In this work, four derivatives of arginine with biologically active acids: acetylsalicylic, butyric, nicotinic, and succinic acids were obtained and characterized using UV-visible, IR, 1H NMR, and 13C NMR spectroscopy. In addition to spectroscopic analyses, DFT calculations were applied to predict the physicochemical properties of the studied compounds. The IR and NMR parameters were evaluated and compared with those experimental results obtained in the spectra. Moreover, the electronic transitions in the UV-Vis region of the electromagnetic spectrum were studied through the visualization of FMOs as well a calculation of energy gap values and TD-DFT calculations. It was found that the compounds maximally absorb the electromagnetic radiation at a wavelength range of 156.78–181.54 nm which can be due to π–π* and n–π* electronic transitions. Finally, QTAIM topological analysis showed that inter-molecular hydrogen bonds have a key role in the formation of arginine derivatives.

A simple, fast, sensitive method for the determination of preservatives (methyl parahydroxybenzoate, propyl parahydroxybenzoate) in the finished dosage form of sodium oxybutyrate syrup based on the simultaneous determination of preservatives using high performance liquid chromatography (HPLC) is proposed. The HPLC method was validated. The correlation coefficient of the linearity of the technique was 0.999 in the application range of 80–120 % of the normalized value. The calibration graph is linear in the region of 0.495–0.990 mg/ml of methyl 4-hydroxybenzoate and 0.165–0.330 mg/ml of propyl 4-hydroxybenzoate. It has been established that the analytical characteristics of the test procedure (selectivity, linearity, correctness, repeatability, reproducibility) satisfy the selected acceptance criteria.

Цель исследования. Сравнительная оценка биоэквивалентности тестируемого лекарственного средства Модафен, капсулы 100 мг, производства ГНУ «ИФОХ НАН Беларуси» и референтного лекарственного средства Вигил, таблетки 100 мг, производства Laboratoires Macors, Осер, Франция (держатель регистрационного удостоверения «Teva Pharmaceuticals CR, s.r.o.», Прага, Чешская Республика). Материалы и методы. Исследование проводилось по схеме простого открытого рандомизированного контролируемого клинического исследования с перекрестным дизайном в 2 периода и в 2 последовательности. Исследование проведено с участием 30 здоровых добровольцев в условиях однократного перорального приема натощак препарата Модафен в сравнении с лекарственным средством Вигил в параллельных группах с перекрестным дизайном. Добровольцы были обоего пола в возрасте от 18 до 55 лет, средний возраст составил 34,93±11,19 года. Средний ИМТ – 23,7±0,5. Группы по 15 человек принимали однократно по 2 капсулы препарата Модафен или 2 таблетки препарата Вигил, что соответствует 200 мг модафинила. Забор крови для количественного определения содержания модафинила производили за 60 мин. до приема препарата (0,0) и затем через 0,5, через 1,0, 1,5, 2,0, 2,5, 3,0, 3,5, 4,0, 6,0, 8,0, 12,0, 24,0, 36,0, 48,0 часа после приема препаратов. Концентрацию модафинила в сыворотке крови определяли методом высокоэффективной жидкостной хроматографии с масс-спектрометрическим детектированием по методике, разработанной и валидированнойв аналитической лаборатории. Результаты. Исследованные фармакокинетические параметры, основанные на измеренных концентрациях модафинила, свидетельствуют об отсутствии различий между сравниваемыми препаратами. Значения Сmax для лекарственного средства Модафен (капсулы 100 мг, содержащие 100 мг модафинила, производства ГНУ «ИФОХ НАН Беларуси», Республика Беларусь) и препарата Вигил (таблетки 100 мг, содержащие 100 мг модафинила, производства Laboratoires Macors, Осер, Франция) составили 3816,210±591,934 нг/мл и 4254,713±545,051 нг/мл, АUС(0–t) – 53709,995±10696,939 нг×ч/мл и 55357,522±10088,705 нг×ч/мл, АUC(0–∞) – 57317,682±12062,538 нг×ч/мл и 58682,743±11176,523 нг×ч/мл. Дисперсионный анализ значений из рассчитанных фармакокинетических параметров не выявил статистически значимых различий, что свидетельствует об отсутствии влияния типа лекарственного средства, последовательности приема лекарственных средств и дизайна исследования на вариабельность полученных данных. Для показателей Cmax, АUС(0–t) и АUC(0–∞) коэффициенты внутрииндивидуальных различий не превышают 30%, применен доверительный интервал в пределах 80–125%. Заключение. Изученные лекарственные формы модафинила биоэквивалентны. Purpose. The purpose of this study is a comparative assessment of the bioequivalence of the tested drug Modafen, capsules 100 mg, produced by the State Scientific Institution "IPOC NAS of Belarus" and the reference drug Vigil, tablets 100 mg, manufactured by Laboratoires Macors, Auxerre, France (holder of the registration certificate "Teva Pharmaceuticals CR, s.r.o.", Prague, Czech Republic). Materials and methods. The study was conducted according to the design of a simple open randomized controlled clinical study with a cross-over design in 2 periods and in 2 sequences. The study was conducted with the participation of 30 healthy volunteers, in conditions of a single oral dose on an empty stomach Modafen, in comparison with the drug VIGIL in parallel groups with a crossover design. Volunteers of both sexes aged 18 to 55 years, the average age was: 34.93±11.19 years. Mean BMI 23.7±0.5. Groups of 15 people took once 2 capsules of the drug Modafen or 2 tablets of the drug Vigil, which corresponds to 200 mg of modafinil. Blood sampling for quantitative determination of the content of modafinil was carried out for 60 minutes before taking the drug (0.0) and then after 0.5 after 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 hours after taking the drugs. The concentration of modafinil in blood serum was determined by high performance liquid chromatography with mass spectrometric detection according to the method developed and validated in the analytical laboratory. Results. The studied pharmacokinetic parameters, based on the measured concentrations of modafinil, indicate no differences between the compared drugs. The Cmax values for MODAFEN medicines (100 mg capsules containing 100 mg of modafinil, produced by IPOC National Academy of Sciences of Belarus, Republic of Belarus) and the drug VIGIL (100 mg tablets containing 100 mg of modafinil, manufactured by Laboratoires Macors, Auxerre, France were 3816.210±591.934 ng/ml and 4254.713±545.051 ng/ml, AUC(0–t) – 53709.995±10696.939 ng×h/ml and 55357.522±10088.705 ng×h/ml, AUC(0–∞) – 57317.682±12062.538 ng×h/ml and 58682.743±11176.523 ng×h/ml. Analysis of variance of the values from the calculated pharmacokinetic parameters did not reveal statistically significant differences, which indicates that the type of drug, the sequence of drug administration and study design did not influence the variability of the data obtained. For indicators Cmax, AUC(0–t) and AUC(0–∞), the coefficients of intra-individual differences do not exceed 30%, a confidence interval of 80–125% is applied. Conclusion. The studied dosage forms of modafinil are bioequivalent.

The effect of the crystallization conditions of modafinil from its methanol solutions on the polymorphic state of the resulting substance was studied using the X-ray powder diffraction method. It is shown that changes in the cooling rate and the concentration of saturated solutions have an effect on obtaining samples of the modafinil substance with differences in diffractometric characteristics. Moreover, the cooling rate practically does not affect the yield of the crystalline product, which depends on the degree of saturation of crystallization solutions. It was found that the I polymorphic form of modafinil can be obtained from modafinil solutions with a concentration in the range of 0.34–0.44 M with slow cooling of solutions, mainly with a temperature gradient of 5–10 °C/hour to a temperature of 5 ± 2 °C. An increase in the cooling rate of saturated solutions and their concentration >0.44 M leads to the production of mixed polymorphic forms of modafinil crystals.

The paper presents the data of semi-empirical and theoretical calculations of molecules in the medium of the solvent, their absorption spectrum and the optimized structure with the value of the total energy of the system.

Validation of the quantitative determination of the threonylthreonine substance was carried out in terms of specificity, linearity, correctness, precision, including repeatability and reproducibility. The linearity correlation coefficient of the method was 0.99998 in the range of 80–120 % of the standardized value. The calculated Student’s coefficients for the range 80, 100, 120 % are respectively equal to 1.32; 0.31; 0.55 and do not exceed the permissible limit values. The open rate was 100.07 %. The repeatability limit for one measurement group was – 0.20; for two – 0.366 in accordance with the eligibility criteria. The calculated Student’s (t = 1.34) and Fisher’s (F = 2.00) criteria for two groups of measurements did not exceed the permissible values. The developed technique for potentiometric titration of the threonylthreonine substance in a non-aqueous medium is valid.

Condensed indole derivatives of the 1,2,4-triazino[5,6-b]indole group show high biological activity and are of interest for the development of pharmaceuticals that have antihypoxic and antisurditant effects. By S-aminoalkylation reactions on a thione group, S-aminoalkyl derivatives of 1,2,4-triazino[5,6-b]indole-3-thione that were subject to hydrobromination in order to obtain the form of hydrobromides were synthesized, isolated and characterized.

Sorbtion of dipeptides leucylisoleucine, threonylthreonine and their monomeric amino acids leucine and threonine by anionite AV-17 and cationite KU-2-8 in a wide range of equilibrium concentrations has been studied. It was shown that the presence of hydrophilic OH-groups in the threonine molecule promotes superequivalent sorbtion of threonine on the cation exchanger. The presence of an OH-groups in the side chein of the dipeptide practically does not affect the sorbtion an KU-2-8. Sorbtion of dipeptides on AV-17-8 is higher in comparison with their monomeric amino acids.

Purpose. To determine the diagnostic significance of blood citrulline level when estimating the short bowel syndrome (SBS) in children under 5 years old. To determine the blood citrulline level in children of different age. Methods. The examined group (N=31) included children under 5 who underwent small or small and large intestine resection and developed (15 children) or not developed (16 children) clinical signs of SBS. The control group included children who underwent no surgery on the GIT and had no congenital malformations and clinical signs of enteropathy (N=42). To determine the level of citrulline, overpressured high performance liquid column chromatography was used. Statistical analysis of the results was done with MedCalc® version 18.11.3. Results. Mean level of blood citrulline is 28.9 µmol/l in the examined group (95% CI 23.2–34.6) and 30.5 µmol/l in the control group (95% CI 25.0–35.1). Reliable data of the ratio between blood level citrulline and age of the child were obtained both among operated and non-operated children. The odds ratio of determining citrulline in blood was below 24.4 µmol/l in development of SBS clinical picture and amounted to 4.08 р < 0,05. Additional use of ROC analysis confirms the presence of interrelation between citrulline level and absence or presence of SBS clinical signs with 100% specificity and 43% sensitivity. The area under curve (categorical variable showing whether SBS is present or lacking) is 0,746, р = 0,005. Conclusion. Determination of serum citrulline as a diagnostic marker of short bowel syndrome in children under 5 found low sensitivity but high specificity. Thus, blood citrulline index can be used as a biomarker to diagnose SBS, to describe the course of SBS in detail and determine the risk of severe forms of this pathology in children under 5.

A method for the "Dissolution" test was developed and validated for tablets of the new bisphosphonate sodium prodronate and was compliant with the general normative requirements. Dissolution was carried out on an instrument with paddles rotating at a rate of 50 rpm. The quantity of drug entering solution over 45 min was assed by UV spectrophotometry via formation of complexes with copper ions, with an absorption peak at 237 nm.

The synthesis was developed and physic-chemical properties of the pharmaceutical substance the di-L-arginine succinate were determined. Its cardioprotective effectiveness in cases of ischemic-reperfusion injury of the myocardium was demonstrated in experiments on rats. The substance was used to obtain the drug Inokardin of cardioprotective action.

Разработана и валидирована методики теста «Растворение» для таблеток нового бисфосфоната — продроната натрия, выполненная в соответствии с общими нормативными требованиями. Растворение проводили на аппарате с вращающимися лопастями со скоростью вращения 50 об/мин. Количество лекарственного вещества, перешедшего в раствор за 45 мин, оценивали методом УФ-спектрофотометрии через образование комплекса с ионами меди с максимумом поглощения при 237 нм.

Tert-butyloxycarbonylprolylleucylglycinamide is obtained both by the interaction of tert-butyloxycarbonylprol ylleucylglycine ethyl ester with a methanolic ammonia solution and by the reaction of glycine amide with a mixed anhydride which was synthesized from tert-butyloxycarbonylprolylleucine and isobutylchloroformate. The removal of the tert-butyloxycarbonyl group by the action of formic acid or a dioxane solution of hydrogen chloride and treatment of the resulting salts with the corresponding base yielded a prolylleucylglycinamide, by the interaction of which with acetic, benzoic or 5-phenylisoxazole-3-carboxylic acids chlorides acyl derivatives of prolylleucylglycinamide are obtained.

Compounds that contain an indole cycle in their structure have biological activity and are a source for the development of new medicinal products. N-acetyl-3-indolinones are actively used as incoming substance for their organic synthesis. Preparative methods for the obtaining of N-acetyl-3-indolinones, used as incoming substances for the synthesis of condensed indole derivatives with high therapeutic activity, have been developed. Synthesis of N-acetyl-3-indolinone was performed by deacetylation and cyclization of N-(2-carboxyphenyl) glycine and its 4-bromo-derivative to form N,O-diacetylindoxyls followed by hydrolysis of the obtained compounds to target indolinones. It was established that brominated derivatives have increased stability as compared with the analogues which do not contain bromine on the benzene ring of the indole nucleus, resulting in the increase in the yield of desired products in the reaction.

A spectrophotometric method for determining sodium prodronate in tablets by measuring the absorption at 237 ± 2 nm of a Cu(II)—prodronate complex in acetate buffer was developed and validated. The method met applicable requirements of the SP RB for quantitative analysis methods for drugs and could be recommended for use by the State Drug Quality Control Inspection and technical control departments of chemical and pharmaceutical plants.

2-Amino-4-acetylthiazolo[5,4-b]indole and its bromosubstituted analogue contain a free amino group and are initial compounds for chemical modification in order to obtain on their basis functional derivatives having high therapeutic activity. By the interaction of these 2-aminо-4-acetylthiazolo[5,4-b]indoles with succinic and maleic anhydrides, the corresponding imides and amides were obtained, which are of interest for use in order to create on their basis antihypoxic and actoprotective agents.

Разработана и валидирована методика спектрофотометрического определения натрия продроната в таблетках, основанная на измерении абсорбции комплекса Cu(II) — продронат в ацетатном буфере при 237 ± 2 нм. Методика отвечает требованиям ГФ РБ, предъявляемым к методикам количественного определения лекарственных веществ, и может быть рекомендована к использованию в Государственной инспекции контроля качества лекарственных средств, а также ОТК химико-фармацевтических предприятий.

Золедроновая кислота — фармацевтическая субстанция высокоэффективного лекарственного средства антирезорбтивного действия Зомета. Описан усовершенствованный синтез золедроновой кислоты реакцией бисфосфонирования 2-(1H-имидазол-1-ил)уксусной кислоты.

Zoledronic acid is the drug substance of the highly efficient antiresorptive medicine Zometa. An improved synthesis of zoledronic acid via bis-phosphonation of 2-(1H-imidazol-1-yl)acetic acid is reported.

Results of the study of the drug from calcium salts of amino acids (calcium diglycinate, calcium di-L-prolinate) on the model of osteoporosis in animals are described. The test substance was found to have better therapeutic effect in the regeneration of bone tissue in comparison with the drug containing calcium carbonate. The drug containing calcium salts of glycine and L-proline can be used for prevention and treatment of osteoporosis.