Nonsteroidal anti-inflammatory drugs (NSAID) are the most frequently observed micropollutants in the effluents of conventional wastewater treatment plants and hybrid technologies could be an alternative to conventional systems. However, the effect on micropollutants' removal has not been well studied. In this study, the impact of hybrid systems on micropollutant removal, as well as the determination of the dominant microbial communities, were investigated. For this purpose, laboratory-scale control hybrid and micropollutant-amended (1 μg/L of diclofenac, ketoprofen, indomethacin, and mefenamic acid, 10 μg/L of ibuprofen, and naproxen) hybrid reactors were operated at organic loading rate of 0.3 kg COD/m[3].day and ammonium concentration of 60 mg/L N with a sludge retention time of 10 days and hydraulic retention time of 24 hrs. Effluent chemical oxygen demand (COD) was below 30 mg/L in the control and micropollutant hybrid reactors. Significant removal efficiencies for ibuprofen (99.7%), indomethacin (99.0%), naproxen (97.6%), mefenamic acid (97%), and ketoprofen (91.4) were achieved. Results revealed that NSAIDs did not have a chronic inhibitory effect on the biodegradation of organic matter and nitrification process. Higher biodiversity observed in attached biomass of micropollutant hybrid reactor might contribute to enhance system stability and performance. Dominant genera detected in hybrid micropollutant reactor were Chitinophagaceae (10.1%), Ferruginibacter (7.8%), and Comamonas (6.8%) for suspended biomass, and Fimbriimonadaceae (8.7%), Parafilimonas (6.5%), and Rickettsia (5.6%) for attached biomass, which might contribute to the removal of NSAIDs. Moreover, the genera Chitinophagaceae and Comamonas which are reported as heterotrophic ammonia-oxidizing bacteria, might contribute to nitrification in hybrid biofilm reactors.

Background/Objectives: Paracetamol is a widely analgesic and antipyretic drug; however, its limited anti-inflammatory efficacy and safety concerns motivate the search for novel non-opioid alternatives. In this study, a series of 4-hydroxyphenylamino-naphthoquinones were designed as paracetamol-inspired analogs and synthesized via a solvent-free, silica-assisted Michael addition, providing a sustainable and efficient synthetic route. Methods: The compounds were evaluated using an integrated strategy combining in silico prediction, density functional theory calculations, molecular docking, ADMET profiling, and in vivo phenotypic pharmacological assays. Results: In vivo evaluation revealed pronounced peripheral antinociceptive activity in the acetic acid-induced writhing model and robust anti-inflammatory effects in carrageenan-induced paw edema, comparable to those of naproxen. These findings suggest a predominantly peripheral mechanism consistent with anti-inflammatory and antinociceptive profiles linked to cyclooxygenase inhibition. A normalization-based multi-criteria analysis integrating peripheral, anti-inflammatory, central, and antipyretic endpoints enabled transparent phenotypic prioritization within the series. Under this framework, compound 7 emerged as the most balanced peripheral-anti-inflammatory candidate, whereas compound 8, evaluated experimentally as a regioisomeric mixture, showed comparatively stronger central antinociceptive activity in the hot plate test. Antipyretic activity in an LPS-induced fever model was limited and not sustained. Conclusions: Overall, these findings indicated that the 4-hydroxyphenylamino-naphthoquinone scaffold emerges as a promising non-opioid platform for peripheral inflammatory pain, supporting further investigation of its pharmacological and mechanistic properties.

Offspring of preeclamptic (PE) mothers are at increased risk of end-organ damage. Given the widespread use of NSAIDs during pregnancy and their reported ability to mitigate organ damage in PE mothers, this study examined whether prenatal naproxen modifies PE-induced lung injury in male and female offspring. PE was induced by orally administered L-nitro-arginine-methyl ester (L-NAME, 50 mg/kg/day for 7 days) to mothers prior to labor, and lung tissues were excised from 3-month-old offspring. Histopathology revealed increased interstitial inflammation and fibrosis in PE versus non-PE offspring lungs. This was more prominent in male than in female PE offspring and was coupled with more pulmonary expression of Axl tyrosine kinase receptor and downstream interleukin-1α (IL-1α) and antiangiogenic Fms-Like Tyrosine Kinase-1(sFlt1) effectors. These sex-related defects disappeared in offspring of PE dams treated prenatally with naproxen (1 mg/kg/day for 7 days). Further, PE offspring exhibited elevations in other inflammatory cytokines, IL-2 and TNFα, and apoptotic markers, caspase-3 and caspase-cleaved cytokeratin 18 (M-30) and total soluble cytokeratin 18 (M-65). The latter effects were evenly seen in both sexes and similarly offset by naproxen. These findings implicate Axl/IL-1α/sFlt1 signaling in the greater lung injury in male PE offspring and suggest a protective effect of gestational naproxen therapy.

The dissolution behaviour of fast-crystallizing amorphous solid dispersions (ASDs) at drug loadings (DLs) far exceeding the amorphous solubility limit remains poorly understood. In this study, we investigate how extreme DLs influence dissolution mechanisms in naproxen-copovidone VA64 ASDs prepared by hot-melt extrusion at 20, 50, and 70 wt% DL. Rapid post-extrusion cooling was applied at 70% DL to kinetically suppress crystal growth, while lower DL formulations remained amorphous as confirmed by DSC and PXRD. Drug-polymer interactions were analysed using ATR-FTIR combined with principal component analysis. Saturation solubility measurements revealed moderate advantages of ASDs over physical mixtures, suggesting that polymer-mediated interfacial effects contribute to solubility enhancement independently of amorphization. Non-sink dissolution testing revealed a non-monotonic, DL-dependent behaviour. At 20% DL, naproxen remained amorphous for at least 2 h, enabling near-congruent drug-polymer release and the highest dissolution performance. At 50% DL, rapid surface crystallization within a dense swollen polymer layer restricted drug release. Unexpectedly, dissolution performance partially recovered at 70% DL despite crystallization, as the reduced polymer fraction generated a more porous hydrated layer that facilitated liquid penetration and drug release compared with 50% DL ASDs and physical mixtures. Spectroscopic analysis showed progressive loss of hydrogen bonding at intermediate and high DLs, while transient non-specific drug-polymer associations persisted and likely contributed to improved wettability. These findings demonstrate that dissolution enhancement in fast-crystallizing ASDs can be sustained above the amorphous solubility limit when the architecture of the hydrated layer - together with persistent non-specific drug-polymer interactions in aqueous media - governs drug transport rather than amorphous stability alone.

Ready-to-use (RTU) long-acting injectable aqueous suspensions offer sustained drug release but present significant challenges for terminal sterilization. While aseptic processing is frequently used for suspension manufacturing, it lacks the sterility assurance of terminal sterilization. This work investigated the viability of gamma sterilization of model RTU aqueous suspensions containing varying polymer types and suspended drug loads. Comprehensive physicochemical characterization revealed that gamma irradiation did not affect the drug solid-state form in both model suspensions, and effectively stabilized particle size, notably stopping particle size growth observed in the non-irradiated GSK model suspension (control group). However, size exclusion chromatography (SEC) and HPLC analyses confirmed significant radiolytic degradation of polymeric surfactants and stabilizers (poloxamer 338 and PEG 3350) in both naproxen and GSK model suspensions, characterized by random chain scission and cross-linking of the polymer chains. This polymer degradation induced by radiolysis resulted in a measurable reduction in viscosity and injection force, thereby easing the force required to push suspension through the narrow needle bore of the syringe. Conversely, radiolysis-induced loss of suspension microstructure compromised long-term physical stability (resuspendability), leading to irreversible caking after 18 months of storage. These findings indicate that while gamma irradiation is a plausible terminal sterilization method for injectable suspensions, careful consideration must be given to formulation design to compensate for radiolytic polymer degradation and maintain suspension physical stability over the desired shelf life.

Water scarcity and water quality degradation have increased the interest in reclaimed water production from wastewater treatment plants. Among quality concerns, emerging contaminants (ECs) have gained attention due to their persistence and potential environmental and health risks. This study investigated the occurrence, spatial distribution, and removal of ECs in a full-scale Water Resource Recovery Facility (WRRF) operating an anaerobic-anoxic-aerobic process followed by membrane bioreactor (MBR) filtration in São Paulo State, Brazil. Wastewater samples were collected at different treatment stages, and surface waters from regional rivers were analyzed for comparison. Target compounds were determined by UPLC-MS/MS and GC-MS. All analytes were detected in raw sewage, with caffeine presenting the highest concentrations. High removal efficiencies were observed for paracetamol, caffeine, ibuprofen, naproxen, and atenolol (> 97%), while diclofenac and propranolol showed moderate removal (60-70%). Estrogenic compounds exhibited variable removal, and carbamazepine and its metabolites showed persistent behavior, with negative removal suggesting back-formation processes. The results confirm carbamazepine as a reliable chemical marker of treatment efficiency and indicate that, although reclaimed water showed high overall quality, complementary treatment may be required to meet stricter standards for emerging contaminants.

Due to the favorable pharmaceutical properties of the azetidine ring, it can serve as a bioisostere to replace saturated heterocycles such as piperazines, piperidines, and pyrrolidines in drug discovery. The diverse methods for azetidine synthesis are still limited and challenging. Herein, we design a new class of 1-azabicyclo[1.1.0]butanes (ABBs) and report the first electrochemical protocol for the synthesis of chemo-selective trifluoromethanesulfonylated and trifluoromethylated azetidine derivatives via direct anodic oxidation. The key features of this strategy involve: (i) electrochemical anodic oxidation of ABB to form a N-centered radical cation, (ii) a rare [2,3]-sigmatropic shift of sulfone, (iii) selective oxidation of Langlois' reagent (NaSO2CF3), and (iv) the kinetic study of the developed methodology. The strategy exhibits broad substrate scope and scalability, making it practical. Installation of generated azetidines into marketed drug motifs, including ibuprofen, naproxen, and olaparib derivative, demonstrates the method's utility. Mechanistic investigations, supported by control experiments, cyclic voltammetry, and electrochemical impedance spectroscopy (EIS), provided key insights into the reaction pathway. This electrochemical approach advances the strain-release chemistry of ABBs and offers a promising platform for future developments.

This study investigates the removal performance of selected micropollutants (ibuprofen, diclofenac, naproxen, carbamazepine, and triclosan) from domestic wastewater using a moving bed membrane biofilm reactor (MBMBR) process, consisting of two moving bed biofilm reactors (MBBRs) in series followed by a membrane bioreactor (MBR). While the integration of MBBR and MBR processes leverages the advantages of both technologies, systematic studies on determining the optimal configuration, particularly in the presence of micropollutants, remain quite limited in the literature. Within the scope of the research, the effects of sludge recirculation (hybrid growth) from the MBR to different MBBR units on treatment performance were evaluated over 140 days with three different periods. The results showed that the COD removal efficiency, which was initially 98% (permeate COD <10 mg/L), gradually decreased following the introduction of micropollutants. The toxicity of micropollutants led to the accumulation of soluble microbial products (SMPs) and extracellular polymeric substances (EPSs), which increased the average supernatant COD up to 370 mg/L in the MBR unit. The membrane rejected most of the SMPs and EPSs, which improved the permeate quality (with permeate COD averaging <50 mg/L in all configurations) but increased the fouling potential. Nitrification almost entirely ceased (with permeate NH4[+]-N averaging 40 mg/L) during the second period (biofilm-only growth) as the system suffered from both micropollutant toxicity and the lack of microbial seeding by sludge recirculation. Regarding micropollutant removal, high efficiencies of over 75% were achieved for ibuprofen and triclosan, while removal efficiencies for recalcitrant compounds such as carbamazepine, diclofenac, and naproxen generally remained below 30%. This study highlights the impact of micropollutants on ammonia oxidizing bacteria (AOB), which may have a critical role in micropollutant removal, and demonstrates the advantages of the hybrid growth mode in maintaining process stability.

Silk sericin protein, a textile industry by-product showing no toxicity on oral/topical administration, has recently been exploited as a drug delivery system. The high serine content in sericin makes its functionalization through covalent ester-type bonds feasible; however, only in a few cases have covalent conjugates of sericin with the drug to be delivered been developed. In this paper, we report the preparation of sericin conjugates with carboxy drugs of dermatological interest, i.e., naproxen, retinoic acid, and azelaic acid. Characterization of the purified products by spectroscopic methods, particularly ATR-FTIR, provided evidence for the formation of the ester bond, while SDS-PAGE indicated a substantial modification of the protein. Proteomic analysis allowed the identification of drug-peptide adducts in the samples. The extent of ester functionalization (1-3 w/w%) was estimated by alkaline hydrolysis. No cytotoxicity of NAP@SER on HaCaT was observed over a broad range of concentrations. Ex vivo tests on defatted pig skin demonstrated effective passage of the free drug through the skin (5% w/w of the applied dose) from a NAP@SER glycerol suspension and a significant retention of the drug (33% w/w) within the dermal or epidermal tissues. These results hint at the potential of sericin conjugates as prodrugs for dermal administration.

Eutectic solvents have become a viable choice to create innovative pharmaceutical technologies within the framework of the green chemistry approach. Despite the growing applicative interest, a general gap remains in the pharmaceutical sector regarding thorough and systematic research of their properties and useful applications. In this work, eutectic solvents have been prepared from choline chloride and polyols (sorbitol, xylitol, mannitol, and isomalt) at different molar ratios (1:1, 2:3, and 3:2), characterised, and used for the solubility enhancement of poorly water-soluble drugs (ibuprofen and naproxen) as well as the potential drug candidate apigenin. The interactions between the eutectic solvent components were investigated by DSC, FTIR, and refractive index methods. In all eutectic solvents, the water content detected by Karl Fischer titration and loss on drying was less than 3%. Solubility studies, carried out using the shake-flask method, showed significant solubility enhancement of the following: ibuprofen: ~152-fold increase, naproxen: ~144-fold increase, and apigenin: ~188-fold increase. These findings highlighted the great potential of eutectic solvents as solubility enhancers in the development of novel and more effective drug delivery systems.

Semen parameters, including sperm counts, have rapidly declined in men across the globe over the last five decades. Although this decline remains unexplained, lifestyle factors may affect male fertility. Recently, several studies highlighted a potential link between non-steroidal anti-inflammatory drug (NSAID) usage, such as naproxen and ibuprofen, and declining male fertility. However, the mechanisms by which these common analgesics affect male fertility, including their effects on the blood-testis barrier (BTB), remain poorly characterized. Utilizing an in vitro rhesus macaque non-human primate (NHP) BTB model, we demonstrate that serum levels of naproxen and ibuprofen alter the function of BTB. Following short-term naproxen and ibuprofen treatment of NHP primary Sertoli cells, we show that these NSAIDs increase the transepithelial electrical resistance, indicating an overall strengthening of the Sertoli cell junctions. Furthermore, naproxen and ibuprofen treatment alter the expression of genes involved in maintaining the BTB. Specifically, the genes that were significantly expressed in response to ibuprofen exposure were enriched for human phenotypic abnormalities linked to male factor infertility. Together, these results suggest that short-term naproxen and ibuprofen treatment disrupt the function of the BTB by altering the integrity of the Sertoli cell junctions, proposing a potential role of NSAIDs in male factor infertility.

The global population has increased the use of pharmaceutical compounds, emerging as contaminants. Due to their persistence in the environment, pharmaceutical residues have been detected in water and soil sources, causing adverse effects on ecosystems. Therefore, methods and techniques are necessary to degrade this pollution. An environmentally sustainable option is fungal remediation, which can decompose or degrade various xenobiotics. In this study, 30 phenanthrene-tolerant fungal isolates were analyzed to determine their potential for pharmaceutical degradation. Nine isolates were tolerant to 100 mg L-1 and three to 200 mg L-1 of naproxen and ampicillin. An enzyme activity analysis detected the production of laccase and manganese peroxidase. Penicillium crustosum H10 causes a high degradation of naproxen 95 % at 5 mg L-1 in 7 days and 100 % at 50 mg L-1 in 15 days and a low degradation of ampicillin (11.15% at 5 mg L-1). These results encourage exploring P. crustosum H10 as a viable alternative for the elimination of non-steroidal anti-inflammatory drugs.