Pharmaceutical Chemical Industries Research Articles

ChemInform Abstract: Exploiting Metal‐Ligand Bifunctional Reactions in the Design of Iron Asymmetric Hydrogenation Catalysts

AbstractReview: 74 refs.

Iron- and Cobalt-Catalyzed Alkene Hydrogenation: Catalysis with Both Redox-Active and Strong Field Ligands.

The hydrogenation of alkenes is one of the most impactful reactions catalyzed by homogeneous transition metal complexes finding application in the pharmaceutical, agrochemical, and commodity chemical industries. For decades, catalyst technology has relied on precious metal catalysts supported by strong field ligands to enable highly predictable two-electron redox chemistry that constitutes key bond breaking and forming steps during turnover. Alternative catalysts based on earth abundant transition metals such as iron and cobalt not only offer potential environmental and economic advantages but also provide an opportunity to explore catalysis in a new chemical space. The kinetically and thermodynamically accessible oxidation and spin states may enable new mechanistic pathways, unique substrate scope, or altogether new reactivity. This Account describes my group's efforts over the past decade to develop iron and cobalt catalysts for alkene hydrogenation. Particular emphasis is devoted to the interplay of the electronic structure of the base metal compounds and their catalytic performance. First generation, aryl-substituted pyridine(diimine) iron dinitrogen catalysts exhibited high turnover frequencies at low catalyst loadings and hydrogen pressures for the hydrogenation of unactivated terminal and disubstituted alkenes. Exploration of structure-reactivity relationships established smaller aryl substituents and more electron donating ligands resulted in improved performance. Second generation iron and cobalt catalysts where the imine donors were replaced by N-heterocyclic carbenes resulted in dramatically improved activity and enabled hydrogenation of more challenging unactivated, tri- and tetrasubstituted alkenes. Optimized cobalt catalysts have been discovered that are among the most active homogeneous hydrogenation catalysts known. Synthesis of enantiopure, C1 symmetric pyridine(diimine) cobalt complexes have enabled rare examples of highly enantioselective hydrogenation of a family of substituted styrene derivatives. Because improved hydrogenation performance was observed with more electron rich supporting ligands, phosphine cobalt(II) dialkyl complexes were synthesized and found to be active for the diastereoselective hydrogenation of various substituted alkenes. Notably, this class of catalysts was activated by hydroxyl functionality, representing a significant advance in the functional group tolerance of base metal hydrogenation catalysts. Through collaboration with Merck, enantioselective variants of these catalysts were discovered by high throughput experimentation. Catalysts for the hydrogenation of functionalized and essentially unfunctionalized alkenes have been discovered using this approach. Development of reliable, readily accessible cobalt precursors facilitated catalyst discovery and may, along with lessons learned from electronic structure studies, provide fundamental design principles for catalysis with earth abundant transition metals beyond alkene hydrogenation.

Nanocrystalline semiconductor doped rare earth oxide for the photocatalytic degradation studies on Acid Blue 113: A di-azo compound under UV slurry photoreactor

Preventive measures for the control of environmental pollution and its remediation has received much interest in recent years due to the world-wide increase in the contamination of water bodies. Contributions of these harmful effluents are caused by the leather processing, pharmaceutical, cosmetic, textile, agricultural and other chemical industries. Nowadays, advanced oxidation processes considered to be better option for the complete destruction of organic contaminants in water and wastewater. Acid Blue 113 is a most widely used di-azo compound in leather, textile, dying and food industry as a color rending compound. In the present study, we have reported the photo catalytic degradation of Acid Blue 113 using a nanocrystalline semiconductor doped rare earth oxide as a photo catalyst under UV light irradiation. The photocatalyst was prepared by a simple precipitation technique and were characterized by XRD, FT-IR, UV-DRS and FE-SEM analysis. The experimental results proved that the prepared photo catalyst was nanocrystalline and highly active in the UV region. The UV-DRS results showed the band gap energy was 3.15eV for the prepared photo catalyst. The photodegradation efficiency was analyzed by various experimental parameters such as pH, catalyst dosage, variation of substrate concentration and effect of electrolyte addition. The photo degradation process followed a pseudo first order kinetics and was continuously monitored by UV–visible spectrophotometer. The experimental results proved the efficacy of the nanocrystalline zinc oxide doped dysprosium oxide which are highly active under UV light irradiations. It is also suggested that the prepared material would find wider applications in environmental remediation technologies to remove the carcinogenic and toxic moieties present in the industrial effluents.

Exploiting metal-ligand bifunctional reactions in the design of iron asymmetric hydrogenation catalysts.

This is an Account of our development of iron-based catalysts for the asymmetric transfer hydrogenation (ATH) and asymmetric pressure hydrogenation (AH) of ketones and imines. These chemical processes provide enantiopure alcohols and amines for use in the pharmaceutical, agrochemical, fragrance, and other fine chemical industries. Fundamental principles of bifunctional reactivity obtained by studies of ruthenium catalysts by Noyori's group and our own with tetradentate ligands with tertiary phosphine and secondary amine donor groups were applied to improve the performance of these first iron(II) catalysts. In particular the correct positioning of a bifunctional H-Fe-NH unit in an iron hydride amine complex leads to exceptional catalyst activity because of the low energy barrier of dihydrogen transfer to the polar bond of the substrate. In addition the ligand structure with this NH group along with an asymmetric array of aryl groups orients the incoming substrate by hydrogen-bonding, and steric interactions provide the hydrogenated product in high enantioselectivity for several classes of substrates. Enantiomerically pure diamines or diphenylphosphino-amine compounds are used as the source of the asymmetry in the tetradentate ligands formed by the condensation of the amines with dialkyl- or diaryl-phosphinoaldehydes, a synthesis that is templated by Fe(II). The commercially available ortho-diphenylphosphinobenzaldehyde was used in the initial studies, but then diaryl-phosphinoacetaldehydes were found to produce much more effective ligands for iron(II). Once the mechanism of catalysis became clearer, the iron-templated synthesis of (S,S)-PAr2CH2CH2NHCHPhCHPhNH2 ligand precursors was developed to specifically introduce a secondary amine in the precatalyst structures. The reaction of a precatalyst with strong base yields a key iron-amido complex that reacts with isopropanol (in ATH) or dihydrogen (in AH) to generate an iron hydride with the Fe-H bond parallel to the secondary amine N-H. In the AH reactions, the correct acidity of the intermediate iron-dihydrogen complex and correct basicity of the amide are important factors for the heterolytic splitting of the dihydrogen to generate the H-Fe-N-H unit; the acidity of dihydrogen complexes including those found in hydrogenases can be estimated by a simple additive ligand acidity constant method. The placement of the hydridic-protonic Fe-H···HN interaction in the asymmetric catalyst structure influences the enantioinduction. The sense of enantioinduction is predictable from the structure of the H-Fe-N-H-containing catalyst interacting with the ketone in the same way as related H-Ru-N-H-containing catalysts. The modular construction of the catalysts permits large variations in order to produce alcohol or amine products with enantiomeric excess in the 90-100% range in several cases.

Differential scanning calorimetry study on caprylins

Monoacylglycerols (MAG) and diacylglycerols (DAG) are nonionic surfactants with several applications in the food, pharmaceutical and other chemical industries. They can be produced by alcoholysis, esterification or partial hydrolysis of triacylglycerols, alternatively using lipase instead of chemical catalysts, generating purer and less degraded lipids. Differential scanning calorimetry (DSC) is a widespread method extensively used for studying the thermal properties of several materials, including the various classes of lipids. In this field, however, the use of DSC has generally been limited to the analysis of the thermal profiles of fats and oils, as well as the characteristics of interesterification reaction products. Therefore, the present study reports the melting and crystallization behavior of chromatographic standards of monocaprylin (MC), dicaprylin (DC) and tricaprylin (TC), as well as binary mixtures of MC and DC in proportions (w/w) of 2:1, 1:1 and 1:2, respectively, aiming to propose the use of DSC as a first step to monitor esterification or hydrolysis reactions for the production of MAG and DAG, as well as the subsequent indispensable purification procedures. It is worth to highlight that little is known about the physical behavior of MAG and DAG of caprylic acid presented herein. The remarkable differences between the behaviors of pure components and binary systems during cooling and heating can be possibly attributed to interactions between molecules by weak chemical bonds such as hydrogen bonds, van der Waals force or hydrophobic interactions, as well as phase transitions or polymorphism. This study indicates that DSC can be a valuable tool to supply important information on catalytic reaction evolution, which should be complemented by other techniques to provide a complete depiction of the reaction under research.

The Role of Bacteria in the Breakdown of Carcinogenic Substances (PCBs) in Wastewater for Safe Recycling Purposes – A Review

Water is one of the most essential natural resources for daily human activities, yet it is so scarce. Treated wastewater and untreated sewage contain bacteria that can be advantageous to the recycling process. The composition of effluent originates from various industries, such as pharmaceutical industries, mining industries, agricultural sector, household waste, chemical industries, and various manufacturing industries, including the oil manufacturers. These introduce potential health-threatening compounds to wastewater. These compounds that remain for a long time without being broken down or changed in their chemical composition and/or structure in the environment are referred to as recalcitrant compounds. Polychlorinated Biphenyls (PCBs) are examples of such compounds. These compounds have serious negative health effects on humans (act as mutagens and carcinogens). The capacity of Polychlorinated Biphenyl’s (PCBs) degradation by bacteria (biodegradation) depends on the diversity and characteristics of naturally occurring populations and their response to environmental conditions. Conventional physical and chemical methods that are used to decontaminate wastewater contaminated by these substances are time and energy consuming. The use of Moringa oleifera seeds, which is currently under trial, is also very costly and not sustainable. This threatens the economic security of most developing countries. Biodegradation is the metabolic ability of microorganisms to transform or mineralize organic contaminants into less harmful, non-hazardous substances, which are then integrated into natural biochemical cycles. This process is not only cost effective, but it is also environmentally friendly. Wastewater that has gone through effective biodegradation can be fully recycled, thus conserving raw water and at the same time ensuring safe available water for all.

English

Fresh water dwelling fishes have scanty information on gut microflora associated with them and there is a paucity of knowledge regarding microbial enzyme activity in fish gastrointestinal tracts. Although some of the enzymes like cellulase, proteases have been reported to be associated in the gut of fish.Amylase is one of the most important enzymes known and is of great significance and contributes of about 25% of the total enzyme market. It has a number of potential applications in food, pharmaceutical and fine chemical industries. This work describes the isolation, characterisation and optimization of amylase producing micro-organisms from gastrointestinal tract ofCatla catla. Biological production of amylase by bacterial isolate PAC4 isolated from fish gut was identified to be Bacilluscereus. The maximum amylase production was reached to 92+ 3 U/ml in 48 hours of incubation.The various physico-chemical factors for optimum amylase fermentationwere found to be 3% sodium chloride concentration,37 °C temperature and pH 7.

ChemInform Abstract: Synthesis Optimization and Catalytic Activity Screening of Industrially Relevant Ruthenium‐Based Metathesis Catalysts

AbstractReview: 58 refs.

Lactic Acid Production by Lactobacillus brevis Isolated from Oral Microbiota

Lactic acid is used in various industrial areas such as the food, pharmaceutical, textile and other chemical industries. In this study, 49 lactic acid bacteria were isolated from oral microbiota of voluntary patients. These isolates were screened for their lactic acid production abilities. The isolate which has a high potential for lactic acid production was selected. The optimal conditions for lactic acid production by Lactobacillus brevis were determined. According to the results obtained, sucrose as carbon source, 50 g/L of sucrose amount, diammonium hydrogen citrate as nitrogen source, 8 g/L of nitrogen amount, 42 °C as temperature, 4.5 x 108 CFU/mL of inoculum amount and 72 hours of incubation time were found to be optimal values.

Environmental sustainability assessments of pharmaceuticals: an emerging need for simplification in life cycle assessments.

The pharmaceutical and fine chemical industries are eager to strive toward innovative products and technologies. This study first derives hotspots in resource consumption of 2839 Basic Operations in 40 Active Pharmaceutical Ingredient synthesis steps through Exergetic Life Cycle Assessment (ELCA). Second, since companies are increasingly obliged to quantify the environmental sustainability of their products, two alternative ways of simplifying (E)LCA are discussed. The usage of averaged product group values (R(2) = 3.40 × 10(-30)) is compared with multiple linear regression models (R(2) = 8.66 × 10(-01)) in order to estimate resource consumption of synthesis steps. An optimal set of predictor variables is postulated to balance model complexity and embedded information with usability and capability of merging models with existing Enterprise Resource Planning (ERP) data systems. The amount of organic solvents used, molar efficiency, and duration of a synthesis step were shown to be the most significant predictor variables. Including additional predictor variables did not contribute to the predictive power and eventually weakens the model interpretation. Ideally, an organization should be able to derive its environmental impact from readily available ERP data, linking supply chains back to the cradle of resource extraction, excluding the need for an approximation with product group averages.

Synthesis Optimization and Catalytic Activity Screening of Industrially Relevant Ruthenium-Based Metathesis Catalysts

Olefin metathesis is a powerful catalytic reaction that has a huge potential in the pharmaceutical, polymer and specialty chemicals industries. Cost-effective industrial applications require large-scale availability of catalyst precursors which combine high activity, high selectivity and long life-time. Among the known numerous families of olefin metathesis catalysts, the Umicore M7-catalyst family represents a novel class of Hoveyda-type complexes showing excellent chemical stabilities and modular activity profiles. Relevant aspects related to their industrial synthesis as well as their catalytic performance in valuable olefin metathesis transformations are overviewed here.

Treatment of industrial waste pharmochemical by fenton’s reagent

This study aims to determine the optimal concentration of Fenton reagent for pharmaceutical chemistry industry, varying the concentration of ferrous sulfate and hydrogen peroxide subsequently monitor the treatment in pilot scale and wastewater treatment (WWTP) station of the main parameters: color, odor, pH and COD. Pilot tests to obtain the guidelines used in formulating the Fenton reagent to be used in large scale in the effluent tank were performed, the pilot test of experiment T12 showed the best result (Color and COD) for the composition of the treatment with: 3.2 mL of H2O2 and 160 mg Ferrous Sulfate. From this parameter the treatment was carried out daily monitoring in the laboratory and pilot scale, and the values were similar for both treatments, with the percentage reduction of COD of 93.57% in the lab test and 94.00% in the ETE test. The process of wastewater treatment using Fenton reagent showed excellent results, with better values than the limits established by law. But the treatment time of 16 days is not feasible for some industries, but is smoothly carried out in the study industry.

Sustainable Catalysis. Challenges and Practices for the Pharmaceutical and Fine Chemical Industries. Edited by Peter J. Dunn, K. K. (Mimi) Hii, Michael J. Krische and Michael T. Williams.

Sustainable Catalysis. Challenges and Practices for the Pharmaceutical and Fine Chemical Industries. Edited by Peter J. Dunn, K. K. (Mimi) Hii, Michael J. Krische and Michael T. Williams.

Study on the separation of binary azeotropic mixtures by continuous extractive distillation

For azeotropic mixtures or close-boiling mixtures which is often observed in the pharmaceutical and specialty chemicals industries, conventional distillation has been shown to be unable to reach the separation desired. In this paper, continuous extractive distillation (CED) was used to separate acetone–tetrahydrofuran, n-hexane–tetrahydrofuran, n-hexane–ethyl acetate and ethyl acetate–ethanol that form azeotropic mixtures. The characters of the CED were simulated with Aspen Plus and experiments also showed the feasibility of the technology in separating the azeotropic mixtures. The mass fraction of the light component in the separation of acetone–tetrahydrofuran, n-hexane–tetrahydrofuran, n-hexane–ethyl acetate and ethyl acetate–ethanol reached 99.02%, 99.00%, 99.15% and 98.80%, respectively. These azeotropic mixtures were separated successfully through solvent selection based on polarity principle and pseudo-binary vapor–liquid equilibrium, simulation via Aspen Plus and experimental verification. This algorithm may become a generally applicable method for solvent selection in developing new extractive distillation processes.

Enantioselective Enzymatic Hydrolysis of rac-Mandelonitrile to R-Mandelamide by Nitrile Hydratase Immobilized on Poly(vinyl alcohol)/Chitosan–Glutaraldehyde Support

Nitriles, amides and carboxylic acids have varied applications in active pharmaceutical intermediate (API), drug and chemical industry, and particularly in the synthesis of pure enantiomers of chiral compounds. The chemical hydrolysis of nitrile compounds is well studied, but it necessitates harsh conditions along with the protection of sensitive functional groups, which on deprotection leads to generation of a large amount of byproducts. Immobilization of nitrile hydratase using a novel support reduces the cost and allows green processes. In this work, enantioselective hydrolysis of rac-mandelonitrile was studied using poly(vinyl alcohol) (PVA)/chitosan–glutaraldehyde cross-linked Rhodococcus rhodochrous ATCC BAA-870 nitrile hydratase (NHase). Immobilized NHase converted rac-mandelonitrile to (R)-amide by dynamic kinetic resolution with enantiomeric excess (ee) up to 81%. The temperature of 40 °C and pH 8 were found to be optimum for the enantioselective nitrile hydrolysis. In the presence of various cosolvents, immobilized NHase showed higher retention of activity in methanol compared to other cosolvents. The kinetic constants for free and immobilized enzyme were obtained from the Lineweaver–Burk plot. The immobilized NHase was found to be reusable up to nine successive batch reactions.

Zeolite Supported Ionic Liquid Catalyst for the Synthesis of Nano-Cellulose from Palm Tree Biomass

Nanocellulose promises to be a very versatile material having wide range of biomedical and biotechnological applications including tissue engineering, drug delivery, wound dressings, medical implants, food, cosmetics, paper and textiles. The current methods for the synthesis of nanocellulose involve harsh chemical treatments which are perpetually hazardous to human and environment. Catalytic synthesis of nanocellulose might be a green approach. Among the various types of catalyst, ionic liquids, which are composed of both cations and anions and have low or negligible vapor pressure, are particularly promising. Ionic liquids also exhibit a relatively wide electrochemically stable window, good electrical conductivity, high ionic mobility, a broad range of room temperature liquid compositions, selective dissolvability to many organic and inorganic materials, and excellent chemical and thermal stabilities. In contrast, zeolite catalysts have been used in petroleum refineries for the removal of sulfur. Zeolite catalysts are also important for the synthesis of bulk chemicals, fine and specialty chemicals, fuels and chemicals. Acidic and metal modified micro porous zeolite catalysts have been used in several commercial processes in petroleum industry, fuel components, abatement of exhaust gas emissions and biomass upgrading, pharmaceutical and fine chemical industries. Currently, zeolite catalysts are synthesized in powder form and to make them industrially useful, such catalysts have to be mixed with a binder and formulated in different shapes. This paper reviewed the introduction, preparation, synthesis and application of nanocellulose from lignocellulosic palm biomass.

Screening for hydroxynitrile lyase activity in non-commercialised plants

Hydroxynitrile lyases are used for the synthesis of enantiomerically pure cyanohydrins which are of great importance in the pharmaceutical and fine chemical industries. In this study, the hydroxynitrile lyase activity of 100 plants from 40 families was investigated, first by screening for cyanogenic activity, followed by a hydroxynitrile lyase activity assay. Of the 100 plants, four were found to be cyanogenic and exhibited specific hydroxynitrile lyase activity: Adenia sp. (0.44U/mg), Adenia firingalavensis (2.88U/mg), Adenia fruticosa (1.99U/mg) and, Adenia pechuelii (2.35U/mg), all from the family Passifloraceae. This is the first report of hydroxynitrile lyase activity in these plants.

Observing the in situ chiral modification of Ni nanoparticles using scanning transmission X-ray microspectroscopy

Enantioselective heterogeneous hydrogenation of CO bonds is of great potential importance in the synthesis of chirally pure products for the pharmaceutical and fine chemical industries. One of the most widely studied examples of such a reaction is the hydrogenation of β-ketoesters and β-diketoesters over Ni-based catalysts in the presence of a chiral modifier. Here we use scanning transmission X-ray microscopy combined with near-edge X-ray absorption fine structure spectroscopy (STXM/NEXAFS) to investigate the adsorption of the chiral modifier, namely (R,R)-tartaric acid, onto individual nickel nanoparticles. The C K-edge spectra strongly suggest that tartaric acid deposited onto the nanoparticle surfaces from aqueous solutions undergoes a keto-enol tautomerisation. Furthermore, we are able to interrogate the Ni L2,3-edge resonances of individual metal nanoparticles which, combined with X-ray diffraction (XRD) patterns showed them to consist of a pure nickel phase rather than the more thermodynamically stable bulk nickel oxide. Importantly, there appears to be no “particle size effect” on the adsorption mode of the tartaric acid in the particle size range ~90–~300nm.

Increasing the sustainability of membrane processes through cascade approach and solvent recovery—pharmaceutical purification case study

Membrane processes suffer limitations such as low product yield and high solvent consumption, hindering their widespread application in the pharmaceutical and fine chemicals industries. In the present work, the authors propose an efficient purification methodology employing a two-stage cascade configuration coupled to an adsorptive solvent recovery unit, which addresses the two limitations. The process has been validated on purification of active pharmaceutical ingredient (API) from genotoxic impurity (GTI) using organic solvent nanofiltration (OSN). The model system selected for study comprises roxithromycin macrolide antibiotic (Roxi) with 4-dimethylaminopyridine (DMAP) and ethyl tosylate (EtTS) as API and GTIs, respectively. By implementing a two-stage cascade configuration for membrane diafiltration, the process yield was increased from 58% to 95% while maintaining less than 5 ppm GTI in the final solution. Through this yield enhancement, the membrane process has been “revamped” from an unfeasible process to a highly competitive unit operation when compared to other traditional processes. The advantage of size exclusion membranes over other separation techniques has been illustrated by the simultaneous removal of two GTIs from different chemical classes. In addition, a solvent recovery step has been assessed using charcoal as a non-selective adsorbent, and it has been shown that pure solvent can be recovered from the permeate. Considering the costs of solvent, charcoal, and waste disposal, it was concluded that 70% solvent recovery is the cost-optimum point. Conventional single-stage diafiltration (SSD) and two-stage diafiltration (TSD) configurations were compared in terms of green metrics such as cost, mass and solvent intensity, and energy consumption. It was calculated that implementation of TSD, depending on the batch scale, can achieve up to 92% cost saving while reducing the mass and solvent intensity up to 73%. In addition, the advantage of adsorptive solvent recovery has been assessed revealing up to 96% energy reduction compared to distillation and a 70% reduction of CO2 footprint.

Synthesis of 4-Chloro-3-nitrobenzotrifluoride: Industrial thermal runaway simulation due to cooling system failure

In pharmaceutical and fine chemical industries, fast and strongly exothermic reactions are often carried out in semibatch reactors (SBRs) to better control the heat evolution by the feeding rate. In fact, for such processes, a thermal runaway event may be triggered whenever the rate of heat removal becomes lower than the rate of heat production. Such a dangerous phenomenon consists in an uncontrolled reactor temperature increase that, occurring in practically adiabatic conditions, can trigger secondary undesired exothermic reactions or, worse, decompositions of the whole reacting mixture with consequent reactor pressurization due to uncontrollable gases formation. In this work, dedicated software has been developed and used to simulate a cooling system breakdown in an industrial SBR where the nitration of 4-Chlorobenzotrifluoride is carried out. The mathematical model is able to simulate both reactor temperature and pressure vs. time profiles thanks to a complete description of both the desired reaction and the unwanted reacting mixture decomposition kinetics. Different accidental scenarios have been simulated, showing both the wide different consequences that can arise from the same initiating event and, therefore, the usefulness of a complete simulation of the hypothesized accidental scenario in the frame of a Quantitative Risk Analysis.