Prediction of Degradation Profiles for Various Sartans under Solvent-Free Mechanochemical Conditions.

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

Fabrication of 3D PCL/PVP scaffolds using monosodium glutamate as porogen by solvent casting/particulate leaching method for oral and maxillofacial bone tissue engineering.

The design of three-dimensional (3D) scaffolds should focus on creating highly porous, 3D structures with an interconnected pore network that supports cell growth. The scaffold's pore interconnectivity is directly linked to vascularization, cell seeding, guided cell migration, and transportation of nutrients and metabolic waste. In this study, different types of food flavors including monosodium glutamate, sugar, and sodium chloride were used as the porogens along with PCL/PVP blend polymer for solvent casting/particulate leaching method. The morphology, porosity, interconnectivity, chemical composition, water absorption, and mechanical properties of the fabricated scaffolds are carefully characterized. The scaffolds are biocompatible in bothin vitroandin vivoexperiments and do not trigger any inflammatory response while enhancing new bone formation and vascularization in rabbit calvaria critical-sized defects. The new bone merges and becomes denser along with the experiment timeline. The results indicate that the 3D PCL/PVP scaffolds, using monosodium glutamate as porogen, exhibited suitable biological performance and held promise for bone tissue engineering in oral and maxillofacial surgery.

Optimization of Phenolic-Enriched Extracts from Olive Leaves via Ball Milling-Assisted Extraction Using Response Surface Methodology.

This study aims to extract phenolic-enriched compounds, specifically oleuropein, luteoloside, and hydroxytyrosol, from olive leaves using ball milling-assisted extraction (BMAE). Response surface methodology (RSM) and the Box-Behnken design (BBD) were used to evaluate the effects of the temperature, solvent-to-solid ratio, and milling speed on extraction recovery. The contents of the extract were determined by ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS) and converted to recoveries to evaluate the extraction efficiency. The optimal extraction conditions for oleuropein, luteoloside, and hydroxytyrosol were identified. Oleuropein had a recovery of 79.0% ± 0.9% at a temperature of 56.4 °C, a solvent-to-solid ratio of 39.1 mL/g, and a milling speed of 429 rpm. Luteoloside's recovery was 74.6% ± 1.2% at 58.4 °C, 31.3 mL/g, and 328 rpm. Hydroxytyrosol achieved 43.1% ± 1.3% recovery at 51.5 °C, 32.7 mL/g, and 317 rpm. The reason for the high recoveries might be that high energy ball milling could reduce the sample size further, breaking down the cell walls of olive leaves, to enhance the mass transfer of these components from the cell to solvent. BMAE is displayed to be an efficient approach to extracting oleuropein, luteoloside, and hydroxytyrosol from olive leaves, which is easy to extend to industrial production.

Green Approaches for the Extraction of Banana Peel Phenolics Using Deep Eutectic Solvents.

Banana peels, comprising about 35% of the fruit's weight, are often discarded, posing environmental and economic issues. This research focuses on recycling banana peel waste by optimizing advanced extraction techniques, specifically microwave-assisted (MAE) and ultrasound-assisted extraction (UAE), for the isolation of phenolic compounds. A choline chloride-based deep eutectic solvent (DES) with glycerol in a 1:3 ratio with a water content of 30% (w/w) was compared to 30% ethanol. Parameters, including sample-to-solvent ratio (SSR), extraction time, and temperature for MAE or amplitude for UAE, were varied. Extracts were analyzed for hydroxycinnamic acid (HCA) and flavonoid content, and antioxidant activity using FRAP and ABTS assays. DES outperformed ethanol, with HCA content ranging from 180.80 to 765.92 mg/100 g and flavonoid content from 96.70 to 531.08 mg/100 g, accompanied by higher antioxidant activity. Optimal MAE conditions with DES were an SSR of 1:50, a temperature of 60 °C, and a time of 10 min, whereas an SSR of 1:60, time of 5 min, and 75% amplitude were optimal for UAE. The polyphenolic profile of optimized extracts comprised 19 individual compounds belonging to the class of flavonols, flavan-3-ols, and phenolic acids. This study concluded that DESs, with their superior extraction efficiency and environmental benefits, are promising solvents for the extraction of high-value bioactive compounds from banana peels and offer significant potential for the food and pharmaceutical industries.

Photomutagenicity of N-nitrosoproline dissolved in non-aqueous solvent, oleic acid.

In the present study, we investigated the genotoxicity of the active products formed from N-nitrosoproline (NPRO) dissolved in oleic acid following ultraviolet A (UVA) irradiation, bypassing the need for metabolic activation. We previously demonstrated the photomutagenicity of NPRO dissolved in a phosphate-buffered solution. It has been suggested that the association of the nitrosamine group with acid ions facilitates rapid photodissociation and photoactivation. We hypothesized that NPRO's inherent carboxyl group may mimic an acid, inducing photodissociation and photomutagenicity, even in a non-aqueous solvent lacking acidic ions. Following UVA irradiation, NPRO dissolved in oleic acid exhibited a dose-dependent mutagenic activity. Similar results were obtained when NPRO was dissolved in linoleic acid and triolein. Nitric oxide formation, which is dependent on NPRO concentration, is accompanied by mutagenic activity. The mutagenicity spectrum obtained in response to NPRO irradiation followed the absorption curve of NPRO dissolved in oleic acid. Irradiated NPRO in oleic acid displayed relative stability, retaining approximately 18, 36, and 63 % of initial mutagenicity after 10 days of storage at 25, 4, and -20 °C, respectively. Thus NPRO stored in a fatty environment undergoes photoactivation upon irradiation, leading to genotoxicity.

A multi-stimuli-responsive fluorescence material based on 1,8-naphthalimide.

A pair of 1,8-naphthalimides (NPIs) were designed and successfully synthesized through embellishing amino-containing NPI with 4-diethylaminosalicyladehyde and 4-diethylaminobenzaldehyde, respectively. Their structures were fully confirmed by 1H/13C NMR, HR-MS and FT-IR spectroscopic studies. Their photophysical properties were systematically investigated in different solvents of varied polarity, in THF/water mixtures with varying water fractions (fw), and in THF solvent with varying concentrations of NPIs. It inferred that the distinct differences in emission between two NPIs during self-assembled process could be ascribed that the hydroxyl-containing NPI allowed the excited-state intramolecular proton transfer process between -OH and CH=N units in the aggregation state. Interestingly, the solid of 4-diethylaminosalicyladehyde-functionalized NPI exhibited multi-stimuli-responsive fluorescence changes involving mechanofluorochromism and HCl/NH3 vapor stimulus-induced conversion. However, no remarkable change was observed in the photoluminescence (PL) spectra for the solid of 4-diethylaminobenzaldehyde-functionalized NPI under the stimuli of mechanical force and organic solvent.

Ultrasound-assisted matrix solid-phase extraction based on deep eutectic solvents and zinc oxide: Extraction and determination of six active ingredients in Ligustri Lucidi Fructus.

In this study, we propose a novel strategy utilizing deep eutectic solvents (DESs) as both the extraction solvent and dispersing liquid, with nanometer zinc oxide (ZnO) serving as the adsorbent. This method incorporates ultrasound-assisted matrix solid phase dispersion (UA-MSPD) for the extraction of six active components (salidroside, echinacoside, acteoside, specnuezhenide, nuezhenoside G13, and oleanolic acid) from Ligustri Lucidi Fructus samples. The extracts were then analyzed using high-performance liquid chromatography equipped with a diode array detector. The effects of various parameters such as dispersant dosage, DESs volume, grinding time, ultrasonication duration, and eluent volume on extraction recovery were investigated and optimized using a central composite design under response surface methodology. The optimized conditions yielded detection limits ranging from 0.003 to 0.01 mg/g and relative standard deviations of 8.7% or lower. Extraction recoveries varied between 93% and 98%. The method demonstrated excellent linearity for the analytes (R2 ≥ 0.9997). The simple, green, and efficient DESs/ZnO-UA-MSPD technique proved to be rapid, accurate, and reliable for extracting and analyzing the six active ingredients in Ligustri Lucidi Fructus samples.

Eco-friendly solvent-based liquid-liquid extraction of phenolic acids from winery wastewater streams.

This study proposes liquid-liquid extraction (LLE) for the recovery of phenolic acids from winery wastewater replacing common volatile organic compounds (VOCs) with environmentally friendly solvents. On one hand, terpenes (α-pinene and p-cymene) and terpenoids (eucalyptol and linalool) were selected as green solvents and compared to common VOCs (ethyl acetate or 1-butanol). On the other hand, gallic acid (GA), vanillic acid (VA), syringic acid (SA) and caffeic acid (CA) were selected as phenolic acids to be recovered. The extraction performance was evaluated under different operation conditions: solvent-to-feed ratio, initial concentration of phenolic acids and temperature. This work also evaluated the back-extraction whole process global recovery and solvent regeneration, by means of aqueous NaOH solution. Eucalyptol has shown the highest overall global extraction performance (21.07 % for GA, 93.21 % for VA, 78.79 % for SA, and 80.57 % for CA) and lower water solubility compared to the best performing VOC solvent (1-butanol). Therefore, eucalyptol can be a potential eco-friendly solvent to replace VOCs for sustainable phenolic acid recovery from winery wastewater. Finally, to ensure a clean water stream after the LLE, the traces of solvent were completely removed by electrooxidation with boron-doped diamond anode at a current density of 422.54 A/m2.

Solvent induced amyloid polymorphism and the uncovering of the elusive class 3 amyloid topology.

Aggregation-prone-motifs (APRs) of proteins are short segments, which - as isolated peptides - form diverse amyloid-like crystals. We introduce two APRs - designed variants of the incretin mimetic Exendin-4 - that both display crystal-phase polymorphism. Crystallographic and spectroscopic analysis revealed that a single amino-acid substitution can greatly reduce topological variability: while LYIQWL can form both parallel and anti-parallel ß-sheets, LYIQNL selects only the former. We also found that the parallel/anti-parallel switch of LYIQWL can be induced by simply changing the crystallization temperature. One crystal form of LYIQNL was found to belong to the class 3 topology, an arrangement previously not encountered among proteinogenic systems. We also show that subtle environmental changes lead to crystalline assemblies with different topologies, but similar interfaces. Spectroscopic measurements showed that polymorphism is already apparent in the solution state. Our results suggest that the temperature-, sequence- and environmental sensitivity of physiological amyloids is reflected in assemblies of the APR segments, which, complete with the new class 3 crystal form, effectively sample all the originally proposed basic topologies of amyloid-like aggregates.

Enhancing Cellulose and Lignin Fractionation from Acacia Wood: Optimized Parameters Using a Deep Eutectic Solvent System and Solvent Recovery.

Cellulose and lignin, sourced from biomass, hold potential for innovative bioprocesses and biomaterials. However, traditional fractionation and purification methods often rely on harmful chemicals and high temperatures, making these processes both hazardous and costly. This study introduces a sustainable approach for fractionating acacia wood, focusing on both cellulose and lignin extraction using a deep eutectic solvent (DES) composed of choline chloride (ChCl) and levulinic acid (LA). A design of experiment was employed for the optimization of the most relevant fractionation parameters: time and temperature. In the case of the lignin, both parameters were found to be significant variables in the fractionation process (p-values of 0.0128 and 0.0319 for time and temperature, respectively), with a positive influence. Likewise, in the cellulose case, time and temperature also demonstrated a positive effect, with p-values of 0.0103 and 0.028, respectively. An optimization study was finally conducted to determine the maximum fractionation yield of lignin and cellulose. The optimized conditions were found to be 15% (w/v) of the wood sample in 1:3 ChCl:LA under a treatment temperature of 160 °C for 8 h. The developed method was validated through repeatability and intermediate precision studies, which yielded a coefficient of variation lower than 5%. The recovery and reuse of DES were successfully evaluated, revealing remarkable fractionation yields even after five cycles. This work demonstrates the feasibility of selectively extracting lignin and cellulose from woody biomass using a sustainable solvent, thus paving the way for valorization of invasive species biomass.

Optimization of a mass spectrometric analytical method for the quality assessment of insulin and its analogs.

The principal aim of this study was to optimize analytical methodology based on mass spectrometry for the evaluation of the quality of recombinant human insulin and its analogs. In this study ESI-MS was used to assess the quality of human insulin, short acting insulin analogs, insulin lispro, insulin aspart and insulin glulisine and long acting analogs including insulin glargine, insulin degludec, and insulin detemir, in respective pharmaceutical formulations. In this study, with the aimed to optimize analytical conditions, different factors influencing the analytical performance such as pH, ionic strength, sample dilution, organic solvent addition were addressed. The study results demonstrated that MS is a suitable technique for the analysis of biotechnological compounds like insulin and its analogs. Although the obtained results provide an important information regarding this methodology, further studies are needed to validate this analytical approach and check for its suitability to be used in the regulatory environment.

Non-Invasive, Continuous, Quantitative Detection of Solvent Content in Vacuum Tray Drying.

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.

Influence of Solvent Polarity on the Conformer Ratio of Bicalutamide in Saturated Solutions: Insights from NOESY NMR Analysis and Quantum-Chemical Calculations.

The study presents a thorough and detailed analysis of bicalutamide's structural and conformational properties. Quantum chemical calculations were employed to explore the conformational properties of the molecule, identifying significant energy differences between conformers. Analysis revealed that hydrogen bonds stabilise the conformers, with notable variations in torsion angles. Conformers were classified into 'closed' and 'open' types based on the relative orientation of the cyclic fragments. NOE spectroscopy in different solvents (CDCl3 and DMSO-d6) was used to study the conformational preferences of the molecule. NOESY experiments provided the predominance of 'closed' conformers in non-polar solvents and a significant presence of 'open' conformers in polar solvents. The proportions of open conformers were 22.7 ± 3.7% in CDCl3 and 59.8 ± 6.2% in DMSO-d6, while closed conformers accounted for 77.3 ± 3.7% and 40.2 ± 6.2%, respectively. This comprehensive study underscores the solvent environment's impact on its structural behaviour. The findings significantly contribute to a deeper understanding of conformational dynamics, stimulating further exploration in drug development.

Green Extraction of Reed Lignin: The Effect of the Deep Eutectic Solvent Composition on the UV-Shielding and Antioxidant Properties of Lignin.

Lignin, the second most abundant natural polymer, is a by-product of the biorefinery and pulp and paper industries. This study was undertaken to evaluate the properties and estimate the prospects of using lignin as a by-product of the pretreatment of common reed straw (Phragmites australis) with deep eutectic solvents (DESs) of various compositions: choline chloride/oxalic acid (ChCl/OA), choline chloride/lactic acid (ChCl/LA), and choline chloride/monoethanol amine (ChCl/EA). The lignin samples, hereinafter referred to as Lig-OA, Lig-LA, and Lig-EA, were obtained as by-products after optimizing the conditions of reed straw pretreatment with DESs in order to improve the efficiency of subsequent enzymatic hydrolysis. The lignin was studied using gel penetration chromatography, UV-vis, ATR-FTIR, and 1H and 13C NMR spectroscopy; its antioxidant activity was assessed, and the UV-shielding properties of lignin/polyvinyl alcohol composite films were estimated. The DES composition had a significant impact on the structure and properties of the extracted lignin. The lignin's ability to scavenge ABTS+• and DPPH• radicals, as well as the efficiency of UV radiation shielding, decreased as follows: Lig-OA > Lig-LA > Lig-EA. The PVA/Lig-OA and PVA/Lig-LA films with a lignin content of 4% of the weight of PVA block UV radiation in the UVA range by 96% and 87%, respectively, and completely block UV radiation in the UVB range.

Monitoring residual solvents in pharmaceutical products using a portable pre-concentration GC-PID.

Pharmaceutical manufacturing utilizes solvents at different stages of production. Some of the harmful solvent residuals may be retained in the final product; therefore, they need to be monitored for quality control and to meet the regulation requirement. Here, a novel method capable of rapidly analyzing residual solvents in pharmaceutical products was developed using a compact-portable gas chromatography with a photoionization detector (GC-PID). The method consists of modified Tedlar® bag sampling, online pre-concentration, separation of volatiles by miniaturized GC, and micro-PID detection. The method detection limits of selected residual solvents were in the range of 26.00 - 52.03 pg/mL which is much lower than the pharmaceutical compliance concentration limits. Limits of detection > 520 pg of analyte per grams of sample was also determined for the over-the-counter drugs. The method performance showed rapid speed (5 min), linear calibration (r2 < 0.99), and repeatable retention time (RSD < 0.4 %). Direct analysis of residual solvents in solid samples was conducted without the need for complex sample preparation. The method validation using over-the-counter pharmaceutical products yielded excellent accuracy (recovery > 91.2 %) and precision (RSD < 6.5 %) for the selected residual solvents, including 1,4-dioxane, benzene, chlorobenzene, cyclohexane, xylenes, and toluene. This portable and rapid method could be deployed during the pharmaceutical drug manufacturing processes for quality control.

AttenGpKa: A Universal Predictor of Solvation Acidity Using Graph Neural Network and Molecular Topology.

Rapid and accurate calculation of acid dissociation constant (pKa) is crucial for designing chemical synthesis routes, optimizing catalysts, and predicting chemical behavior. Despite recent progress in machine learning, predicting solvation acidity, especially in nonaqueous solvents, remains challenging due to limited experimental data. This challenge arises from treating experimental values in different solvents as distinct data domains and modeling them separately. In this work, we treat both the solutes and solvents equally from a perspective of molecular topology and propose a highly universal framework called AttenGpKa for predicting solvation acidity. AttenGpKa is trained using 26,522 experimental pKa values from 60 pure and mixed solvents in the iBonD database. As a result, our model can simultaneously predict the pKa values of a compound in various solvents, including pure water, pure nonaqueous, and mixed solvents. AttenGpKa achieves universality by using graph neural networks and attention mechanisms to learn complex effects within solute and solvent molecules. Furthermore, encodings of both solute and solvent molecules are adaptively fused to simulate the influence of the solvent on acid dissociation. AttenGpKa demonstrates robust generalization in extensive validations. The interpretability studies further indicate that our model has effectively learnt electronic and solvent effects. A free-to-use software is provided to facilitate the use of AttenGpKa for pKa prediction.

Supramolecular eutectogel as new oral paediatric delivery system to enhance benznidazole bioavailability.

Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format. This green and sustainable formulation strategy relies on the gelation of drug-loaded Natural Deep Eutectic Solvents (NaDES) with xanthan gum (XG) and water. Specifically, choline chloride-based NaDES form stable and biocompatible 5 mg/mL BNZ-loaded EGs. Rheological and Low-field NMR investigations indicate that EGs are viscoelastic materials comprised of two co-existing regions in the XG network generated by different crosslink distributions between the biopolymer, NaDES and water. Remarkably, the shear modulus and relaxation spectrum of EGs remain unaffected by temperature variations. Upon dilution with simulated gastrointestinal fluids, EGs results in BNZ supersaturation, serving as the primary driving force for its absorption. Interestingly, after oral administration of EGs to rats, drug bioavailability increases by 2.6-fold, with a similar increase detected in their cerebrospinal fluid. The noteworthy correlation between in vivo results and in vitro release profiles confirms the efficacy of EGs in enhancing both peripheral and central BNZ oral bioavailability.

Hydrophobic deep eutectic solvent (HDES) as oil phase in lipid-based drug formulations.

There is increasing pharmaceutical interest in deep eutectic solvents not only as a green alternative to organic solvents in drug manufacturing, but also as liquid formulation for drug delivery. The present work introduces a hydrophobic deep eutectic solvent (HDES) to the field of lipid-based formulations (LBF). Phase behavior of a mixture with 2:1 M ratio of decanoic- to dodecanoic acid was studied experimentally and described by thermodynamic modelling. Venetoclax was selected as a hydrophobic model drug and studied by atomistic molecular dynamics simulations of the mixtures. As a result, valuable molecular insights were gained into the interaction networks between the different components. Moreover, experimentally the HDES showed greatly enhanced drug solubilization compared to conventional glyceride-based vehicles, but aqueous dispersion behavior was limited. Hence surfactants were studied for their ability to improve aqueous dispersion and addition of Tween 80 resulted in lowest droplet sizes and high in vitro drug release. In conclusion, the combination of HDES with surfactant(s) provides a novel LBF with high pharmaceutical potential. However, the components must be finely balanced to keep the integrity of the solubilizing HDES, while enabling sufficient dispersion and drug release.

Activity and product distribution in Ni-Co and Ni-Cu catalyst-mediated lignin depolymerization into phenolic substances with isopropanol H-donating solvent.

Lignin, a vital renewable biopolymer, serves as the Earth's primary source of aromatics and carbon. Its depolymerization presents significant potential for producing phenolic fine chemicals. This study assesses promoted Ni-based bimetallic catalysts (Ni-Co/C and Ni-Cu/C) supported on activated carbon in isopropanol for lignin depolymerization, compared to monometallic counterparts. BET, SEM, EDX, and XPS analyses highlight their physicochemical properties and promotional effects, enhancing hydrogenolysis activity and hydrogen transformation. Reaction parameter exploration elucidates the influence on lignin depolymerization, with cobalt and copper as promoters notably increasing conversion and monomer yield. Ni-Co/C exhibits the highest lignin conversion (94.2%) and maximum monomer yield (53.1 wt%) under specified conditions, with lower activation energy (36.1 kJ/mol) and higher turnover frequency (31.6 h-1) compared to Ni/C. FT-IR, GPC, GC-FID, and GC-MS analyses confirm effective depolymerization, identifying 20 monomer products. Proposed reaction mechanisms underscore the potential of Ni-based bimetallic catalysts for lignin valorization, offering insights into developing efficient catalytic systems for lignin hydrogenolysis. This research enhances understanding and facilitates the development of selective catalytic processes for lignin valorization.

Poly(3-Hydroxybutyrate-co-3-Hydroxyvalerate) Self-Reinforced Composites via Solvent-Induced Interfiber Welding of Nanofibers.

In this study, we explore an approach to enhance the mechanical performance of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) by utilizing the self-reinforcing effect of ß-phase-induced PHBV electrospun nanofiber mats. This involves electrospinning combined with low-temperature postspun vapor solvent interfiber welding. Scanning electron microscopy imaging confirmed fiber alignment, while XRD diffraction revealed the presence of both α and ß crystalline phases under optimized electrospinning conditions. The resulting composite exhibited significant improvements in mechanical properties attributed to the formation of more perfectly structured α and ß polymorphs and enhanced interfacial adhesion of electrospun nanofibers after vapor solvent treatment. This approach offers entirely recyclable and biodegradable materials, presenting the potential for a new family of sustainable bioplastics.