Determination Of Elemental Impurities Research Articles

Determination of Elemental Impurities in Gelatine Capsules by Inductively Coupled Plasma Mass Spectrometry

INTRODUCTION. Gelatine capsules are an essential dosage form used for many medicinal products. Gelatine capsules are subject to quality control in accordance with the requirements of the general monograph on capsules of the State Pharmacopoeia of the Russian Federation. This monograph does not standardise the content of elemental impurities, as these impurities are controlled at the raw material level. However, the equipment and excipients used in the production of gelatine capsule shells may be additional sources of impurities. Preliminary screening for chemical elements will help to assess the need for limiting elemental impurities in gelatine capsule shells.AIM. This study aimed to identify the chemical elements that contribute to gelatine capsule shell contamination the most by inductively coupled plasma mass spectrometry, to list the elements requiring specification, and to limit their content from a risk-based pharmaceutical quality control perspective.MATERIALS AND METHODS. The study used 18 samples of hard gelatine capsules by different national and international manufacturers. The elemental analysis was performed using an Agilent 7900 inductively coupled plasma mass spectrometer (Agilent Technologies).RESULTS. The As, Ba, Co, Cr, Cu, Li, Mo, Ni, Pb, Sb, and V content in gelatine capsule shells did not exceed the permitted daily exposure (PDE) thresholds for oral dosage forms specified in the State Pharmacopoeia of the Russian Federation. Ag, Au, Cd, Hg, Ir, Os, Pd, Pt, Rh, Se, Sn, or Tl were not detected in any of the samples within the established detection limits. The Fe content in 67% of the tested shell samples was above the safety-based PDE for medical gelatine.CONCLUSIONS. The greatest contributors to gelatine capsule shell contamination are Al, Fe, and Zn. The lack of established PDE thresholds for these elements presents a challenge in assessing the risks of adverse effects associated with ingesting these elements with gelatine capsules.

Determination of elemental impurities in lomefloxacin hydrochloride ear drops by ICP-MS Using Oxygen Reaction Mode and study of their catalytic effect on photodegradation reaction.

According to the requirements of ICH Q3D, a method for simultaneous determination of 12 element impurities in lomefloxacin hydrochloride ear drops by inductively coupled plasma mass spectrometry (ICP-MS) was established. However, this product contains high concentrations of organic compounds such as glycerol and ethanol, and there will be interference of soluble carbon when it is determined by direct injection method. Therefore, we applied ICP-MS using oxygen reaction mode to reduce the effect of high organic matter on plasma body. The catalytic effect of trace metal ions on the photodegradation of lomefloxacin hydrochloride was also investigated. The sample was dissolved, diluted and directly determined by direct injection using oxygen reaction mode of ICP-MS with 45 Sc, 73 Ge and 115 In as the internal standards. The direct injection using oxygen reaction mode was equipped with argon-oxygen mixer. To investigate the catalytic effect of metal ions on photodegradation, a series of combinations of lomefloxacin hydrochloride mixed with different metal ions were designed. After being irradiated under ultraviolet light for 10 days, the photodegradation impurities in combinations were determined by HPLC. The linear relationships in the corresponding concentration range for 12 element impurities were good (r>0.9993). Limits of detection were between 0.002~1.294 ng·mL-1 . The average recoveries were 93.7%-108.2%, and the precision RSD were 0.04% ~ 0.55% (n=6). The experimental results showed that metal ions had a certain catalytic effect on photodegradation of lomefloxacin when EDTA, Mg2+ and Cu2+ coexisted. The ICP-MS using oxygen reaction mode is suitable to direct determination of the sample rich in organic matter without digestion, can effectively eliminate the interference of high organic matter in this product. The established method was rapid, sensitive, accurate, and can be used for the quality control of elemental impurities in lomefloxacin hydrochloride ear drops.

Determination of elemental impurities in valproic acid an epilepsy drug by using ICP-MS

BackgroundAccording to previously published research, different analytical methods (GC, HPLC, etc.) were used to determine Valproic acid and its Genotoxic impurities. The heavy metals were also attempted to be determined using the ICP-MS technique in other drug substances. MethodsThe present work evaluated the 10 elemental impurities (Cd, Pb, As, Hg, Co, V, Ni, Fe, Al, and Sn) in Valproic acid by ICP-MS method utilising a microwave-assisted acid digestion process as there is no analytical method for the heavy metal analysis in Valproic acid. ResultsThe developed analytical method was selective, sensitive and rapid for capable of detecting heavy metal at 0.19 ppm As, 0.38ppm Hg, 0.06 ppm Pb, 0.06ppm Cd, 0.63 ppm Co, 1.25ppm V,2.5 ppm Ni, 25 ppm Fe, 25 ppm Al and 75 ppm Sn and further quantified from 0.375ppm As,0.75ppm Hg, 0.125 ppm Pb, 0.125ppm Cd, 1.25ppm Co, 2.5ppm V, 5 ppm Ni, 50 ppm Fe, 50ppm Al and 150 ppm Sn to 200 percent of limit concentration. The analytical method found to be linear with correlation coefficient > 0.99. The percentage recoveries of heavy metals at three different concentrations with spiking in samples of Valproic acid were achieved an acceptable range at 70% to 150 %. The method was precise and robust and its relative standard deviation was below 20%. The actual % RSD in precision are 1.0 % As, 0.5 % Hg, 0.5 % Pb, 1.2 % Cd,0.6 % Co, 0.6 % V, 0.6 % Ni, 0.5% Fe, 0.9 % Al and 0.3 % Sn. ConclusionHeavy metal analysis by ICP-MS is a powerful technique, Therefore the developed method can use for routine quantitative determination of 10 elemental impurities in Valproic Acid.

Measurement Uncertainty Estimation for the Quantitative Determination of Elemental Impurities in Active Pharmaceutical Ingredients Using Microwave Digestion Followed by ICP-OES According to USP <232> and <233> Specifications

Measurement Uncertainty Estimation for the Quantitative Determination of Elemental Impurities in Active Pharmaceutical Ingredients Using Microwave Digestion Followed by ICP-OES According to USP <232> and <233> Specifications

Development of Green Methods for the Determination of Elemental Impurities in Commercial Pharmaceutical Tablets

In this study, two methods based on the use of diluted acids were developed: microwave-assisted wet digestion (MAWD) and microwave-assisted ultraviolet digestion (MAWD-UV). These methods are evaluated for the digestion of oral pharmaceutical drugs and further determination of elemental impurities from classes 1 (As, Cd, Hg and Pb) and 2A (Co, Ni and V) by inductively coupled plasma optical emission spectrometry (ICP-OES). Commercial drugs for the treatment of type 2 diabetes are used. No prior comminution is performed. For MAWD, the optimized conditions were 2 mol L−1 or 3 mol L−1 HNO3, 1 mL of 50% H2O2 and a 45 min or 55 min irradiation program. For MAWD-UV, the condition using 1 mol L−1 HNO3, 1.6 mL of 50% H2O2 and a 55 min irradiation program enabled the digestion of all samples. In this way, efficient methods are proposed for the digestion of commercial pharmaceutical tablets for further determination of class 1 and 2A elemental impurities (ICH Q3D guidelines).

Determination of Elemental Impurities in a Nasal Spray by ICP-MS

Instrumental methods of analysis are frequently used to determine the level of a compound, class of compounds, or other chemical property on the studied item. The ability to adequately quantify measurement result uncertainty is crucial for the objective that triggered the chemical analysis. A tutorial and spreadsheet for the validation and bottom-up uncertainty evaluation of quantifications performed by instrumental methods of analysis based on linear weighted calibrations was presented by Ricardo J.N. Bettencourt da Silva of the University of Lisbon in Lisbon, Portugal, and his colleagues. This software tool was successfully applied to the determination of the mass concentration of cadmium, lead, arsenic, mercury, cobalt, vanadium, and nickel in a nasal spray by inductively coupled plasma–mass spectrometry (ICP-MS) after samples dilution and acidification. Bettencourt da Silva spoke to Spectroscopy about applying this software tool and the implications for a better understanding of quantitative analytical results.

Determination of elemental impurities of Arsenic, Cadmium, Mercury, Lead and Palladium content in Testosterone propionate by using ICP-MS

The aim of the present work is to develop and establish a validated analytical method for the determination of arsenic, cadmium, mercury, lead and palladium content in testosterone propionate by using inductive coupled plasma mass spectroscopy (ICP-MS). Samples were analyzed after a preparation of sample solution by dissolving in suitable solvents of concentrated nitric acid and concentrated hydrochloric acid. In the present method, RF power of 1550 watts, RF matching is 1.80 V, nebulizer flow of 0.10 rps and plasma view at spectrum mode were used. Octopole conditions are He flow is on, He flow rate is 4.3 mL/min and energy discrimination is 3.0 V were used. Significant savings in sample volumes, reagents, analysis cost and time are realized. Arsenic, cadmium, mercury, lead and palladium are primary concerned due to their high toxicity and potential contaminants should be limited in testosterone propionate and the developed method was validated according to ICH and USP guidelines. The correlation coefficient, recovery rate, LOD and LOQ reached the acceptable limits. The validated method was selective, sensitive, rapid and capable of the determination of elemental impurities of arsenic, cadmium, mercury, lead and palladium content in bulk drugs.

Tutorial and spreadsheet for the evaluation of instrumental quantification uncertainty by the linear weighted regression model: Determination of elemental impurities in a nasal spray by ICP-MS

A tutorial and spreadsheet for the validation and bottom-up uncertainty evaluation of quantifications performed by instrumental methods of analysis based on linear weighted calibrations is presented. The developed tool automatically assesses if calibrator values uncertainty is negligible given instrumental signal precision, assesses signal homoscedasticity by the Levene's test, guides the selection of weighting factors and evaluates the fitness of the regression model to define the calibration curve. The spreadsheet allows the use of the linear weighted regression model without the need for collecting many replicate signals of calibrators and sample by taking previously developed detailed models of signal precision variation in the calibration interval after adjustments to the daily precision conditions. This tool was successfully applied to the determination of the mass concentration of Cd, Pb, As, Hg, Co, V and Ni in a nasal spray by ICP-MS after samples dilution and acidification. The developed uncertainty models were checked through the analysis of nasal sprays after spiking with known analyte concentration levels. The metrological compatibility between estimated and reference analyte levels for 95% or 99% confidence level supports uncertainty model adequacy. The spiked samples were quantified from many replicate signals but uncertainty evaluation from duplicate calibrator and sample signals was assessed by randomly selecting calibrators and sample signals and by numerically defining a minimum acceptable success rate of the compatibility tests. The developed model was proven adequate to quantify the uncertainty of the studied measurements.

Measurement uncertainty evaluation from correlated validation data: Determination of elemental impurities in pharmaceutical products by ICP-MS

Pharmaceutical products as well as active pharmaceutical ingredients (APIs) are checked for levels of elemental contaminants to guarantee medicines administration will not involve the consumption of level of contaminants greater than their maximum admissible intake. However, the conformity decision is affected by the measurement uncertainty function of analytical steps performance, used standards quality and how measurement performance is assessed during method validation. When an ingredient is considered conform, since the measured concentration is lower than the maximum limit, the risk of a false acceptance depends on how close the measured concentration is from the limit and on the measurement uncertainty. The analytical methods used for pharmaceutical analysis should be validated by ICH and USP recommendations, in order to prove measurements are fit for purpose. The validation must also be economically feasible and have an acceptable duration. This work discusses how to evaluate the uncertainty of elemental analysis in pharmaceutical ingredients from data collected during the validation of the analytical method by following ICH guidelines and USP chapters. A top-down uncertainty evaluation based on results from the analysis of a model API intermediate, with the native analyte after spiking at three concentration levels, where analyses are performed by two analysts in two different days, is presented. The impact of the correlation of some uncertainty components of collected results on the uncertainty evaluation is discussed and considered in the calculations. The developed measurement model was checked by a cross-validation procedure where some validation data was randomly removed and used for an independent model control. The developed uncertainty evaluation methodology was successfully applied to the analysis of Pd in a model API intermediate by ICP-MS after a micro-wave assisted acid digestion, where the risk of a false acceptance of the pharmaceuticals is determined. The measurement performance data and used spreadsheet are made available as Supplementary Material.

Microwave-assisted digestion using dilute nitric acid solution and investigation of calibration strategies for determination of As, Cd, Hg and Pb in dietary supplements using ICP-MS

This study proposes an analytical procedure for microwave-assisted sample preparation of dietary supplements for athletes using dilute nitric acid solution followed by determination of elemental impurities (As, Cd, Hg and Pb) by inductively coupled plasma mass spectrometry (ICP-MS) according to the United States Pharmacopeia Chapters 2232 and 233. Calibration strategies as internal standardization (IS), multi-isotope calibration (MICal), and one-point standard addition (OP SA) were applied for correction of matrix effects. The optimization of the sample preparation procedure was performed using Doehlert experimental design based on overall desirability results (residual acidity, dissolved organic carbon and recoveries reached for certified reference material of Typical Diet) for each calibration method evaluated. Accuracy was also evaluated by recovery experiments according to the permissible daily exposure specific for each element and samples were spiked with element concentrations of 0.5J and 1.5J in order to check accuracies for As, Cd, Hg and Pb. Recoveries ranged from 82 to 120% using IS, 90 to 125% using MICal, 88 to 120% using OP SA and the repeatability was demonstrated by a precision lower than 10% RSD. Ten samples of dietary sport supplements were analyzed using the three calibration methods evaluated and the concentrations of As, Cd and Pb determined in eight samples were lower than the limits established by the Chapter 2232.

Microwave-induced combustion of graphene for further determination of elemental impurities using ICP-OES and TXRF

An analytical method of microwave induced combustion (MIC) combined with ICP-OES and TXRF is proposed to determine elemental impurities in graphene.

Screening of TiO2 and Au nanoparticles in cosmetics and determination of elemental impurities by multiple techniques (DLS, SP-ICP-MS, ICP-MS and ICP-OES)

Cosmetics are part of the daily life of most of the people. Thus, a complete characterization of the products we applied in our skin is necessary. In this work, an analytical investigation of a wide variety of cosmetics from the point of view of total element content and metallic nanoparticles (NPs) has been performed. Firstly, we analyzed the total element content by ICP-MS and ICP-OES after acid digestion as an assessment of the presence of metal impurities. Prohibited elements in cosmetics, according to the European Commission regulation No 1223/2009, were not detected, and only elements mentioned in the label were found (e.g. Al, Fe, Ti and Si). Secondly, a screening of the presence of NPs has been performed by Dynamic Light Scattering (DLS) and Single Particle Inductively-Coupled Plasma Mass Spectrometry (SP-ICP-MS). Two sample preparation procedures were applied. The first protocol consisted in the preparation of suspensions in 0.1% w/v SDS and the second based on defatting with hexane followed by resuspension in water. DLS was employed as a routine method for a fast analysis of NPs, but this technique showed limitations due to the lack of specificity. SP-ICP-MS analyses were then performed, first as a screening technique to evaluate the presence of TiO2 and Au NPs in cosmetics suspensions prepared in SDS; and second, when a positive answer was obtained about the presence of NPs from the screening, SP-ICP-MS was used for particle size determination. Results showed that only TiO2 NPs were present in two sunscreens, one anti-wrinkle day cream, one lip balm protector labeled as ‘nano’ and in one brand of toothpaste not labeled as ‘nano’. Sizes obtained for both sample preparations were compared and ranged from 30 to 120nm in most of the samples.

Determination of elemental impurities in pharmaceutical products and related matrices by ICP-based methods: a review

Interest in the determination of elemental impurities in pharmaceuticals has increased in recent years because of changes in regulatory requirements and the need for changing or updating the current limit tests recommended in pharmacopeias. Inductively coupled plasma (ICP) optical emission spectrometry and ICP mass spectrometry are suitable alternatives to perform multielemental analysis for this purpose. The main advantages and limitations of these techniques are described, covering the applications reported in the literature in the last 10years mainly for active pharmaceutical ingredients, raw materials, and pharmaceutical dosage forms. Strategies used for sample preparation, including dissolution in aqueous or organic solvents, extraction, wet digestion and combustion methods are described, as well as direct solid analysis and ICP-based systems applied for speciation analysis. Interferences observed during the analysis of pharmaceutical products using ICP-based methods are discussed. Methods currently recommended by pharmacopeias for elemental impurities are also covered, showing that the use of ICP-based methods could be considered as a trend in the determination of these impurities in pharmaceuticals. However, the development of a general method that is accurate for all elemental impurities and the establishment of an official method are still challenges. In this regard, the main drawbacks and suitable alternatives are discussed.

Determination of elemental impurities in polymer materials of electrical cables for use in safety systems of nuclear power plants and for data transfer in the Large Hadron Collider by instrumental neutron activation analysis

Using instrumental neutron activation analysis with both short- and long-time irradiations, we determined up to 38 elements in polymers used in cables for new nuclear power plants (NPP) generation and for the Large Hadron Collider (LHC). Contrary to our previous work concerning the element contents in polymers presently used in several NPP, the values found in new cables for NPP were mostly below maximum allowable contents set by European regulations. In case of cables for LHC, several trials were needed to obtain a cable, whose polymer materials satisfied the requirement of an international guide on halogen-free composition.

Determination of elemental impurities in poly(vinyl chloride) by inductively coupled plasma optical emission spectrometry

In this work, a method for poly(vinyl chloride) (PVC) analysis by inductively coupled plasma optical emission spectrometry (ICP-OES) was developed. Samples were digested by microwave-induced combustion (MIC) and thirteen elements (Ba, Cd, Co, Cu, Fe, Mg, Mn, Mo, Ni, Pb, Sr, V and Zn) were determined by ICP-OES. Operational conditions of MIC were investigated allowing quantitative determination of all the analytes and suitable results were achieved using a 3molL−1 HNO3 solution. Microwave-assisted wet digestion (MAWD) using closed quartz vessels and a single reaction chamber microwave digestion system (MAWD–SRC), were also evaluated for PVC digestion for results comparison. All the evaluated sample preparation methods were considered suitable for PVC digestion but MIC was preferable due to the possibility of using diluted HNO3 instead of concentrated reagents and due to the better digestion efficiency. The residual carbon content (RCC) in digests obtained by MIC was significantly lower in comparison with the values obtained after MAWD and by MAWD–SRC. Accuracy for the proposed method was better than 94% for all analytes by comparison of results with those obtained by neutron activation analysis (NAA). Using MIC, it was possible to digest a relatively high sample mass (500mg) and up to 8 samples in less time (25min) in comparison with MAWD and MAWD–SRC (about 60min for both methods). The efficiency of digestion by MIC was higher 99% and lower limits of detection (as low as 0.1µgg−1) were obtained avoiding the use of concentrated acids that is of great concern according to the current green chemistry recommendations.

Determination of Elemental Impurities in Acyclovir Ointment and Raw Materials Using Microwave Acid Digestion (MW-AD) and ICP-MS

Inorganic elements present in pharmaceutical products were determined by inductively coupled plasma-mass spectrometer (ICP-MS), employing microwave acid digestion as a sample preparation method. The most abundant isotopes, 75As+ , 65Cu+ , 52Cr+ , 58Ni+ , 208Pb+ , and 51V+ , were determined in acyclovir ointment and its constituents. Elemental impurities in the pharmaceutical samples were determined using an inductively coupled plasma-universal cell technology-mass spectrometer (ICP-UCT-MS) operated in kinetic energy discrimination (KED) and standard mode. The accuracy of the method was assessed by means of addition and recovery experiments. Except for Cr, spiked recoveries of the elements added to the samples before microwave acid digestion (MW-AD) step were between 95.1 and 126%, and after MW-AD step ranged from 85.6 to 132%. Limits of detection (LOD) obtained by proposed method is in agreement to those required by the U.S. Pharmacopeia Convention (USP), showing that the ICP-MS technique is well suited for quantification of these elements. The LOD?s (ng L-1) for 51V+ , 52Cr+ , 58Ni+ , 65Cu+ , 75As+ and 208Pb+ in 1% v v-1 HNO3 medium were: 2.2, 81.3, 91.9, 6.9, 0.2 and 3.1, respectively. The concentration of the analytes in these samples presented a wide range, varying from 2.3 ± 0.8 µg kg-1 for As to 3446 ± 47 µg kg-1 for Cr.

Study and determination of elemental impurities by ICP-MS in active pharmaceutical ingredients using single reaction chamber digestion in compliance with USP requirements

In this work a method for active pharmaceutical ingredients (APIs) digestion using the single reaction chamber (SRC—UltraWaveTM) system was proposed following the new recommendations of United States Pharmacopeia (USP). Levodope (LEVO), primaquine diphosphate (PRIM), propranolol hydrochloride (PROP) and sulfamethoxazole (SULF) were used to evaluate the digestion efficiency of the proposed method. A comparison of digestion efficiency was performed by measuring the carbon content and residual acidity in digests obtained using SRC and in digests obtained using conventional microwave-assisted digestion system (MultiwaveTM). Three digestion solutions (concentrated HNO3, aqua regia or inverse aqua regia) were evaluated for digestion of APIs. The determination of Cd, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru was performed using inductively coupled plasma mass spectrometry (ICP-MS) in standard mode. Dynamic reaction cell (DRC) mode was used for the determination of 51V, 52Cr, 53Cr, 63Cu and 65Cu in order to solve polyatomic ion interferences. Arsenic and Hg were determined using chemical vapor generation coupled to ICP-MS (FI-CVG-ICP-MS). Masses of 500mg of APIs were efficiently digested in a SRC-UltraWaveTM system using only HNO3 and allowing a carbon content lower than 250mgL−1 in final digests. Inverse aqua regia was suitable for digestion of sample masses up to 250mg allowing the determination of Ir, Pd, Pt, Rh and Ru. By using HNO3 or inverse aqua regia, suitable recoveries were obtained (between 91 and 109%) for all analytes (exception for Os). Limits of quantification were in agreement with USP requirements and they ranged from 0.001 to 0.015µgg−1 for all elemental impurities (exception for Os). The proposed method was suitable for elemental impurities determination in APIs and it can be used in routine analysis for quality control in pharmaceutical industries.

Determination of elemental impurities in phosphoric acid by INAA employing a novel method of phosphate precipitation

Banned irradiation of liquid acids in many nuclear reactors requires a transformation of these compounds into a solid substance to be able to perform the determination of impurities using instrumental neutron activation analysis. For this purpose, a novel, simple, and contamination-free procedure for the transformation of phosphoric acid into ammonium phosphate has been developed, which is based on isothermal distillation of ammonia vapours. Favourably low detection limits for more than 35 elements have been achieved and the accuracy of the results has been established by analysis of NIST SRM 1515 Apple Leaves.

Determination of elemental impurities in polymer materials of electrical cables of safety systems of nuclear power plants by k 0-INAA

Instrumental neutron activation analysis with k0 standardization (k0-INAA) was employed for elemental characterization of individual components of electrical cables currently used in safety systems of nuclear power plants (NPP). The analysis yielded information about the content of 35 elements. It has been found that the presently used cables would not satisfy requirements of qualification set for the new generation of NPP by “The European Utility Requirements for LWR Nuclear Power Plants”, because content of several elements exceeded the maximal admissible levels. This demonstrates that cable polymer materials for safety systems of the new generation NPP must be synthesized and controlled regarding the content of additives, which are undesired from the hygienic and radiological points of view. k0-INAA proved to be a method of choice for elemental characterization of polymer materials of electrical cables as part of their qualification for use in NPP.

Determination of elemental impurities in plastic calibration standards using laser-induced breakdown spectroscopy

Dual-energy computed tomography (CT) scanning is a rapidly emerging imaging technique employed in nondestructive evaluation of various materials. CT has been used for characterizing rocks and visualizing multiphase flow through rocks for over 25 years. The most common technique for dual-energy CT scanning relies on homogeneous calibration standards to produce the most accurate decoupled data. However, the use of calibration standards with impurities increases the probability of error in the reconstructed data and results in poor rock characterization. Laser-induced breakdown spectroscopy was used to determine impurity concentration in a set of commercially purchased calibration standards used in dual-energy scanning for material identification with coal samples. Two calibration models were developed by using univariate calibration with the internal ratio method and multiple linear regression. Seven elements (Al, Fe, Mg, Na, Ni, Sr, and Ti) were examined in five different samples containing varying amounts of each ion to compare calibration from univariate data analysis and from multivariate data analysis. The contaminant concentrations were also measured by a commercially available inductively coupled plasma optical emission spectroscopy instrument, and the data were used as a reference in developing calibration curves for a modified version of the single linear regression model and the multiple linear regression model.