A new ultrasound-assisted microextraction for elemental impurities determination in tablets by ICP-MS according to USP chapters 232 and 233.

Along with the United States Pharmacopeia (USP) chapters 232 and 233 regarding elemental impurities in pharmaceutical products, new challenges have been imposed in terms of sample preparation procedures prior to inductively coupled plasma mass spectrometry analysis, considering the matrix complexities. As so, a new microextraction procedure assisted by ultrasound using a cup-horn sonoreactor, minimal reactants, and sample was proposed and validated according to USP. The procedure was optimized with samples of milled tablets and 3 different acid mixtures (HNO3, 3HNO3:1HCl, and 9HNO3:1HF) and it was compared with microwave-assisted acid digestion. In the validation step, recoveries ranging from 85 to 120 % and RSD below 10 % were obtained for 22 analytes (except Ag and Pt) with satisfactory linearity and good sensitivity. The method was then applied for 37 samples of antidepressants, which presented trace levels of As, Ba, Cd, Co, Cr, Cu, Ni, Pb, Pd, Sn, and V.

Dispersive liquid-liquid microextraction of Cd, Hg and Pb from medicines prior to ICP OES determination according to the United States Pharmacopeia.

A simple, sensitive and matrix-effect free analytical method for simultaneous determination of Cd, Hg and Pb in drug samples (i.e., commercial dosage tablets) by inductively coupled plasma optical emission spectrometry (ICP OES) has been developed. According to the United States Pharmacopeia (USP) Chapter 232, those metals are considered elemental impurities from class 1 and they must be assessed in pharmaceutical production as well as in quality control evaluation. In order to increase the sensitivity of the analysis, dispersive liquid-liquid microextraction (DLLME) was performed and seven factors affecting analyte extraction were optimized by multivariate analysis. A microvolume of analyte enriched phase was directly introduced into the plasma using a multi-nebulizer, providing a high enrichment factor. When compared to conventional ICP OES analysis, DLLME improves the limit of quantitation (LOQ) values on average 40-fold for all analytes. Consequently, LOQ values were significantly lower than their permissible daily exposure limits for oral drugs. Accuracy was evaluated by addition and recovery experiments following USP recommendations in eight commercial drug samples. Recovery and RSD values were within the range of 90-108% and 1-9%, respectively.

Dispersive liquid-liquid microextraction based on deep eutectic solvent for elemental impurities determination in oral and parenteral drugs by inductively coupled plasma optical emission spectrometry.

A simple, fast, sensitive and green pretreatment method for determination of Cd, Co, Hg, Ni, Pb and V in oral and parenteral drug samples using inductively coupled plasma optical emission spectrometry (ICP OES) has been developed. According to United States Pharmacopoeia (USP), those metals must be reported in all pharmaceutical products for quality control evaluation (i.e., elemental impurities from classes 1 and 2A of USP Chapter 232). To improve the analytical capabilities of ICP OES, a dispersive liquid-liquid microextraction (DLLME) has performed using a safe, cheap and biodegradable deep eutectic solvent (DES) as extractant solvent (a mixture of 2:1 M ratio of DL-menthol and decanoic acid). Seven parameters affecting the microextraction efficiency have carefully optimized by multivariate analysis. Under optimized conditions, the DES-based DLLME-ICP OES procedure improved limit of quantitation (LOQ) values on range from 12 to 85-fold and afforded an enrichment factor on average 60-times higher than those obtained to direct ICP OES analysis. Consequently, LOQ values for Cd, Co, Hg, Ni, Pb and V have been on average 10-times lower than target limits recommended for drugs from parenteral route of administration. Trueness has evaluated by addition and recovery experiments following USP recommendations for three oral drug samples in liquid dosage form and three parenteral drugs. Recovery and RSD values have been within the range of 90-109% and 1-6%, respectively. All analytes were below the respectives LOQ values, hence, lower than the limits proposed by USP Chapter 232.

Effects of multiwalled carbon nanotubes co-exposure with cadmium on zebrafish cell line: Metal uptake and accumulation, oxidative stress, genotoxicity and cell cycle.

Carbon nanotubes presence in the environment increases every year because of exponential industrial production around the world. In aquatic environments, carbon nanotubes can interact with other pollutants based on their adsorbent surface chemistry properties. Heavy metal ions represent one of the biggest concerns in water resources nowadays due to anthropogenic activities, in which cadmium (Cd) is one of the most harmful metal for aquatic organisms. This study investigated the influence of two co-exposure protocols differing by the order of interaction of oxidized multiwalled carbon nanotubes (ox-MWCNT) with Cd in zebrafish liver cell line (ZFL). The ox-MWCNT was characterized, Cd content in culture medium and uptake by cells were quantified using ICP-MS and, the reactive oxygen species (ROS), the biotransformation enzymes activity of phase I and II as well as the antioxidants defenses and oxidative damage were analyzed. The effects on the cell cycle were investigated by flow cytometry and DNA damage by comet assay. The exposure to ox-MWCNT alone decreased the activity of catalase, glutathione peroxidase, and glutathione S-transferase and altered the cell cycle with a reduction of cells in the G2/M phase. Cd exposure alone decreased the activity of catalase and glutathione S-transferase, increased ROS, metallothionein, and lipid peroxidation content and causes genotoxicity in the cells. Despite different incubation protocol, the co-exposure ox-MWCNT-Cd increased the Cd content in ZFL cells after 24 h exposure, increased ROS production and DNA damage without differences between them. Our results showed the modulation of ox-MWCNT on Cd effects and contributed to future co-exposure toxicity investigations and nanosafety regulations involving carbon nanomaterials and aquatic pollutants.

Elemental impurities analysis in name-brand and generic omeprazole drug samples.

Elemental impurities in drug samples can generate unwanted pharmacological-toxicological effects, therefore they must be carefully monitored. In order to update the elemental analysis of pharmaceutical products, new regulations for elemental impurities were published by the United States Pharmacopoeia (USP). This work presents elemental analysis of 23 analytes in omeprazole drug samples from seven different commercial brands considering reference, similar and generic medicines using inductively coupled plasma mass spectrometry (ICP-MS). Microwave-assisted digestion using 2.0 mol L-1 HNO3 (partial digestion) was applied successfully for omeprazole drugs. Most analytes were below the respective limits of quantification, except for As, Ba, Cd, Co, Cu, Cr, Li, Mo, Ni, Pb, Sb and V. However, the determined concentrations for these analytes were lower than the limits proposed by the USP Chapter 232 and similar for all products, inferring that for the seven analyzed samples there is no difference among reference, similar and generic drugs considering contaminants contents. Discussions considering potential risks of elemental contamination taking into account diverse brands were presented.

Microwave-assisted sample preparation of medicines for determination of elemental impurities in compliance with United States Pharmacopeia: How simple can it be?

This work proposed a procedure for microwave-assisted sample preparation of medicines using diluted nitric acid followed by determination of elemental impurities using inductively coupled plasma optical emission spectrometry (ICP OES) and inductively coupled plasma mass spectrometry (ICP-MS) according to the United States Pharmacopeia Chapters 232 and 233. Three solutions, i.e. inverse aqua regia, 7.0 and 2.0 mol L-1 HNO3, were evaluated for microwave-assisted digestion of nine drugs samples. The applicability of each digestion procedure was assessed by comparison of analyte concentrations determined using total (reference procedure) and partial digestions (proposed procedure) as well as by determining dissolved carbon content and evaluating matrix effects. There were none significant differences at a 95% confidence level among the concentrations determined applying reference and proposed procedures. Internal standardization (ICP OES) and aerosol dilution (ICP-MS) were applied for minimization and correction of matrix effects. Addition and recovery experiments were performed according to oral permissible daily exposures values specific for each element and each sample was spiked with element concentrations of 0.5J and 1.5J in order to check accuracies for 24 analytes. Recoveries ranged from 70 to 138% for ICP OES and from 72 to 128% for ICP-MS, for all elements but Os. All analytes were below the respective limits of quantification when applying all sample preparation procedures, except As, Ba, Co, Cu, Cr, Mo, Ni, Pb, Sb, Sn, Tl and V, however the determined concentrations for these elements were lower than the limits proposed by Chapter 232.

Aerosol dilution as a simple strategy for analysis of complex samples by ICP-MS.

This study investigated the capability of High Matrix Introduction (HMI) strategy for analysis of dialysis solution and urine samples using inductively coupled plasma mass spectrometry. The use of HMI enables the direct introduction of urine samples and dialysis solutions 2-fold diluted with 0.14molL-1 HNO3. Bismuth, Ge, Ir, Li, Pt, Rh, Sc and Tl were evaluated as internal standards for Al, Ag, As, Be, Cd, Cr, Pb, Sb, Se, Tl, and Hg determination in dialysis solution and As, Cd, Hg and Pb determination in urine samples. Helium collision cell mode (4.5mLmin-1) was efficient to overcome polyatomic interferences in As, Se and Cr determinations. Mercury memory effects were evaluated by washing with 0.12molL-1 HCl or an alkaline diluent solution prepared with n-butanol, NH4OH, EDTA, and Triton X-100. This later solution was efficient for avoiding Hg memory effects in 6h of analysis. Linear calibration curves were obtained for all analytes and detection limits were lower than maximum amounts allowed by Brazilian legislations. Recoveries for all analytes in dialysis solutions and urine samples ranged from 82% to 125% and relative standard deviations for all elements and samples were lower than 7%. Analysis of control internal urine samples was in agreement with certified values at 95% confidence level (t-test; p < 0.05).