Introduction. One of the intensive ways to increase the therapeutic efficacy and safety of a drug is a combination of several already known substances or chemical compounds, leading to the appearance of a synergistic effect. This method of creating a medicinal product is one of the most important trends in recent times, since the synergistic effect allows one to achieve greater pharmacological activity, expand the range of medical applications and reduce the toxic effect of the drug on the organism. These pharmaceutical active substances include a binary mixture "Dimixan"(mixture 4,6-dinitro-5,7-dichlorobenzofuroxan (4,6-DNDHBFO) and 5-nitro-4,6-dichlorobenzofuroxan (5-NDHBFO). They demonstrate potentiated synergism to the ultra-resistant mold fungus of the species Aspergillius niger. However, the synergy mechanism of the mixture of 5-NDHBFO and 4,6-DNDHBFO is not fully studied. The results of determining the thermodynamic characteristics and phase equilibria in these systems will make it possible to determine the nature of the interaction between 5-NDCBPO and 4,6-DNDCBPO, which will undoubtedly contribute to the optimal organization of the production of a promising drug.

Aim. Establishing the nature of the interaction between 5-NDHBFO and 4,6-DNDHBFO in the system.

Materials and methods. Using differential scanning calorimetry (DSC), phase equilibria in the 5-NDHBFO and 4,6-DNDHBFO systems were studied in a wide range of component concentrations. From the state diagram, the thermodynamic characteristics of the eutectic were determined: the enthalpy and entropy of melting of mixtures of 5-NDHBFO – 4,6-DNDHBFO at different ratios of components.

Results and discussion. Based on the results of the study, phase reactions with the physicochemical interaction of 5-NDHBFO and 4,6-DNDHBFO in two-component systems with the formation of eutectic alloys of the "solid solution" type are identified. The specific values of the enthalpies of melting of alloys of eutectic compositions were determined, from which the entropies of melting were calculated. The results of a study of the density of eutectic compositions of 5-NDHBFO – 4,6-DNDHBFO indicate the formation of an interstitial solid solution.

Conclusion. The nature of the interaction between 5-NDHBFO and 4,6-DNDHBFO in the system, leading to the appearance of a synergy effect, has been established. The results obtained are important for predicting the eutectic compositions of 5-NDHBFO and 4,6-DNDHBFO as active pharmaceutical ingredient with increased biological activity.

Introduction. Biologically active compounds 4,6-dinitro-5,7-dichlorobenzofuroxan (4,6-DNDHBFO) and 5-nitro-4,6-dichlorobenzofuroxan (5-NDHBFO) effectively in-hibit ultra-resistant microorganisms: Staphylococcus aureus, pathogenic fungi – Aspergillius niger, Coniophora cerebella, Candida albicanas and other microor-ganisms. Mixed systems based on 4,6-DNDHBFO and 5-NDHBFO exhibit high potentiated synergistic activity against Aspergillius niger. Currently, there are no full-fledged studies about the mechanism of synergism of 5-NDHBFO and 4,6-DNDHBFO in a solidphase system. The results of the study of solid-phase sys-tems 5-NDHBFO – 4,6-DNDHBFO by IR spectroscopy will make it possible to establish the nature of the interaction between the components of the binary mix-ture.

Aim. Experimental study of the intermolecular interaction of 5-NDHBFO with 4,6-DNDHBFO by the IR spectroscopy method.

Materials and methods. The intermolecular interaction of 5-NDHBFO with 4,6-DNDHBFO at different ratios in a solid-phase system was studied by the IR spectroscopy method.

Results and discussion. Based on the results of the study, the physico-chemical interaction of 5-NDHBPO with 4,6-DNDHBFO in solid-phase systems was revealed. Shifts and changes in the intensities of the characteristic frequencies of functional groups involved in the formation of intermolecular bonds between 5-NDHBPO and 4,6-DNDHBPO were revealed.

Conclusion. The nature of the interaction between 4,6-DNDHBFO and 5-NDHBFO in the solid-phase system was established, leading to the appearance of a synergy effect. The interaction of 5-NDHBFO with 4,6-DNDHBFO in a bi-nary system is due to the formation of an intermolecular hydrogen bond. The in-teraction involves the proton of the 5-NDHBFO molecule, the oxygen of the fu-roxan ring of 4,6-DNDHBFO, as well as the halogen atom of 4,6-DNDHBFO at an equimolar ratio of the components of the solid-phase system.

Introduction. Lipids are a widespread group of biologically active substances in nature, making up the bulk of the organic substances of all living organisms. They accumulate in plants in seeds, as well as in fruits and perform a number of vital functions: they are the main components of cell membranes and the energy reserve for the body.

Aim. Study of neutral lipids of sown oats (Avena sativa L.).

Materials and methods. The objects of the study were fruits (grains) of oats of the sown variety "Tashkent 1," harvested in the Republic of Uzbekistan.

 Results and discussions. Neutral lipids of oat grains have been found to contain 13 fatty acids with a predominance of the sum of oleic, linolenic and linoleic acids. The total degree of unsaturation was almost 78%. Absorption bands characteristic of these substances were observed in the IR spectrum of MEGC.

Conclusion. According to the results of the NL analysis, oat grains consisted of triacylglycerides and free LCDs, which were accompanied by hydrocarbons, phytosterols, triterpenoids and tocopherols.

Introduction. An innovative pharmaceutical substance based on the 3,7-diazabicyclo[3.3.1]nonane derivative provides long-term activation of AMPA receptors and the production of neurotrophic factors, which makes it possible to use it for the treatment of cognitive impairments and rehabilitation of patients who have undergone acute brain hypoxia. Given that this substance is able to be absorbed through the walls of the gastrointestinal tract and pass through the blood-brain barrier, there are no restrictions on the development of an oral dosage form. In addition, the oral dosage form has significant advantages when used in geriatric and pediatric practice.

Aim. The aim of the work was to carry out a comparative study of the possibility of using gelatin and hypromellose capsules for the development of the composition and technology for obtaining a dosage form containing a pharmaceutical substance based on a 3,7-diazabicyclo[3.3.1]nonane derivative.

Materials and methods. The study of the «Dissolution» test of gelatinous and hypromellose capsules was carried out on an ERWEKA DT 720 «Paddle stirrer» apparatus at a stirrer rotation speed of 50 rpm in three media: pH 1.2, pH 4.5 and pH 6.8. The content of the substance in each sample was determined by high performance liquid chromatography with UV detection.

Results and discussion. The results of the development and testing of capsules containing an original pharmaceutical substance of nootropic action based on a derivative of 3,7-diazabicyclo[3.3.1]nonane, which has low pharmaceutical and technological characteristics and is practically insoluble in water, are presented. The D/S value was ≥250.00 ml in each physiological pH range. The results of determining the dissolution of the developed dosage form in three media at pH values of 1.2, 4.5 and 6.8 showed a positive effect of the technology used on the solubility of the substance.

Conclusion. A significant increase in the solubility of the practically insoluble substance of the 3,7-diazabicyclo[3.3.1]nonane derivative in the developed dosage form was shown, which is the result of the use of a well-founded complex of excipients and the technology of moisture-activated granulation. According to the results obtained, (77.60 ± 2.50) % of the substance passes into the dissolution medium with a pH of 4.5 in 45 minutes. The research results are used to develop a technological scheme for obtaining a finished dosage form, its indicators and quality standards.

Introduction. Vibration cavitation homogenizers are increasingly used in various industries, including the pharmaceutical industry – for the preparation of creams, gels to give them a homogeneous composition, and more recently for the extraction of valuable substances from plant materials. As we have shown earlier, a comparison of the extraction of dioscin from fenugreek seeds, carried out in devices of various designs, under the same conditions for organizing the process showed that the most effective method was the extraction method in a vibro-cavitation field. Obviously, this is due to the fact that cavitation reduces the diffusion resistance of the process and, thus, increases the intensity of the process of transferring the mass of a substance from the solid phase to the solution. However, the extraction process in apparatus of this type is complex and is accompanied by crushing of seeds, which leads to a change in the dispersed composition of the solid phase.

Aim. Conduct a theoretical and experimental analysis of the process of grinding hay fenugreek seeds particles in a vibrocavitation homogenizer, accompanied by the extraction of biologically active substances, as well as obtaining dependences that allow evaluating the contribution of grinding to the formation of the dispersed composition of the meal in this apparatus and determining the average particle size as a result of crushing. In earlier works, using the example of the extraction of dioscin from fenugreek seeds, it was shown that an increase in the rotor speed increases the yield of biologically active substances. However, fine grinding of raw materials often leads to the formation of a sediment layer that pollutes the solution with ballast substances and complicates its purification, and also reduces the yield of biologically active substances, therefore, the study of this process is necessary to control the dispersed composition in order to ensure the highest extraction efficiency in devices of this type.

Materials and methods. The first stage of the study was the theoretical analysis of the grinding process, since it is a special case of a large class of processes in which the dispersed composition of the solid phase is not constant. Therefore, in this work, for the mathematical description of particle grinding, a model is used that takes into account the kinetic features of the process under consideration. An experimental study of the extraction of valuable components from plant raw materials was carried out in a laboratory setup with a vibro-cavitation homogenizer of periodic action. As a raw material, we used fenugreek seeds purchased from LLC «Stoing», Moscow (Russia), which we used for research. Commodity analysis showed the compliance of raw materials with the requirements of the GF XIV edition. The initial, aqueous solution of ethanol (volume concentration 60 %) with fenugreek seeds was loaded into glass 6, in a volume of 0.2 liters, then the rotor of the apparatus was brought into rotation and brought to a given rotation frequency. The experiments were carried out at a rotation frequency of 1000, 3000 and 5000 rpm (16.7; 50 and 83.3) 1/s. At each value of the rotor speed, the process time varied in the range from 0 to 50 minutes, and the process was carried out for 60, 120, 180, 240 and 300 seconds. Studies carried out for 5 minutes or more showed that the dispersed composition of the meal practically does not change over time, but significantly depends on the rotor speed. Thus, after 5 minutes, a certain stabilization of the dispersed composition occurs and further residence of the material in the apparatus does not lead to a noticeable change in the dispersed composition. After each experiment, the meal was taken, dried, and sieve analysis of the dispersed composition was carried out.

Results and discussion. Based on the results obtained by processing the experimental data according to the equation, the values of the average probability of particle crushing were calculated and, as it turned out, it practically does not depend on time, but depends only on the rotor speed. The dependence of the change in the average probability of particle grinding at different rotor speed was obtained. The analysis of these results showed that the value of the average probability of particle grinding in the cavitation homogenizer increases with an increase in the rotor speed, which is quite expected, since the frequency of contacts of particles with the working organs of the apparatus increases. In addition, the obtained dependence for the average probability of particle crushing is linear. This Expression quite accurately describes the values of the change in time of the relative mass of particles in the working range n = 16.7 – 83.3 1/s. Taking these values into account, the experimental and calculated results are in good agreement.

Conclusions. The proposed approach and the results obtained can be used to assess the dispersed composition of particles obtained in other designs of devices of similar action.

Introduction. This article provides a tentative justification of use of soft contact lenses as a carrier of ophthalmological solutions to eye tissues.

Aim. The aim of the research is to develop the composition of the ophthalmic transport system for the treatment of glaucoma. Also, the proposed manufacturing algorithms were proposed for drug loading ophthalmological solutions.

Materials and methods. Preparation of sodium hyaluronate solution was carried out based on the methodology described in EP 7.0 [01/2011:1472] (Sodium hyaluronate).

Results and discussion. The conducted investigation with the purpose to justify a concentration of sodium hyaluronate helped to determine its concentration that gives the viscosity level as close to the upper limit stated in Russian Pharmacopoeia as possible. Buffer solution was chosen with criteria to use as less components in ophthalmological solution as possible. Also, it was found out that the more components are added to the viscous solution, the more viscosity level is decreased. Thus, initial viscosity of solution containing sodium hyaluronate was 149.59 mm²/s, and after addition of active pharmaceutical substance it dropped down to 88.49 mm²/s and 81.36 mm²/s for model solution number 1 and 2, respectively. After addition of citric acid and disodium hydrophosphate, the viscosity of model solution was found to be 78.11 mm²/s and 75.28 mm²/s for model solution number 1 and 2, respectively.

Conclusion. As a result of the studies, two alternative model compositions of an ophthalmic solution for the saturation of soft contact lenses for the treatment of glaucoma were proposed. The choice of active pharmaceutical substances, and excipients has been justified. Technological procedure of preparation of model solution was described and explained, where the most attention was paid on dissolving of sodium hyaluronate in purified water.

Introduction. Skin cancers came first in Russia in numbers of oncological diseases. Melanoma, making up only a small part of these cases, leads to the most serious consequences. The nuclear medicine methods application is necessary at the stages of clarifying the diagnosis, searching for remote metastases and the treatment monitoring. The work is devoted to one of the stages of the radiopharmaceutical development for the diagnostics of malignant melanoma and its metastases based on the synthetic analog of α-melanocyte stimulating hormone (SAH) and radionuclide Tc-99m.

Aim. The selection of optimal conditions for the preparation of the SAH ∙ ^99mTc complex and the study of the using possibility it as a diagnostic tool in in vitro experiments.

Materials and methods. Experimental work was carried out to optimize the conditions for obtaining the complex compound SAH ∙ ^99mTc. The binding and internalization of this compound by B16-F0 melanoma cells has been studied.

Results and discussion. The results of labeling SAH with a ^99mTc radionuclide under a wide range of conditions were obtained both by the direct method and using the intermediate complex. The target compound rapidly binds to B16-F0 melanoma cells. The degree of internalization is more than 85 %.

Conclusion. Based on the results of chemical experiments and data from in vitro experiments, optimal conditions for obtaining a complex compound SAH ∙ ^99mTc with a radiochemical yield of more than 90 % were found. The mechanism of binding of this compound to malignant melanoma cells has been established.

Introduction. This article considers the ways to optimize the motherwort tincture formulation while reducing the content of ethyl alcohol in the finished product. Qualitative and quantitative tincture test items depending on extraction method used and extractant concentration have been studied.

Aim. To study the possibility of reducing the content of ethyl alcohol in motherwort tincture.

Materials and methods. Comparison of quantitative and qualitative test items of tincture samples prepared by percolation, maceration, fractional maceration, modified fractional maceration is carried out. Quantitative comparative test items: dry residue, ethyl alcohol content, microbiological purity, quantitation, qualitative reactions – the presence of phenolic compounds, flavonoids in the samples (qualitative reactions, HPLC), iridoids (TLC) was used.

Results and discussion. The developed method of modified fractional maceration consists in extracting herb materials with a more concentrated extractant (in the study, 80 %, 60 %, 40 % ethyl alcohol), then the subsequent extraction of herb materials with purified water. Comparison of the presence of different classes of biologically active substances in tinctures obtained by different technological methods and in infusions is carried out.

Conclusion. It has been established that the most rational method is to obtain a tincture by modified fractional maceration method with ethyl alcohol content NLT 35 % in the finished product. The obtained results can be used in pharmaceutical industry for drug production by extractive methods, as well as for studies on technology optimization for obtaining extractive drugs from medicinal herb materials.

Introduction. 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil is a substance of scientific interest intended for the treatment of HIV-infection. However, its low bioavailability is a major limitation in successful drug delivery by oral route. Therefore, the objective of the present work was to enhance itssolubility by using solid dispersion technique followed by the development of a solid dosage form.

Aim. Development of the composition and technology of tablets based on 1- [2-(2-benzoylphenoxy)ethyl]-6-methyluracil with the appropriate technological properties providing the most complete release of the active pharmaceutical ingredient (API) in vitro.

Materials and methods. The pharmaceutical substance 1-[2-(2-benzoylphenoxy) ethyl]-6-methyluracil is a crystalline powder with poor solubility. Solid dispersions were prepared using Lactose, Kollidon® 17PF, Kollidon® 30, Kollidon® VA64, Kollidon 90F, and PEG-6000 as a carrier mostly in 1:4 ratio by two methods – co-melting and solvent evaporation. The technological properties of substance, tablet masses and tablet quality were determined according to the methods described in the State Pharmacopoeia of the Russian Federation (14th edition).

Results and discussion. Article shows the results of development of the composition and technology of a medicine in the form of tablets based on the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil. Solid dispersion technique was used to improve the biopharmaceutical properties of 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil.

Conclusion. In vitro dissolution studies showed enhanced dissolution rate of the drug-loaded solid dispersion with Kollidon 17PF as a carrier as compared to pure drug.

Introduction. Dental gel is one of the modern dosage forms with optimal biopharmaceutical properties for the treatment and prevention of oral diseases An isoquinoline alkaloid berberine is the promising active substance with antibacterial and anti-inflammatory effect, capable of forming stable dispersed systems with gel-forming components. It is noteworthy that, despite the pronounced antimicrobial activity of the alkaloid berberine, there is currently no dental dosage form with this component on the pharmaceutical market, and therefore research in this direction is of great interest.

Aim. Selection of the optimal technology for obtaining dental gel with berberine for the treatment of oral diseases.

Materials and methods. Berberine bisulfate (manufactured by CJSC «Vifitech», Obolensk, Moscow region, RF), poloxamers P407 and P338 (EP, USP/N; BASF, Germany), propylene glycol (USP; BASF, Germany), sodium chloride (Sigma-Aldrich, Germany, Cat. No. S9888), mucin type II from a pig stomach (Sigma-Aldrich, Germany, Cat. No. M2378). In the development of the composition and technology for the preparation of gels, a magnetic stirrer with a temperature control function (C-MAG HS 7 from IKA, Germany) was used. Gels were prepared by the «hot method» and «cold method».

Results and discussion. The production of the gel by the «hot method» provided a uniform dosage form. The obtained pH value is within the range of optimal diapason. Measurement of the specific peel force of the model gel sample showed pronounced mucoadhesive properties, which indicates that there is no need to adjust this parameter by introducing additional components into the formulation. The spectroscopic method is applicable for the analysis of berberine gel. It has been found that a significant dilution of the reference substance sample is required to develop an identification procedure.

Conclusion. The production of a sample of the dosage form by the «hot method» is optimal, which is probably due to the effect of solubilization and better distribution of the active substance in the base.

Introduction. Quantitative assessment of the active substance is necessary and perhaps the most significant part of the drug quality control. Validation of the analytical methods of quantitative assessment ensures their compliance with high requirements. The present study describes the development and validation of a spectrophotometry method for the quantitative evaluation of the active substance in the drug form of the national antitumor and antiangiogenic drug «Dimeric macrocyclic tannin (DMT) lyophilizate for solution for injection, 100 mg».

Aim. The development and validation of the assay method for the standardization of «DMT lyophilizate for solution for injection, 100 mg».

Materials and metods. The study used «DMT lyophilizate for solution for injection, 100 mg» and the active substance DMT. Method – spectrophotometry.

Results and discussion. The methodof the quantitative assessment of the active substance in the DMT lyophilized drug by direct UV spectrophotometry was developed and the validation characteristics of the method were defined as a result of the study.

Conclusion. The validation results showed that the assay method of DMT in the drug form has the appropriate accuracy, precision and linearity. The obtained results correspond to the approved criteria that allow the use of the developed methodology for evaluating the quality of the drug.

Introduction. Promising sources of preparation of antiinflammatory drugs of interest for practical medicine are substances of plant origin. One of them is eucalimine, isolated from leaves or shoots of eucalyptus prutoid (Eucalyptus viminalis Labil) of the myrtle family (Myrtaceae), is a purified sum of terpenoid phenoloaldehydes of the floroglucine series (euglobals) and triterpenoids.

Aim. The purpose of the present work is to create drug pencils with eucalimine for the prevention and treatment of inflammatory skin diseases.

Materials and methods. The object of research is eucalymin. The study of the shape and size of ekalimine particles and its distribution in various dispersion media: cetyl alcohol, stearyl alcohol, emulsion wax, castor oil, peach oil, medical petroleum jelly was carried out.

Results and discussion. The paper presents the results of experimental studies justifying the selection of adjuvants for medical pencils and their standardization.

Conclusion. The composition and technology of medicinal pencils with eucalimine for external use has been developed, quality indicators have been established.

Introduction. Modern pharmacognostic research is aimed at searching for plant biologically active individual compounds (hereinafter referred to as RBAIS) isolated from plant extracts.

Aim. Validation of HPLC-UV quantitative determination of sapogenin diosgenin in plant extracts from fenugreek seeds.

Materials and methods. The object of study was raw materials-fenugreek seeds produced as medicinal plant raw materials by LLC «Sage» (Irkutsk). Validation of the method was carried out according to the parameters: specificity, linearity, correctness, precision in accordance with the requirements of SP XIV. One series of medicinal plant raw materials was used for the analysis, such as serial number – 010117, release date – 15 february 2017.

Results and discussion. Validation characteristics were determined and their compliance with the necessary acceptance criteria was experimentally confirmed.

Conclusion. It is established that the developed method of identification and quantitative determination of diosgenin in fenugreek seed extracts by HPLC-UV is correct, precise, specific and linear in the analytical field.

Introduction. In order to standardize the quality indicators during the expected shelf life of the developed drug naltrexone hydrochloride in the form of a nasal spray containing a high concentration of poloxamer and benzalkonium chloride as a preservative, a microbiological study was carried out. The possibility of using the membrane filtration method for testing prototypes recommended by the State Pharmacopoeia XIV.

Aim. Study and selection of test conditions for the «microbiological purity» indicator of nasal spray samples containing naltrexone hydrochloride.

Materials and methods. As an object of research, a naltrexone hydrochloride nasal spray was used. When analyzing the microbiological purity, the membrane filtration method recommended in the State Pharmacopoeia XIV.

Results and discussion. As part of the study, it was found that the samples of the drug meet the requirements for a microbiological indicator for drugs of category 2. Testing the suitability of the method for samples of the dosage form showed that the antimicrobial effect of the drug was completely removed by washing the filter, which was proved by inoculation of indicator test microorganisms, the quantitative and qualitative nature of growth, which did not differ from the control without the drug.

Conclusion. As a result of the studies carried out, the optimal test conditions for the «Microbiological purity» indicator for the nasal spray containing naltrexone hydrochloride were selected and substantiated.

Introduction. Benzalkonium chloride is widely used as a conservation agent in medicines. For quantitative determination, the methods described in the European and American Pharmacopoeias by chromatography using columns with nitrile sorbent are often used. However, in order to unify the methods and simplify the quality control technology in the production process, it is advisable to adapt the existing methods for new goals and objectives.

Aim. To develop a method for the quantitative determination of benzalkonium chloride in a nasal spray containing a thermosensitive polymer Poloxamer 407 and validate it.

Materials and methods. As an object of research, a naltrexone hydrochloride nasal spray was used. The quantitative determination of naltrexone in the test sample was developed using a Dionex UltiMate 3000 high-performance liquid chromatograph (Thermo Fisher Scientific, USA) equipped with a diode-matrix detector.

Results and discussion. The paper explored the possibility of using an earlier developed method for the quantitative determination of naltrexone hydrochloride for the quantitative determination of benzalkonium chloride in the composition of a nasal spray. Based on the results obtained, changes were made to the quantitative determination method, and the sample preparation of the samples under study was adapted.

Conclusion. As a result of the studies carried out, the most acceptable conditions for the preparation of the nasal spray for the quantitative determination of the preservative were selected. The developed technique provides for the chromatographic conditions previously used for the determination of naltrexone hydrochloride, which makes it possible to use the equipment as efficiently as possible in the analysis of the finished drug. The method has been validated and its specificity, linearity, correctness and precision have been proven.

Introduction. Currently, more than 600 thousand people a year are affected by malignant tumors on the territory of the Russian Federation. Despite the large selection of antitumor drugs and the variety of mechanisms of their action, the effectiveness of existing drugs continues to be insufficient. The main disadvantages of most antitumor drugs are the emergence of tolerance to them of tumor cells, a limited range of action and high toxicity. In this regard, the creation of effective original domestic antitumor drugs still remains relevant. Among the numerous natural and synthetic heterocyclic compounds that exhibit antitumor activity, indolo[2,3-a]carbazole derivatives that can initiate various pathways of tumor cell death are of increasing interest. The main targets for their action are topoisomerases and protein kinases, which play an important role in the processes of replication, transcription, repair or recombination of deoxyribonucleic acid (DNA). Due to this, in addition to antitumor activity, this group of compounds shows antibacterial, аntiprotozoal and immunomodulatory activity, which makes them a very promising class of candidates for the creation of new drugs.

Text. The purpose of this review is to discuss instrumental methods for qualitative and quantitative analysis of indolo[2,3-a]carbazole derivatives used in the world's leading pharmacopoeias. These methods can be used both in pharmacokinetic studies, and in the standardization of these compounds, in the form of pharmaceutical substances, or as part of drug forms.

Conclusion. To further introduce a new group of antitumor drugs based on indole[2,3-a]carbazole derivatives into medical practice, a deep and thorough study of their physical and chemical properties is necessary. Justification and development of analysis methods allow us to develop methods applicable to pharmacokinetic studies, as well as to create regulatory documents for quality control and standardization of indolo[2,3-a]carbazole derivatives as pharmaceutical substances. A study of the literature that describes methods for analyzing indolo[2,3-a]carbazole derivatives indicates that spectrometric (infrared and ultraviolet spectrometry) and chromatographic (thin-layer chromatography and high-performance liquid chromatography) methods are most often used to determine the authenticity and quantitative analysis of these compounds.

Introduction. This review describes the physicochemical properties that determine the use of hyaluronic acid in ophthalmology. We have studied methods for determining hyaluronic acid using various analytical methods.

Text. Hyaluronic acid is a high molecular weight glycosaminoglycan that consists of repeating disaccharides of N-acetylglucosamine and D-glucuronic acid. Carboxyl, hydroxyl and acetoamide groups give hydrophilic properties to the molecule of this anionic heteropolysaccharide. Depending on how the hyaluronic acid is obtained, its molecular weight varies over a wide range. Researchers developed methods for controlling hyaluronic acid, which include the turbidimetric titration method, the method of high-performance capillary electrophoresis and high-performance liquid chromatography and IR spectroscopic method.

Conclusion. Due to its properties, hyaluronic acid is widely used as an active ingredient in pharmaceutical preparations. Today, there are a number of methods for the determination of hyaluronic acid, including the method of turbidimetric titration, the method of capillary electrophoresis. High performance liquid chromatography (HPLC) and IR spectroscopy methods are presented in the Japanese Pharmacopoeia and the European Pharmacopoeia. These techniques are widely used due to their high reproducibility, accuracy, and relative simplicity.

Introduction. Recently, there has been a growing trend in the number of obese and overweight patients. To date, sibutramine is the most effective drug for treating obesity and overweight. The drug is an inhibitor of the reuptake of serotonin and norepinephrine, which leads to a decrease in hunger, and therefore, to weight loss.

Aim. To develop and validate a methodology for the determination of sibutramine in drugs by capillary electrophoresis (CE) using an ultraviolet diode array detector.

Materials and methods. Quantitative determination of sibutramine in drugs was carried out using the CE method with an ultraviolet diode array detector. A solution of phosphate buffer 50 mmol pH = 7.0 was used as a solvent and working electrolyte; to separate the peaks – quartz capillary 56 cm, 50 μm.

Results and discussion. The developed method was validated according to the following parameters: specificity, linearity, correctness, precision, limit of detection and limit of quantification.

Conclusion. A method for the quantitative determination of sibutramine in drugs by the CE method using an ultraviolet diode array detector has been developed and validated. This method meets all the requirements of General Pharmacopoeia Monograph 1.1.0012.15 «Validation of the analytical method» and can be used to control the quality of drugs, the active pharmaceutical substance of which is sibutramine.

Introduction. B-cell malignancies of the plasma cell leads to the second most spread hematological malignancy disease, called multiple myeloma. Pomalidomide is used in case of previous multiple myeloma ineffective treatment. Pomalidomide is a thalidomide synthetic derived, approved as immunomodulatory drug by the Food and Drug Administration (FDA). Nowadays, detection of pomalidomide in blood plasma by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) is not spread. Moreover, the detection and the experimental setting accumulated data are varying greatly. This investigation provides development and validation of pomalidomide aiming to determine human blood plasma by HPLC-MS/MS method. The samples were processed by methanol protein precipitation.

Aim. The aim of this study is to develop a method for the pomalidomide in human plasma by HPLC-MS/MS for pharmacokinetic studies.

Materials and methods. Determination of pomalidomide in plasma by HPLC-MS/MS. The samples were processed by methanol protein precipitation.

Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, spike recovery, lower limit of quantification, detection limit, carry-over and stability.

Conclusion. The method of the determination of pomalidomide in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 1,00 – 500,00 ng/ml. Method could be applied to pomalidomide determination in plasma for PK and BE studies.

Introduction. A fixed dose combination of telmisartan and amlodipine is widely used in clinical practice during hypertension treatment. Combination of telmisartan and amlodipine demonstrates potentiating synergistic effect on blood pressure decrease. A bioequivalence study of Telzap® AM with coadministered Mikardis® and Norvask® was conducted with 60 volunteers.

Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® AM (telmisartan + amlodipine, tablets, 80 + 10 mg, Zentiva ks company, Czech Republic) and coadministrated monocomponent drug products Mikardis® (telmisartan, tablets 80 mg, Beringer Ingelheim International GmbH, Germany) and Norvask® [amlodipine, tablets 10 mg, Pfizer HCP Corporation (USA), Russia] in healthy volunteers after a single administration under fasting.

Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period replicate clinical trial was conducted. The concentrations of amlodipine and telmisartan in plasma samples were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters C_max and AUC_0-72 were calculated.

Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of amlodipine and telmisartan. All 90 % confidence intervals for the estimated pharmacokinetic parameters of amlodipine were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC_0-72, and 76.73–130.32 % for C_max.

Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

Introduction. The article is focused on differences in quality assurance-related obligations and responsibilities between Marketing Authorisation Holders (MAHs) and manufacturing authorisation holder (manufacturers) in pharmaceutical industry. In case of outsourcing and technical agreements there is a need to differentiate responsibilities related to quality assurance between the above mentioned categories.

Text. The guidelines for the pharmaceutical sector of the European Union (EU) provide guidance on the responsibilities of the MAHs in relation to the GMP rules, which are scattered throughout the various chapters of the GMP and its appendices. In addition, certain provisions on this topic are contained in the EU directives. With this in mind the European Medicines Agency (EMA) issued in January 2020 a draft Reflection paper on Good manufacturing practice and Marketing Authorisation Holders. The draft clarifies that while certain activities of an MAH may be delegated to the manufacturer, MAH retains ultimate responsibility for the performance of a medicinal product, its safety, quality and efficacy. The important obligation of MAH in this context is to facilitate GMP compliance by establishing a robust two-way communication system with national competent authorities, manufacturing sites, Qualified Persons (QPs) certifying batches before release, and other interested parties. The MAH ought to communicate to manufacturing personnel, normally through QPs, production processes and related quality control procedures, including subsequent variations, described in registration dossiers.

Conclusion. A general one conclusion: in view of rapid developments in the EU GMP Guide, the Eurasian Economic Union GMP requirements ought to be updated. In respect of specific responsibilities of MAH pertaining to GMP compliance the EMA draft Reflection paper merits attention as a guidance regarding separation of obligations and responsibilities between MAH and personnel of manufacturing sights.

Introduction. At the stage of transition from national to a uniform of circulation of pharmaceutical products regulation at the Eurasian Economic Union (EAEU) framework, harmonization of requirements for the development of medicines determines the need of use modern approaches, including the use of new methods and tools, thus to assure EAEU and other integration associations markets entry for effective and safe medicinal products. The new medicinal products development model, described in the ICH guidelines (The International Conference of Harmonization), involves a science-based approach to developing, using appropriate tools, such as defining a target product profile, establishing of critical quality indicators, risk assessment, establishment of design space, development of control strategy, drug lifecycle management and continuous improvement of existing processes. These approaches and techniques are not a part of the traditional paradigm of pharmaceutical development; although they are poorly understood and expensive, they are ensure the market entry of effective products with the desired quality parameters.

Aim. Main purposes of this work are to compare two concepts of pharmaceutical developmentof medicinal products: traditional and improved, and to consider the necessity of new model usingin generic products development.

Materials and methods. Research materials of this study were available literature sources, regulatory documents and guidelines regarding pharmaceutical products development, registration dossier documents, reports of regulatory authorities, pharmaceutical development reports. The achieving of study purposes was carried out on the basis of scientific research methods in the framework of comparative and logical analysis, and through the analysis and interpretation of the obtained data regarding pharmaceutical development of medicinal products.

Results and discussion. On the basis of the data provided, author assess that modern concept it is a new, improved tool for development of medicinal products with specified quality parameters.

Conclusion. The modern paradigm requires new expensive methods, stuff special knowledge and skills, investment and time, but it is effectively oriented on development of effective and safe medicinal products.

Introduction. N-nitrosamine compounds are potent genotoxic agents in animal species and some are classified as probable human carcinogens. This group of genotoxic impurities was found in drugs such as angiotensin II receptor blockers, histamine H1 receptor antagonists, and synthetic antidiabetic drugs. This discovery caused a flurry of alarm in the global pharmaceutical industry and resulted in a series of international investigations trying to determine root causes of nitrosamine formation in medicinal products and to find ways to minimize risks associated with nitrosamine contamination.

Text. This paper provides an overview of the current state of the problem. It summarises the main pathways of N-nitrosamine formation in medicinal products at the stages from synthesis of active pharmaceutical ingredients to storage of finished pharmaceutical products. The paper describes the main mechanism responsible for the toxic effect of this group of impurities in human body. It also describes methods of extraction and analysis of N-nitrosamines found in medicinal products. It was demonstrated that high-performance liquid chromatography and gas chromatography-mass spectrometry are a golden standard for the detection of these contaminants. The paper also touches upon the main principles of setting limits for nitrosamine impurities in medicinal products.

Conclusion. The data presented give a picture of the root causes of N-nitrosamine formation in medicinal products, as well as current detection and control methods used worldwide. Meanwhile, the paper raises a key issue about the need to develop Russian standards that would control the purity of medicinal products in terms of N-nitrosamine impurities. For that end, it will be necessary to draw on the experience of the leading USA and EU regulatory authorities.