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In the current study, it was demonstrated that three commercially available grades of hydrogenated phospholipids (HPL) differing in their content of phosphatidylcholine may be used as components for hot melt-extruded binary (HPL as sole excipient) or ternary (in combination with copovidone) solid dispersions of fenofibrate (FEN) at mass fractions between 0.5 and 20% (ternary) or 80% (binary). X-ray powder diffraction indicated complete conversion of crystalline fenofibrate into the amorphous state by hot melt extrusion for all ternary blends. In contrast, both the binary blends (HPL- and copovidone-based) contained minor remaining crystallites. Irrespectively, all solid dispersions induced during dissolution studies a supersaturated state of FEN, where the ternary ASDs showed enhanced and more complete release of FEN as compared to the binary blends and, even more pronounced, in comparison to the marketed micronized and nano-milled formulations. In terms of the cumulated amount permeated, there were marginal differences between the various formulations when combined dissolution/permeation was done using FeSSIF as donor medium; with FaSSIF as donor medium, the binary HPL-ASD containing the grade with the highest phosphatidylcholine fraction performed best in terms of permeation, even significantly better than the marketed nano-crystal formulation. Otherwise, no significant differences were seen between the various grades of HPL when FEN dissolution and permeation were analyzed for ternary solid dispersions. In conclusion, the in-vitro biopharmaceutical behaviour of hydrogenated phospholipid-containing blends manufactured by hot melt extrusion appears promising. They can be a viable formulation option for poorly water-soluble and lipophilic drug compounds like FEN., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Diosgenin, a bioactive molecule; is one of the deeply explored saponin with a wide spectrum of benefits against various ailments. The extraction and yield enhancement of diosgenin from a wide range of naturally occurring medicinal products has always been a challenging task for its commercial usage. The current research work envisages the use of a novel resin to maximize the yield of diosgenin. The extracted diosgenin was characterized using modern techniques. The current method qualifies for the extraction of diosgenin at a large scale making it a commercially viable technique., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to evaluate the pressure distribution and comfort of transtibial prosthesis wearers using an affordable ethyl-vinyl acetate (EVA) roll-on (AERO) liner., Method: Fifteen unilateral transtibial prosthesis users wore patella tendon bearing (PTB) sockets with a polyethylene foam (PE-lite) liner were enrolled this study. AERO liners were provided to all participants. Six force sensors were applied to the residual limb to evaluate pressure distribution during treadmill walking, and the socket comfort score (SCS) was used to evaluate comfortability. Fourier transform infrared (FT-IR) spectroscopy was performed on the EVA and PE-lite liners., Results: Eleven participants used prefabricated AERO liners and four participants used custom-made AERO liners. The pressure distribution was analysed by the coefficient of variation (CV): PE-lite was 75.7 ± 6.0 and AERO liner 83.3 ± 4.1. Residual limb pressure was significantly decreased when using the AERO liner ( p  = .0007), with a large effect size ( r  = 0.87). Mean SCS was 7.5 ± 1.3 and 8.9 ± 1.1 for PE-lite and AERO liner respectively., Conclusion: Better pressure distribution and comfort were observed when the participants used the AERO liner. AERO had a greater proportion of calcium carbonate (CaCO 3 ). These findings suggest that the AERO liner is a better off-the-shelf option for persons using traditional prosthetic sockets and liners.

Transition metal-catalyzed cross-coupling with aryl halides has revolutionized the way of diversifying aromatic compounds. Aryl ethers are attractive alternatives to aromatic halides as coupling partners considering the accessibility and potential environmental benefits. The last two decades have witnessed a striking success in the field of C-O bond activation of aryl ethers, including the construction of C-C bond and C-X bond, as well as reductive deoxygenation. Here, we present a comprehensive review of C-O bond activation in the context of aryl, vinyl, and benzylic ethers. This review elaborates on the current state-of-the-art methods, categorized by different catalytic systems, including transition metal catalysis, photoredox catalysis, and other innovative approaches. The newly developed methods allow C-O bond activation under mild conditions with exceptional functional group tolerance, potentially enabling the late-stage functionalization of pharmaceuticals. The limitations and future perspectives of the methods are also presented., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Conformationally constrained nucleotides, LNA or α-L-LNA, at the 5' terminus of the antisense strand impeded gene silencing of small interfering RNA (siRNA) by hindering phosphorylation, thereby deterring loading into the RNA-induced silencing complex. Installation of a phosphate mimic, ( E )-vinyl phosphonate (VP), improved activity considerably. Gene silencing was more efficient when the antisense strand of the siRNA was modified with 5'-VP-α-L-LNA, which adopts a C3'- exo (south) conformation, than when the antisense strand was modified with 5'-VP-LNA, which adopts a C3'- endo (north) pucker. These data underscore the critical role of conformation of nucleotides in RNA interference.

Hot-melt extrusion (HME) is a widely used method for creating amorphous solid dispersions (ASDs) of poorly soluble drug substances, where the drug is molecularly dispersed in a solid polymer matrix. This study examines the impact of three different copovidone excipients, their reactive impurity levels, HME barrel temperature, and the distribution of colloidal silicon dioxide (SiO 2 ) on impurity levels, stability, and drug release of ASDs and their tablets. Initial peroxide levels were higher in Kollidon VA 64 (KVA64) and Plasdone S630 (PS630) compared to Plasdone S630 Ultra (PS630U), leading to greater oxidative degradation of the drug in fresh ASD tablets. However, stability testing (50 °C, closed container, 50 °C/30% RH, open conditions) showed lower oxidative degradation impurities in ASD tablets prepared at higher barrel temperatures, likely due to greater peroxide degradation. Plasdone S630 is suitable for ASDs with drugs prone to oxidative degradation, while standard purity grades may benefit drugs susceptible to free radical degradation, as they generate fewer free radicals post-HME. ASD tablets exhibited greater physical stability than milled extrudate samples, likely due to reduced exposure to stability conditions within the tablet matrix. Including SiO 2 in the extrudate composition resulted in greater physical stability of the ASD system in the tablet; however, it negatively affected chemical stability, promoting greater oxidative degradation and hydroxylation of the drug substance. No impact of the distribution of SiO 2 on drug release was observed. The study also confirmed the congruent release of copovidone, the drug substance, and Tween 80 using flow NMR coupled with in-line UV/vis. This research highlights the critical roles of peroxide levels and SiO 2 in influencing the dissolution and physical and chemical stability of ASDs. The findings provide valuable insights for developing stable and effective pharmaceutical formulations, emphasizing the importance of controlling reactive impurities and excipient characteristics in ASD products prepared by using HME.

MicroRNAs (miRNAs) regulate gene expression through RNA interference. Consequently, miRNA inhibitors, such as anti-miRNA oligonucleotides (AMOs), have attracted attention for treating miRNA overexpression. To achieve efficient inhibition, we developed 2-amino-6-vinylpurine (AVP) nucleosides that form covalent bonds with uridine counterparts in RNA. We demonstrated that mRNA cross-linked with AVP-conjugated antisense oligonucleotides with AVP were protected from gene silencing by exogenous miRNA. However, endogenous miRNA function could not be inhibited in cells, probably because of slow cross-linking kinetics. We recently developed ADpVP, an AVP derivative bearing a 7-propynyl group - which boasts faster reaction rate than the original AVP. Here, we synthesized dADpVP - a deoxy analog of ADpVP - through a simplified synthesis protocol. Evaluation of the cross-linking reaction revealed that the reaction kinetics of dADpVP were comparable to those of ADpVP. In addition, structural analysis of the cross-linked adduct discovered N3 linkage against uridine. Incorporating dADpVP into two types of miRNA inhibitors revealed a marginal impact on AMO efficacy yet improved the performance of target site blockers. These results indicate the potential of cross-linking nucleosides for indirect miRNA function inhibition., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Vinyl acetate is a volatile organic compound widely used in the chemical industry, and there is a need for effective and economic removal of this volatile organic compound from wastewater and waste gases in chemical industries. This study aims to determine the biological treatability of vinyl acetate both under aerobic and anoxic conditions using mixed cultures obtained from a wastewater treatment plant. Considering the previous studies in the literature, testing the biodegradability of vinyl acetate under both aerobic and anoxic conditions, together with evaluating the effect of other mechanisms, such as adsorption and volatilization, on the removal of vinyl acetate, can be regarded as the prominent part of this study. Wastewater containing artificially prepared vinyl acetate was treated in a batch bioreactor, and performance and kinetic constants were investigated. Aerobic treatment under batch conditions conformed to the Haldane biokinetic equation, and the biokinetic constants of μ max , K s , and K i were calculated as 0.66 h -1 , 19.67 mg L -1 and 50.56 mg L -1 , respectively. Anoxic treatment under batch conditions conformed to the Monod biokinetic equation, and the biokinetic constants of μ max and K s were calculated as 0.31 h -1 and 33.88 mg L -1 , respectively. Experiments revealed that vinyl acetate was not volatile, and its adsorption and biological treatment performances were 28% and 72%, respectively. The mixed culture had a very high performance for removing vinyl acetate under batch operating conditions. The primary mechanism of vinyl acetate removal was found to be biological treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alper Nuhoglu reports financial support was provided by the Scientific and Technological Research Council of Turkey. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The reported chemoenzymatic strategy involves the employment of vinyl 3-(dimethylamino)propanoate as an irreversible acyl donor in a chromatography-free lipase-catalyzed kinetic resolution (KR) of racemic sec-alcohols. This biotransformation is achieved in a sequential manner using CAL-B to affect the kinetic resolution, followed by a simple acidic extractive work-up furnishing both KR products with excellent enantioselectivity (E>200; up to 98 % ee). The elaborated method eliminates a single-use silica gel chromatographic separation and significantly reduces organic solvent consumption to foster a more environmentally friendly chemical industry., (© 2024 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Native lipid bilayer mimetics, including those that use amphiphilic polymers, are important for the effective study of membrane-bound peptides and proteins. Copolymers of vinyl ether monomers and maleic anhydride were developed with controlled molecular weights and hydrophobicity through reversible addition-fragmentation chain-transfer polymerization. After polymerization, the maleic anhydride units can be hydrolyzed, giving dicarboxylates. The vinyl ether and maleic anhydride copolymerized in a close to alternating manner, giving essentially alternating hydrophilic maleic acid units and hydrophobic vinyl ether units along the backbone after hydrolysis. The vinyl ether monomers and maleic acid polymers self-assembled with lipids, giving vinyl ether maleic acid lipid particles (VEMALPs) with tunable sizes controlled by either the vinyl ether hydrophobicity or the polymer molecular weight. These VEMALPs were able to support membrane-bound proteins and peptides, creating a new class of lipid bilayer mimetics.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which leads to demyelination, axonal loss, and neurodegeneration. Increased oxidative stress and neurodegeneration have been implicated in all stages of MS, making neuroprotective therapeutics a promising strategy for its treatment. We previously have reported vinyl sulfones with antioxidative and anti-inflammatory properties that activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of cytoprotective genes against oxidative stress. In this study, we synthesized vinyl sulfoximine derivatives by modifying the core structure and determined therapeutic potential as Nrf2 activators. Among them, 10v effectively activated Nrf2 (EC 50 = 83.5 nM) and exhibited favorable drug-like properties. 10v successfully induced expression of Nrf2-dependent antioxidant enzymes and suppressed lipopolysaccharide (LPS)-induced inflammatory responses in BV-2 microglial cells. We also confirmed that 10v effectively reversed disease progression and attenuated demyelination in an experimental autoimmune encephalitis (EAE) mouse model of MS.

Plasmalogens are glycerophospholipids distinguished by their O -( Z )-vinyl ether at the sn -1 position. These lipids are implicated in several disease states requiring analytical, diagnostic and therapeutic interventions, which demand synthetic availability for a variety of structural types. By deploying the new O -protecting group 1,4-dimethoxynaphthyl-2-methyl ('DIMON') and a new stereospecific method for accessing Z -vinyl ethers, a reproducible, versatile synthetic route to plasmalogens [plasmenyl phosphocholines] has been developed. A key intermediate is ( S , Z )-1-((1,4-dimethoxynaphthalen-2-yl)methoxy)-3-(hexadec-1-en-1-yloxy)propan-2-ol, which in principle, permits plasmalogen synthesis 'à la carte' at scale. The methodology compares favourably with all previous synthetic routes by virtue of the very high configurational (>99% Z ) and optical purity (>99% ee ), including the ability to incorporate polyunsaturated fatty acyl chains ( e.g. all Z docosahexaenoic acid) reliably at the sn -2 position.

Chemical linkages that respond to biological stimuli are important for many pharmaceutical and biotechnological applications, making it relevant to explore new variants with different responsivity profiles. This work explores the responsiveness of a TAT peptide-based sulfonium vinyl sulfide probe that responds to nucleophilic thiols, radical thiol species (RTS), and reactive nitrogen species (RNS). Under model conditions, response to nucleophilic thiols was very slow (hours/days), though fast with down to molar equivalents of either RTS or RNS (minutes). These reactions led to the traceless release of a methionine-containing peptide in the first two cases and to a hydroxy nitration adduct in the third case. Despite the sensitive nature of the probe, it remained stable for at least ∼2 h in the presence of cells during TAT-mediated trafficking, even under pro-inflammatory stimulation. The thiol-responsiveness is intermediate to that observed for disulfide linkers and conventional cysteine-maleimide linkers, presenting opportunities for biotechnological applications.

This work aims at synthesizing tailor-made poly(vinyl alcohol- co -vinyl acetate) (PVA) amphiphilic copolymers, obtained by alcoholysis of poly(vinyl acetate) (PVAc) that could display improved properties as stabilizers compared to commercially available PVAs. Well-defined PVAs with different alcoholysis degrees were produced from a library of PVAc homopolymers synthesized by macromolecular design via interchange of xanthate polymerization and exhibiting different degrees of polymerization degrees. Subsequently, these PVAs were evaluated as stabilizers in the emulsion copolymerization of VAc and vinyl neodecanoate (VERSA 10, referred to as V10) and compared to a commercially available reference PVA obtained by alcoholysis of PVAc formed by conventional radical polymerization. In all cases, stable latexes were obtained and compared in terms of their colloidal characteristics. To identify the best stabilizer candidate, the amount of PVA remaining in water and not participating to the particle stabilization was evaluated in each case.

Thermosets having low dielectric constant (D k < 3) and low dielectric dissipation factor (D f < 0.003), high glass transition temperature (T g > 150 °C), and good adhesion to copper are desirable for the low loss layers of the copper clad laminates (CCL) in next generation printed circuit boards. Three different difunctional diazirines are evaluated for both thermal and photochemical crosslinking of a high T g vinyl-addition polynorbornene resin: poly(5-hexyl-1-norbornene) (poly(HNB)). The substrate polymer, crosslinked by the carbenes generated from the activated diazirines, forms thermosets with D k < 2.3 and D f < 0.001 at 10 GHz depending on the identity of the diazirine and the loading. The D k and D f values for one composition are stable for 1600 h at 125 °C in air and for 1400 h at 85 °C and 85% relative humidity, suggesting good long-term reliability of this thermoset. Adhesion of poly(HNB) to copper can be enhanced by priming the copper surface with a diazirine prior to high temperature lamination; peel strength values of greater than 7.5 N cm -1 are achieved. Negative-tone photopatterning of poly(HNB) with diazirines upon exposure to 365 nm light is demonstrated., (© 2024 The Author(s). Macromolecular Rapid Communications published by Wiley‐VCH GmbH.)

The appearance of an extrudate formulation was monitored during hot-melt extrusion (HME) continuous manufacturing over 3 days. The formulation matrix consisted of a polymeric component, copovidone, and a low molecular weight surfactant, polysorbate 80. Based on studies prior to the continuous manufacturing, the desired appearance of the target extrudate is translucent. Although process parameters such as feed rate and screw speed were fixed during the continuous manufacturing, the extrudate appearance changed over time from turbid to translucent. For root-cause investigation, the extrudates were analyzed offline by differential scanning calorimetry (DSC) and advanced polymer chromatography (APC ™ ). Although the polysorbate 80 content of both turbid and translucent extrudates was within target, the glass transition temperature of the turbid extrudate was 2 °C above expected value. The observed turbidity was traced to lot-to-lot variability of the polysorbate 80 used in the continuous manufacturing, where APC ™ analysis revealed that the relative content of the low molecular weight component varied from 23% to 27% in correlation with the evolution from turbid to translucent extrudates. This work stresses the importance of taking feeding material variability into account during continuous manufacturing.

The role of G-quadruplex (G4) in cellular processes can be investigated by the covalent modification of G4-DNA using alkylating reagents. Controllable alkylating reagents activated by external stimuli can react elegantly and selectively. Herein, we report a chemical activation system that can significantly boost the reaction rate of methylamine-protected vinyl-quinazolinone (VQ) derivative for the alkylation of G4-DNA. The two screened activators can transform low-reactive VQ-NHR' to highly reactive intermediates following the Michael addition mechanism. This approach expands the toolbox of activable G4 alkylating reagents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Additive manufacturing (AM) enables the production of complex, lightweight, and customized components with superior quality. Selecting the right materials considering their thermal properties, printability, and layer adhesion is crucial in melting-based AM techniques. This study investigates Droplet Deposition Modelling (DDM), an innovative material extrusion process that utilizes thermoplastic granules. DDM is distinguished by its shorter manufacturing times and a wider range of materials, setting it apart from traditional material extrusion methods such as fused filament fabrication. We investigated the printability and part quality in DDM using two common pharmaceutical excipients: Polyvinylpyrrolidone/vinyl acetate 6:4 (PVP/VA), which is highly brittle, and Polycaprolactone (PCL), known for its low solubility and role in controlled drug release. Different ratios of PVP/VA and PCL were compounded via hot melt extrusion (HME) and used in DDM to study the impact of ingredient content on printability and part quality, employing geometrical models to assess material compatibility and printability. The study revealed that increasing PVP/VA content leads to higher viscosity, reduced flowability, and uneven deposition, with formulations of 80 % and 100 % PVP/VA showing poor processability. In contrast, formulations with 60 % and 40 % PVP/VA exhibited smooth processing and compatibility with DDM. We identified processing temperature and Drop Aspect Ratio (DAR) as key factors influencing material printability and part quality. Elevated processing temperatures and reduced DAR were found to increase interface temperatures, reduce diffusion, and potentially cause the 'elephant feet' issue. Additionally, smaller droplet sizes and material characteristics, such as higher interfacial tension in PCL, could lead to coalescence. Our findings highlight the complexities in optimizing DDM processing parameters and material blends, underscoring the need for careful formulation design to achieve high-quality 3D printed products., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polymer monoliths can be polymerised within different molds, but limited options are available for the preparation of free-standing polymer monoliths for analytical sample preparation, and in particular, solid-phase extraction (SPE). Commercial melamine-formaldehyde sponges can be used as supports for the preparation of polymer monoliths, due its flexibility, giving various shapes to monoliths. Herein, the crosslinker/porogen ratio of highly porous sponge-nested divinylbenzene (DVB) polymer monoliths has been evaluated. Monoliths prepared using different crosslinker/porogen ratios were applied to the extraction of bisphenol F, bisphenol A, bisphenol AF, and bisphenol B. Monoliths containing 50 wt % DVB and 50 wt % porogens presented the highest recovery of bisphenols. Under the optimised conditions, the developed method showed a linear range between 2.5 µg L -1 and 150 µg L -1 for BPA and BPAF, and between 5 µg L -1 and 150 µg L -1 for BPB and BPF. The limits of detection (LOD, S/N = 3) and limits of quantification (LOQ, S/N = 10) ranged from 0.36 µg L -1 to 1.09 µg L -1 , and from 1.20 µg L -1 to 3.65 µg L -1 , respectively. The recoveries for spiked bisphenols (10 µg L -1 ) in tap water and water contained in a polycarbonate containers were between 82 % and 114 %., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Drug-polymer intermolecular interactions, and H-bonds specifically, play an important role in the stabilization process of a compound in an amorphous solid dispersion (ASD). However, it is still difficult to predict whether or not interactions will form and what the strength of those interactions would be, based on the structure of drug and polymer. Therefore, in this study, structural analogues of diflunisal (DIF) were synthesized and incorporated in ASDs with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as a stabilizing polymer. The respective DIF derivatives contained different types and numbers of H-bond donor groups, which allowed to assess the influence of these structural differences on the phase behavior and the actual interactions formed in the ASDs. The highest possible drug loading of these derivatives in PVPVA were evaluated through film casting. Subsequently, a lower drug loading of each compound was spray dried. These spray dried ASDs were subjected to an in-depth solid-state nuclear magnetic resonance (ssNMR) study, including 1D spectroscopy and relaxometry, as well as 2D dipolar HETCOR experiments. The drug loading study revealed the highest possible loading of 50 wt% for the native DIF in PVPVA. The methoxy DIF derivative reached the second highest drug loading of 35 wt%, while methylation of the carboxyl group of DIF led to a sharp decrease in the maximum loading, to around 10 wt% only. Unexpectedly, the maximum loading increased again when both the COOH and OH groups of diflunisal were methylated in the dimethyl DIF derivative, to around 30 wt%. The ssNMR study on the spray dried ASD samples confirmed intermolecular H-bonding with PVPVA for native DIF and methoxy DIF. Studies of the proton relaxation decay times and 2D 1 H- 13 C dipolar HETCOR experiments indicated that the ASDs with native DIF and methoxy DIF were homogenously mixed, while the ASDs containing DIF methyl ester and dimethyl DIF were phase separated at the nm level. It was established that, for these systems, the availability of the carboxyl group was imperative in the formation of intermolecular H-bonds with PVPVA and in the generation of homogenously mixed ASDs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Patiromer (Veltassa®) is a crosslinked, insoluble co-polymer drug used as a nonabsorbent potassium binder, approved for treatment of hyperkalemia. Quantitative solid-state 13 C nuclear magnetic resonance (NMR) analysis with comprehensive peak assignment, component quantification, and calculation of mole and weight fractions of monomer units was performed on three doses of patiromer. The workflow is documented in detail. Spectrally edited solid-state 13 C NMR spectra of patiromer show =CH n peaks of matching intensity at 116 and 141 ppm, characteristic of -CH=CH 2 vinyl groups. Similar spectral features can be observed in earlier studies but were previously ignored. In this study, the vinyl signals are well-resolved in a 2-s direct polarization (DP) spectrum without and with dipolar dephasing, which confirms that these sp 2 -hybridized carbons are bonded to hydrogen and partially mobile, consistent with vinyl side groups from incompletely reacted divinyl crosslinkers. The vinyl groups account for 1.6% of all carbon, 3% of the monomer units, and nearly 1/3 of the crosslinkers. Furthermore, an unexpected OCH 3 moiety accounting for ∼1.2% of all carbons was identified by spectral editing; its chemical shift of 54 ppm is more consistent with a methyl ester than with a methyl ether. It can originate from incomplete hydrolysis of ∼6% of methyl-2-fluoroacrylate, the main monomer of patiromer. Characteristic cross peaks in two-dimensional 1 H- 13 C heteronuclear correlation NMR confirm the presence of the vinyl and OCH 3 groups. Trace amounts of xanthan gum are also detected. The quantitative 13 C NMR spectrum of patiromer has been matched in a simulation using a model with five monomer units., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A non-invasive capacitance instrument was embedded in the base of a vacuum-drying tray to monitor continuously the residual amount of solvent left in a pharmaceutical powder. Proof of concept was validated with Microcrystalline Cellulose laced with water, as well as water/acetone mixtures absorbed in a spray-dried Copovidone powder. To illustrate the role of impermeability of the base, we derive a model of vapor sorption that reveals the existence of a kinetic limit when solids are thinly spread, and a diffusion limit with greatly diminished effective diffusivity at large powder thickness. By monitoring the residual solvent content of powders, this new in situ technique offers advantages over indirect methods like mass spectrometry of vapor effluents, but without complications associated with probe fouling. To prescribe design guidelines and interpret signals, we model the electric field shed by the probe when a powder holds variable solvent mass fraction in the vertical direction., (© 2024. Merck & Co., Inc., Rahway NJ, USA and its affiliates.)

A series of D-ring modified steroids bearing a vinyl ketone pendant were synthesized and evaluated for antiproliferative activity against breast cancer cell line and cytochromes P450. The lead compound, 21-vinyl 20-keto-pregnene (2f) (IC 50  = 2.4 µM), was shown to be a promising candidate for future anticancer drug design, particularly against estrogen receptor α (ERα)-positive breast cancer. The lead compound was found to have a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells. Compound 2f modulated the ERK, cyclin D1, and CDK4 pathways and blocked the expression of ERα, the main driver of breast cancer growth. Compound 2f significantly reduced 17β-estradiol-induced progesterone receptor expression. Accumulation of cleaved poly(ADP-ribose) polymerase in cells treated with compound 2f indicated induction of apoptosis. The selectivity analysis showed that lead compound 2f produces no significant effects on cytochromes P450, CYP19A1, CYP21A2, and CYP7B1., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Sustainability and circularity are key issues facing the global polymer industry. The search for biodegradable and environmentally-friendly polymers that can replace conventional materials is a difficult challenge that has been met with limited success. Alternatives must be cost-effective, scalable, and provide equivalent performance. We report that latexes made by the conventional emulsion polymerization of vinyl acetate and functional vinyl ester monomers are efficient thickeners for consumer products and biodegrade in wastewater. This approach uses readily-available starting materials and polymerization is carried out in water at room temperature, in one pot, and generates negligible waste. Moreover, the knowledge that poly(vinyl ester)s are biodegradable will lead to the design of new green polymer materials.

The physical stability of amorphous solid dispersions (ASDs) is a major topic in the formulation research of oral dosage forms. To minimize the effort of investigating the long-term stability using cost- and time-consuming experiments, we developed a thermodynamic and kinetic modeling framework to predict and understand the crystallization kinetics of ASDs during long-term storage below the glass transition. Since crystallization of the active phrarmaceutical ingredients (APIs) in ASDs largely depends on the amount of water absorbed by the ASDs, water-sorption kinetics and API-crystallization kinetics were considered simultaneously. The developed modeling approach allows prediction of the time evolution of viscosity, supersaturation, and crystallinity as a function of drug load, relative humidity, and temperature. It was applied and evaluated against two-year-lasting crystallization experiments of ASDs containing nifedipine and copovidone or HPMCAS measured in part I of this work. We could show that the proposed modeling approach is able to describe the interplay between water sorption and API crystallization and to predict long-term stabilities of ASDs just based on short-term measurements. Most importantly, it enables explaining and understanding the reasons for different and sometimes even unexpected crystallization behaviors of ASDs.

Sucrose and trehalose pharmaceutical excipients are employed to stabilize protein therapeutics in a dried state. The mechanism of therapeutic protein stabilization is dependent on the sugars being present in an amorphous solid-state. Colyophilization of sugars with high glass transition polymers, polyvinylpyrrolidone (PVP), and poly(vinylpyrrolidone vinyl acetate) (PVPVA), enhances amorphous sugar stability. This study investigates the stability of colyophilized sugar-polymer systems in the frozen solution state, dried state postlyophilization, and upon exposure to elevated humidity. Binary systems of sucrose or trehalose with PVP or PVPVA were lyophilized with sugar/polymer ratios ranging from 2:8 to 8:2. Frozen sugar-PVPVA solutions exhibited a higher glass transition temperature of the maximally freeze-concentrated amorphous phase ( T g ') compared to sugar-PVP solutions, despite the glass transition temperature ( T g ) of PVPVA being lower than PVP. T g values of all colyophilized systems were in a similar temperature range irrespective of polymer type. Greater hydrogen bonding between sugars and PVP and the lower hygroscopicity of PVPVA influenced polymer antiplasticization effects and the plasticization effects of residual water. Plasticization due to water sorption was investigated in a dynamic vapor sorption humidity ramping experiment. Lyophilized sucrose systems exhibited increased amorphous stability compared to trehalose upon exposure to the humidity. Recrystallization of trehalose was observed and stabilized by polymer addition. Lower concentrations of PVP inhibited trehalose recrystallization compared to PVPVA. These stabilizing effects were attributed to the increased hydrogen bonding between trehalose and PVP compared to trehalose and PVPVA. Overall, the study demonstrated how differences in polymer hygroscopicity and hydrogen bonding with sugars influence the stability of colyophilized amorphous dispersions. These insights into excipient solid-state stability are relevant to the development of stabilized biopharmaceutical solid-state formulations.

There is a growing need for a mouthguard sheet material with higher shock absorption and dispersion capacity than those obtained by conventional materials. A five-layer mouthguard sheet material was previously developed using laminated ethylene vinyl acetate and polyolefin copolymer resin. In this study, the shock absorption capacity and dispersion capability of the new sheet material were investigated and compared with those of other materials. Impact testing for the new sheet material showed that the force required to displace the sheet by 1 mm was significantly higher at all thicknesses (p<0.001), whereas the puncture energy and displacement were significantly lower than those for ethylene vinyl acetate (p<0.05). The five-layer mouthguard sheet material successfully absorbed and resisted shock. Therefore, the sheet material potentially increases resistance to applied deformation in teeth and alveolar bone and maintains structure. The five-layer sheet material could expand the range of mouthguard products and help prevent oral trauma.

Purpose: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors., Methods: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs., Results: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64., Conclusions: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aim: The interaction between the ethylene-vinyl acetate (EVA) with distinct materials utilized for obtaining dental models can affect the performance of resulting mouthguards. This study attempted to evaluate the effect of different materials for conventional (dental stone) or 3D-printed (resin) models on EVA's physical and mechanical properties and surface characteristics., Material and Methods: EVA sheets (Bioart) were laminated over four model types: GIV, conventional Type IV dental stone model (Zhermak); ReG, resin-reinforced Type IV dental stone model (Zero Stone); 3DnT, 3D resin printed model (Anycubic) without surface treatment; 3DT, 3D-printed model (Anycubic) with water-soluble gel (KY Jelly Lubricant, Johnson & Johnson) coating during post-curing process. The EVA specimens were cut following the ISO 37-II standard (n = 30). Shore A hardness was measured before and after plasticization on the contact (internal) or opposite (external) surfaces with the model. The breaking force (F, N), elongation (EL, mm), and ultimate tensile strength (UTS, MPa) were measured using a universal testing machine. Macro-photography and scanning electron microscopy were adopted for classifying the EVA surface alteration. Data were analyzed by one-way ANOVA with repeated measures, followed by Tukey's test (α = .05)., Results: Plasticization significantly decreased Shore A values for the tested EVA regardless of the model type (p < .001). Higher F, El, and UTS values were verified for the EVA with 3DT and GIV models compared to ReG and 3DnT (p < .001). 3DnT models resulted in severe surface alteration and a greater reduction of the mechanical properties of the EVA., Conclusion: The interaction of EVA with 3D resin-printed models without surface treatment or resin-reinforced Type IV dental stone models significantly affected the physical and mechanical properties of this material. The utilization of water-soluble gel coating during the post-curing process of 3D resin printed models improved the mechanical properties of the EVA, similarly when this material was plasticized over conventional Type IV dental stone model., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Arylsulfonyl group-bearing α,β-unsaturated enol esters were readily assembled via the Cs 2 CO 3 -mediated union of 2-bromoallyl sulfones and cinnamic acids. The overall transformation is equivalent to an sp 2 carbon-oxygen coupling reaction, and therefore constitutes a formal vinylic substitution. Several of the products display promising levels of antiproliferative activities higher than that of the anticancer drug carboplatin. Thiophenol reacted with 2-bromoallyl sulfones under identical conditions to afford α-thiophenyl-α'-tosyl acetone via an apparent aerial oxidation.

The R 3 m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial R 3 m dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of R 3 m values for each API. Although different conformations displayed R 3 m values that differed by as much as 0.4, the median of each R 3 m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R 3 m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of each API.

Diseases and diagnoses are predominant in the human population. Early diagnosis of etiological agents plays a vital role in the treatment of bacterial infections. Existing standard diagnostic platforms are laborious, time-consuming, and require trained personnel and cost-effective procedure, though they are producing promising results. These shortcomings have led to a thirst for rapid diagnostic procedures. Fluorescence-based diagnosis is one of the efficient rapid diagnostic methods that rely on specific and sensitive bacterial detection. Emerging bio-sensing studies on conducting polymers (CPs) are gaining popularity in medical diagnostics due to their promising properties of high fluorescence efficiency, good light stability, and low cytotoxicity. Poly[2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV), is the first identified soluble polymer and model material for understanding the fundamental photophysics of conventional CPs. In this present study, MEH-PPV is used as a fluorescent dye for direct pathogen detection applications by interacting with the microbial cell surface. An optimized concentration of MEH-PPV solution used to confirm the presence of selective bacterial structures. The present study endeavours towards bacterial detection based on the emission from bacteria due to interfacial interaction between polymer and bacterial surface., (© 2024. The Author(s).)