Fine Chemical Technologies

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Vol 14, No 5 (2019)
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7-20 326

Objectives. Over the last few years, medicinal chemistry research has been focusing on the creation of molecules that can target particular body systems, organs and tissues, thus abating systemic toxicity and side effects, and, most of all, boosting therapeutic potential. This goal can be achieved through the specific interaction of such drugs with active sites of cellular receptors. For example, glycoprotein receptors that can be found on cellular surfaces in neural tissues and liver parenchyma, selectively bind various glycoproteins and glycosides, facilitating their penetration into cells. This review describes how certain parameters of ligand structure (the nature and length of the spacer between carbohydrate and non-carbohydrate fragments of the molecule, number of carbohydrate residues per molecule, etc.) influence the penetration efficiency of synthetic glycoconjugates into liver cells.

Methods. This review article summarizes 75 research papers and discusses data from in vitro and in vivo experiments showing which structures of synthetic carbohydrate derivatives are optimal for targeted drug delivery into liver cells.

Results. The surface of liver cells (hepatocytes) contains a significant number of asialoglycoprotein receptors (ASGP-R) that are almost never found elsewhere. This makes ASGP-R an ideal target for the directed treatment of liver diseases, including such difficult, socially important conditions as hepatocellular carcinoma and Hepatitis C. A number of various ligands and targeted (to ASGP-R) delivery systems have been designed. Such molecules always contain derivatives of mono- and disaccharides, most commonly D-glucose, D-galactose, D-lactose and N-acetylglucosamines. This review contains the chemical structures of carbohydrate-based ligands.

Conclusions. Glycolipids based on D-carbohydrates, when in liposomes, facilitate penetration into liver cells by a receptor-mediated, clathrin-dependent endocytosis mechanism that is activated upon contact of the carbohydrate-containing ligand fragment with the active site of ASGP-R. It can be addressed by the use of monovalent derivatives of carbohydrates as well as polyvalent glycoconjugates. Alterations in the ligand structure and the number of liposomal modifications can boost the therapeutic effect. The distance between the liposomal surface and the carbohydrate residue (spacer length), as well as the hydrophilic-lipophilic balance of the ligand molecule, have a great effect on the affinity and cellular response.


21-30 268

Objectives. The intensification of modern large-tonnage Russian technologies requires a deep investigation into the theoretical foundations of these processes and searching for ways that would significantly reduce the time and cost of their development, as well as to ensure the access of high-quality products on the world market. The aim of the work was to study the options regarding technological changes in the process of obtaining cyclohexanone at two stages: 1) oxidate (cyclohexane oxidation product after the stage of neutralization and removal of the main amount of unreacted cyclohexane) saponification and 2) end product rectification. The changes should ensure the high quality of the product without requiring significant energy and investment costs.

Methods. Studies of heterophase alkaline hydrolysis with NaOH solutions were carried out at 30–80 °C in the presence of and without a phase transfer catalyst (PTC) (saponification conditions in the industry are 70 °C). The homophase process was studied in the presence of KOH at 120 °C (industrial conditions for raw cyclohexanone rectification are 90–130 °C) on artificial mixtures based on industrial samples of the oxidate with the addition of model substances (oxygencontaining impurities with a main substance content of no less than 95%). Analysis of the initial and obtained products was carried out using gas-liquid chromatography and chromatographymass spectrometry.

Results. The totality of the obtained data provides theoretical justification for the fact: 50– 70% of esters and unsaponifiable impurities can be removed by using heterophase alkaline saponification in industrial environments. The post-treatment of crude cyclohexanone by rectification in the presence of KOH decreases the ester number by a factor of 3–5, however, the number of cyclohexanone condensation products in the bottom sharply increases. The amount of these substances varies from 10 to 20 kg/t of cyclohexanone depending on compliance with the conditions. In the presence of PTC, the conversion of esters at the saponification stage is 95–100%, aldehydes 100%, and unsaturated ketones 80%.

Conclusions. If the proposed technology for saponification in the presence of PTC is adopted there will be no need to use an alkali during the process of cyclohexanone rectification. This makes the process more stable, reduces the losses of cyclohexanone, reduces the amount of tars, and normalized indicators of cyclohexanone quality are attained.

31-38 195

Objectives. The problem of optimizing chemical flow sheets according to energy costs associated with recycling flows is at present quite relevant. The current article investigates the influence of temperature conditions on the recycle flow rate, securing the specified conversion of the recycled flow sheet “reactor – separation unit.”

Methods. The study’s main method is the mathematical simulation of a recycled flow sheet based on material balance and chemical kinetics equations. This model assumes that the separation unit can form the recycle and outlet flows of any specified compositions.

Results. The mathematical model recycle flows provides the full reagent conversion of recycled flow sheet depends on the reactor type and the temperature conditions in it. It was established that the dependence of the recycle flow rate on the reactor temperature for endothermic reactions has monotonously decreasing shape. The most interesting are exothermic reactions for which the dependence of the recycle flow rate on the reactor temperature curve has a minimum. It is proved that the “reactor – separation unit” system with the plug flow reactor has lower optimal recycle flow rate than the recycled system with the continuous stirred tank reactor. For the adiabatic reactor the dependence of total conversion recycle flow rate on the inlet reactor temperature was investigated. It has been proven that the optimal recycle flow rate is equal to the minimum recycle flow rate for total conversion in the “reactor – separation unit” system.

Conclusions. It has been established that isothermal operation conditions are the best in terms of the recycle flow rate, securing the specified conversion for the system.

39-50 239

Objectives. The development of microfluidic systems is one of the promising areas of science and technology. In most procedures performed using microfluidic systems, effective mixing in microfluidic channels of microreactors (chips) is of particular importance, because it has an effect on the sensitivity and speed of analytical procedures. The aim of this study is to describe and evaluate the major parameters of the flow and mixing processes in a passive microfluidic micromixer, and to develop an information-measuring system to monitor the dynamics of flow (mixing) of liquids.

Methods. This article provides an overview of the concept of microfluidic mixing chips (micromixers) and their classification, and analyzes the kinds of points of mixing and microfluidic channels for mixing. The article presents the description and calculations of the hydrodynamic similarity criteria (Reynolds, Dean and Peclet numbers), which are the critical parameters for creating and optimizing micromixers (for example, straight and curved channels in the flow rate range between 100 and 1000 µl/min). We have developed an information-measuring system to monitor the dynamics of flow (mixing) of liquids in a microfluidic channel, which consists of a microscope with a digital eyepiece (LOMO MIB, Russia), an Atlas syringe pump (Syrris Ltd., UK) and a passive mixing microfluidic chip of interest (made of clear glass). This system was designed to quickly illustrate the principles of mixing in microfluidic channels of different configurations.

Results. The developed system has allowed carrying out a colorimetric analysis of the modes and dynamics of mixing two liquids (5% aqueous solution of azorubine dye and water) at the T-shaped mixing point, at the straight and curved (double-bend shaped) sections of the microfluidic channel of the passive-type micromixer with flow rates varying from 100 to 400 µl/min.

Conclusions. According to the obtained calculations, the share of the advective mixing processes (formation of vortex flows and increase in the contact area of the mixed substances) in flowing liquids is significantly higher in curved microchannels. The developed information-measuring system to monitor the dynamics of flow (mixing) of liquids in a microfluidic channel is a convenient tool for optimizing the mixing modes in the channels of micromixers, and for designing new configurations of channels in microchips. It would allow intensifying processes and increasing the performance of microfluidic systems.

51-60 444

Objectives. The paper is a comparative analysis of methyl acetate + methanol + acetic acid + acetic anhydride industrial mixture separation flowsheets based on the use of special distillation methods (extractive distillation and pressure-swing distillation). The results obtained illustrate the variability of the structure of the technological separation flowsheet.

Methods. Mathematical modeling using the software package Aspen Plus V. 10.0 was chosen as the research method. The simulation was based on the local composition equation NRTL and the Hayden–O’Connell equation of state. The relative uncertainties of phase equilibrium description do not exceed 3%.

Results. The vapor–liquid diagram of the quaternary mixture of methyl acetate + methanol + acetic acid + acetic anhydride was studied using thermodynamic topological analysis. It was shown that the system contains one binary azeotrope and is characterized by one distillation region. Although the structure is not complex, there is a possibility of using several methods for mixture separation: pressure-swing distillation, and extractive distillation with different entrainers. Twelve flowsheets with different structure were proposed, and 29 variants of separation were compared.

Conclusions. It was shown that the most perspective structure for the separation of a methyl acetate + methanol + acetic acid + acetic anhydride mixture is a combination of distributed sequence separation and extractive distillation.


61-70 270

Objectives. Biologically active polymeric surfactants are a new promising class of macromolecules that can find application in medicine, cosmetology, and agriculture. In this study, a number of new biologically active amphiphilic polymers based on branched silatrane-containing polyesters and polyethers were obtained, and their surface-active properties were investigated.

Methods. The branched polymers were represented by polyethers and polyesters, obtained respectively via the anionic polymerization of 1,2-epoxypropanol or a combination of equilibrium polycondensation and ring opening polymerization. The polymers were modified with 3-isocyanopropylsilatrane and trimethylethoxysilane to obtain the amphiphilic compounds containing silatrane groups bonded to the polymer backbone by the urethane bond. The structure of the synthesized polymer silatranes was confirmed via nuclear magnetic resonance spectroscopy and gel permeation chromatography. The surface active properties of all the copolymers obtained were investigated in connection with their obvious amphiphilicity. In particular, the formation of micelles in aqueous solutions is such a property. The critical micelle concentrations were determined by a method of quenching the fluorescence of the polymers.

Results. It was shown that the values of the critical micelle concentrations and the hydrophilic-lipophilic balance values of polymers determined by the Griffin equation correlate well with each other. A linear relationship between the hydrophilic-lipophilic balance and the critical micelle concentrations was established. At the same time, polyether-based polymers generally showed higher critical micelle concentrations than polyester-based polymers, although the hydrophilic-lipophilic balance values for polymers of different series, but with close degrees of substitution, were close. It was found that the use of all synthesized polymers as stabilizers of direct and reverse emulsions leads to an increase in the aggregative stability of both types of emulsions. The stability of emulsions depended both on the degree of substitution of peripheral hydroxyl groups of polymers by silatranes and on the molecular weight and structure of the branched block of polymers. The stability of direct emulsions increased for all polymers, while that of inverse emulsions decreased with an increasing degree of substitution of hydroxyl groups by silatranes. The increase of the branched block molecular weight led to an increase of droplet sizes for both direct and inverse emulsions. The smallest droplet size for direct and inverse emulsions was obtained using polymers with low molecular weight branched polyester blocks as surfactants.

Conclusions. The results obtained prove the possibility of creating polymer surfactants containing silatrane groups. By varying the structure of the polymer, its molecular weight and the degree of substitution of peripheral functional groups, it is possible to obtain surfactants with desired surface properties.

71-78 275

Objectives. Modern atraumatic wound dressings are based on polyethylene terephthalate, or Lavsan, which is shaped to form threads. The aim of the study was to determine the reasons for Lavsan woven nets’ hardening and becoming more trauma-prone during storage, and to find ways of eliminating these effects.

Methods. We used differential scanning calorimetry, performed on a NETZSCH DSС 204 F1 Phoenix device, in a dynamic mode with a temperature range from 20 to 300 °C in argon flow to determine phase states, glass transition temperatures, and melting temperatures of Lavsan fibers (including those treated with polyethylene glycol mixtures). We performed rheoviscometry studies on a Brookfield DV2TLV rotational viscometer, with a SC4-16 thermostatic control unit, at the following temperatures: 25, 36.6, 40, 45, 50, and 55 °C, with shear rates ranging from 120 to 200 s–1 to determine dynamic viscosity and investigate the mixing characteristics of polyethylene glycols with different molecular weights.

Results. We have established that samples of Lavsan woven nets, stored long-term in laboratory conditions (up to 2, 3, and 16 years), are in the crystalline state with a high degree of crystallinity. Upon heating these nets to 300 °C, it is possible to reduce the degree of crystallinity by 19–32%, but it does not completely eliminate the effect. Polyethylene glycols and their mixtures which exhibit non-Newtonian flow behavior and are used as an ointment base, have a significant effect on Lavsan’s crystallinity. We have determined that the optimal ratio of polyethylene glycols for the modification of Lavsan nets is PEG-400:PEG-1500 = 80:20 wt %. Upon storing Lavsan woven nets in this mixture at room temperature, the Lavsan’s crystallinity is greatly reduced, and upon heating the system, the crystallinity practically disappears.

Conclusions. The effect of polyethylene glycol mixtures (the base for therapeutic ointments) with various molecular weights on the phase organization of Lavsan has been evaluated. As a result of this study, we can offer a new approach to reduce the injuring effect of synthetic (Lavsan) bases of atraumatic wound dressings.

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The article is dedicated to the 90th birthday of Leonid Antonovich Serafimov, an outstanding scientist, Doctor of Engineering Sciences, professor at the M.V. Lomonosov Moscow State University of Fine Chemical Technologies. Serafimov made an invaluable contribution to the development of the theoretical foundations of chemical technology. The article briefly describes the research conducted by the scientific school "Theoretical Foundations and Technological Principles of Mass-Transfer and Combined Processes of Organic Synthesis" founded and led by him. Special attention is given to the ideological component of his scientific and pedagogical activity; and his active civil position, encyclopedic knowledge and remarkable personal qualities are also duly noted.

ISSN 2410-6593 (Print)
ISSN 2686-7575 (Online)