MECHANOCHEMICAL ACTIVATION OF PHARMACEUTICAL SUBSTANCES AS A FACTOR FOR MODIFICATION OF THEIR PHYSICAL, CHEMICAL AND BIOLOGICAL PROPERTIES

Objective: Study the influence of the mechanical preparation methods (grinding, fluidization) of solid pharmaceutical substances (PS) and herbal raw material on their physicochemical properties and biological activities. Methods: Test substances and solvents-Lactose monohydrate (DFE Pharma, Germany). Sodium chloride, bendazol hydrochloride (all Sigma-Aldrich, USA) and herbal raw material (Callisia fragrans). The dispersity and native structure of pharmaceutical substances were analyzed by several methods: optical microscopy–Altami BIO 2 microscope (Russia); low angle laser light scattering (LALLS) method (Malvern Instruments, UK); Spirotox method–Quasichemical kinetic of cell transition of cellular biosensor Spirostomum ambiguum; Fourier-transform infrared spectroscopy–the analysis in the middle IR region was carried out using an IR Cary 630 Fourier spectrometer (Agilent Technologies, USA). The analysis of dried leaves of C. fragrans before and after mechanical activation was performed using Shimadzu EDX-7000 X-ray fluorescence spectrophotometer without mineralization (Shimadzu, Japan). Results: It was established that the mechanical change, such as dispersion and drying, alters the biological activity of PS and herbal raw materials. The observed increase in the influence of the dispersed substance on the biosensor S. ambiguum is quantitatively estimated from the values of the activation energy (obsEa), which turns to be valued 1,5 (P≤0,05) times more than for the native form substance. In the study of the dependence of the availability of chemical elements K, Ca, Zn on the degree of dispersion of herbal raw materials was established a quantitative 4-fold (P≤0,05) increase in the concentration of elements in mechano-activated raw materials. Conclusion: By the example of the biological model of Spirotox (single-celled biosensor S. ambiguum) and herbal raw materials obtained from C. fragrans, the increase of biological activity of PS at the dispersion of initial preparations was proved

Arrhenius Kinetics As a Bioactivity Assessment Criterion for Drug Substances and Excipients

Arrhenius kinetic principles, in particular, Ea values, were used to assess the biological activity of drug substances in aqueous solutions with different D/H ratios. The obtained activation energies indicated that deuterium-depleted solutions had lower toxicity and biological activity. © 2016, Springer Science+Business Media New York

Arrhenius Kinetics As a Bioactivity Assessment Criterion for Drug Substances and Excipients

Arrhenius kinetic principles, in particular, Ea values, were used to assess the biological activity of drug substances in aqueous solutions with different D/H ratios. The obtained activation energies indicated that deuterium-depleted solutions had lower toxicity and biological activity. © 2016, Springer Science+Business Media New York

On the possibility of chiral structure-density submillimeter inhomogeneities existing in water

The existence of stable formations representing submillimeter density inhomogeneities in aqueous solutions was confirmed by using the laser light diffraction (LALLS) method and also the dynamic (DLS) and two-dimensional light scattering methods. The effect of low angle light scattering by giant water clusters depends on the presence of ions or dissolved substances in water solution, and also on the concentration of deuterium (heavy hydrogen isotope). It has been shown that the reduction of deuterium concentration results in the reduction of light scattering ability of protein nanoparticle preparations and water. The formation of long-living discrete water cluster structures possessing chiral properties was substantiated for explaining the manifestation of effects of weak impacts and low concentrations on biological objects. © 2017, Allerton Press, Inc

On the possibility of chiral structure-density submillimeter inhomogeneities existing in water

The existence of stable formations representing submillimeter density inhomogeneities in aqueous solutions was confirmed by using the laser light diffraction (LALLS) method and also the dynamic (DLS) and two-dimensional light scattering methods. The effect of low angle light scattering by giant water clusters depends on the presence of ions or dissolved substances in water solution, and also on the concentration of deuterium (heavy hydrogen isotope). It has been shown that the reduction of deuterium concentration results in the reduction of light scattering ability of protein nanoparticle preparations and water. The formation of long-living discrete water cluster structures possessing chiral properties was substantiated for explaining the manifestation of effects of weak impacts and low concentrations on biological objects. © 2017, Allerton Press, Inc

The new two-dimensional light scattering method for recognition of pharmaceutical enantiomers

The results of applying the developed mathematical model of the folding of two-dimensional light scattering (2D-LS) patterns into a descriptor to identify the enantiomers of optically active pharmaceutical substances are presented in the article. The following pharmaceutical substances were a subject of this research: L-valine, D-valine, racemic mixture L, D-valine, L-glucose, D-glucose, and L-ascorbic acid. A digital microscope with high spectral density was used to obtain instant 2D-LS patterns. The obtained data were mathematically processed using the original computer program “Vidan”, which uses a mathematical model for the folding of the 2D-LS pattern into descriptors, which are analogs of topological indices in quantitative structure-activity correlations approaches to drug analysis. The 10 descriptors were used as criteria for the difference in the 2D distribution of the scattered light intensity. The use of mono- and multidescriptor analyses allowed us to determine the authenticity of pharmaceutical substances of different classes and their optical isomers. It was found that the dispersion of crystalline substances of optical antipodes up to submicron size led to the leveling of light scattering patterns. The mathematical model was developed and applied for the folding of 2D-LS diagrams into a descriptor. This allowed us to identify the optical antipodes of pharmaceutical substances. © 2020. All rights reserved

Deuterium as a tool for changing the properties of pharmaceutical substances (Review)

The review is devoted to the influence of the hydrogen isotope–deuterium on biological models of organisms and the biological activity of pharmaceutical substances. The positions of the influence of deuterium on the properties of active pharmaceutical ingredients and excipients are examined from different perspectives. The first position reflects an increase in the kinetic isotope effect (KIE) in processes involving known pharmaceutical substances in aqueous solutions with a deuterium/protium ratio (D/H) below natural. For the first time, the dose-response diagram shows the identity of deuterium with essential trace elements, when a deficiency and excess of an element reduces the organism's vitality. Improved kinetic characteristics are demonstrated for the molecular and organism levels of different hierarchical gradations. In particular, they consist in the possibility of increasing the dissolution rate of substances by influencing the carbohydrate mutarotation processes and the optical activity of chiral substances, increased accumulation of essential elements in medicinal plants and other processes associated with a possible change in metabolic pathways in the cell and the organism as a whole. The second considered position of the influence of deuterium is associated with the use of deuterated substances–new compounds or obtained by substitution of protium in known protium analogues. The KIE is presented, which is expressed in a decrease in the biotransformation rate as a result of deuteration, it allows predicting a rapid development of the new direction in the development of drugs. Having an identical therapeutic effect, deuterated analogs provide improved pharmacokinetic characteristics, such as reduced toxicity, blocked epimerization of optically active substances, and a change in the mechanisms of biotransformation. The obtained results make it possible to predict the mechanisms of the effect of deuterium on the biochemical transformations of pharmaceutical substances in the organism. © 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd

Quasichemical description of the cell death kinetics of cellular biosensor Spirostomum ambigua for testing the biological activity of aqueous solutions

A kinetic method of biotesting of aqueous solutions using isolated cells of unicellular organism Spirostomum ambigua has been described. A kinetic scheme of interaction of cellular biosensor with ligands based on the Michaelis-Menten mechanism was proposed. It was shown that the death rate of S. ambigua featured the Arrhenius-type dependence on temperature. The activation energy was determined for different toxicants and drugs. For many compounds the activation energy of slow stage of the process of cellular biosensor death linearly correlates with parameter DL50 for the same substances at their oral administration to laboratory animals. © 2017, Allerton Press, Inc

The influence of deuterium on the properties of pharmaceutical substances (Review)

Introduction. The study discusses the hydrogen isotope2 H effect on the biological activity of pharmaceutical substances. Text. Two aspects of the deuterium effect on the properties of active pharmaceutical ingredients and excipients are considered. The first one involves the use of deuterated substances, new compounds or substituted counterparts. Replacing protium with deuterium is used to reduce the rate of biotransformation. The kinetic isotope effect (KIE), expressed in a decrease in the rate of biotransformation as a result of deuteration, allows us to predict the rapid development of new directions in the development of pharmaceuticals. With the same therapeutic effect, an improvement in pharmacokinetic characteristics, a decrease in toxicity, a blocking of the epimerization of optically active substances, a change in the mechanisms of action are observed. The second aspect of the deuterium effect is associated with an increase in KIE of known pharmaceutical substances in aqueous solutions with a deuterium/protium ratio (D/H) lower than in natural water. For the first time, dose-response diagrams for deuterium demonstrate identity with essential microelements. There is a safety zone for the certain D/H relationship, beyond which the organism's vitality decreases. Improved kinetic characteristics are demonstrated for molecular level and for biological objects of various hierarchical levels. In particular, they include the possibility of increasing the dissolution rate of substances, the influence on the processes of mutarotation and the optical activity of chiral substances, the degree of accumulation of necessary elements in medicinal plants, and other processes. Conclusion. The results make it possible to predict the mechanisms of deuterium influence on the biochemical transformations of pharmaceutical substances in the body. © Syroeshkin A. V., Elizarova T E., Pleteneva T. V., Uspenskaya E. V., Levitskaya O. V., Zlatskiy I. A., Maksimova T. V., 2020