Organic Solvent-free Research Articles

Bioinspired Injectable Polyurethane Underwater Adhesive with Fast Bonding and Hemostatic Properties.

Underwater adhesives with injectable, organic solvent-free, strong, fast adhesion, and hemostatic properties have become an urgent need in biomedical field. Herein, a novel polyurethane underwater adhesive (PUWA) inspired by mussels is developed utilizing the rapid post-cure reaction of isocyanate esterification without organic solvents. The PUWA is created through the injectable two component curing process of component A (biocompatible polyurethane prepolymer) and component B (dopamine modified lysine derivatives: chain extender-LDA and crosslinker-L3DA). The two-component adhesive cures quickly and firmly underwater, with an impressive bonding strength of 40kPa on pork skin and excellent burst pressure of 394mmHg. Moreover, the PUWA exhibits robust adhesion strength in hostile environments with acid, alkali and saline solutions. Combined with excellent biocompatibility and hemostatic performance, the PUWA demonstrates effectively sealing wounds and promoting healing. With the ability to bond diverse substrates rapidly and strongly, the PUWA holds significant potential for application in both biomedical and industrial fields.

Sustainable and versatile selective oxidation of sulfides to sulfones in deep eutectic solvent

Deep eutectic solvents (DES) have emerged as a promising class of solvents that offer unique properties and applications in various fields. The oxidation of sulfide with readily available oxidants remains a major challenge. Herein, we report a straightforward and efficient approach for selective oxidation of sulfides to sulfones using only DES as a green solvent and catalyst. A variety of sulfides including dialkyl, aryl-alkyl, and diaryl were selectively oxidized to sulfones using H2O2 in good to excellent yields at ambient temperature. This method emphasized, organic solvent-free, and acid-free characteristics making it a new, sustainable, and eco-friendly way to realize direct sulfones. The DES showed a stable catalytic performance through consecutive reuses and were recovered and reused for five times without decrease in the reaction yield.

Design, optimization, and evaluation for a long-time-released transdermal microneedle delivery system containing estradiol.

Transdermal drug delivery systems (TDDS) have drawbacks such as poor absorption, low blood concentration, and delayed effects. Dissolving microneedle has sharp tips and short length, which overcome patients' pain and improve transdermal efficiency but has low mechanical strength and drug loading capacity. This study thereby proposes a microemulsion-encapsulated and long-time-released transdermal microneedle (MN) delivery system with estradiol (Es) as the model drug. The microemulsion (ME) was optimized by utilizing the pseudo-ternary phase diagram and D-optimal mixture design. The estradiol microemulsion-encapsulated microneedle (Es-ME-MN) was optimized by Box-Behnken design and prepared by freeze-thaw method. The Es-ME-MN obtained was characterized and evaluated through a large variety of studies. Es-ME-MN had sufficient mechanical strength to pierce skin and was safe enough, the length of which was 600 μm, and the Es content was 177.12 ± 0.72 μg/patch without drug-excipient chemical interaction. In vitro permeation study showed that Es-ME-MN has a higher transdermal efficiency and lower retention capacity than commercial estradiol patch and conventional MN. Es plasma concentration began to increase at 3 h and remained at 12.98-23.52 ng/mL until 72 h by pharmacokinetic experiments in the Es-ME-MN group. Es-ME-MN rapidly achieves effective blood concentrations through needle puncture and microemulsion delivery and maintains blood concentrations through the baseplate long-time release. Microemulsion-encapsulated, organic solvent-free, and long-time-released transdermal microneedle will make progress and provide a new idea for transdermal delivery of lipophilic drugs.

Reagentless Chemistry "On-Water": An Atom-Efficient and "Green" Route to Cyclic and Acyclic β-Amino Sulfones via aza-Michael Addition Using Microwave Irradiation.

A reagentless, catalyst-free, and sustainable methodology was developed for facile access to cyclic and acyclic β-amino sulfones "on-water" using a microwave. A variety of aromatic and aliphatic amines undergo double aza-Michael addition on the surface of the water with water-insoluble divinyl sulfones upon microwave irradiation at 150 °C for 10 min to mostly afford solid cyclic β-amino sulfones as easily separable products in excellent yields by simple filtration avoiding any workup steps. Thus, all atoms of the substrates are reflected in the product making it a 100% atom-efficient method. Both electron-rich and electron-deficient amines participated well in the reaction as well as good functional group tolerance was observed. The competitive experiments expectedly revealed faster reaction kinetics for electron-rich amines. The methodology was extended to acyclic β-amino sulfones by interacting phenyl/ethyl vinyl sulfones with various amines in a similar manner. Expectedly, the method afforded very low environmental factors (in a range of 0.05-0.5) and a high Ecoscale score (up to 94). In an attempt toward sustainable development, this reagent-free, metal-free, organic solvent-free, cost-effective protocol is certainly a viable alternative to the available methods for β-amino sulfones.

A quality by design framework for developing nanocrystal bioenabling formulations

The present study aims to outline a rational framework for the design and development of a 1.0% (w/v) hydrocortisone nanocrystal-based formulation, resorting to a simple, efficient, and scalable nanonization methodology, based on the high-pressure homogenization (HPH) technique. Accordingly, the innovative product was comprehensively optimized following a Quality by Design (QbD) approach. The thorough selection of formulation composition was driven by a dual purpose: improving skin permeation and stability. In the early stage of development, a Failure Mode, Effects and Criticality Analysis (FMECA) diagram was employed to identify the most impactful variables for the critical quality attributes (CQAs). In this sense, a rotatable, three-factor and five-level circumscribed central composite design (CCCD) was applied to investigate how squalene concentration (x1), soluplus concentration (x2) and HPH-time (x3) influence physicochemical properties, performance and physical stability of the formulation. A robust Design Space (DS) was defined, establishing the optimal settings for the critical variables, whose combination meets the requirements set in the quality target product profile (QTPP). Morphological analysis revealed the cuboidal shape of hydrocortisone nanocrystals. In what concerns colloidal properties, the most promising formulation disclosed a small particle size (Dx(50) = 311.8 ± 1.5 nm), along with narrow size distribution (span value = 1.91 ± 0.17). Zeta potential results (−2.19 ± 0.15 mV–−12.1 ± 0.4 mV) suggested a steric hindrance stabilization. FTIR spectra showed no chemical interactions between drug and formulation components. XRD diffractograms confirmed loss of crystallinity during the downsizing process. In vitro studies revealed an improvement on drug release rate (316 ± 21–516 ± 35 μg/cm2/√t), compared to the coarse suspension and commercial products, and a straight dependence on the stabilizer concentration and HPH time. The permeation flux across the skin (0.16 ± 0.02–1.2 ± 0.5 μg/cm2/h) appeared to be dependent on the drug physicochemical properties, in particular saturation solubility. Further characterization of the experimental formulations pointed out the role of the stabilizing component to prevent against physical instability phenomena. This organic solvent-free, and therefore “green” nanocrystal production technology offers great potential for pharmaceutical R&D and drug delivery by enabling the development of new forms of conventional drugs with optimal physicochemical properties and performance.

Natural small molecule self-assembled hydrogel inhibited tumor growth and lung metastasis of 4T1 breast cancer by regulating the CXCL1/2-S100A8/9 axis

It is crucial to inhibit tumor growth and distant metastasis for breast cancer (BC) therapy. However, the treatment primarily dependent on surgery, chemotherapy, and radiotherapy is far from satisfactory. It had been demonstrated that the CXCL1/2-S100A8/9 axis played an essential role in BC therapy. Therefore, we constructed a natural product hydrogel for BC therapy by blocking CXCL1 signaling. The GK-GA (phytochemicals of Genkwa Flos-glycyrrhizic acid) hydrogel was designed in a one-step “green” approach. The pharmacodynamics study showed GK-GA exhibited significant anti-tumor and anti-lung metastasis activities, resulting in the inhibition rate of tumor growth (IRG) over 90 % at 6.25 mg·kg−1, and did not display any obvious toxicity. In addition, the potent antitumor efficiency was also attributed to aggregation/assembly-induced retention (AIR) property. RNA sequencing analysis revealed the gene expression was significantly down-regulated in the GK-GA group, which were BCL2, CASP3, CXCL1, CXCL2, CXCR2, S100A8, S100A9, and confirmed further by western blot (WB). Our findings indicated natural product GK-GA hydrogel inhibited tumor growth and lung metastasis via the BCL2-CASP3 mitochondrial apoptosis pathway as well as the CXCL1/2-S100A8/9 pathway. This study provides inspiration for the fabrication of new excipients-free nano-dispersion in a one-step, no‐carrier‐added, organic solvent-free, “green” approach, particularly for small molecular antitumor agents.

Organic solvent-free synthesis of dendritic mesoporous bioactive glass nanoparticles with remineralization capability

Dendritic mesoporous bioactive glass nanoparticles (DMBGNs) are emerging biomaterials for various biomedical applications. However, their synthesis usually involves extensive volatile organic solvents, causing significant environmental and economic issues. We report an organic solvent-free strategy to produce DMBGNs, in which cationic and anionic surfactants were used as dual templates free of organic solvents to assemble silicate nanoparticles before incorporation of Ca by impregnation. The Ca incorporation did not affect the dendritic mesoporous structure of the nanoparticles. DMBGNs exhibited remineralization capacity as evidenced by hydroxyapatite (HA) formation after soaking in simulated body fluid (SBF). The results indicate the feasibility of the proposed organic solvent-free, two-step strategy for producing DMBGNs highlighting also the great potential of DMBGNs as remineralization agents.

Preparation of organic-solvent free liposome of Piper albi Linn extract in solution and powder form

Piperine is bioactive alkaloid extracted from white pepper (Piper albi Linn) with several beneficial pharmacological activities. It is also known to enhance the bioavailability of several limited solubilities of other compounds such as curcumin and resveratrol. Nevertheless, due to its poorly water-soluble character, piperine and extract of white pepper are less applied among other plant extracts. Therefore, our research focussed on the engineering of white pepper extract standardized to piperine in liposome solution and liposome powder for further preparation of various pharmaceutical dosage forms.Our research in preparation of extracted white pepper in liposome delivery system successfully prepared spheric liposome solution with 98.92%±1.17% and an average size of 398.7 nm. The liposome was also successfully prepared in dry powder form with sucrose as a carrier for liposome protection. The rehydration is successfully forming a spheric shape with a similar profile to the initial liposome solution. This research paves the way for scalable white pepper extract liposome preparation without the utilization of toxic organic solvent, to produce the commercial solvent-free product in the future.Keywords: Piperine, Piper albi Linn, liposome, extract, organic solvent-free, drug delivery system, spray dry

The enhancement and mechanism of potential-assisted method on 2-mercaptobenzobthiazole assembled film for copper protection

Self-assembled organothiol is a well-known process to endow specific protective properties and usually involves passive incubation. Researchers have recently confirmed that the potential-assisted method is more selective and faster than the passive method. This paper provides an original and promising approach for Cu protection by 2-mercaptobenzobthiazole (MBT) assembled film prepared from an aqueous solution within minutes under potential control. Electrochemical studies, salt spray tests, and XPS highlight and confirm the benefits of this method to result in film features, organic solvent-free, and considerable savings of preparation time. Experimental results also demonstrate that the substrate potential exerts a significant effect on the quality of MBT film. The effectiveness of negative potential in MBT film formation can be attributed to two aspects: first, it can inhibit the oxidation of Cu metal to Cu(II) in the aqueous solution, and second, it can make MBT molecule bond to Cu mainly through forming thiolate Cu-S bond with its exocyclic S atom.

Organic Solvent Free Process to Fabricate High Performance Silicon/Graphite Composite Anode

Cycling stability is a key challenge for application of silicon (Si)-based composite anodes as the severe volume fluctuation of Si readily leads to fast capacity fading. The binder is a crucial component of the composite electrodes. Although only occupying a small amount of the total composite mass, the binder has major impact on the long-term electrochemical performance of Si-based anodes. In recent years, water-based binders including styrene-butadiene rubber (SBR) and carboxymethyl cellulose (CMC) have attracted wide research interest as eco-friendly and low-cost alternatives for the conventional poly(vinylidene difluoride) (PVDF) binder in Si anodes. In this study, Si-based composite anodes are fabricated by simple solid mixing of the active materials with subsequent addition of SBR and CMC binders. This approach bypasses the use of toxic and expansive organic solvents. The factors of binder, silicon, and graphite materials have been systematically investigated. It is found that the retained capacities of the anodes are more than 440 mAh/g after 400 cycles. These results indicate that organic solvent free process is a facile strategy for producing high performance silicon/graphite composite anodes.

Bioinspired Microenvironment Responsive Nanoprodrug as an Efficient Hydrophobic Drug Self-Delivery System for Cancer Therapy.

Artemisinin compounds have shown satisfactory safety records in anti-malarial clinical practice over decades and have revealed value as inexpensive anti-tumor adjuvant chemotherapeutic drugs. However, the rational design and precise preparation of nanomedicines based on the artemisinin drugs are still limited due to their non-aromatic and fragile chemical structure. Herein, a bioinspired coordination-driven self-assembly strategy was developed to manufacture the artemisinin-based nanoprodrug with a significantly increased drug loading efficacy (∼70 wt %) and decreased preparation complexity compared to conventional nanodrugs. The nanoprodrug has suitable size distribution and robust colloidal stability for cancer targeting in vivo. The nanoprodrug was able to quickly disassemble in the tumor microenvironment with weak acidity and a high glutathione concentration, which guarantees a better tumor inhibitory effect than direct administration and fewer side effects on normal tissues in vivo. This work highlights a new strategy to harness a robust, simplified, organic solvent-free, and highly repeatable route for nanoprodrug manufacturing, which may offer opportunities to develop cost-effective, safe, and clinically available nanomedicines.

Dual closed-loop chemical recycling support sustainable mitigation of plastic pollution

Recently, the Feringa Nobel Prize Scientist Joint Research Center demonstrated a green method to synthesize plastics from natural small thioctic acid (TA) monomers. This novel recycling system provides successful chemical recycling using a dual closed-loop process under mild operating conditions. Here, we discuss the critical environmental sustainability dynamics of these recycling systems and their potential to support a plastic circular economy.

Selective oxidation of biomass-derived furfural to 2(5H)-furanone using trifluoroacetic acid as the catalyst and hydrogen peroxide as a green oxidant

In this work, biomass-derived furfural has been selectively oxidized to 2(5H)-furanone using aqueous hydrogen peroxide as the green oxidant. Among various homogeneous acid catalysts screened for the transformation, trifluoroacetic acid (TFA) was found to be the most suitable candidate that afforded up to 52% isolated yield of 2(5H)-furanone under mild conditions (RT, 1 h). In addition, succinic acid was recovered in nearly 20% yield from the aqueous layer. The organic solvent-free, gram-scale reaction was optimized on temperature, the molar ratio of H2O2 and furfural, and the amount of TFA used.

High-Performance n -Hexane Purification by Nonporous Adaptive Crystals of Leaning Pillar[6]arene

The production of high-purity n-hexane under mild conditions is of great significance in both the petrochemical industry and synthetic chemistry. Here, we report an easy-to-operate and energy-effic...

One-Pot, Regioselective Synthesis of Homopropargyl Alcohols using Propargyl Bromide and Carbonyl Compound by the Mg-mediated Reaction under Solvent-free Conditions

The elimination of volatile organic solvents in organic synthesis is the most important goal in “Green” chemistry. We report a simple, efficient and facile method for the addition of progargyl bromide to carbonyl compounds using Mg metal as a mediator under solvent-free conditions which could regioselectively generate homopropargyl alcohols efficiently in good to excellent yields. The procedure has advantages such as short reaction time, operationally simple, excellent product yields, high regioselectivity and organic solvent-free.

Design of Engineered Cyclodextrin Derivatives for Spontaneous Coating of Highly Porous Metal-Organic Framework Nanoparticles in Aqueous Media.

Nanosized metal-organic frameworks (nanoMOFs) MIL-100(Fe) are highly porous and biodegradable materials that have emerged as promising drug nanocarriers. A challenging issue concerns their surface functionalization in order to evade the immune system and to provide molecular recognition ability, so that they can be used for specific targeting. A convenient method for their coating with tetraethylene glycol, polyethylene glycol, and mannose residues is reported herein. The method consists of the organic solvent-free self-assembly on the nanoMOFs of building blocks based on β-cyclodextrin facially derivatized with the referred functional moieties, and multiple phosphate groups to anchor to the nanoparticles’ surface. The coating of nanoMOFs with cyclodextrin phosphate without further functional groups led to a significant decrease of macrophage uptake, slightly improved by polyethylene glycol or mannose-containing cyclodextrin phosphate coating. More notably, nanoMOFs modified with tetraethylene glycol-containing cyclodextrin phosphate displayed the most efficient “stealth” effect. Mannose-coated nanoMOFs displayed a remarkably enhanced binding affinity towards a specific mannose receptor, such as Concanavalin A, due to the multivalent display of the monosaccharide, as well as reduced macrophage internalization. Coating with tetraethylente glycol of nanoMOFs after loading with doxorubicin is also described. Therefore, phosphorylated cyclodextrins offer a versatile platform to coat nanoMOFs in an organic solvent-free, one step manner, providing them with new biorecognition and/or “stealth” properties.

Novel Soy β-Conglycinin Core-Shell Nanoparticles As Outstanding Ecofriendly Nanocarriers for Curcumin.

The development of high-performance nanocarriers for nutraceuticals or drugs has become one of the topical research subjects in the functional food fields. In this work, we for the first time propose a novel and ecofriendly process to obtain a kind of nanostructured soy β-conglycinin (β-CG; a major soy storage globulin) as outstanding nanocarriers for poorly soluble bioactives (e.g., curcumin), by a urea-assisted disassembly and reassembly strategy. At urea concentrations > 4 M, the structure of β-CG gradually dissociated into its separate subunits (α, α', and β) and even denatured (depending on the type of subunits); after dialysis to remove urea, the dissociated subunits would reassemble into a kind of core-shell nanostructured particles, in which aggregated β-subunits acted as the core while the shell layer was mainly composed of α- and α'-subunits. The core-shell nanoparticles were favorably formed at protein concentrations of 1.0-2.0 wt %. Curcumin crystals were directly introduced into the β-CG solution at high urea concentrations (e.g., 8 M) and would preferentially interact with the denatured β-subunits. As a consequence, almost all of the curcumin molecules were encapsulated in the core part of the reassembled core-shell nanoparticles. The loading amount of curcumin in these nanoparticles could reach 18 g of curcumin per 100 g of protein, which far exceeds those reported previously. The encapsulated curcumin exhibited a high water solubility, extraordinary thermal stability, and improved bioaccessibility, as well as a sustained release behavior. The findings provide a novel strategy to fabricate a kind of high-encapsulation-performance, organic solvent-free, and biocompatible nanocarrier for hydrophobic nutraceuticals and drugs.

Centrifugal fractionation of softwood extracts improves the biorefinery workflow and yields functional emulsifiers

Centrifuging softwood extracts separated the hemicellulose-rich fraction and lignin-rich micro- and nanoparticles. The hemicellulose-rich fraction and lignin-rich nanoparticles formed stable emulsions.

Organic Solvent-Free, Pd(II)-Salan Complex-Catalyzed Synthesis of Biaryls via Suzuki-Miyaura Cross-Coupling in Water and Air.

With use of a Pd(II)-sulfosalan complex as a water-soluble catalyst, we have developed an efficient synthesis of biaryls via Suzuki-Miyaura cross-coupling in water under aerobic conditions. The water-insoluble target molecules were isolated by simple filtration in analytical purity after washing with 0.01 M aqueous HCl (20 examples). In most cases, palladium contamination was below 5 ppm considered acceptable for active pharmaceutical ingredients. The established method is scalable, reproducible, and provides biaryl products in isolated yields up to 91%.

Development of organic solvent‐free micro‐/nano‐porous polymer scaffolds for musculoskeletal regeneration

The use of biomaterial scaffolds has been an enormous field of research in tissue engineering, where the aim is to use graft materials for assisting the human body in recovering lost functions. Currently, there are many ways biomaterial scaffolds can be fabricated; however, many of these techniques involve the use of toxic organic solvents during the process. As biocompatibility is one of the mandatory requirements in designing a successful scaffold, there is an interest in fabricating scaffolds that are completely organic solvent-free. This paper describes the development and characterization of novel micro-/nano-fibrillar composites (MFC/NFC) that can produce scaffolds which are completely free from organic solvents. In this research, the cytocompatibility of these materials have been tested in vitro using mouse osteoblast-like cells and primary rat tenocytes, where cell numbers increase over the culture period, demonstrating the material viability. Gene expression analysis of primary rat tenocytes on MFC/NFC scaffolds demonstrate tenocytic behavior, and histology studies show an increase in cell formation on NFC scaffolds. This study establishes the potential of using the MFC/NFC technique to produce completely organic solvent-free scaffolds capable of hosting musculoskeletal cells, in the hope of providing a graft material for non-union skeletal fractures and rotator cuff repairs. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1393-1404, 2017.