Solvent 2-methyltetrahydrofuran Research Articles

Bulk bismuth anodes for wide-temperature sodium-ion batteries enabled by electrolyte chemistry modulation

Sodium ion batteries (SIBs) are considered reliable supplies for next-generation energy devices. However, there is a limited understanding of strategies to prevent the performance deterioration of SIBs under extreme temperature conditions. This study aimed to address this challenge by developing modified electrolyte chemistry to achieve stable wide-temperature SIBs. Weakly Na+-solvating solvent 2-methyltetrahydrofuran (MeTHF) was used to promote the kinetics of Na+ de-solvation. Moreover, 1,2-dimethoxyethane (DME) was introduced as a co-solvent because of the high solubility for Na salts and the coupling reaction mechanism with the Bi electrode. The formulated electrolyte not only endows an anion-dominated NaF-rich solid electrolyte interface (SEI) layer, but also reduces the energy required for the Na+ across the SEI layer (from 291.2 to 89.6 meV). Consequently, Na||Bi half batteries achieve stable cycles at 400 mA g−1 at −20, 20 and 60 °C, respectively. Meanwhile, the extreme operating temperature of the batteries can be extended to −40 and 80 °C, which exceeds those of most current lithium/sodium-based batteries. Furthermore, full batteries employing Na3V2(PO4)3 as the cathode material exhibit stable operation over a wide temperature range of −20 to 60 °C. This electrolyte design strategy presented in this study shows significant promise for enabling wide-temperature SIBs with improved performance.

A greener route for smart PNIPAm microgel synthesis using a bio-based synthesis-solvent

A novel route for poly(N-isopropylacrylamide) (PNIPAm) microgel synthesis using the bio-based solvent 2-Methyltetrahydrofuran (2-MeTHF) is described. Functional and chemical characterization of the PNIPAm microgels synthesized in 2-MeTHF indicates that they are equivalent to microgels synthesized using conventional organic solvents. The volume phase transition temperature was 31.7 °C, the glass transition temperature was observed at 157 °C, and the swelling ratio was 3.7 (dry mass basis). XRD and FT-IR spectroscopic analysis confirmed the successful synthesis of crosslinked PNIPAm microgels. The role of 2-MeTHF as a chain transfer agent in the polymerization can be explained by hydrogen abstraction from the C2 atom position of 2-MeTHF during the chain transfer step of free radical polymerization. An eco-sustainability analysis of the synthesis of PNIPAm microgels in bio-based 2-MeTHF indicates that this route has a much lower carbon footprint than synthesis in conventional solvents, thus providing a more sustainable route for the synthesis of smart microgels for environmental and biomedical applications.

Improved Production of 5-Hydroxymethylfurfural in Acidic Deep Eutectic Solvents Using Microwave-Assisted Reactions.

Hydroxymethylfurfural (5-HMF) is a key platform chemical, essential for the production of other chemicals, as well as fuels. Despite its importance, the production methods applied so far still lack in sustainability. In this work, acidic deep eutectic solvents (DES), acting both as solvent and catalyst, were studied for the conversion of fructose into 5-HMF using microwave-assisted reactions. These solvents were screened and optimized by varying the hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA). The bio-based solvent γ-valerolactone (GVL) was also applied as additive, leading to a boost in 5-HMF yield. Then, a response surface methodology was applied to further optimize operating conditions, such as reaction time, temperature and wt.% of added GVL. The highest 5-HMF yield attained, after optimization, was 82.4% at 130 °C, in 4 min of reaction time and with the addition of 10 wt.% of GVL. Moreover, a process for 5-HMF recovery and DES reuse was developed through the use of the bio-based solvent 2-methyltetrahydrofuran (2-Me-THF), allowing at least three cycles of 5-HMF production with minimal yield losses, while maintaining the purity of the isolated 5-HMF and the efficacy of the reaction media.

Green Solvent to Substitute Hexane for Bioactive Lipids Extraction from Black Cumin and Basil Seeds.

A comparative study of bioactive lipids extraction from black cumin (Nigella sativa L.) and basil (Ocimum basilicum L.) seeds using conventional petroleum-based solvent and green solvent 2-methyltetrahydrofuran (MeTHF) was performed. MeTHF extraction allowed obtaining the highest oil yield in black cumin (34%). Regarding fatty acids composition, linoleic acid (61%) and α-linolenic (78%) were relevant in black cumin and basil green and conventionally extracted oils, respectively. Besides, MeTHF allowed obtaining higher tocopherols and total phenolics contents in black cumin (400 mg/kg of oil and 12 mg EGA/g oil) and basil (317 mg/kg oil and 5 mg EGA/g oil) compared to hexane-extracted ones. The content of major phenolic compounds in the two seed oils, trans-hydroxycinnamic acid, rosmarinic acid, and thymol was enhanced by MeTHF extraction. Furthermore, MeTHF-extracted oils possess stronger antioxidant activities (radical scavenging, total antioxidant, and β-carotene bleaching activities) and high and similar anti-inflammatory capacity to hexane-extracted oils. In conclusion, the results revealed that MeTHF is efficient to replace hazardous solvents to extract oil from black cumin and basil seeds rich in compounds relevant to the human diet, including essential polyunsaturated fatty acids (n-6 and n-3), tocopherols, and phenolic compounds with improved biological activities.

Optimisation of the lipid extraction of fresh black soldier fly larvae (Hermetia illucens) with 2-methyltetrahydrofuran by response surface methodology

While black soldier fly larvae (BSFL, Hermetia illucens) have the potential to become a renewable, industrial feedstock; lipid extractions are typically performed with hexane. Green solvents, however, are gaining more popularity to replace these harmful solvents such as hexane. In this study, the green solvent 2-methyltetrahydrofuran (2-MeTHF) was compared with hexane for extracting lipids from fresh BSFL at moderate temperature. Response surface methodology was used to investigate these wet extractions with a Soxhlet extraction as benchmark. Two sets of optimal process settings were predicted and validated for (1) maximising solvent efficiency and (2) maximising lipid recovery. The resulting extracts were characterised by their fatty acid profile and lipid class composition. The results of the benchmark extraction (Soxhlet) showed that 2-MeTHF could extract significantly more lipids from dried BSFL than hexane (43.23 vs. 40.34 g lipids/100 g DM). No significant difference was found between the maximum solvent efficiencies of hexane and 2-MeTHF. By performing the wet extraction with 2-MeTHF at 45 °C with 15 w/w % fresh BSFL, 40 w/w % 2-MeTHF, and 45 w/w % water; the highest lipid recovery was obtained (94.9 ± 1.8% of total BSFL lipids). These results indicated that the wet extraction was able to extract a similar amount of lipids compared to the Soxhlet extraction. Although the fatty acid profiles did not differ between extraction conditions, 2-MeTHF extracted a higher quantity of free fatty acids and valuable phospholipids compared to hexane. Consequently, the wet lipid extraction with 2-MeTHF can be considered a suitable, more ecologic alternative for the conventional extraction of dried BSFL with hexane.

Environmentally Friendly SPPS II: Scope of Green Fmoc Removal Protocol Using NaOH and Its Application for Synthesis of Commercial Drug Triptorelin.

With the growing necessity to consider environmental impacts when synthesizing peptide-based drugs and to expand upon the recently published short communication report, we herein present a thorough evaluation of a green Fmoc removal protocol. Our protocol avoids the use of hazardous components (using piperidine as a base and dichloromethane (DCM) and N,N-dimethylformamide (DMF) as solvents) and relies on the utilization of the green mineral base NaOH in combination with the greener solvent 2-methyltetrahydrofuran (2-MeTHF) mixed with MeOH. For the original Fmoc removal cocktail (solvents ratio of 1:1), we evaluated the impact of quality/purity of the used 2-MeTHF, scale-up, ratio of 2-MeTHF/MeOH, utilized hydroxide, temperature, and reaction time. An alternative 3:1 protocol was examined using various amino acids, and only Gly required the optimization of the Fmoc removal cocktail composition. The optimized protocol used to remove Fmoc from Gly residue was proved by the synthesis of Leu-enkephalin. We also investigated the stability of the conventional amino acid side-chain-protecting groups, t-Bu, Boc, Trt, and Pbf, and the formation of aspartimide as an undesirable side reaction that occurs during Fmoc solid-phase peptide synthesis (SPPS). The applicability of this synthesis strategy was documented by evaluating the SPPS of a commercial drug used for prostate and breast cancer treatments-decapeptide triptorelin.

Recyclable Heterogeneous Palladium-Catalyzed Cyclocarbonylation of 2-Iodoanilines with Acyl Chlorides in the Biomass-Derived Solvent 2-Methyltetrahydrofuran.

A highly efficient, green palladium-catalyzed cyclocarbonylation of 2-iodoanilines with acyl chlorides has been developed that proceeds smoothly in a biomass-derived solvent 2-methyltetrahydrofuran with N,N-diisopropylethylamine as base at 100 °C under 20 bar of carbon monoxide using an 2-aminoethylamino-modified MCM-41-anchored palladium acetate complex [2N-MCM-41-Pd(OAc)2] as a heterogeneous catalyst, yielding a wide variety of 2-substituted 4H-3,1-benzoxazin-4-one derivatives in good to excellent yields. This supported palladium catalyst could be facilely obtained by a two-step procedure from easily available starting materials and readily recovered via a simple filtration process and recycled at least 8 times without any apparent decrease in catalytic efficiency. The developed methodology not only avoids the use of toxic solvents such as tetrahydrofuran and dimethylformamide but also solves the basic problem of expensive palladium catalyst recovery and reuse and prevents effectively palladium contamination of the desired product.

A ‘greener’ one-pot synthesis of monoterpene-functionalised lactide oligomers

In this work we aimed to achieve a totally sustainable Ring Opening Polymerisation (ROP) process, by harmonising the use of naturally occurring or derivable initiators and the green solvent 2-Methyltetrahydrofuran (2-MeTHF). First, a library of novel monoterpene-alcohols and existing terpenoids was used to provide renewably sourced initiators for a metal-free ROP synthetic step. A number of these initiators are derived from waste materials, further improving their sustainability. Secondly, we selected lactide (LA) as a monomer, because not only is it derived from biomass, but its resultant polymers are biocompatible and biodegradable. Interestingly, these new polymers self-assembled in water producing well defined, biocompatible nanoparticles (NPs) via direct nanoprecipitation without the use of additional stabilisers. We have highlighted a novel and promising (ROP) approach to produce biodegradable, amphiphilic ester-based macromolecules, based on lactide and terpenes (as initiators) in a green solvent, 2-MeTHF thus reducing solvent toxicity in an efficient, simple and sustainable new synthesis. The monoterpenes may provide a highly functionalisable and bio-renewable toolbox for a new generation of ROP initiators.

Process development for separation of lignin from OrganoCat lignocellulose fractionation using antisolvent precipitation

For the sustainable production of chemicals, lignocellulosic biomass can be fractionated into cellulose, hemicellulose and lignin, which can be subsequently converted into valuable intermediates. In the OrganoCat pulping process, lignin is separated from other fractionation products by in situ extraction into the organic solvent 2-methyltetrahydrofuran. However, a suitable concept for the subsequent separation of lignin from this solvent has not yet been identified. In this work, a technically feasible process for the separation of lignin from 2-methyltetrahydrofuran solutions using antisolvent precipitation is developed and evaluated based on lignin precipitation yield, solvent recovery and energy efficiency. For the determination of suitable antisolvents, an experimental solvent screening is performed. The conceptual process design is accomplished on the basis of lignin solubility measurements and process simulations. High lignin precipitation yields are achieved using n-hexane and n-pentane. An efficient process for lignin separation by combining solvent evaporation and precipitation using n-pentane is presented. The proposed separation process leads to lignin which can be separated by filtration and is characterized by low energy consumption and effective antisolvent recovery.

Green Extraction of Fennel and Anise Edible Oils Using Bio-Based Solvent and Supercritical Fluid: Assessment of Chemical Composition, Antioxidant Property, and Oxidative Stability

The aim of this study was to evaluate the replacement aspects of conventional methods (petroleum-based solvent and Folch assay) by alternative methods (bio-based and biodegradable solvent 2-methyltetrahydrofuran (MeTHF) and supercritical CO2 (SC-CO2)) for seed oil extraction from anise (Pimpinella anisum L.) and fennel (Foeniculum vulgare Mill.). Results showed that the highest oil yield of aniseeds was obtained by using Folch (24.07%) and MeTHF (23.65%) extraction methods whereas fennel seeds had 20.02% and 18.72%, respectively. Fatty acid composition of both seed oils obtained by the two green extraction methods was similar to the conventional ones with the predominance of petroselinic acid (54.22–61.25% in fennel and 42.39–48.97% in anise). Besides, SC-CO2 method allowed to obtain the maximum of sterol content in anise (3.85 mg/g of oil) and fennel (4.64 mg/g of oil) seed oils. Furthermore, anise and fennel seed oils extracted with MeTHF method significantly showed higher total phenolic content (2.43 and 1.32 mg GA/g oil, respectively), stronger antioxidant activity (9.23 and 5.04 μmol TEAC/g oil, respectively), and oxidative stability (8.23 and 10.15 h, respectively) than the other methods (p < 0.05). In conclusion, MeTHF appeared to be a good substitute to petroleum solvents for recovery of high oil quality from Pimpinella anisum and Foeniculum vulgare seeds.

Green extraction of oil from Carum carvi seeds using bio-based solvent and supercritical fluid: Evaluation of its antioxidant and anti-inflammatory activities.

The consumption of health-promoting products such as oil seeds may improve human health and prevent certain diseases. Carvi seeds have the potential to produce oil with nutritional and functional properties rich in active compounds. To extract bioactive lipids from Carum carvi seeds using green methodologies. Supercritical-carbon dioxide (Sc-CO2 ) and ethanol as co-solvent and bio-based solvent 2-methyltetrahydrofuran (MeTHF) were used to extract the oil from Carum carvi. The yield, the chemical composition, as well as antioxidant and anti-inflammatory activities of green extracted oils were investigated and compared to those obtained with conventional methods (hexane and Folch system). MeTHF extraction gave higher oil yield than that obtained by hexane. Fatty acids composition of the two obtained green extracted oils was similar to conventional extracted ones where petroselinic (39-43%), linoleic (29-31%) and oleic (19-21%) acids were the major compounds. Furthermore, MeTHF and Sc-CO2 green extracted oils were enriched of bioactive compounds including sterols (5.4 and 7.3mg/g oil) and total polyphenols (9.3 and 7.6mg GAE/g oil) which were correlated to enhanced antiradical capacity. Moreover, the green extracted oils exhibited high anti-inflammatory capacity inhibiting nitric oxide (NO) release in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages with IC50 values of 28 and 24μg/mL. Green solvents are a good alternative to petroleum solvents to recover oil from carvi seeds with high amount of nutritionally important fatty acids, along with significant antioxidant and anti-inflammatory potential.

Continuous flow synthesis of diaryl ketones by coupling of aryl Grignard reagents with acyl chlorides under mild conditions in the ecofriendly solvent 2-methyltetrahydrofuran.

An efficient continuous flow sequential synthesis of diaryl ketones was achieved by coupling of aryl Grignard reagents with acyl chlorides in the bio-derived “green” solvent 2-methyltetrahydrofuran (2-MeTHF) under mild reaction conditions (ambient temperature, 1 hour), allowing a safe and on-demand generation of 2-(3-benzoylphenyl)propionitrile with a productivity of 3.16 g hour−1.

Whole-Cell Catalytic Synthesis of Puerarin Monoesters and Analysis of Their Antioxidant Activities.

Puerarin, an important isoflavonoid from the edible root of Pueraria lobata, shows multiple bioactivities but suffers from low bioavailability. In this study, a new whole-cell catalytic method for acylation modification of puerarin was developed. Among the 12 strains tested, Aspergillus oryzae showed the highest catalytic activity and selectively catalyzed acylation of puerarin at the 6″-hydroxyl group. The organic solvents used significantly influenced the catalytic efficiency of the cells. In the green solvent 2-methyltetrahydrofuran, the reaction showed high substrate conversion (92.5%) and regioselectivity (95.8%), with results similar to those with tetrahydrofuran (94.2% and 98.5%, respectively) under optimal conditions. The monoester products showed higher liposolubility in comparison to puerarin, and those with C3-C8 fatty acid chain lengths showed evidently improved antioxidant activity toward erythrocyte hemolysis. Considering the operational stability of the cells and efficiency of the scaled-up reactions, this method is efficient and cost effective, with promising applications in the health food industry.

Carbonate-Catalyzed Room-Temperature Selective Reduction of Biomass-Derived 5-Hydroxymethylfurfural into 2,5-Bis(hydroxymethyl)furan

Catalytic reduction of 5-hydroxymethylfurfural (HMF), deemed as one of the key bio-based platform compounds, is a very promising pathway for the upgrading of biomass to biofuels and value-added chemicals. Conventional hydrogenation of HMF is mainly conducted over precious metal catalysts with high-pressure hydrogen. Here, a highly active, sustainable, and facile catalytic system composed of K2CO3, Ph2SiH2, and bio-based solvent 2-methyltetrahydrofuran (MTHF) was developed to be efficient for the reduction of HMF. At a low temperature of 25 °C, HMF could be completely converted to 2,5-bis(hydroxymethyl)furan (BHMF) in a good yield of 94% after 2 h. Moreover, a plausible reaction mechanism was speculated, where siloxane in situ formed via hydrosilylation was found to be the key species responsible for the high reactivity.

Isobaric Vapour–Liquid Equilibrium Data Measurement for a Binary System of Green Solvent 2-Methyltetrahydrofuran and Acetic acid at 101.3 kPa

Green solvents are eco-friendly solvents that can play significant role in the reduction in health hazard and safety issues caused by classical solvents. The use of green solvents can be supported and enhanced by providing the data banks of these solvents, particularly vapour–liquid equilibrium (VLE) data that are required for the design of separation systems. A dynamic VLE still based on the Raal modification of Yerazunis et al. (1964) apparatus was employed in the measurement of isobaric VLE data. The VLE still was maintained at 101.3 kPa pressure. The thermodynamic consistency of the measured VLE data was confirmed by Herington’s area test and Van Ness’s point-to-point test. The correlation of VLE data was established by excess Gibbs energy models NRTL, Wilson and UNIQUAC and the result showed that all three models were in good agreement with the experimental data. The absolute average deviation in temperature was 0.3953 K, 0.3823 K, 0.3977 K and the absolute average deviation in vapour-phase composition was 0.0053, 0.0052, 0.0053 for NRTL, Wilson and UNIQUAC models, respectively. The relative volatility chart of 2-MeTHF/Acetic acid versus 2-MeTHF liquid mole fraction showing $$\pm \,5\%$$ deviation of experimental data from Wilson model data was also depicted. The comparison of the experimental VLE data with the data predicted by UNIFAC and modified UNIFAC Dortmund methods was made. The VLE data were generated through binary interaction parameters from Aspen Hysys for Wilson, NRTL and UNIQUAC models and compared with the experimental data.

Aqueous Electrolyte Compatible Electrochromic Polymers Processed from an Environmentally Sustainable Solvent.

Developing aqueous electrolyte compatible, redox-active polymers that can be processed from environmentally sustainable solvents is desirable because these traits will effectively reduce environmental impact and human health hazards during processing procedures and in the final device architecture. To achieve organic solvent solubility and aqueous compatibility, a poly(3,4-propylenedioxythiophene) containing four ester functionalities was synthesized via direct arylation polymerization. The resulting polymer was spray-cast into a thin film from the environmentally sustainable solvent 2-methyltetrahydrofuran, and the presence of multiple polar functionalities rendered the film aqueous electrolyte compatible. The multiester-functionalized polymer exhibits a relatively low onset of oxidation (∼0.4 V vs Ag/AgCl) and electrochromic character by transitioning from a colored neutral state to a colorless oxidized state with increasing potential in 0.1 M NaCl aqueous electrolyte. Additionally, the ester-functionalized polymer exhibits similar electrochromic properties in aqueous electrolytes when compared to traditional alkyl-substituted poly(3,4-propylenedioxythiophenes) in organic electrolytes, as evidenced by contrast values of ∼70% and switching speeds of ∼2 s. This work highlights the use of multipolar functionalities as a design strategy for synthesizing organic solvent processable, aqueous electrolyte compatible redox-active polymers without postpolymerization modifications or the sacrifice of electrochromic properties.

Lewis acid-catalyzed biphasic 2-methyltetrahydrofuran/H2O pretreatment of lignocelluloses to enhance cellulose enzymatic hydrolysis and lignin valorization

Lewis acid-catalyzed pretreatment in a biphasic system consisting of bio-based solvent 2-methyltetrahydrofuran (2-MeTHF) and water for a highly integrated one-pot catalytic transformation of lignocelluloses have been achieved. The aim of this work was to study the effects of different Lewis acid catalysts and pretreatment temperatures on the structural characteristics of precipitated lignin and enzymatic hydrolysis of the pretreated substrates, as well as the quantitative analysis of precipitates, solid residues, soluble carbohydrates and inhibitors. After the AlCl3-catalyzed biphasic 2-MeTHF/H2O pretreatment at 180 °C, its maximum cellulose conversion rate was enhanced by 7.4-fold as compared to the raw material. The precipitated lignin exhibited the representative structure, relatively low molecular weight and high purity for preparing value-added aromatic chemicals or renewable polymers. Overall, AlCl3-catalyzed biphasic 2-MeTHF/H2O pretreatment may offer a promising approach for enhancing enzymatic hydrolysis and obtaining valorized lignin by-product.

Quaternary and ternary LLE measurements for solvent (2-methyltetrahydrofuran and cyclopentyl methyl ether) + furfural + acetic acid + water between 298 and 343 K

Abstract The suitability of two promising solvents for the extraction of furfural from aqueous streams is assessed through novel quaternary and ternary liquid-liquid equilibria data for mixtures of solvent (2-methyltetrahydrofuran or cyclopentyl methyl ether) + acetic acid + furfural + water. The measured data between 298 and 343 K at atmospheric pressure are reported along with regressed binary interaction parameters for UNIQUAC-HOC activity coefficient model and further analyzed through distribution coefficients and selectivity for both acetic acid and furfural. Cyclopentyl methyl ether shows promising characteristics towards selective furfural extraction from a stream containing both studied solutes. Distribution coefficients below 1 are observed for acetic acid and as high as 9 for furfural in the quaternary mixtures.

Heteropoly acid catalysts in upgrading of biorenewables: Cycloaddition of aldehydes to monoterpenes in green solvents

Acidic Cs salt of tungstophosphoric heteropoly acid, Cs2.5H0.5PW12O40 (CsPW), is excellent solid acid catalyst for liquid-phase cycloaddition reactions of biomass-based and easily available from essential oils monoterpenic compounds, such as limonene, α-terpineol, α-pinene, β-pinene and nerol, with aldehydes, including benzaldehyde, crotonaldehyde as well as biomass-derived cuminaldehyde and trans-cinnamaldehyde. The reactions give oxabicyclo[3.3.1]nonene compounds potentially useful for the fragrance and pharmaceutical industries in good to excellent yields. The process is environmentally benign and can be performed in biomass-derived solvent 2-methyltetrahydrofuran and eco-friendly “green” organic solvents such as dimethylcarbonate and diethylcarbonate under mild conditions at low catalyst loadings without leaching problems. The solid CsPW catalyst can be easily separated from the reaction media and low-boiling solvents can be removed by distillation. Silica-supported H3PW12O40 also demonstrated good performance in these reactions.

Calculation of a permitted daily exposure value for the solvent 2-methyltetrahydrofuran

In response to increasing concerns around the potential environmental impact of industrial chemicals, the pharmaceutical industry is seeking alternatives for traditional solvents used during the manufacturing process. Taking into consideration the principles of green chemistry, 2-methyltetrahydrofuran (2-MeTHF) is proposed as a suitable replacement for the structurally similar solvent tetrahydrofuran (THF). 2-MeTHF is derived from renewable sources and is more easily recovered thereby facilitating its reuse. However, 2-MeTHF is currently not included in the International Conference on Harmonisation (ICH) Q3C residual solvent guidelines and there is no Permitted Daily Exposure (PDE) limit proposed below which there would be negligible safety concerns for patients exposed to it as a residual impurity in a drug product.To enable the calculation of a PDE, a GLP compliant 3-month repeat-dose oral toxicity study in rats with a 1-month recovery period was conducted with doses of 2-MeTHF of 0, 80, 250, 500 and 1000 mg/kg/day. Administration of doses of up to 1000 mg/kg/day was tolerated. Based upon minimal observed effects on the liver at ≥500 mg/kg/day, the NOAEL in this study was considered to be 250 mg/kg/day.Inclusion of this NOAEL, and a safety factor of 250 a PDE of 50 mg/day was derived to support the safe use of 2-MeTHF in the pharmaceutical industry.