The awareness of possible environmental hazards caused by the widespread global use of volatile methylsiloxanes (VMSs) in personal care products (PCPs) and industrial processes has been increasing. Sewage containing these compounds may reach wastewater treatment plants (WWTPs), which are hotspots of their release into the environment. The levels, distribution, and potential risks of VMSs were studied in an unprecedently comprehensive sampling strategy (four seasonal campaigns) along the water line of a WWTP: the main influent entrance (SA1), after the preliminary treatment (SA2), after the primary treatment (SA3) and after the secondary treatment (the treated effluent; SA4). This WWTP was selected as a representative of the conventional set up based on a secondary treatment, allowing a similar approach in numerous facilities worldwide. Seven VMSs (L3, L4, L5, D3, D4, D5, D6) were analysed in wastewater samples by a small-scale liquid-liquid extraction (LLE) protocol, followed by gas chromatography-mass spectrometry (GC-MS), and the cyclic VMSs were dominant at all sampling sites and in all seasons. Considering the whole year, the total VMSs ranged from 0.4 to 22.5 μg L-1 for SA1, 0.03 to 33.7 μg L-1 for SA2, below method detection limit (MDL) to 13.2 μg L-1 for SA3 and 98 %). According to the risk quotients (RQ), only 18 SA4 samples (32 %) presented a minimal risk to the receiving media (0.01 ≤ RQ < 0.1). However, considering the absence of a secondary treatment or a direct discharge without treatment, there may be a risk to the environment.

This review considers the role of in vitro permeation testing (IVPT) for the evaluation of drug delivery from topical formulations applied to the skin. The technique was pioneered by Franz in the 1970\'s and today remains an important tool in the development, testing and optimization of such topical formulations. An overview of IVPT as well as selection of skin for the experiment, integrity testing of the membrane, and required number of replicate skin samples is discussed. In the literature many researchers have focused solely on permeation and have not reported amounts of the active remaining on and in the skin at the end of the IVPT. Therefore, a particular focus of this article is determination of the complete mass balance of the drug. It is noteworthy that for the evaluation of bioequivalence of topical formulations the draft guideline issued by the European Medicines Agency (EMA) requires the IVPT method to report on both the skin deposition and distribution of the active in the skin as well as amount permeated. Other aspects of current guidance from the EMA and United States Food and Drug Agency for IVPT are also compared and contrasted. Ultimately, harmonisation of IVPT protocols across the regulatory agencies will expedite the development process for novel topical formulations as well as the availability of generic products.

D-Phenylalanine (D-Phe) is a small chiral organic molecule that is both an important pharmaceutical intermediate and used as a calibrator for quantifying amino acids in liquid chromatography-circular dichroism. We have developed a process for a national certified reference material (CRM) for D-Phe following ISO 17034:2016. The identity of D-Phe was confirmed using mass spectrometry (MS) and nuclear magnetic resonance (NMR), infrared, and ultraviolet (UV) spectroscopy. The absolute optical conformation was also determined using circular dichroism (CD) spectroscopy and optical rotation measurements. Impurities were identified via liquid chromatography (LC) with a UV-Vis detector and a charged aerosol detector (CAD) and LC-MS. Both mass balance and quantitative NMR were employed for value assessment, and the associated uncertainty was evaluated. The certified purity was determined to be 0.995 ± 0.003 g/g, a validation that was confirmed by CD using L-Phe CRM as a calibrator. Twenty milligrams of raw material was packed in sealed brown glass tubes for storage, and no inhomogeneity was observed. Stability tests revealed that the D-Phe CRM remained stable at -20 °C for at least 26 months, at 4 °C for at least 14 days, and at 25 °C and 60 °C for at least 7 days. The D-Phe CRM can be used to ensure the accuracy and reliability of D-Phe quantitation in the pharmaceutical field and also as a calibrator to ensure traceability to the International System of Units (SI) for L-Phe quantitation and protein purity analysis using LC-CD methods. The approach outlined in this paper also has potential for use in the development of other chiral CRMs.

Anaprazole is a proton pump inhibitor. This study aims to elucidate absorption, metabolism, and excretion pathways of anaprazole sodium in the human body. A total of 4 healthy Chinese male subjects were administered a single oral dose of 20 mg/100 µCi of [14C]-anaprazole sodium enteric-coated capsules. The whole blood, plasma, and excreta were analyzed for a total radioactivity (TRA) and metabolite profile. The cumulative radioactivity excretion rate was 93.2%, with 53.3% and 39.9% of the radioactive dose excreted in urine and feces, respectively, and 91.6% of dose recovered within 96 hours after dosing. The parent drug, anaprazole, showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism. Overall, 35 metabolites were identified in plasma, urine, and fecal samples. Anaprazole was the most abundant component in plasma followed by the thioether M8-1, accounting for 28.3% and 16.6%, respectively, of the plasma TRA. Thioether carboxylic acid XZP-3409 (26.3% of urine TRA) and XZP-3409 oxidation and dehydrogenation product M417a (15.1% of fecal TRA) were the major metabolites present in urine and feces, respectively. Anaprazole was undetectable in urine, while fecal samples showed traces (0.07% dose). Blood/plasma ratios of the radioactivity (approximately 0.60) remained consistent over time. Anaprazole showed good absorption and was extensively metabolized majorly to thioether M8-1 via nonenzymatic metabolism, and cytochrome P450 3A4 also contributed to its metabolism in healthy individuals.

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 × 4.6 mm, 3 µm) 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 0.8 mL/min, 10 µL, 55 °C, and 240 nm, 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.

Real-time monitoring of critical quality attributes, such as residual water in granules after drying which can be determined through loss-on-drying (LOD), during wet granulation and drying is essential in continuous manufacturing. Near-infrared (NIR) spectroscopy has been widely used as process analytical technology (PAT) for in-line LOD monitoring. This study aims to develop and apply a model for predicting the LOD based on process parameters. Additionally, the efficacy of an orthogonal PAT approach using NIR and mass balance (MB) for a vibrating fluidized bed dryer (VFBD) is demonstrated. An in-house-built, cost-effective NIR sensor was utilized for measurements and exhibited good correlation compared to standard method via infrared drying. The combination of NIR and MB, as independent methods, has demonstrated their applicability. A good correlation, with a Pearson r above 0.99, was observed for LOD up to 16 % (w/w). The use of an orthogonal PAT method mitigated the risk of false process adaption. In some experiments where the NIR sensor might have been covered by powder and therefore did not measure accurately, LOD monitoring via MB remained feasible. The developed model effectively predicted LOD or process parameters, resulting in an R2 of 0.882 and a RMSE of 0.475 between predicted and measured LOD using the standard method.

Due to the increasing number of chemicals released into the environment, nontarget screening (NTS) analysis is a necessary tool for providing comprehensive chemical analysis of environmental pollutants. However, NTS workflows encounter challenges in detecting both known and unknown pollutants with common chromatography high-resolution mass spectrometry (HRMS) methods. Identification of unknowns is hindered by limited elemental composition information, and quantification without identical reference standards is prone to errors. To address these issues, we propose the use of inductively coupled plasma mass spectrometry (ICP-MS) as an element-specific detector. ICP-MS can enhance the confidence of compound identification and improve quantification in NTS due to its element-specific response and unambiguous chemical composition information. Additionally, mass balance calculations for individual elements (F, Br, Cl, etc.) enable assessment of total recovery of those elements and evaluation of NTS workflows. Despite its benefits, implementing ICP-MS in NTS analysis and environmental regulation requires overcoming certain shortcomings and challenges, which are discussed herein.

There is an increasing interest in edible insects in Europe for feed and food purposes. Quantitative information on the transfer of chemical hazards from substrates to larvae is needed to evaluate food and feed safety aspects. This evaluation is especially needed when organic substrates or residual streams such as manure will be applied as substrate, contributing to a circular food system. This study investigated the transfer of veterinary drugs from spiked substrate to black soldier fly larvae (Hermetia illucens). Veterinary drugs that are commonly administered to chicken, fattening pigs, and cattle and regularly detected in manure were included: three different antibiotics (enrofloxacin, oxytetracycline, sulfamethoxazole), three coccidiostats (narasin, salinomycin, toltrazuril) and one antiparasitic drug (eprinomectin). The chemicals were spiked to insect substrate to reach final concentrations of 0.5 and 5 mg/kg for the antibiotics and the antiparasitic drug, and 5 and 50 mg/kg for the coccidiostats. Black soldier fly larvae were reared for 1 week on the spiked substrates, and the transfer of the veterinary drugs to the larvae and frass was quantified using liquid chromatography coupled with tandem mass spectrometry. Only oxytetracycline and eprinomectin reduced the average weight and/or survival of the black soldier fly larvae. The transfer of the veterinary drugs to the larvae was on average 19.2% for oxytetracycline, 12% for enrofloxacin, 9.5% for narasin, 8.1% for eprinomectin, 3.9% for salinomycin, 4.2% for toltrazuril, and 0.2% for sulfamethoxazole, relative to concentrations in the substrate. Mass-balance calculations revealed that the larvae seem to metabolise veterinary drugs, and indeed, metabolites of enrofloxacin, sulfamethoxazole, and toltrazuril were detected in the larvae and frass. In conclusion, insect-rearing substrates should be evaluated for the presence of veterinary drug residues to ensure feed (and food) safety, as well as because of possible effects on insect growth.

Emerging pollutants (EPs) are prevalent in aquatic environments globally. Researchers strive to understand their occurrence and behavior prior to their release into the environment. In this study, we examined five wastewater treatment plants (WWTPs), collected 50 wastewater samples and 10 sludge samples. We explored the sources and destinations of phthalic acid esters (PAEs) within these WWTPs using mass balance equations. Wastewater treatment diminished the frequency and concentration of PAEs, and decreased the fraction of short-chain PAEs. We confirmed the increased concentration of PAEs post-primary treatment and modified the mass balance equation. Calculations suggest that weaker \"the mix\" in winter than in summer and stronger sedimentation in winter than in summer resulted in high efficiency of PAEs removal by winter wastewater treatment. The mass flux of biodegradation was influenced by the combination of biodegradation efficiency and the strength of the particular type of PAEs collected, with no seasonal differences. Mass fluxes for sludge sedimentation were mainly influenced by season and were higher in winter than in summer. This study enhances our understanding of emerging pollutants in manual treatment facilities and offers insights for optimizing wastewater treatment methods for water professionals.

OBJECTIVE: Understanding polyelectrolyte complexation remains limited due to the absence of a systematic methodology for analyzing the distribution of components between the polyelectrolyte complex (PEC) and the dilute phases.
METHODS: We developed a methodology based on NMR to quantify all components of solid-like PECs and their supernatant phases formed by mixing different ratios of poly(allylamine hydrochloride) (PAH) and poly(acrylic acid)-sodium salt (PAA). This approach allowed for determining relative and absolute concentrations of polyelectrolytes in both phases by 1H NMR studies. Using 23Na and 35Cl NMR spectroscopy we measured the concentration of counterions in both phases.
RESULTS: Regardless of the mixing ratio of the polyelectrolytes the PEC is charge-stoichiometric, and any excess polyelectrolytes to achieve charge stoichiometry remains in the supernatant phase. The majority of counterions were found in the supernatant phase, confirming counterion release being a major thermodynamic driving force for PEC formation. The counterion concentrations in the PEC phase were approximately twice as high as in the supernatant phase. The complete mass balance of PEC formation could be determined and translated into a molecular picture. It appears that PAH is fully charged, while PAA is more protonated, so less charged, and some 10% extrinsic PAH-Cl- pairs are present in the complex.