Organic Solvent-free Process Research Articles

Preparation of (NH4)2SO4 Spherical Particles with Functions of Sustained-Release and Anticaking by an Organic Solvent-Free Process

Preparation of (NH₄)₂SO₄ Spherical Particles with Functions of Sustained-Release and Anticaking by an Organic Solvent-Free Process

Continuous Synthesis of Cinnarizine Salt with Malic Acid by Applying Green Chemistry Using Water-Assisted Twin Screw Extrusion.

Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pHmax of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state 13C and 15N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.

Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

The pharmaceutical industry is required to constantly broaden its development areas and accelerate technical transformation because of the continued global rise in medicine consumption. However, the usage of organic solvents in pharmaceutical production results in up to 20 million tons annually of chemical waste, causing a serious environmental problem. Here, we proposed a solvent-free sustainable chemical technology, sublimation crystallization, for highly efficient screening and preparation of pharmaceutical solid forms (i.e., polymorphs), which eliminates the wastes associated with solvent use from the source. By adjusting the parameters of sublimation crystallization, we have obtained multiple polymorphs of several important drugs, including the antituberculosis drug pyrazinamide (PZA) and nonsteroidal anti-inflammatory drugs (NSAIDs), flufenamic acid (FFA) and mefenamic acid, particularly γ form of PZA and polymorphs IV and VII of FFA, which are difficult to produce from conventional solution crystallization methods. Mechanical property measurements from both powder and single crystal tests reveal that the γ form of PZA readily prepared by sublimation crystallization has the most excellent tabletability properties. In situ crystal growth observations indicate a direct vapor-to-crystal growth mechanism for the sublimation crystallization process consistent with conventional vapor phase deposition. Furthermore, the governing factors and growth mechanisms of sublimation and solution crystallization processes were analyzed and discussed, and it was found that the rate-limiting step of crystal growth is the surface-integration process in solution crystallization, whereas it becomes the surface diffusion process in sublimation crystallization. Overall, our developed sublimation crystallization provides a promising green technology for the development and production of (new) drugs, broadening the thinking behind the development of sustainable chemicals.

Catalyst-free synthesis of 5-hydroxymethylfurfural from fructose by extractive reaction in supercritical CO2 – subcritical H2O two-phase system

An extractive reaction configuration using supercritical carbon dioxide (scCO2) as the extracting solvent was tested for the production of 5-hydroxymethyl furfural (HMF) from a 5 wt% fructose aqueous feed. In this configuration, extraction of HMF by scCO2 prevents HMF degradation in the aqueous phase. Because of water co-extraction by scCO2, the volume of the reactional mixture was maintained by continuous injection of water. Reaction was operated in a 90 mL high pressure reactor, where an HMF maximum yield of 62.4 % was achieved at 160 °C and 25 MPa, with a CO2 flow rate of 20 g.min−1 for 420 min. This is the first time that HMF is reportedly produced with such a yield by a catalyst-and organic solvent-free process. Besides, the separation efficiency reached 97.3 % and the relative purity of HMF in the extract was 95.8 wt%. Therefore, this configuration avoids post reactional purification which is needed in conventional batch processes or in extractive reaction processes using organic solvents. Based on kinetic and thermodynamic studies, modeling of the extractive reaction process was developed to perform a sensitivity analysis for CO2 flow rate and extraction efficiency, upon the HMF yield. As an example, it was shown that for 800 min reaction duration, a CO2 flow rate of 100 g.min−1 or an extraction efficiency increase by a 10-fold factor could theoretically led to HMF yields of 73.0 % and 73.7 %, respectively.

Mushroom-Mediated Reductive Bioconversion of Aldehyde-Rich Essential Oils for Aroma Alteration: A Rose-like Floral Bioflavor from Citronella Oil.

The bioflavors are of high demand in food and beverage industries. The current study identified reductive processes mediated by mushroom species to alter the aroma of aldehyde-rich essential oils in the submerged culture. Neofomitella polyzonata, a polypore mushroom, reduced citronellal and citral in the citronella oil into corresponding alcohols that altered the oil aroma, creating a new bioflavor. The screening with 43 aldehydes showed its broad substrate scope within aromatic and linear aldehydes, yet influenced by the electronic and steric factors. Under an optimized condition, it efficiently converted up to 1.5 g/L citrusy and sharp citronella oil into a terpene alcohol-rich (citronellol and geraniol) floral, sweet, fresh, and rosy oily product within 12 h. The preparative-scale fermentation in the shake flask followed by distillation, an organic solvent-free downstream process, furnished the product in 87.2% w/w yield. Detailed sensory analyses and volatile chemo-profiling established the uniqueness in the product aroma and identified citronellol and geraniol as the key odorants. The chemometric analysis found best compositional similarity of this product with Damask or Turkish rose oils. The preference test for the water flavored with the fermented product (0.001-0.005% v/v) indicated its potential as a rosy bioflavor for the beverages.

Preparation of ethyl vanillin spherical particles with functions of sustained release and anti-caking by an organic solvent-free process

Ethyl vanillin is an important synthetic flavor that occupies a large market share in food additives. However, the shortcomings in terms of too fast aroma release rate and poor powder properties have severely limited its further application. In this work, the intrinsic mechanism of ethyl vanillin oiling-out process is revealed with the help of process analytical technologies. Further, a green and efficient spherical particles preparation technology is developed by constructing the oiling-out phase diagram of ethyl vanillin in the aqueous solution of sodium chloride. The ethyl vanillin spherical product has excellent powder properties with high bulk density (0.74 g/cm3), good sphericity (93.4 %), high flowability (29°), high yield (>95 %) and adjustable particle size distribution. More importantly, the spherical product exhibits 57.9 % lower aroma release rate at 323.15 K and 1400 % higher critical caking cycle compared to irregularly shaped powder, which confirms its sustained release and anti-caking function.

Waste to treasure: Superwetting foam enhanced by bamboo powder for sustainable on-demand oil-water separation

Low-cost and sustainable superwetting materials are urgently required for oily wastewater treatment. Many poly(vinylidene fluoride) (PVDF)-based materials have been designed for oil-water separation. However, their fabrication processes frequently require toxic organic solvents and high-cost materials (e.g., carbon tubes and graphene). In this study, a highly porous and superhydrophobic bamboo powders (BP)-enhanced PVDF foam (SBPF) was fabricated via an organic solvent-free process. The SBPF exhibits efficient adsorption and recovery for various oils and organic solvents. Moreover, the SBPF shows high adsorption and separation performance under ultraviolet exposure and turbulent environments. It can also be used for water-in-oil emulsions separation, with a high separation efficiency more than 99.3 % under gravity. Interestingly, the amphiphilic PVDF-BP foam (ABPF) shows underwater superoleophobicity and underoil superhydrophobicity after delignification of SBPF. Owing to the conversion of wettability, it presents a high performance in treatment of both surfactant-stabilied water-in-oil and oil-in-water emulsions with the high separation efficiency achieving more than 99.6 % and 99.5 % respectively under gravity. In addition, the ABPF shows a high separation performance even after ten cycles. Hence, this fabricated organic solvent-free foams are promising candidates for sustainable on-demand separation of oils or organic solvents and water in complex environments.

Heat-stable liposomes from milk fat globule membrane phospholipids for pH-triggered delivery of hydrophilic and lipophilic bioactives

Heat-stable, multivitamin-loaded, and surface-coated liposomes tailored for pH-triggered delivery of both lipophilic and hydrophilic bioactives were synthesized from a cocktail of milk fat globule membrane (MFGM) phospholipids, supercritically extracted from buttermilk powder. Liposomes from MFGM-phospholipids (ML) were fabricated using a novel organic solvent free process based on venturi-based rapid expansion of a supercritical solution. A commercially available pH-responsive polymer, Eudragit® S100 was used to coat ML (Eu-ML). Eu-MLs were heated to 60, 75, and 90 °C for 30 min and were observed to be heat-stable as established by CLSM images, structural characterizations, and encapsulation efficiency measurements. Coating of liposomes with Eudragit® S100 protected encapsulated payload from deleterious gastric environment and facilitated site-specific pH-triggered release in the simulated intestinal condition. This study established a green method to fabricate heat-stable liposomal vehicles for pH-triggered delivery of bioactive compounds with excellent potential for scale-up and applications in the food, pharmaceutical, and cosmetic industries.

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.

Organic Solvent-Free Process for the Rapid Fabrication of Nickel Ferrite-Reduced Graphene Oxide as a Magnetic Nanosorbent Using Supercritical Water

Organic Solvent-Free Process for the Rapid Fabrication of Nickel Ferrite-Reduced Graphene Oxide as a Magnetic Nanosorbent Using Supercritical Water

Modified porous carboxymethyl chitin microspheres by an organic solvent-free process for rapid hemostasis

Rapid and effective hemorrhage control is essential to reduce mortality following traumatic injuries. Herein we developed an organic solvent-free process to prepare carboxymethyl chitin microsphere (CMCHm) in an aqueous two-phase system through heating and freeze-drying. To further enhance the hemostatic performance of CMCHm, we loaded calcium ions and in-situ polymerized dopamine to get modified hemostatic microspheres CMCHm-Ca2+ and CMCHm-PDA, respectively. The size of these microspheres was mainly distributed between 50 μm and 150 μm, and the porous microstructure was observed by SEM. The data of in vitro degradation, cell cytotoxicity, and hemolysis test indicated good biocompatibility of these microspheres. Importantly, CMCHm-Ca2+ and CMCHm-PDA displayed better hemostatic performance compared with CMCHm and the positive controls Yunnan baiyao® and Quickclean®. Especially, the bleeding time was reduced to 59 s (CMCHm-Ca2+) and 45 s (CMCHm-PDA) in the femoral artery/vein cut model, respectively. All these demonstrate CMCHm-Ca2+ and CMCHm-PDA hold great potential for rapid hemostasis.

Natural Antimicrobials from Cloudberry (Rubus chamaemorus) Seeds by Sanding and Hydrothermal Extraction

We have developed an organic solvent-free process to enrich natural antimicrobials from the important Nordic Rubus berry species, especially from cloudberry. The process utilizes industrial berry byproducts as raw-material, and it is based on seed sanding technology and water-based extraction. The extracts showed strong antimicrobial activity against Gram-positive Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). A concentration of 5 mg/mL totally eliminated these bacteria in 24 h. Effects against Gram-negative bacteria were modest. Polyphenol analysis of the hydrothermal extracts showed that the antimicrobial activity is correlated to ellagitannins, mainly dimeric sanguiin H-6 and sanguiin H-10 isomers. Sanguiin H-10 is not commonly found in intact cloudberry seeds, but it is formed from the dimeric and trimeric ellagitannins, during the extraction. Surprisingly hydrothermal extracts had no or minor effects on beneficial bacteria, Lactobacillus rhamnosus. This interesting finding might offer an application potential in controlling skin microbial pathogens, for example, in wound healing.

Disposable Nitric Oxide Generator Based on a Structurally Deformed Nitrite-Type Layered Double Hydroxide.

The inhalation of nitric oxide (NO), which acts as a selective vasodilator of pulmonary blood vessels, is an established medical treatment. However, its wide adoption has been limited by the lack of a convenient delivery technique of this unstable gas. Here we report that a solid mixture of FeIISO4·7H2O and a layered double hydroxide (LDH) containing nitrite (NO2-) in the interlayer spaces (NLDH) stably generates NO at a therapeutic level (∼40 ppm over 12 h from freshly mixed solids; ∼80 ppm for 5-10 h from premixed solids) under air flow (0.25 L min-1) if the NLDH has been prepared by using a reconstruction method. Mg/Al-type LDH was calcined at 550 °C to remove interlayer CO32- and then treated with NaNO2 in water to reconstruct the NLDH. This one-pot, organic solvent-free process can be performed at large scales and is suitable for mass production. Humid air promotes anion exchange between NO2- and SO42- in the solid mixture, resulting in persistent interactions of NO2- and Fe2+, generating NO. In contrast to the previously reported NLDH prepared using an anion-exchange method, the reconstructed NLDH exhibits stable and persistent generation of NO because of partial deformation of the layered structures (e.g., particle aggregation, reduced crystallinity, and enhanced basicity). Degradation of the solid mixture is suppressed under dry conditions, so that a portable cartridge column that is readily available as an NO source for emergency situations can be prepared. This work demonstrates that the interlayer nanospace of LDH serves as a reaction mediator for excellent controllability of solid-state reactions. This inexpensive and disposable NO generator will facilitate NO inhalation therapy in developing countries and nonhospital locations.

Chelating Fabrics Prepared by an Organic Solvent-Free Process for Boron Removal from Water.

A chelating fabric was prepared by graft polymerization of glycidyl methacrylate (GMA) onto a nonwoven fabric, followed by attachment reaction of N-methyl-D-glucamine (NMDG) using an organic solvent-free process. The graft polymerization was performed by immersing the gamma-ray pre-irradiated fabric into the GMA emulsion, while the attachment reaction was carried out by immersing the grafted fabric in the NMDG aqueous solution. The chelating capacity of the chelating fabric prepared by reaction in the NMDG aqueous solution without any additives reached 1.74 mmol/g, which further increased to above 2.0 mmol/g when surfactant and acid catalyst were added in the solution. The boron chelation of the chelating fabric was evaluated in a batch mode. Fourier transform infrared spectrophotometer (FTIR) was used to characterize the fabrics. The chelating fabric can quickly chelate boron from water to form a boron ester, and a high boron chelating ability close to 18.3 mg/g was achieved in the concentrated boron solution. The chelated boron can be eluted completely by HCl solution. The regeneration and stability of the chelating fabric were tested by 10 cycles of the chelation-elution operations. Considering the organic solvent-free preparation process and the high boron chelating performance, the chelating fabric is promising for the boron removal from water.

Development of rapid and selective epoxidation of α-pinene using single-step addition of H2O2 in an organic solvent-free process.

This study reports substantial improvement in the process for oxidising α-pinene, using environmentally friendly H2O2 at high atom economy (∼93%) and selectivity to α-pinene oxide (100%). The epoxidation of α-pinene with H2O2 was catalysed by tungsten-based polyoxometalates without any solvent. The variables in the screening parameters were temperatures (30–70 °C), oxidant amount (100–200 mol%), acid concentrations (0.02–0.09 M) and solvent types (i.e., 1,2-dichloroethane, toluene, p-cymene and acetonitrile). Screening the process parameters revealed that almost 100% selective epoxidation of α-pinene to α-pinene oxide was possible with negligible side product formation within a short reaction time (∼20 min), using process conditions of a 50 °C temperature in the absence of solvent and α-pinene/H2O2/catalyst molar ratio of 5 : 1 : 0.01. A kinetic investigation showed that the reaction was first-order for α-pinene and catalyst concentration, and a fractional order (∼0.5) for H2O2 concentration. The activation energy (Ea) for the epoxidation of α-pinene was ∼35 kJ mol−1. The advantages of the epoxidation reported here are that the reaction could be performed isothermally in an organic solvent-free environment to enhance the reaction rate, achieving nearly 100% selectivity to α-pinene oxide.

Highly-efficient production of spherical co-agglomerates of drugsviaan organic solvent-free process and a mechanism study

A highly-efficient drug co-agglomeration technique was developed, overcoming the limitations of the current methods where biohazardous solvents and complex equipment were involved.

Carbonized core-shell diatomite for efficient catalytic furfural production from corn cob

A novel core-shell sulfonated tin-loaded diatomite catalyst, namely SO42−/CX-DMSn, was synthesized by hybridizing sulfuric carbon layer on DM-Sn intermedium. Lewis and Brønsted acid sites displayed on the surface of DM core and on the coated carbon layer of the SO42−/CX-DMSn, respectively. The catalyst exhibited excellent catalytic ability, high water tolerance and good stability. The existence of acid sites and carbon layer on the diatomite were characterized by SEM, EDS, XRD, XPS, NH3-TPD and Py-IR. The unique core-shell structure of the carbonized diatomite catalyst significantly improved furfural production from xylose and lignocellulosic matrix even in organic solvent-free process. Results showed 66.24% of furfural yield and 79.92% of selectivity were obtained from xylose, whilst 65.74% of furfural yield and 66.83% of selectivity from corn cob, implying the side reactions for furfural production were well-eliminated. This strategy shows a promising application for novel SO42−/CX-DMSn material toward effective and green catalytic production of furfural from biomass materials.

Biocatalytic synthesis of vanillin by an immobilised eugenol oxidase: High biocatalyst yield by enzyme recycling

Vanilla is the second most expensive spice in the world. This issue triggered the necessity to obtain its flavour compound, vanillin, by alternative methods, most of which have focused on biosynthesis since it can be labelled as “natural” and sold at higher price. In this work, a process for the enzymatic synthesis of vanillin has been optimised, not only from a process metrics point of view but also from an environmentally sustainable perspective. The maximum biocatalyst activity and stability was taken into account for the selection of the reaction conditions. Soluble and immobilised eugenol oxidase (EUGO) was tested under both reaction conditions. The optimum conditions obtained lead to an organic solvent free process reaching 9.9 g prod L−1 h−1. Moreover, the use of immobilised EUGO allowed the biocatalyst to be reused up to 18 reaction cycles, improving the biocatalyst yield more than 12-fold, thus also reducing the biocatalyst associated cost.

High temperature and low voltage AC poling for 0.24Pb(In1/2Nb1/2)O3-0.46Pb(Mg1/3Nb2/3)O3-0.30PbTiO3 piezoelectric single crystals manufactured by continuous-feeding Bridgman method

Alternating current poling (ACP) in air by changing poling temperature (70–130 °C) and voltages (2–6 kVrms/cm) on pseudo-ternary 0.24 Pb(In1/2Nb1/2)O3-0.46 Pb(Mg1/3Nb2/3)O3-0.30PbTiO3 (PIMN-0.30PT) single crystals (SCs) manufactured by continuous-feeding Bridgman (CF BM) method was investigated. Free dielectric permittivity (εT33/ε0) and piezoelectric constant (d33) were improved to be 7000 and 2340 pC/N, which were 29% higher than those of direct current poling (DCP) at 90 °C with 4 kV/cm (εT33/ε0 = 5440, d33 = 1810 pC/N). However, phase change temperature (Tpc) decreased from 94 °C to 78 °C as opposite results reported by other groups. We demonstrated that the high temperature (HT) ACP improved piezoelectric performance of CF BM SCs, however, the Tpc were different from other crystal growth method. The well-designed ACP process was a promising method for mass production not only to enhance the electrical properties for the pseudo-ternary SCs but also reduce the risk of breakdown and realizes organic solvent-free poling process.

High performance loose nanofiltration membranes obtained by a catechol-based route for efficient dye/salt separation

Loose nanofiltration membranes with excellent dye rejection and high inorganic salt transmission are promising for dye/salt separation. Herein, a mussel-inspired organic solvent-free method was chosen to prepare loose nanofiltration membranes with tunable surface structures and properties. A low-cost material, 1,2-dihydroxybenzene (catechol), was used to replace dopamine for the mussel-inspired surface coating strategy. With the assistance of CuSO4/H2O2, a catechol/PEI coating layer was formed on the polyethersulfone (PES) substrate in only 10 min. Through constructing the coating layer based on polyethylenimine (PEI) with different molecular weights, catechol/PEI ratios and solution deposition times, different membranes were obtained. The separation performance of the membrane is tested by a lab-scale crossflow setup under the pressure of 4 bar. Especially, LNM-3 have an ultrahigh water permeability (24.5 LMH bar−1) and an extremely low rejection for both NaCl and Na2SO4 in the concentrations between 1.0 and 50.0 g L−1. Meanwhile, LNM-3 shows superior rejection for different types of dyes, demonstrating their great potential in practical applications. Overall, such an approach enabled by an organic solvent-free process and low-cost chemicals may offer a new strategy for the environmental-friendly and economical manufacturing of multifunctional loose nanofiltration membrane.