Determination Of Impurity Profiles Research Articles

Use of online sequential segmented heart cutting modulation and orthogonality approach for determination of isomeric impurity profile of a drug molecule using parallel 2-dimensional mass spectroscopy

Determination of impurity profile including chiral and achiral impurities is challenging as well as time consuming while analysis of the active moiety. With the recent evolution of 2-Dimensional separation modes, significant improvement can be made for simultaneous determination of both achiral and chiral impurities in a single set-up. Herein, the present work represents example of how both chiral and achiral impurities can be determined simultaneously. To represent the work, galantamine HBr was selected as the active moiety since it has achiral as well as many chiral impurities. Further, a 1D UPLC method with shorter runtime was developed to determine the achiral impurities and simultaneous heart cutting approach was used to cut the impurities and active compound and transfer to 2D chiral setup to separate out chiral impurities and perform its quantification. Both methods were proven to be orthogonal to each other with orthogonality factor of 0.241.

Implementation of QbD Approach to the Development of Chromatographic Methods for the Determination of Complete Impurity Profile of Substance on the Preclinical and Clinical Step of Drug Discovery Studies.

The purpose of this work was to demonstrate the use of the AQbD with the DOE approach to the methodical step-by-step development of a UHPLC method for the quantitative determination of the impurity profile of new CPL409116 substance (JAK/ROCK inhibitor) on the preclinical and clinical step of drug discovery studies. The critical method parameters (CMPs) have been tested extensively: the kind of stationary phase (8 different columns), pH of the aqueous mobile phase (2.6, 3.2, 4.0, 6.8), and start (20–25%) and stop (85–90%) percentage of organic mobile phase (ACN). The critical method attributes (CMAs) are the resolution between the peaks (≥2.0) and peak symmetry of analytes (≥0.8 and ≤1.8). In the screening step, the effects of different levels of CMPs on the CMAs were evaluated based on a full fractional design 22. The robustness tests were established from the knowledge space of the screening step and performed by application fractional factorial design 2(4−1). Method operable design region (MODR) was generated. The probability of meeting the specifications for the CMAs was calculated by Monte-Carlo simulations. In relation to literature such a complete AQbD approach including screening, optimization, and validation steps for the development of a new method for the quantitative determination of the full profile of nine impurities of an innovative pharmaceutical substance with the structure-based pre-development pointed out the novelty of our work. The final working conditions were as follows: column Zorbax Eclipse Plus C18, aqueous mobile phase 10 mM ± 1 mM aqueous solution of HCOOH, pH 2.6, 20% ± 1% of ACN at the start and 85% ± 1% of ACN at the end of the gradient, and column temperature 30 °C ± 2 °C. The method was validated in compliance with ICH guideline Q2(R1). The optimized method is specified, linear, precise, and robust. LOQ is on the reporting threshold level of 0.05% and LOD at 0.02% for all impurities.

Development and Validation of Stability Indicating RP-HPLC Method for the Determination of Impurity Profile in Gamendazole: Experimental Male Oral Contraceptive

A novel RP-HPLC method has been developed for the simultaneous determination of Gamendazole and its process impurities and degradation impurities. Chromatographic separation was achieved on a C18 column (size: 250 mm × 4.6 mm; 5 µm particle size) using a gradient program at a flow rate of 1.0 mL/min and an injection volume of 10 µL with 210 nm detection. The mobile phase was water–acetonitrile (pH of water was adjusted to 3.0 with orthophosphoric acid) through gradient elution.The product was subject to stress conditions like acid, base, peroxide, thermal, and photolytic degradation. Similar degradants were observed in acid and base degradation. No degradants were observed in peroxide degradation. Several new degradants were observed in photolytic degradation. However, no interference was observed due to degradation impurities and Gamendazole, known impurities and unknown impurities.As part of the method validation, specificity, limit of detection (LOD), limit of quantitation (LOQ), linearity, accuracy, precision, robustness, and ruggedness were determined. LOQ values for Gamendazole, Impurity-A, Impurity-B, and Impurity-C were 0.04%, 0.04%, 0.02%, and 0.04%, respectively. Good linearity (r2 > 0.99) was obtained ranging from LOQ to 150%. Recovery was verified for all impurities at concentrations ranging from LOQ to 150%. %Recovery for Impurity-A, Impurity-B, and Impurity-C were 99.7–107.1%, 99.1–108.9%, 98.6–107.2%, respectively.

Lokesh Bhattacharyya and Jeffrey S. Rohrer (Eds): Applications of Ion Chromatography for Pharmaceutical and Biological Products

Ion chromatography revolutionized the analysis of small inorganic ions by replacing tedious individual gravimetric and titration methods with a single automated process, capable of analysing a number of ions simultaneously. Today the range of potential applications has grown to include a wider range of ionic and ionizable materials such as biopolymers. This book focuses on a segment of those applications arising from the use of ion chromatography in the pharmaceutical industry, and does so very well. The book is a little gem, and those readers attracted to the book by its title will find that it delivers exactly what it promises. The book contains 24 chapters under four general section headings with an appendix containing acid dissociation constants for compounds of pharmaceutical interest. Part I describes instrumentation, retention mechanisms, and operating principles in five chapters. These are quite general and useful to novice and more experienced chromatographers alike. There is a good discussion of ion exchange and ion exclusion mechanisms, modelling and method development, and instrumentation (focused on the design of ion suppressors and the pulsed electrochemical detector). The pulsed electrochemical detector is discussed further in later chapters, particularly its applications in biotechnology, where it has played a major role in the expansion of ion chromatography from its origins. Later chapters also discuss the use of the charged aerosol detector and mass spectrometry for the detection and identification of compounds difficult to determine by conductivity and electrochemical methods. These are novel detection methods at present, but have the potential to play a significant role in the development of ion chromatography for the analysis of unconventional samples. The coupling of ion chromatography to mass spectrometry (electrospray ionization of the desalted eluent) tackles the problem of how to identify compounds for which standards are not available, particularly impurities in high molecular weight biopolymers or the totally unexpected compound in a chromatogram. Part II covers pharmaceutical applications in 11 chapters. As well as the expected identification of small anions and cations used in drug formulations, the analysis of aminoglycoside antibiotics and cholinergic compounds is described. About half of all drugs are formulated as salts so the assay of active ingredients and excipients, determination of impurity profiles, identification of contaminants, and forensic source identity of raw materials can be performed by ion chromatography. This section also contains chapters on sample preparation, validation and pharmacopeial methods. The chapters are copiously illustrated with chromatograms, appreciated by this old chromatographer. There is also a focus on regulatory issues of interest to those who work according to the dictates of good laboratory practice. Part III covers biotechnology applications in five chapters. Topics covered include glycan, monosaccharide, oligosaccharide, glycoprotein, amino acid, and carbohydrate C. F. Poole (&) Wayne State University, Detroit, MI, USA e-mail: cfp@chem.wayne.edu

On-Line Sample Treatment LC System for MS Compatibility

In the present work, a new liquid chromatography–mass spectrometry (LC–MS) system with on-line pretreatment using column switching and a dilution function was developed. This system can be used under conventional high-performance liquid chromatography (LC) separation conditions, including mobile phases containing phosphate buffer. The built-in autodilution function greatly improves the trapping efficiency for target compounds, followed by desaltation that optimizes the ionization conditions for MS analysis. This fully automated two-dimensional LC system interfaced with mass spectrometry provided a powerful tool for the determination of impurity profiles in pharmaceutical research and the identification of traditional Chinese medicine in natural products.

Determination of new pyridoquinoline derivatives and their quantification in urine by capillary liquid chromatography

AbstractCapillary liquid chromatography (CLC) in reversed separation mode was applied to the quantification and impurity profile determination of eight newly synthesized pyridoquinolines. The CLC separation system consisted of Nucleosil C18 stationary phase and methanol containing 1% (v/v) of triethylamine (TEA) as the mobile phase. The optimized separation system enabled the separation of impurities from the main component and their quantification in a reasonable analysis time. The presence of TEA in the mobile phase greatly improved the peak shape and decreased the analysis time of the studied derivatives on the C18 stationary phase. Calibration curves of pyridoquinolines were plotted in a concentration range from 1.0×10–6 to 1.0×10–3 mol/L at two parallel detector wavelengths of 254 and 265 nm and subsequently used for quantification of pyridoquinoline derivatives in human urine. No pretreatment of the real biological sample was needed. Detection and quantification limits were calculated for all the derivatives and the detection limits of most of the pyridoquinolines were found to lie in the μmol/L concentration range. The proposed CLC separation system has proved to be a suitable method for quantification of test derivatives in samples containing human urine matrix.

Quantification and purity determination of newly synthesized thioacridines by capillary liquid chromatography

Capillary liquid chromatography (CLC) was applied for quantification and impurity profile determination of ten newly synthesized acridine thioderivatives. A reversed-phase CLC system employing two different stationary phases, Nucleosil C 18 and LiChrosorb RP-select B, was used. The mobile phase composition was optimized to get a satisfactory separation of impurities from the main acridine component in a reasonable analysis time. Significant differences in the chromatographic behavior between acridine derivatives containing and lacking amino groups were observed. Optimized separation conditions were used in CLC to measure the calibration curves of the acridine derivatives in a concentration range from 1.0·10 −6 to 1.0·10 −3 M at two different detector wavelengths (214 and 230 nm). Limits of detection and quantification of all the substances were determined. The detection limits went down to units of μ M for most of the derivatives. CLC was also demonstrated to be a suitable method for the purity determination of test batches of the acridine thioderivatives.

Determination of impurity profiles in drugs and related materials : II. Detection and quantification of a diastereomeric impurity in the peptide RGH-0205 (Arg—Lys—Asp)

Determination of impurity profiles in drugs and related materials : II. Detection and quantification of a diastereomeric impurity in the peptide RGH-0205 (Arg—Lys—Asp)

The Depth Resolution of Dynamic Sims: Experiments and Calculations

AbstractThis study is concerned with the fundamental limitations imposed by cascade mixing and recoil implantation on the depth resolution of secondary ion mass spectrometry (SIMS), and the effects of these limitations on the determination of impurity profiles in semiconductors.We present experimental results of measurements on atomically, or near atomically abrupt impurity profiles in Si using magnetic sector (Cameca) and quadrupole (Atomica) SIMS machines. The analysis conditions and samples have been chosen to minimize instrument (crater wall resputtering) and surface (equilibration time) effects. Under such conditions the leading edge of an abrupt signal is smeared to a complimentary error function, while the trailing edge exhibits an exponential decay reminiscent of recoil implantation profiles.Modifications of the Boltzmann Transport Equation (BTE) approach to ion implantation in multilayer targets will be shown to provide a first principles calculation of such SIMS knock-on phenomena, which is in good agreement with the empirical results.

Application of the approximate solution of Poisson's equation to derive new formulae for impurity profile determination by the C-V method : Andrzej Ostrowski. Electron Technol.15 (3/4) 57 (1982)

Application of the approximate solution of Poisson's equation to derive new formulae for impurity profile determination by the C-V method : Andrzej Ostrowski. Electron Technol.15 (3/4) 57 (1982)

Oxygen self-diffusion studies using negative-ion secondary ion mass spectrometry (SIMS)

The determination of accurate oxygen self-diffusion coefficients has proved difficult in the past because of the absence of a suitable radioactive isotope of oxygen. Modern secondary ion mass spectrometers, developed for the determination of impurity profiles in semiconductors, can also be used to obtain high-quality diffusion profiles for the stable isotope 18O. In this paper we will describe recent oxygen self-diffusion data on several technologically important materials including the magnetic ferrites, Fe 3O 4, substituted with Ni, and yttrium iron garnet (YIG). Particular attention is given to the accuracy attainable and a comparison of single-crystal and polycrystalline data will be given.

Impurity profile determination and DC modeling of the JIGFET

The junction and insulated gate FET (JIGFET) is a novel type of JFET which is formed by implantation of a deep channel between source and drain through a MOST gate. For high voltages on the gate an inversion layer is created underneath the oxide. This inversion layer is laterally connected to the substrate. In this way a new channel control mechanism for FET's is achieved in which the inversion layer is used as a substitute for a p+-n- or an n+-p-junction. This results in a very high bulk transconductance, which is of considerable importance in many applications. In this paper the n-channel JIGFET's with implanted channels of 2.4 × 1012p+ions/cm2at 100 keV and 3.4 × 1012p+ ions/cm2at 160 keV are investigated. The implantation profiles are calculated from pulsed C-V measurements. From these data the dc characteristics are calculated with the abrupt space charge layer edge (ASCE) approximation and compared with the experiments for both high and low drain voltages.

A fast algorithm for the calculation of junction capacitance and its application for impurity profile determination : H. J. J. De Man. Solid St. Electron.15 (1972), p. 177

Silicon dioxide thin films were prepared from silicon tetraacetate by low-pressure direct photochemical vapor deposition (photo-CVD) using an ArF excimer laser. The film prepared by a vertical irradiation of laser to an unheated substrate showed the lowest relative dielectric constant which is comparable to that of the film prepared by thermal-CVD at a substrate temperature of 300 °C. The relative dielectric constant was approximately proportional to the absorbance of Si-O · bond at about 950 cm−1. This indicates that an ionic polarization due to the nonbridging oxygen is closely connected with the relative dielectric constant of the film prepared by the decomposition of silicon tetraacetate at a low substrate temperature. Low-temperature annealing in air decreased the dangling bond and made the film denser.

A fast algorithm for the calculation of junction capacitance and its application for impurity profile determination

A fast algorithm is described which calculates the space charge layer width and junction capacitance for an arbitrary impurity profile and for plane, cylindrical and spherical junctions. The algorithm is based on the abrupt space charge edge (ASCE) approximation. A method to use the algorithm for the determination of impurity profiles for two-sided junctions is presented. An expression is derived for the built-in voltage to be used for capacitance calculations with the ASCE approximation. Experimental evidence is given that the algorithm permits very accurate capacitance calculations and also predicts the exact temperature dependence of the junction capacitance.

Determination of impurity profiles in presence of deep levels by the second-harmonic method

Determination of impurity profiles in presence of deep levels by the second-harmonic method

Anodic oxidation as sectioning technique for the analysis of impurity concentration profiles in silicon

Abstract Anodic oxidation is a commonly used technique for impurity profile determination in silicon. Optimum electrolyte composition, anodization conditions and problems involved in the determination of silicon removed by anodization are examined together with effects due to sample preparation and silicon characteristics. Experimental data are presented for the use of the ethylene glycol electrolyte together with the limits of accuracy of the technique. The use of the ellipsometric method in the evaluation of refractive index and thickness of silicon anodic oxides is illustrated and discussed.

An Electrodiffusion Apparatus for Solid Semiconductors

An apparatus has been developed for the study of the influence of applied electric fields and currents on solid state diffusion of impurities in semiconductors. Special features of the apparatus are simple procedures, versatility, and allowance for determination of impurity profiles.