Impurity Potential Research Articles

Industrial Genotoxicology Group (IGG): 36th Annual Meeting Report.

The proceedings of the 36th annual meeting of the Industrial Genotoxicology Group (IGG) are shared here. The meeting held at Lhasa Limited, Leeds, UK on 28th November 2023, focussed two aspects; New Approach Methodologies (NAM's), including those for the assessment of non-standard modalities such as gas-vapour assessments and nanomaterials, and addressing the regulatory challenges associated with understanding the genotoxic and carcinogenic potential of N-nitrosamines and N-nitrosamine impurities. New approach methodologies, such as error-corrected sequencing and enhanced Ames tests that may help address these challenges were also discussed.

Simple and robust method for the synthesis of Metopimazine by utilising smile’s rearrangement. Elimination of genotoxic impurities via derivatization

A simple, efficient and scalable methodology has been developed for the synthesis of Metopimazine, a dopamine D2–receptor antagonist. Starting from nitrophenylthio substituted methylsulfonyl benzenamine subjected to simple N–formylation using formic acid followed by base–catalysed cyclization resulted the formation of 2–(methylsulfonyl)–10H–phenothiazine. This method does not involve the conventional peracid oxidation that exemplifies the formation of several oxidized species that are tedious to separate. The later derivative is proven effective in the synthesis of title active pharmaceutical ingredient via N–chloroproylation followed by treating piperidine–4–carboxamide resulted in the formation of Metopimazine in high yield. The potential genotoxic impurities such as nitroaromatic derivatives were effectively removed by reduction using simple zinc dust formic acid treatment, which effectually converts nitro derivatives into amine hydrochlorides that are water soluble. Similarly, the N–alkylation of phenothiazine derivative forms potential impurities such as the formation of N–allyl and propyl bridged dimer derivatives that are removed by effective recrystallization. This method has been scaled up and evidenced no compromise with the yield and hence can be considered as industry ready.

Validation of a radiosynthesis method and a novel quality control system for [68 Ga]Ga-MAA: is TLC enough to assess radiopharmaceutical quality?

BackgroundTechnetium-99 m-labelled macroaggregated human serum albumin ([99mTc]Tc-MAA) is commonly used for lung perfusion scintigraphy. The European Pharmacopoeia (Eu.Ph.) specifies thin-layer chromatography (TLC) as the only method to assess its radiochemical purity (RCP). Similarly, TLC is the sole method reported in the literature to evaluate the RCP of Gallium-68-labelled MAA [68 Ga]Ga-MAA, recently introduced for lung perfusion PET/CT imaging. Since [68 Ga]Ga-MAA is prepared from commercial kits originally designed for the preparation of [99mTc]Tc-MAA, it is essential to optimize and validate the preparation methods for [68 Ga]Ga-MAA.ResultsWe tested a novel, simplified method for the preparation of [68 Ga]Ga-MAA that does not require organic solvents, prewash or final purification steps to remove radioactive impurities. We assessed the final product using radio-TLC, radio-UV-HPLC, and radio SDS-PAGE. Overall, our quality control (QC) method successfully detected [68 Ga]Ga-MAA along with all potential impurities, including free Ga-68, [68 Ga]Ga-HSA, unlabeled HSA, which may occur during labelling process and HEPES residual, a non-toxic but non-human-approved contaminant, used as buffer solution. We then applied our QC system to [68 Ga]Ga-MAA prepared under different conditions (25°–40°–75°–95 °C), thus defining the optimal temperature for labelling. Scanning Electron Microscopy (SEM) analysis of the products obtained through our novel method confirmed that most [68 Ga]Ga-MAA particles preserved the morphological structure and size distribution of unlabeled MAA, with a particle diameter range of 25–50 μm, assuring diagnostic efficacy.ConclusionsWe optimized a novel method to prepare [68 Ga]Ga-MAA through a QC system capable of monitoring all impurities of the final products.

A Simultaneous Quantification of Four Potential Genotoxic Impurities Purinediol Hydrochloride, N7-Isomer, Monoalkyl Contaminant and Diacetyl Purine Present in Penciclovir Using LC-MS/MS

A Simultaneous Quantification of Four Potential Genotoxic Impurities Purinediol Hydrochloride, N7-Isomer, Monoalkyl Contaminant and Diacetyl Purine Present in Penciclovir Using LC-MS/MS

Measurement of ascorbic acid samples’ optical rotation via an improvised polarimeter for purity assessment

Abstract The polarization of light finds practical application in physics and chemistry through the optical activity phenomenon, where polarimeters play a crucial role. This research builds on the improvised polarimeter designed by Kvittingen and Sjursnes [1], implemented with relevant modifications, to measure optical rotations of over-the-counter ascorbic acid samples. The study aims to assess the purity of two brands of ascorbic acid through polarimetry, comparing the calculated specific rotation with the literature values and supplementing the characterization with melting point determination. The constructed polarimeter, assembled using Lego bricks, provides an affordable alternative for educational purposes, addressing the challenges observed in the accessibility of commercial polarimeters for classroom demonstrations. The methodology encompasses pre-experiment steps involving polarimeter construction, the experiment utilizing polarimetry and complementary melting point determination, and post-experiment analysis to determine specific rotation from the measured optical rotations. Results indicate that Brand X exhibited specific rotations close to theoretical values, inferring high purity. Conversely, Brand Y shows significant deviations, suggesting potential impurities. These conclusions are supported by melting point data. The comprehensive approach combining polarimetry and melting point determination enhances the reliability of purity assessments, showcasing the effectiveness of the improvised polarimeter in practical applications.

Development and Validation of LC-MS method for determination of Genotoxic Impurity N, O-Dimethyl Hydroxylamine by Chemical Derivatization in Investigational Drug Substance

Background: Conventional chromatographic techniques and direct analysis pose challenges in detecting certain potential genotoxic impurities, primarily due to factors such as the absence of a chromophore, low molecular weight, and insufficient chromatographic retention caused by high polarity. One such compound, N, O-Dimethyl Hydroxylamine, is of particular concern due to its structural similarity to Hydroxylamine, a recognized genotoxic impurity. Method: In response to this challenge, this article proposes a rapid derivatization approach utilizing Dansyl Chloride, coupled with Liquid Chromatography-Mass Spectrometry (LC-MS) for the detection of the derivatized product in the investigational drug substance. To preserve confidentiality, the specific name and structure of the drug substance have not been disclosed. Results: The developed method exhibits a reliable range of detection spanning from 5 ppm to 60 ppm with respect to a nominal drug substance concentration of 10 mg/mL. Throughout the method validation process, it demonstrated specificity, sensitivity, linearity, accuracy, and repeatability. Conclusion: This methodology presents a versatile solution applicable in scenarios where N, ODimethyl Hydroxylamine serves as a reagent in the synthesis process of drug substances.

Impurity affected transport properties of quantum well heterostructures with electronic and high-κ dielectric quantum screening

The effect of electronic and high-κ dielectric quantum screening (ES and DS) on the impurity-limited electron transport properties of quantum well/high-κ dielectric barrier type heterostructures with two-dimensional electron gas (2DEG) is studied theoretically. Characteristic of these heterosystems the 2D compound forms of screened impurity potential are employed for the first time. In the framework of 2D Debye-Hückel potential form an electron momentum relaxation time (τ) expression depending on the impurity 2D screening radius is obtained analytically. A numerical analysis of τ is carried out for the realistic HfO/InSb/HfO2QW heterostructure taking account both the finite mismatch of the energy bands at the heterointerface and the energy band non-parabolicity of InSb. The contributions of screened potential compound 2D forms to τ are established depending on QW width. A significant suppression of the scattering rate τ−1 (by an order of magnitude) is received with accounting of ES + DS combined effect.

Identification and quantitative analysis of genotoxic impurities in rifampicin: Development and validation of a targeted LC-MS/MS method for 1-amino-4-methylpiperazine

Rifampicin, essential for long-term tuberculosis treatment, requires rigorous control of non-therapeutic impurities due to their potential adverse, including mutagenic effects. Reports on control strategies for genotoxic impurities in rifampicin have been limited. This study introduced an analytical method to identify potential genotoxic impurities from the synthesis of raw materials. The structure of the 25-deacetyl-23-acetyl-rifampicin genotoxic impurity was confirmed using nuclear magnetic resonance, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC). An HPLC-HRMS method was established and validated for detecting another genotoxic impurity, 1-amino-4-methylpiperazine, adhering to the International Council on Harmonization guidelines, which include specificity, linearity, detection and quantification limits, accuracy, precision, and robustness. These developments improve the quality control strategy for genotoxic impurities in rifampicin, ensuring product safety.

Boundary-localized many-body bound states in the continuum

Bound states in the continuum (BICs), referring to spatially localized bound states with energies falling within the range of extended modes, have been extensively investigated in single-particle systems, leading to diverse applications in photonics, acoustics, and other classical-wave systems. Recently, there has been theoretical interest in exploring many-body BICs in interacting quantum systems, which necessitate the careful design of impurity potentials or spatial profiles of interaction. Here, we propose a type of many-body BICs localized at boundaries, which can be purely induced by the uniform onsite interaction without requiring any specific design of impurity potential or nonlocal interaction. We numerically show that three or more interacting bosons can concentrate on the boundary of a homogeneous one-dimensional lattice, which is absent at single- and two-particle counterparts. Moreover, the eigenenergy of multi-boson bound states can embed within the continuous energy spectra of extended scattering states, thereby giving rise to interaction-induced boundary many-body BICs. Furthermore, by mapping Fock states of three and four bosons to nonlinear circuit networks, we experimentally simulate boundary many-body BICs. Our findings enrich the comprehension of correlated BICs beyond the single-particle level, and have the potential to inspire future investigations on exploring many-body BICs.

Sliding Dynamics of Current-Driven Skyrmion Crystal and Helix in Chiral Magnets.

The skyrmion crystal (SkX) and helix (HL) phases, present in typical chiral magnets, can each be considered as forms of density waves but with distinct topologies. The SkX exhibits gyrodynamics analogous to electrons under a magnetic field, while the HL state resembles topological trivial spin density waves. However, unlike the charge density waves, the theoretical analysis of the sliding motion of SkX and HL remains unclear, especially regarding the similarities and differences in sliding dynamics between these two spin density waves. In this Letter, we systematically explore the sliding dynamics of SkX and HL in chiral magnets in the limit of large current density. We demonstrate that the sliding dynamics of both SkX and HL can be unified within the same theoretical framework as density waves, despite their distinct microscopic orders. Furthermore, we highlight the significant role of gyrotropic sliding induced by impurity effects in the SkX state, underscoring the impact of nontrivial topology on the sliding motion of density waves. Our theoretical analysis shows that the effect of impurity pinning is much stronger in HL compared with SkX, i.e., χ^{SkX}/χ^{HL}∼α^{2} (χ^{SkX}, χ^{HL}: susceptibility to the impurity potential, α (≪1) is the Gilbert damping). Moreover, the velocity correction is mostly in the transverse direction to the current in SkX. These results are further substantiated by realistic Landau-Lifshitz-Gilbert simulations.

Identification and simultaneous quantification of potential genotoxic impurities in first-line HIV drug dolutegravir sodium using fast ultrasonication-assisted extraction method coupled with GC–MS and in-silico toxicity assessment

Dolutegravir (DLG) has become a distinctive first-line antiretroviral therapy for the treatment of HIV in most countries due to its affordability, high efficacy, and low drug-drug interactions. However, the evaluation of genotoxic impurities (GTIs) in DLG and their toxicity assessment has not been explored thoroughly. Thus, in this study, a simple, fast, and selective analytical methodology was developed for the identification and determination of 7 GTIs in the comprehensive, explicit route of synthesis for the dolutegravir sodium (DLG-Na) drug. A facile, fast ultrasonication-assisted liquid–liquid extraction procedure was adapted to isolate the GTIs in DLG-Na and then analyzed using the gas chromatography (GC)-electron impact (EI)/mass spectrometer (MS) quantification (using selective ion monitoring mode) technique. This EI-GC/MS method was validated as per the current requirements of ICH Q2 (R1) guidelines. Under optimal method conditions, excellent linearities were achieved with R between 0.9959 and 0.9995, and high sensitivity was obtained in terms of detection limits (LOD) between 0.15 to 0.63 µg/g, and quantification limits (LOQ) between 0.45 to 1.66 µg/g for the seven GTIs in DLG. The obtained recoveries ranged from 98.2 to 104.3 % at LOQ, 15 µg/g, and 18 µg/g concentration levels (maximum daily dose of 100 mg). This developed and validated method is rapid, easy to adopt, specific, sensitive, and accurate in estimating the seven GTIs in a relatively complex sodium matrix of the DLG-Na drug moiety. As a method application, two different manufactured samples of DLG-Na drug substances were analyzed for the fate of the GTIs and drug safety for the intended dosage applications. Moreover, an in-silico QSAR toxicity prediction assessment was carried out to prove scientifically the potential GTI nature of each impurity from the alerting functional groups.

Inverse Faraday effect in superconductors with potential impurities

Inverse Faraday effect in superconductors with potential impurities

Eco-Friendly Graphene-Based Electrochemical Sensor for Selective Determination of Lesinurad in Its Pharmaceutical Formulation and in the Presence of Its Degradation Products

The objective of the present study was to create solid contact ion selective electrodes (SC-ISEs) for the purpose of selectively determining lesinurad (LES) in both its pure form and pharmaceutical dosage form where potential degradation products and impurities may be present. To achieve that goal, an electrochemical sensor with graphene nanomaterial as an ion-to-electron transducer was constructed using the glassy carbon electrode (GCE) as a substrate. A number of plasticizers were tested to find the best plasticizer for creating the potentiometric sensors, where 2-nitrophenyloctyl ether (o-NPOE) revealed the optimum response and nearly Nernstian slope. Sensor was characterized and the linear range was 5.0 × 10−7 to 1.0 × 10−3 M, and the calculated LOD was found to be 4.9 × 10−7 M. The developed sensor’s performance was evaluated as per the IUPAC requirements. Lesinurad was successfully determined in its pharmaceutical tablets using the proposed sensor. Additionally, statistical comparison of the developed method with the reported HPLC results has been carried out using student’s t-test and F-value, where no significant difference was found. Using the AGREE tool, the suggested method’s greenness was assessed and contrasted with the published HPLC one.

New stability indicating RP-HPLC methods for the determination of related substances and assay of trametinib acetic acid: a mass balance approach.

New stability indicating related substances and assay methods for trametinib acetic acid by RP-HPLC have been developed and validated through forced degradation and mass balance studies for the first time. In related substances (RS) method, trametinib acetic acid was successfully separated from its six related substances namely, cyclopropanamide impurity, desiodo trametinib, desacetyl trametinib, trione acetamide intermediate, trione intermediate, and trione PTSA intermediate using YMC-Triart C18 (150 × 4.6mm, 3µm) column. Orthophosphoric acid (0.15%) in water was used as buffer. Gradient elution was programmed using mobile phase-A (buffer and acetonitrile mixture in 80:20 v/v ratio) and mobile phase-B (buffer and acetonitrile mixture in 20:80 v/v ratio). Acetonitrile and methanol mixture (1:1 v/v) was used as diluent. Flow rate, injection volume, column temperature, and wavelengths were kept as 0.8mL/min, 10µL, 55°C, and 240nm, respectively. Desacetyl trametinib and cyclopropanamide impurity were identified as potential degradation impurities in acid and base degradation conditions, respectively. Assay method specific to above six related substances was also developed. Assay of forced degradation samples was also determined, and the mass balance was established by adding total impurities formed in RS method to assay of trametinib acetic acid.

Physicochemical Stability of Doravirine (Pifeltro®): Characterization of Main Degradation Products and Assessment of Stability of Tablets Repackaged in Single-Dose Unit Containers.

Doravarine (DOR) is an antiviral drug with a marketed authorization for the management of occupational blood and body fluid exposure. The currently existing packaging, consisting of multiple unit bottles comprising 30 tablets, is not fully appropriate for daily nominative dispensing at the hospital. This study aims at assessing the impact of the change in packaging on the key attributes of the drug: assay, impurity profile, and dissolution. As the first step, which is not fully depicted in the literature, the main potential impurities that could appear during storage (i.e., degradation products (DPs) of DOR) were characterized using a forced degradation protocol followed by an LC-MS/MS analysis. These results paved the way for in silico toxicological assessment and targeted degradation product profiling. Based on this study, the assessment of the implication of repackaging on the formation of DOR's degradation products should be a primary focus.

Mutagenic Azido Impurities in Drug Substances: A Perspective.

Contamination of drug products and substances containing impurities is a significant concern in the pharmaceutical industry because it may impact the quality and safety of medicinal products. Special attention is required when mutagenic impurities are present in pharmaceuticals, as they may pose a risk of carcinogenicity to humans. Therefore, controlling potential mutagenic impurities in active pharmaceutical ingredients to an acceptable safety limit is mandatory to ensure patient safety. As per the International Council for Harmonization (ICH) M7 (R2)3 Guideline, mutagenic impurities are those compounds or materials that induce point mutations. In 2018, the sartan class of drugs was recalled due to the presence of N-nitrosamine impurities, which are potential mutagens. In addition to the primary impurities being detected, this class of products, especially losartan, irbesartan and valsartan, have been identified as having organic azido contaminants, which are again highly reactive toward DNA, leading to an increased risk of cancer. These azido impurities form during the preparation of the tetrazole moiety via the reaction of a nitrile intermediate with sodium azide. Given that this is a newly raised issue in the pharmaceutical world, it should be noteworthy to review the related literature. Thus, this review article critically accounts for (i) the toxicity of azido impurities and the proposed mechanism of mutagenicity, (ii) the regulatory perspective, and (iii) the sources and control strategies used during the preparation of drug substances and (iv) future perspectives.

Effect of secondary metabolites from several leaf extracts on the green synthesized-ZnO nanoparticles

This study explores a green synthesis approach for zinc oxide nanoparticles (ZnO NPs) using eco-friendly leaf extracts from mango (Mangifera indica), kapok (Ceiba pentandra), and oil palm (Elaeis guineensis Jacq.) trees. The research investigates the effect of the extracts' secondary metabolites on the synthesized ZnO NPs. Qualitative analysis identified the presence of alkaloids, phenols, steroids, and saponins in varying concentrations within each extract. ZnO nanoparticles were successfully synthesized using all three extracts, confirmed by FT-IR spectroscopy with a characteristic Zn–O peak at 416.3 cm−1. XRD analysis revealed the crystalline structure of the nanoparticles, with an additional peak in ZnO_CPLE suggesting potential impurities. SEM images demonstrated the influence of secondary metabolites on particle size and morphology. ZnO_EGLE, containing both phenols and saponins, exhibited the smallest and most uniform nanoparticles (43.3 nm) compared to ZnO_CPLE (94.5 nm) and ZnO_MILE (74.9 nm). TEM analysis further supported these findings, highlighting the crucial role of phenols and saponins as capping agents in controlling particle size and agglomeration. This research suggests a promising green synthesis route for ZnO NPs using these leaf extracts, potentially tailoring particle properties based on the specific secondary metabolite profile.

Development and validation of analytical method for determination of elemental impurities in micafungin for injection

Elemental impurities contained in drug product create a risk for patients and potential toxic elemental impurities defined and classified in Guideline for Elemental Impurities Q3D(R1). Among the finished product dosage forms, parenteral products could be critical for elemental impurities because elemental impurities are given directly to systemic circulation. For determination of elemental impurities, one of the most frequently used methods is inductively coupled plasma–mass spectrometry (ICP–MS). In this study we aimed to develop and validate an ICP-MS method for determination of 24 elemental impurities in micafungin powder for concentrate for solution for infusion manufactured in our own facility. Results showed that correlation coefficients of calibration curves were found higher than 0.99 for all elements in determined ranges and all validation parameters were achieved successfully. With this method, all 24 elemental impurities can be tracked throughout the shelf life of the product.

Performance Changes of Lithium-Ion-Batteries due to Electrolyte-Introduced Metal Oxalate Contaminants

This work highlights how different metal oxalates (lithium, nickel, cobalt, manganese, aluminum, and copper) as possible contaminants from certain recycling technologies impact calendar and cyclic aging of NMC811 based LIBs. It also outlines the differences between their two aging modes. By comparing calendar and cyclic aging, differences become apparent: E.g., the presence of copper oxalate resulted in reduced calendar aging effects, while aluminum oxalate negatively affected calendar aging performance but cyclic aging less. Our method is also suitable for screening other materials, especially if one of the aging modes appears more important. By adding lithium oxalate to LIBs, overcharges strongly affected the SoH during cyclic aging. To optimize recycling performance by evaluating the impact of potential impurities, special attention should be given to particularly aluminum and, if economically viable, eliminated.

Conduction-type conversion in Ni(OH)2 by intercalation of eosin Y

AbstractNickel hydroxide (Ni(OH)2) is one of the wide bandgap semiconductors. By controlling its conduction type, Ni(OH)2 could be used as a semiconductor material in various applications. Since Ni(OH)2 is a layered material, anions are intercalated into the interlayer spaces. Anion intercalation can be a potential impurity doping technique for Ni(OH)2 films. In this study, we investigated the conduction type of Ni(OH)2 intercalated with eosin Y. Ni(OH)2 films formed by electrochemical deposition were n-type. After the intercalation of eosin Y, the Ni(OH)2 films showed a p-type photocurrent response in photoelectrochemical measurements. The conduction type of the films was changed from n-type to p-type by the intercalation of eosin Y. In addition, the p-type Ni(OH)2 films were used to form heterojunctions. The n-type ZnO/p-type Ni(OH)2 heterojunction diode exhibited a rectifying behavior. Graphical Abstract