A Direct Digitizing Chopped Neural Recorder Using a Body-Induced Offset Based DC Servo Loop.

This article presents a direct digitizing neural recorder that uses a body-induced offset based DC servo loop to cancel electrode offset (EDO) on-chip. The bulk of the input pair is used to create an offset, counteracting the EDO. The architecture does not require AC coupling capacitors which enables the use of chopping without impedance boosting while maintaining a large input impedance of 238 M Ω over the whole 10 kHz bandwidth.

Rapid screening of anti-infective drug products for counterfeits using Raman spectral library-based correlation methods.

A new spectral library-based approach that is capable of screening a diverse set of finished drug products using only an active pharmaceutical ingredient spectral library is described in this paper. This approach obviates the need for a comprehensive drug product library, thereby streamlining the use of spectral library-based tests for anti-counterfeiting efforts, specifically to target finished drug products containing the wrong active ingredient or no active ingredient at all. Both laboratory-based and portable spectrometers are used in the study to demonstrate the usefulness and transferability of the spectral correlation method for field screening.

Elemental Impurities in Pharmaceutical Excipients.

Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients.

Synthesis and detection of N-sulfonated oversulfated chondroitin sulfate in marketplace heparin.

N-sulfonated oversulfated chondroitin sulfate (NS-OSCS), recently reported as a potential threat to the heparin supply, was prepared along with its intermediate derivatives. All compounds were spiked into marketplace heparin and subjected to United States Pharmacopeia (USP) identification assays for heparin (proton nuclear magnetic resonance [(1)H NMR], chromatographic identity, % galactosamine [%GalN], anti-factor IIa potency, and anti-factor Xa/IIa ratio). The U.

Deep-Ultraviolet Resonance Raman (DUVRR) Spectroscopy of Therapeutic Monoclonal Antibodies Subjected to Thermal Stress.

The structural assessment of Rituximab, an IgG1 mAb, was investigated with deep-ultraviolet resonance Raman (DUVRR) spectroscopy. DUVRR spectroscopy was used to monitor the changes to the secondary structure of Rituximab under thermal stress. DUVRR spectra showed obvious changes from 22 to 72 °C.

Raman imaging of pharmaceutical materials: refractive index effects on contrast at buried interfaces.

Resolution targets composed of bilayer polydimethylsiloxane (PDMS) devices with buried polyethylene glycol (PEG) channels have been fabricated using traditional photolithographic and micromolding techniques to develop resolution targets that mimic pharmaceutical materials. Raman chemical images of the resulting PEG-in-PDMS devices composed of varying parallel line widths were investigated by imaging the PEG lines through a thin overlayer of PDMS. Additionally, a scattering agent, Al2O3, was introduced at varying concentrations to each layer of the device to explore the effects of scattering materials on Raman images.

Deep-ultraviolet (UV) resonance raman spectroscopy as a tool for quality control of formulated therapeutic proteins.

A deep-ultraviolet (UV) Raman spectrometer with excitation source tunable from 193 to 210 nm has been built and characterized. The dispersion of the spectrometer over the entire range was measured and described theoretically. The relative sensitivity of the spectrometer was estimated using the integrated intensity ratio of two Raman bands of cyclohexane.

Qualitative screening for adulterants in weight-loss supplements by ion mobility spectrometry.

Ion mobility spectrometry (IMS) served as a rapid, qualitative screening tool for the analysis of adulterated weight-loss products. We have previously shown that sibutramine extracted into methanol from dietary supplements can be detected at low levels (2ng) using a portable IMS spectrometer, and have adapted a similar method for the analysis of additional weight-loss product adulterants. An FDA collaborative study helped to define the limits for fluoxetine with a limit of detection of 2ng.

Selective melamine detection in multiple sample matrices with a portable Raman instrument using surface enhanced Raman spectroscopy-active gold nanoparticles.

Melamine adulteration of food and pharmaceutical products is a major concern and there is a growing need to protect the public from exposure to contaminated or adulterated products. One approach to reduce this threat is to develop a portable method for on-site rapid testing. We describe a universal and selective method for the detection of melamine in a variety of solid matrices at the 100-200 μg L(-1) level by surface enhanced Raman spectroscopy (SERS) with gold nanoparticles.

Libraries, classifiers, and quantifiers: a comparison of chemometric methods for the analysis of Raman spectra of contaminated pharmaceutical materials.

In this study, pharmaceutical grade sorbitol was used as a model system for comparison of Raman based library spectral correlation methods with more sophisticated methods of chemometric data analysis. Both crystallizing sorbitol (CS) and non-crystallizing sorbitol (NCS) from several manufacturers were examined. The Raman spectrum of each sample was collected and identified by correlation with a spectral library that included the CS spectrum but not the NCS spectrum.

Standardization of Raman spectra for transfer of spectral libraries across different instruments.

In this paper we evaluate methods for standardization of Raman spectra that are required to improve spectral correlation computations between spectra measured on different instruments. Five commercially-available 785 nm Raman spectrometers from different vendors were included in the study. These spectrometers have diverse specifications and performance levels and range in size from laboratory-based instruments to field-deployable portable and handheld platforms.

Quantitative evaluation of the sensitivity of library-based Raman spectral correlation methods.

Library-based Raman spectral correlation methods are widely used in surveillance applications in multiple areas including the pharmaceutical industry, where Raman spectroscopy is commonly used in verification screening of incoming raw materials. While these spectral correlation methods are rapid and require little or no sample preparation, their sensitivity to the presence of contaminants has not been adequately evaluated. This is particularly important when dealing with pharmaceutical excipients, which are susceptible to economically motivated adulteration by substances having similar physical/chemical/spectroscopic properties.

Multivariate calibration and instrument standardization for the rapid detection of diethylene glycol in glycerin by Raman spectroscopy.

The transfer of a multivariate calibration model for quantitative determination of diethylene glycol (DEG) contaminant in pharmaceutical-grade glycerin between five portable Raman spectrometers was accomplished using piecewise direct standardization (PDS). The calibration set was developed using a multi-range ternary mixture design with successively reduced impurity concentration ranges. It was found that optimal selection of calibration transfer standards using the Kennard-Stone algorithm also required application of the algorithm to multiple successively reduced impurity concentration ranges.

Rapid limit tests for metal impurities in pharmaceutical materials by X-ray fluorescence spectroscopy using wavelet transform filtering.

We introduce a new method for analysis of X-ray fluorescence (XRF) spectra based on continuous wavelet transform filters, and the method is applied to the determination of toxic metals in pharmaceutical materials using hand-held XRF spectrometers. The method uses the continuous wavelet transform to filter the signal and noise components of the spectrum. We present a limit test that compares the wavelet domain signal-to-noise ratios at the energies of the elements of interest to an empirically determined signal-to-noise decision threshold.

Detection of diethylene glycol adulteration in propylene glycol--method validation through a multi-instrument collaborative study.

Four portable NIR instruments from the same manufacturer that were nominally identical were programmed with a PLS model for the detection of diethylene glycol (DEG) contamination in propylene glycol (PG)-water mixtures. The model was developed on one spectrometer and used on other units after a calibration transfer procedure that used piecewise direct standardization. Although quantitative results were produced, in practice the instrument interface was programmed to report in Pass/Fail mode.

Using a portable ion mobility spectrometer to screen dietary supplements for sibutramine.

In response to recent incidents of undeclared sibutramine, an appetite suppressant found in dietary supplements, we developed a method to detect sibutramine using hand-held ion mobility spectrometers with an analysis time of 15 s. Ion mobility spectrometry is a high-throughput and sensitive technique that has been used for illicit drug, explosive, volatile organic compound and chemical warfare detection. We evaluated a hand-held ion mobility spectrometer as a tool for the analysis of supplement extracts containing sibutramine.

Propagation of uncertainty in nasal spray in vitro performance models using Monte Carlo simulation: Part II. Error propagation during product performance modeling.

Monte Carlo simulations were applied to investigate the propagation of uncertainty in both input variables and response measurements on model prediction for nasal spray product performance design of experiment (DOE) models in the first part of this study, with an initial assumption that the models perfectly represent the relationship between input variables and the measured responses. In this article, we discard the initial assumption, and extended the Monte Carlo simulation study to examine the influence of both input variable variation and product performance measurement variation on the uncertainty in DOE model coefficients. The Monte Carlo simulations presented in this article illustrate the importance of careful error propagation during product performance modeling.

Qualitative and quantitative comparison of brand name and generic protein pharmaceuticals using isotope tags for relative and absolute quantification and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry.

The capability of iTRAQ (isotope tags for relative and absolute quantification) reagents coupled with matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) as a qualitative and quantitative technique for the analysis of complicated protein pharmaceutical mixtures was evaluated. Mixtures of Somavert and Miacalcin with a small amount of bovine serum albumin (BSA) as an impurity were analyzed. Both Somavert and Miacalcin were qualitatively identified, and BSA was detected at levels as low as 0.

Propagation of uncertainty in nasal spray in vitro performance models using Monte Carlo simulation: part I. Model prediction using Monte Carlo simulation.

Design of experiment (DOE) methodology can provide a complete evaluation of the influences of nasal spray activation and formulation properties on delivery performance which makes it a powerful tool for product design purposes. Product performance models are computed from complex expressions containing multiple factor terms and response terms. Uncertainty in the regression model can be propagated using Monte Carlo simulation.

Detection of undeclared erectile dysfunction drugs and analogues in dietary supplements by ion mobility spectrometry.

An ion mobility spectrometry (IMS) method was developed to screen for the presence of undeclared synthetic erectile dysfunction (ED) drugs or drug analogues in herbal dietary supplements claiming to enhance male sexual performance. Ion mobility spectra of authenticated reference materials including three FDA approved drugs (sildenafil citrate, tadalafil, vardenafil hydrochloride trihydrate) and five previously identified synthetic analogues (methisosildenafil, homosildenafil, piperidenafil, thiosildenafil, thiomethisosildenafil) were measured to determine their reduced ion mobilities (K(0)). All eight compounds exhibited reduced mobilities between 0.

Screening of heparin API by near infrared reflectance and Raman spectroscopy.

Near infrared (NIR) reflectance and laser Raman spectra for a set of 69 heparin powder samples obtained from several foreign and domestic suppliers were measured. Both the NIR and Raman spectra of individual heparin API powder samples were correlated with sample compositions determined from response corrected relative peak areas of the capillary electropherograms of the samples using a partial least squares (PLS) regression model. Twenty-eight sample spectra were used to develop PLS models for the three major sample components; heparin, oversulfated chondroitin sulfate (OSCS) and glycosaminoglycans (GAGs).

Evaluation of impaction force of nasal sprays and metered-dose inhalers using the Texture Analyser.

The impaction force from an inhalation product is an important characteristics by which to characterize the spray plume. It is one of the plume characteristics that can be perceived by a patient, and is expected to be good measures of local delivery equivalence for inhalation drugs. A Stable Micro Systems TA-XT.

Raman detected differential scanning calorimetry of polymorphic transformations in acetaminophen.

Acetaminophen is known to crystallize in three polymorphic forms. Thermally induced transformations between the crystalline forms and the super-cooled liquid have been observed by differential scanning calorimetry (DSC), but the assignment of calorimetric transitions to specific polymorphic transformations remains challenging, because the transition temperatures for several transformations are close to one another, and the characteristics of the observed transitions depend on experimental variables that are often poorly controlled. This paper demonstrates the simultaneous application of DSC and Raman microscopy for the observation of thermally driven transitions between polymorphs of pharmaceutical materials.

Assessment of the influence factors on in vitro testing of nasal sprays using Box-Behnken experimental design.

The purpose of the research was to investigate the influences of actuation parameters and formulation physical properties on nasal spray delivery performance using design of experiment (DOE) methodology. A 3-level, 4-factor Box-Behnken design with a total of 27 experimental runs was used in this study. Nine simulated aqueous formulations with different viscosities and surface tensions were prepared using carboxymethylcellulose sodium (CMC, gelling agent) and Tween80 (surfactant) each at three concentration levels.