isolates and growth stages for Penicillium camemberti grown on cheese substrate. The best classification results were obtained by temperatureand wavelength-extended multivariate signal correction (TWEMSC) preprocessing, whereby three patterns of variation in nearinfrared (NIR) log(1/R) spectra of fungal colonies could be separated mathematically: (1) physical light scattering and its wavelength dependency, (2) differences in light absorption of water due to varying sample temperature, etc., and (3) differences in light absorption between different fungal isolates. With this preprocessing, discriminant partial least squares (PLS) regression yielded 100% correct classification of three isolates, both within the cross-validated calibration set and in two independent test sets of samples.     

Magnetic-resonance-imaging-coupled broadband near-infrared tomography system for small animal brain studies

A novel magnetic-resonance-coupled broadband near-infrared (NIR) tomography system for small animal brain studies is described. Several features of the image formation approach are new in NIR tomography and represent major advances in the path to recovering high-resolution hemoglobin and oxygen saturation images of tissue. The NIR data were broadband and continuous wave and were used along with a second-derivative-based estimation of the path length from water absorption. The path length estimation from water was then used along with the attenuation spectrum to recover absorption and reduced scattering coefficient images at multiple wavelengths and then to recover images of total hemoglobin and oxygen saturation. Going beyond these basics of NIR tomography, software has been developed to allow inclusion of structures derived from MR imaging (MRI) for the external and internal tissue boundaries, thereby improving the accuracy and spatial resolution of the properties in each tissue type. The system has been validated in both tissue-simulating phantoms, with 10% accuracy observed, and in a rat cranium imaging experiment. The latter experiment used variation in inspired oxygen (FiO2) to vary the observed hemoglobin and oxygen saturation images. Quantitative agreement was observed between the changes in deoxyhemoglobin values derived from NIR and the changes predicted with blood-oxygen-level-dependent (BOLD) MRI. This system represents the initial stage in what will likely be a larger role for NIR tomography, coupled to MRI, and illustrates that the technological challenges of using continuous-wave broadband data and inclusion of a priori structural information can be met with careful phantom studies.     

Direct determination of the experimentally observed penetration depth of the evanescent field via near-infrared absorptions enhanced by the off-resonance of surface plasmons

Recently, absorption-sensitive surface plasmon resonance (SPR) techniques have attracted much attention. SPR near-infrared spectroscopy (SPR-NIRS) based on the Kretschmann configuration is one of the techniques for absorption enhancement. The enhanced spectrum obtained by SPR-NIRS basically corresponds to the measurement of an NIR absorption spectrum with a very short path length. However, the path length cannot be applied for Lambert's law due to the enhanced evanescent field. A direct determination of the penetration depth of the evanescent field is carried out via NIR absorptions enhanced by the off-resonance of surface plasmons, which is a principle of SPR-NIRS. The signal intensities of the enhanced NIR spectra of micrometer-thick polymer films having various thicknesses are compared with the classic theory of penetration depth. It is confirmed that the effective depth of the SPR-NIRS measurement can be expressed by the classic theory of penetration depth of the evanescent field proposed by Harrick.     

Particle size determination in aluminum hydroxide suspensions using near-infrared transmittance spectroscopy

A new method for particle size determination in polystyrene and aluminum hydroxide suspensions using near-infrared transmittance spectroscopy is described. Mono-dispersed polystyrene particle size standards were used to establish the calibration model. The particle sizes used in the study are similar to the wavelength range of 700-1300 nm, where light scattering is wavelength dependent. The wavelength dependency of near-infrared (NIR) absorbance is found to be linear with the particle size when the analysis is based on the same spectrum starting point (the same absorbance at 700 nm). Partial least squares regression (PLSR) is applied to model this linear relationship. Compared to laser diffraction (LD) the NIR method has similar accuracy and precision in the measurement of particles with a uniform size. For a sample containing multiple sizes of particles, the mean size measured by the NIR method is shown to be weighted by the particle mass. The application of the model to aluminum hydroxide suspension shows that the NIR method is suitable for the detection of particle size changes during the production process and storage. The advantages of the NIR method are that no knowledge of the refractive index and the concentration of a sample are necessary and that the method is fast and easy to operate.     

Simple Mathematical Models for Temporal,Spatial, Angular,and Attenuation Characteristics of Light Propagating Through the Atmosphere for Space Optical Communication:

Abstract

Mathematical models are developed to characterize propagation through a turbid medium at three different wavelengths in the visible and near infrared spectral range. These models are based upon relations between the temporal, angular, and spatial spread of electromagnetic unpolarized radiation, geometrical path length, particle size distribution, and the medium's propagation parameters such as Mie scattering, and absorption coefficients, Mie phase-function, and optical thickness. Calculations of the radiation characteristics were carried out using Monte Carlo simulations. Here, atmospheric particulates are used to model turbid media for optical thickness between 1 and 6, emphasizing optical communication applications, The advantage of this work is the ability to predict simply and in real time important radiation parameters relevant to any optical communication system. Results indicate very high correlation between optical thickness and propagation characteristics. For transmission, comparison is made to Bucher's model. Results are similar except for absorption effects which are not included in Bucher's model. Some important conclusions are derived such as the prediction that it is advantageous to use longer wavelength radiation through the atmosphere. In addition, there is a very dominant back scattering effect, involving up to 50% of transmitted power for optical densities as low as 6. On the other hand, power density of received scattered light is very low for conventional distances relevant to satellite optical communication, and can be neglected. On the basis of simulation results, the received radiation is of unscattered light only for any optical communication application. The dominant mechanism relating to radiation attenuation is scattering rather than absorption.     

Assessment of near-infrared path length in fibrous phantom and muscle tissue

The first derivative of the pseudo-absorption spectrum of a water-loaded cotton wool (water-CW) phantom, which mimics muscle tissues, was used to determine the light path length in the near-infrared (NIR) region. The light path length increased as the density of the turbid medium decreased. It is independent of both water content in the range of 75-85% (by weight) and the diffuse reflecting reference used to determine the pseudo-absorbance. The path length determination procedure was verified by measurements of diffuse reflectance in chicken breast tissue for which the path length of 1.8 mm (differential path length factor, DPF = 2.1) was found to be similar to the path length of NIR light of 1.5-2.2 mm (DPF = 1.8-2.6) in a water-CW phantom of density similar to chicken breast. We conclude that the NIR light path length can serve as a characteristic of muscle tissue density.