Ternary Solvent System Research Articles

Enabling the drug combination of celecoxib through a spherical co-agglomeration strategy with controllable and stable drug content and good powder properties

Combining celecoxib with other chemopreventive drugs is a promising method of chemoprevention for cancer, especially for colorectal cancer. However, the traditional drug combination approaches are restricted with high-cost apparatus, complex and numerous unit operations. This work aims to develop an efficient spherical co-agglomeration strategy for celecoxib in combination with lovastatin, which can achieve drug combination in a single crystallization unit. The ternary solvent system was determined based on molecular simulation, and then a stable spherical agglomeration process was developed through the design of molar fraction of anti-solvent (MFA) and stirring rate to produce spherical agglomerates with high sphericity (84.2–89.9 %) and narrow size distribution. On this basis, celecoxib-benzoic acid spherical co-agglomerates were designed to form a complete spherical co-agglomeration strategy, which includes solvent system selection, spherical agglomeration and spherical co-agglomeration. Finally, celecoxib-lovastatin spherical co-agglomerates with synergistic efficacy were successfully produced by this strategy, with controllable and stable drug content (fluctuation < 2.7 %), good powder properties, and improved tabletability.

Study of system properties in reversed-phase liquid chromatography for binary and ternary solvent mobile phase compositions using the solvation parameter model

System maps for the individual system constant of the solvation parameter model and five binary solvent containing 20–70% (v/v) acetonitrile, acetone, methanol, 2-propanol, and tetrahydrofuran on a single octadecylsiloxane-bonded silica column (Luna C18) are used to provide insight into the variation of system properties with mobile phase composition and solvent type. Selectivity differences are dominated by variation in solute size and hydrogen-bond basicity with solvent-dependent variation in dipole-type and hydrogen-bond acid interactions. Interactions involving lone pair electrons are important only in the case of the alcohols and to a lesser extent tetrahydrofuran. Selectivity differences are also dependent on solvent strength. To expand the selectivity space four ternary solvent systems (acetonitrile-methanol-water, acetonitrile-2-propanol-water, methanol-tetrahydrofuran-water, and tetrahydrofuran-2-propanol-water) 1:1:2% (v/v) containing 50% (v/v) total organic solvent are compared with the binary solvent systems at the same organic solvent composition. There is no simple model that links the system properties of the ternary solvents to the binary solvent systems, but it is demonstrated that the ternary solvent systems expand the selectivity space available for reversed-phase separations. The solvation properties of the bulk organic solvents provide insufficient information to predict selectivity in RPLC because of the dominant contribution of water and effects related to the selective solvation of the stationary phase and possible changes in the solvent-dependent microstructure of the mobile phase.

A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson’s disease

Apomorphine, a dopamine agonist, is a highly effective therapeutic to prevent intermittent off episodes in advanced Parkinson's disease. However, its short systemic half-life necessitates three injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Here, we report a deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day therapy into an every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline-geranate, a cosolvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate this self-emulsification process as the mechanism of action for sustained release. In vivo pharmacokinetics studies in rats and pigs further confirmed the extended release and improvement over the clinical comparator Apokyn. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows the maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

Molecular Dynamics Simulation on the Crystal Morphology of Β-Hmx Affected by Binary and Ternary Solvent Systems

Molecular Dynamics Simulation on the Crystal Morphology of Β-Hmx Affected by Binary and Ternary Solvent Systems

Efficient and Selective Extraction of Glabridin from Glycyrrhiza Glabra Crude Extract by Sbe-Β-Cd in a Ternary Solvent System

Efficient and Selective Extraction of Glabridin from Glycyrrhiza Glabra Crude Extract by Sbe-Β-Cd in a Ternary Solvent System

Efficient Continuous Dehydration of Fructose to 5-Hydroxymethylfurfural in Ternary Solvent System

Efficient Continuous Dehydration of Fructose to 5-Hydroxymethylfurfural in Ternary Solvent System

Efficient PTB7-Th:Y6:PC71BM ternary organic solar cell with superior stability processed by chloroform

Blend morphology is crucial for the efficiency and stability of organic solar cells. Exploring and understanding the correlations between is meaningful and greatly desired. In this work, based on polymer donor (PTB7-Th), fullerene and non-fullerene acceptors (PC 71 BM and Y6), we systematically study the influence of ternary strategy and solvent system on device performance and stability. It is found that insufficient and excessive phase separation of blend could result in the depressed performance of corresponding devices. Appropriate phase separation/blend morphology can be achieved by utilizing a ternary strategy or suitable solvent. Chloroform-processed ternary blend PTB7-Th:Y6:PC 71 BM delivers efficiency of 9.55%, with dramatically enhanced J SC of 24.68 mA cm −2 due to optimized absorption, blend morphology and optoelectronic properties. More importantly, superior device stability is demonstrated for the optimal ternary device under both thermal stress and maximum power point operation, by maintaining 80% of initial efficiency at 85 °C for 880 h and presenting almost zero efficiency decay in 200 h under MPP operation. • Morphology of active blend is tuned by ternary and solvent strategy. • Ternary PTB7-Th:Y6:PC 71 BM cells deliver PCE 9.55% and J SC 24.68 mAcm −2 . • Superior thermal and operational stability is demonstrated for optimal device. • Zero decay is recorded for optimal device in 200 h under MPP operation.

Improved synthesis of the antifungal isobutyl o-coumarate catalyzed by the Aspergillus terreus type B feruloyl esterase

Hydroxycinnamic acids and some of their derivatives are molecules with interesting biological activities; for instance, hydroxylated hydroxycinnamic esters have proved to have antifungal properties, and thus the generation of these molecules is of industrial importance. In this study, the direct esterification capacity of the pure recombinant type B feruloyl esterase from Aspergillus terreus (AtFAE B) was evaluated by its ability to catalyze the synthesis of isobutyl o- coumarate, an interesting antifungal molecule. A ternary solvent system (isooctane/isobutanol/water) was employed to improve the synthesis of isobutyl o- coumarate, assessing different substrate concentrations, enzyme load, water percentages and pH and temperature values. AtFAE B showed the highest initial rate at 18% (v/v) isobutanol and 50 mM o- coumaric acid, 0.04 mg/ml of enzyme, 4% (v/v) water without buffer and 40°C. AtFAE B half-lives at 30°C, 40°C and 50°C were 16.5 h, 1.75 h and 3.5 min, respectively. Thus, we decided to evaluate the bioconversion yield at 30°C, where the enzyme showed the highest operational stability. At this temperature, we obtained a yield of ~80% after only 8 h of reaction, using a 78:18:4 isooctane:isobutanol:water ternary solvent system, with 50 mM of o- coumaric acid. Under these improved conditions, the productivity was 1.06 g isobutyl o -coumarate/L*h with a biocatalyst yield of 209.6 kg isobutyl o -coumarate/kg free AtFAE B, demonstrating the promising potential of AtFAE B to accept the non-canonical o- coumaric acid as the substrate and to achieve the synthesis of isobutyl o- coumarate. How to cite: Vega-Rodríguez AD, Armendáriz-Ruiz MA, Grajales-Hernández DA, et al. Improved synthesis of the antifungal isobutyl o -coumarate catalyzed by the Aspergillus terreus type B feruloyl esterase. Electron J Biotechnol 2021;54. https://doi.org/10.1016/j.ejbt.2021.08.001

DMSO/IL solvent systems for cellulose dissolution: Binary or ternary mixtures?

The mechanism of cellulose dissolution in ionic liquid (IL)/dimethyl sulfoxide (DMSO) solvent systems has attracted much attention due to the possible replacement of synthetic materials. However, the solvent behaviour is not completely understood. This work has found an explanation for the solvent behaviour in cellulose dissolution, considering the almost unavoidable presence of the water. Ternary [C4mim]Cl/DMSO/H2O mixtures were studied with Nuclear Magnetic Resonance experiments and molecular dynamics simulations to explore IL/molecular solvents interactions and disclose the water interactions in these complex media. Titration of binary and ternary solvent systems with water and DMSO disclosed a relation between water’s proton chemical shift and the molar fraction of the mixture components, creating an unprecedent theory to predict the cellulose solvation ability. A “working range” for IL/DMSO/H2O ratio was observed, tested in cellulose dissolution, and rationalized using cellobiose interaction. Within this solvent ratio, the interactions between components are maximized, being switched on, while out of the range, the interactions are no longer detected.

Liquid–Liquid Equilibrium Data for Cyclohexane–Ethanol–Solvent Ternary Systems and Their Correlation with the Nonrandom Two-Liquid Model

Liquid–Liquid Equilibrium Data for Cyclohexane–Ethanol–Solvent Ternary Systems and Their Correlation with the Nonrandom Two-Liquid Model

A one-step deconstruction-separation organosolv fractionation of lignocellulosic biomass using acetone/phenoxyethanol/water ternary solvent system

A novel ternary solvent system for organosolv fractionation of lignocellulosic biomass, named APW process, which is composed of acetone, phenoxyethanol and water with the advantages of monophasic deconstruction and biphasic separation of components was developed. Through fractionation of amorpha as a case study, a monophasic APW solution (acetone/phenoxyethanol/water = 5:11:4, volume ratio) with the best lignin affinity was constructed based on Hansen solubility parameters. According to Taguchi experimental design, the optimal conditions were 130 °C, 70 min, 0.15 M sulfuric acid and 20 LSR. Under optimal conditions, removal of lignin and hemicellulose reached 95.60% and 98.39%, respectively. While 80.48% of cellulose was retained in residue and its digestibility was 80.36%. Then, 83.74% of hemicellulose was recovered from aqueous as sugars, and 35.64% of lignin was recovered by precipitation. Moreover, APW process also have effective fractionation of sugarcane bagasse, corn cob and pine, cellulose and hemicellulose recovery were both over 80%.

Solvent assisted dyeing of wool fibers with reactive dyes in a ternary solvent system for protecting fibers against damage

Severe effluent pollution and chemical damage to protein fibers generated from conventional aqueous dyeing process have stimulated interest in exploiting sustainable dyeing of wool. Herein, an ethanol (EtOH)-carbon tetrachloride (CCl4)-water (H2O) ternary solvent system was used as the dyeing medium to protect wool fibers from being damaged in the dyeing process. The wool fibers were firstly pretreated in an aqueous acid solution, followed by dyeing in the EtOH-CCl4-H2O (45:50:5) ternary solvent system with reactive dyes. The results indicated that the acid pretreatment solution could be reused for several times, the samples dyed in the EtOH-CCl4-H2O mixture with the investigated dyes showed higher K/S values compared to the conventional approach, implying the increased dye utilization and decreased effluents discharge were realized. Furthermore, acceptable permeability, good colorfastness, and satisfactory leveling properties of the dyed samples were achieved using the developed method. Additionally, the solvent-assisted dyed samples showed improved mechanical properties compared with the conventionally dyed samples. The dyeing mechanisms of wool fibers in the EtOH-CCl4-H2O mixture were illustrated in detail. The proposed dyeing technology consumes fewer energy, freshwater, and chemicals compared with the conventional wool dyeing method. Future work will principally concentrate on the reuse of the dye-contaminated EtOH-CCl4-H2O mixture.

Isolation and structure elucidation of anti-malarial principles from Terminalia mantaly H. Perrier stem bark

Emergence of malaria parasite resistance to drugs has raised global public health concerns for a compelling need to develop improved malaria therapy. This study is a bio-guided isolation of triterpenoid antimalarial compounds from Terminalia mantaly. Methanol extract of the plant was subjected to column chromatography, and eluted with a ternary solvent system gradient-wise. Two compounds, 1 and 2, were isolated and characterised by spectroscopic data (IR, 1H and 13C NMR, COSY, HMQC, HMBC) and by comparison with literature. Isolated compounds were investigated for antimalarial property by spectrophotometric determination of inhibition of β-Hematin formation, absorbance taken at 405 nm. Results were analysed using Graghpad Prism® (6.0) and presented as mean IC50±SEM. Statistical significance, determined using Student’s t-test and one-way ANOVA, set at p-value of 0.05. Quantitative β-Hematin formation inhibitory activities gave IC50±SEM values of (compound 1; 4.434±0.47), (compound 2; 5.140±4.2) with (chloroquine; 0.335±0.1 mg/ml). Compound 1 was identified as 2,3,19,23-tetrahydroxyolean-12-en-28-oic acid glucopyranoside (arjunglucoside I), and compound2 as its aglycone, 2,3,19,23-tetrahydroxyolean-12-en-28-oic acid (arjungenin). This study provided credence for folkloric use of Terminalia mantaly to treat malaria, and this observed activity was probably due to these isolated triterpenoids.Keywords: β-Hematin, triterpenoids, nuclear magnetic resonance spectroscopy

Analysis of the Performance of Narrow-Bandgap Organic Solar Cells Based on a Diketopyrrolopyrrole Polymer and a Nonfullerene Acceptor.

The combination of narrow-bandgap diketopyrrolopyrrole (DPP) polymers and nonfullerene acceptors (NFAs) seems well-matched for solar cells that exclusively absorb in the near infrared but they rarely provide high efficiency. One reason is that processing of the active layer is complicated by the fact that DPP-based polymers are generally only sufficiently soluble in chloroform (CF), while NFAs are preferably processed from halogenated aromatic solvents. By using a ternary solvent system consisting of CF, 1,8-diiodooctane (DIO), and chlorobenzene (CB), the short-circuit current density is increased by 50% in solar cells based on a DPP polymer (PDPP5T) and a NFA (IEICO-4F) compared to the use of CF with DIO only. However, the open-circuit voltage and fill factor are reduced. As a result, the efficiency improves from 3.4 to 4.8% only. The use of CB results in stronger aggregation of IEICO-4F as inferred from two-dimensional grazing-incidence wide-angle X-ray diffraction. Photo- and electroluminescence and mobility measurements indicate that the changes in performance can be ascribed to a more aggregated blend film in which charge generation is increased but nonradiative recombination is enhanced because of reduced hole mobility. Hence, while CB is essential to obtain well-ordered domains of IEICO-4F in blends with PDPP5T, the morphology and resulting hole mobility of PDPP5T domains remain suboptimal. The results identify the challenges in processing organic solar cells based on DPP polymers and NFAs as near-infrared absorbing photoactive layers.

Solubility of paracetamol in the ternary solvent mixtures of water + ethanol + glycerol at 298.2 and 303.2 K

ABSTRACT The solubility of paracetamol in the ternary mixtures of water + ethanol + glycerol at 298.2 and 303.2 K is determined via the shake-flask method. The reported data extend the solubility database for paracetamol in various solvent mixtures and also is employed to investigate the prediction capability of the cosolvency models for solubility prediction in the sub-binary and the ternary solvent systems. The solubility data are correlated with some cosolvency models and their accuracies are evaluated by the mean relative deviation (MRD) computed for back-calculated solubilities. The results show that the investigated models fit well and can be applied to the ternary solvent system, and the experimental data is relatively more consistent with the calculated values. The prediction ability of the trained Jouyban-Acree model for predicting drug solubility behaviour in the corresponding sub-binary systems is also investigated.

Risk-Based Operation of a Continuous Mixed-Suspension-Mixed-Product-Removal Antisolvent Crystallization Process for Polymorphic Control

Innovations in the continuous crystallization field are required for the pharmaceutical industry to go through the paradigm shift from batch to continuous processing. To do so, different risks associated with the continuous crystallization have to be identified and discussed. In this work, a continuous antisolvent crystallization of the model compound indomethacin (IMC) from a ternary solvent system in a mixed-suspension-mixed-product-removal (MSMPR) to produce the desired polymorphic γ-form is evaluated, and potential risks for process failure are identified. One of the main risks identified with the continuous crystallization is gaining a balance between the inlet and outlet flows. Two novel and different level controls are proposed in this work to overcome this risk, an ultrasonic sensor and image analysis based on a video recording of the level. These two methods demonstrate improved process robustness upon implementation. Additionally, different process parameters were investigated and showed that the seed load has a significant effect on maintaining the desired polymorph and avoiding process failure. To the best of our knowledge, this is the first study on continuous crystallization of IMC for the polymorphic control of γ-IMC.

Continuous Industrial-Scale Centrifugal Partition Chromatography with Automatic Solvent System Handling: Concept and Instrumentation

Centrifugal partition chromatography (CPC) is an emerging separation technology in pharmaceutical and natural product purifications, reaching recently industrial-scale solutions. Because both the stationary and mobile phases are liquids in CPC, the solvent consumption of such separation processes is considered significant. Thus, automation is highly required in the preparation and recycling of the solvent mixtures for economical (i.e., continuous) CPC operation. Here, we report a feasible solution for this industrial issue, including the concept, algorithm, and instrumentation of solvent system handling. For majority of ternary solvent systems used in CPC separations, the linear correlation between the density and composition of the phases was recognized and utilized during the continuous solvent recycling. Hence, an efficient density-based composition adjustment algorithm was established in a mixer-settler unit using Coriolis flow meters for precise density monitoring of the upper and lower phases of the biphasic liquid system (BLS). In addition, a complete cascade consisting of a buffer, waste, a recycler (evaporator), and mixer-settler units was designed around the industrial-scale CPC device. The proof of concept was demonstrated by sequential industrial-scale CPC separations of a binary model mixture in the n-hexane/methanol/water (5/4/1, v/v/v) solvent system, followed by the purification of a crude steroid active pharmaceutical ingredient performed in the methyl isobutyl ketone/acetone/water (2/2/1, v/v/v) solvent system. The reproducibility of chromatographic performance and the productivity of the mixer-settler and evaporator units were satisfactory, enabling a robust and continuous operation of the developed separation process.

Effect of the ionic strength on the redox reaction of dicyanobis(bipyridine)iron(III)‐iodide in binary and ternary solvent systems

AbstractThe redox reaction between dicyanobis(bipyridine)iron(III) and iodide ion follows first‐order kinetics in 10% (v/v) tertiary butyl alcohol‐water. The reaction was found first and zero order in iodide and dicyanobis(bipyridine)iron(III), respectively, at 0.06 M ionic strength and 293 ± 1 K. The thermodynamic parameters of activation such as EA (16.07 kJ mol−1), A (1 × 10−4 M s−1), ΔH# (13.6 kJ mol−1), ΔS# (−329.81 J K−1 mol−1), and ΔG# (90.1 kJ mol−1) were determined. The effect of the ionic strength on the rate constant leads to recognizing the stabilization or destabilization of the transition state complex that forms during the rate‐determining step of the reaction. The value of the zero‐order rate constant was decreased with increasing ionic strength that yielded a negative value of the slope in each binary and ternary solvent systems. This negative sign refers to the electron transfer between opposite charge carriers such as [FeIII(bpy)2(CN)2]+ and I− during the rate‐determining step. The destabilization of the transition state complex is surfaced by the increasing slope, that is, 5 &lt; 10 &lt; 15% (v/v) tertiary butyl alcohol‐water with a gradual decrease in the rate constant. However, its stability emerges by relatively small values of the slope in 17.5 &lt; 25 ≤ 30% (v/v) tertiary butyl alcohol‐water and 8:2:90 &lt; 6:4:90% (v/v) dioxane: tertiary butyl alcohol: water with reasonably fast rate of reaction.

Approach for simultaneous cannabidiol isolation and pesticide removal from hemp extracts with liquid-liquid chromatography

In this work, a computer-aided approach for selecting biphasic solvent systems for simultaneous cannabidiol (CBD) isolation and pesticide removal from hemp extracts with liquid-liquid chromatography (LLC) was investigated. By taking advantage of a fully predictive thermodynamic model (COSMO-RS), a considerable number of ternary solvent systems were screened and potential systems were identified with practically no experimental effort; the partition coefficient of the target component CBD was used as screening parameter. After the experimental validation, three solvent systems were chosen: solvent system I: n-heptane/methanol/water 4/3/1 v/v/v, solvent system II: n-heptane/acetone/water 2/5/1 v/v/v and solvent system III: n-heptane/acetonitrile/water 5/3/2 v/v/v. The 59 pesticides regulated by the state of Oregon in cannabis products were included in the next step with the aim to propose a classification system of the most critical pesticides for obtaining pesticide-free CBD. Based on CBD/pesticide separation factors (αCBD/PEST), four critical levels were defined. Depending on the solvent system, it was shown that 50–70 % of the Oregon-listed pesticides were found to be non-critical (αCBD/PEST > 4), while only 13–22 % were retrieved as highly and medium critical (αCBD/PEST < 2). Using the acquired knowledge, a guideline for the selection of the best solvent system candidate for the simultaneous LLC separation of CBD and removal of Oregon-listed pesticides from hemp extracts was proposed. Following a series of LLC experiments with a pesticide-spiked hemp extract, it was shown that the pesticide classification lists can be used to select the most promising solvent system to achieve the removal of most of the contaminating pesticides.

Analysis, Formation and Inhibition of Heterocyclic Amines in Foods: An Overview

Heterocyclic amines (HAs), an important class of toxicological compounds, can be formed through heating of four precursors, amino acids, creatinine, creatine and sugars. Numerous studies have shown that most HAs are mutagenic and carcinogenic, and the safety of HAs-containing foods has become a major concern for the public. This paper deals with an overview of analysis, formation and inhibition of HAs in foods. Analysis of HAs from foods is routinely conducted by protein precipitation, followed by acid-base solvent partition, purification with column chromatography and identification and quantification by high-performance liquid chromatography (HPLC), or gas chromatography-mass spectrometry (GC-MS). However, most of these methods result in low recovery. With HPLC, all 16 HAs can be simultaneously separated by a binary or ternary gradient solvent system and detected by UV. Using fluorescence detection, only nine HAs can be detected. For GC-MS, only a number of HAs are separated and identified by employing a temperature programming method. GC-MS provides rapid identification and quantification of HAs in foods, however, this technique requires a time-consuming derivatization and the number of HAs separation is limited. Also, some HAs may degrade and result in peak tailing. The application of HPLC with photodiode-array detection (HPLC-DAD) can not only permit rapid identification and quantification of HAs, but also enhance sensitivity and selectivity. Broiling and frying are two major processing methods causing the formation of high amount of HAs. The formation of HAs in foods during cooking can be inhibited by incorporating additives such as antioxidants and amino acids. However, the results have been controversial. Further research is necessary to study the effect of various additives on inhibition of HAs formation in foods.