Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-137-146
N. A. Epshtein
Introduction. Different approaches are used for transfer of impurities determination methods. In most cases, comparative testing of samples or partial validation of methods is performed. At the same time, a number of issues important for practice are still relevant.Text. The features of methods validation and comparative testing of samples during the transfer of impurities determination methods are considered. Potential acceptance criteria – requirements to the permissible difference between results of transmitting and receiving laboratories – are given. The calculation formulas of the TOST test are considered, and the critical condition for the comparative testing of samples is given. The key points that should be taken into account when transferring the methods are discussed.Conclusion. The data and recommendations are presented, which are important for increasing the reliability of the transfer of the impurities determination methods.
{"title":"Transfer of Impurities Determination Methods: Comparative Testing, Validation, Acceptance Criteria (Review)","authors":"N. A. Epshtein","doi":"10.33380/2305-2066-2021-10-2-137-146","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-137-146","url":null,"abstract":"Introduction. Different approaches are used for transfer of impurities determination methods. In most cases, comparative testing of samples or partial validation of methods is performed. At the same time, a number of issues important for practice are still relevant.Text. The features of methods validation and comparative testing of samples during the transfer of impurities determination methods are considered. Potential acceptance criteria – requirements to the permissible difference between results of transmitting and receiving laboratories – are given. The calculation formulas of the TOST test are considered, and the critical condition for the comparative testing of samples is given. The key points that should be taken into account when transferring the methods are discussed.Conclusion. The data and recommendations are presented, which are important for increasing the reliability of the transfer of the impurities determination methods.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"137-146"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69657912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-69-79
O. V. Trineeva
Introduction. As is known, the selection of optimal conditions for the analysis of extracts from medicinal plant raw materials (MPМ), as well as medicinal herbal preparations and pharmaceutical substances of plant origin, characterized by a complex variable composition of biologically active substances (BAS) by TLC, presents certain difficulties. For the design of mobile phases for the separation of mixtures of BAS of plant origin, in a thin layer of sorbent, the following approaches are used: literary sources; standard mobile phases; spot elution method; the scheme proposed by the firm Camag (Switzerland); model "PRISMA"; variocameras and others. In foreign literature, there are publications on the generalization of the available experimental data on the determination of various natural groups of BAS in objects of plant origin. However, such reviews did not reveal the regularities of the chromatographic behavior of individual BAS in a thin layer, as well as the influence of various factors on the reproducibility of Rf values. The study of the possibility of a theoretical approach to the choice of optimal conditions for chromatography of groups of BAS of different polarity, allowing them to separate, identify and quantify by TLC is a relevant and poorly developed area of chromatography in general.Aim. The aim of this work was to develop a theoretical approach to the choice of optimal conditions for the chromatographic separation of various groups of BAS of plant origin in a thin layer of sorbent.Materials and methods. To study the regularities of chromatographic behavior in a thin layer of representatives of the main classes of BAS present in MPМ (amino acids, flavonoids, tannins, simple sugars, ascorbic acid, fat-soluble vitamins), the value of the main factor affecting the parameters of the efficiency of the chromatographic process, the polarity of the eluent, was studied. As objects of research, we used ready-made chopped raw material of nettle leaves, produced by a domestic manufacturer, that meets the requirements of regulatory documents, as well as sea buckthorn fruits collected on the territory of the Voronezh region, according to the rules for harvesting MPМ of various morphological groups in fresh and dried form.Results and discussion. The regularities of elution and mathematical models describing the chromatographic behavior of plant BAS in a thin layer of sorbent have been established. Based on the totality of the results obtained, from the standpoint of the efficiency of the chromatographic process, the optimal conditions for their TLC analysis were selected and theoretically substantiated. To study the qualitative composition of BAS and to achieve a clear separation of zones on chromatograms, TLC methods were developed and tested on the studied MPМ using simple, frontal or two-dimensional chromatography.Conclusion. It is shown that the determination and separation in a thin layer of the sorbent of hydrophilic and lipophilic BAS of MP
{"title":"Development of Theoretical Approaches to Determination of the Main Groups of Biologically Active Substances of Medicinal Plant Raw Materials by TLC Method","authors":"O. V. Trineeva","doi":"10.33380/2305-2066-2021-10-2-69-79","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-69-79","url":null,"abstract":"Introduction. As is known, the selection of optimal conditions for the analysis of extracts from medicinal plant raw materials (MPМ), as well as medicinal herbal preparations and pharmaceutical substances of plant origin, characterized by a complex variable composition of biologically active substances (BAS) by TLC, presents certain difficulties. For the design of mobile phases for the separation of mixtures of BAS of plant origin, in a thin layer of sorbent, the following approaches are used: literary sources; standard mobile phases; spot elution method; the scheme proposed by the firm Camag (Switzerland); model \"PRISMA\"; variocameras and others. In foreign literature, there are publications on the generalization of the available experimental data on the determination of various natural groups of BAS in objects of plant origin. However, such reviews did not reveal the regularities of the chromatographic behavior of individual BAS in a thin layer, as well as the influence of various factors on the reproducibility of Rf values. The study of the possibility of a theoretical approach to the choice of optimal conditions for chromatography of groups of BAS of different polarity, allowing them to separate, identify and quantify by TLC is a relevant and poorly developed area of chromatography in general.Aim. The aim of this work was to develop a theoretical approach to the choice of optimal conditions for the chromatographic separation of various groups of BAS of plant origin in a thin layer of sorbent.Materials and methods. To study the regularities of chromatographic behavior in a thin layer of representatives of the main classes of BAS present in MPМ (amino acids, flavonoids, tannins, simple sugars, ascorbic acid, fat-soluble vitamins), the value of the main factor affecting the parameters of the efficiency of the chromatographic process, the polarity of the eluent, was studied. As objects of research, we used ready-made chopped raw material of nettle leaves, produced by a domestic manufacturer, that meets the requirements of regulatory documents, as well as sea buckthorn fruits collected on the territory of the Voronezh region, according to the rules for harvesting MPМ of various morphological groups in fresh and dried form.Results and discussion. The regularities of elution and mathematical models describing the chromatographic behavior of plant BAS in a thin layer of sorbent have been established. Based on the totality of the results obtained, from the standpoint of the efficiency of the chromatographic process, the optimal conditions for their TLC analysis were selected and theoretically substantiated. To study the qualitative composition of BAS and to achieve a clear separation of zones on chromatograms, TLC methods were developed and tested on the studied MPМ using simple, frontal or two-dimensional chromatography.Conclusion. It is shown that the determination and separation in a thin layer of the sorbent of hydrophilic and lipophilic BAS of MP","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"69-79"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69657963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-80-86
О. Понкратова, Кристофер Уэйли, А. А. Орлова, Станислав Смирнов, Е. Б. Серебряков, Владимир Геннадьевич Лужанин, Anastasiia O. Ponkratova, A. Whaley, A. Orlova, S. Smirnov, E. Serebryakov, V. Luzhanin
Introduction. Urinary tract infections are a common group of diseases worldwide, affecting more than 150 million people every year. In about 30 % of patients with initial infection, UTI becomes chronic. Herbal medicines, along with synthetic diuretics and antibiotics, are widely used for the prevention and treatment of UTIs, which makes the search and isolation of various substances from plant materials an important task. The present study is devoted to the isolation of compounds belonging to the class of proanthocyanidins from the aerial part of the black crowberry (Empetrum nigrum L.).Aim. Method development for the isolation of individual dimeric type A proanthocyanidins from the aerial part of Empetrum nigrum and the elucidation of their chemical structure using modern physicochemical methods of analysis.Materials and methods. Shoots of Empetrum nigrum were collected next to the Saint Petersburg State Chemical-Pharmaceutical University Nursery Garden of Medicinal Plants (Leningrad region, Vsevolozhsky district, Priozerskoe highway, 38 km) in August 2019. Fraction analysis was performed through analytical high-performance liquid chromatography (HPLC) using a Prominence LC-20 (Shimadzu corp., Japan) equipped with a SPD-M20A diode-array detector, as well as by high performance thin layer chromatography (HPTLC) using a CAMAG HPTLC system (Switzerland). The isolation of compounds was carried out by open column chromatography using sorbents with different selectivity, as well as by preparative HPLC using a Smartline system (Knauer, Germany) equipped with a spectrophotometric detector. The structures of the isolated compounds were established by 1D and 2D NMR experiments (Bruker Avance III 400 MHz, Germany), as well as high-resolution mass spectrometry (HR-ESI-MS) (Bruker Micromass Q-TOF, Germany).Results and discussion. Using the developed methods, from the Empetrum nigrum shoots we managed to isolate and characterised three individual compounds belonging to the class of A-type proanthocyanidins. According to NMR and mass spectrometry data, compound 1 is epicatechin-(2β → O → 5, 4β → 6)-epicatechin, with an extremely rare type of intermonomer bond (2β → O → 5, 4β → 6). Compounds 2 and 3 are epicatechin-(2β → O → 7, 4β → 8)-epicatechin (procyanidin A2) and epicatechin-(2β → O → 7, 4β → 8)-catechin (procyanidin A1), respectively. All individual compounds (1-3) were found and isolated from Empetrum nigrum for the first time.Conclusion. As a result of the research, three individual compounds (A-type proanthocyanidins) were isolated from the aerial part of Empetrum nigrum. All individual compounds (1-3) were found and isolated from Empetrum nigrum for the first time. Future assessment of the isolated compounds biological activity is presumed.
{"title":"Isolation and Structure Elucidation of Three Dimeric A-type Proanthocyanidins from Empetrum Nigrum L.","authors":"О. Понкратова, Кристофер Уэйли, А. А. Орлова, Станислав Смирнов, Е. Б. Серебряков, Владимир Геннадьевич Лужанин, Anastasiia O. Ponkratova, A. Whaley, A. Orlova, S. Smirnov, E. Serebryakov, V. Luzhanin","doi":"10.33380/2305-2066-2021-10-2-80-86","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-80-86","url":null,"abstract":"Introduction. Urinary tract infections are a common group of diseases worldwide, affecting more than 150 million people every year. In about 30 % of patients with initial infection, UTI becomes chronic. Herbal medicines, along with synthetic diuretics and antibiotics, are widely used for the prevention and treatment of UTIs, which makes the search and isolation of various substances from plant materials an important task. The present study is devoted to the isolation of compounds belonging to the class of proanthocyanidins from the aerial part of the black crowberry (Empetrum nigrum L.).Aim. Method development for the isolation of individual dimeric type A proanthocyanidins from the aerial part of Empetrum nigrum and the elucidation of their chemical structure using modern physicochemical methods of analysis.Materials and methods. Shoots of Empetrum nigrum were collected next to the Saint Petersburg State Chemical-Pharmaceutical University Nursery Garden of Medicinal Plants (Leningrad region, Vsevolozhsky district, Priozerskoe highway, 38 km) in August 2019. Fraction analysis was performed through analytical high-performance liquid chromatography (HPLC) using a Prominence LC-20 (Shimadzu corp., Japan) equipped with a SPD-M20A diode-array detector, as well as by high performance thin layer chromatography (HPTLC) using a CAMAG HPTLC system (Switzerland). The isolation of compounds was carried out by open column chromatography using sorbents with different selectivity, as well as by preparative HPLC using a Smartline system (Knauer, Germany) equipped with a spectrophotometric detector. The structures of the isolated compounds were established by 1D and 2D NMR experiments (Bruker Avance III 400 MHz, Germany), as well as high-resolution mass spectrometry (HR-ESI-MS) (Bruker Micromass Q-TOF, Germany).Results and discussion. Using the developed methods, from the Empetrum nigrum shoots we managed to isolate and characterised three individual compounds belonging to the class of A-type proanthocyanidins. According to NMR and mass spectrometry data, compound 1 is epicatechin-(2β → O → 5, 4β → 6)-epicatechin, with an extremely rare type of intermonomer bond (2β → O → 5, 4β → 6). Compounds 2 and 3 are epicatechin-(2β → O → 7, 4β → 8)-epicatechin (procyanidin A2) and epicatechin-(2β → O → 7, 4β → 8)-catechin (procyanidin A1), respectively. All individual compounds (1-3) were found and isolated from Empetrum nigrum for the first time.Conclusion. As a result of the research, three individual compounds (A-type proanthocyanidins) were isolated from the aerial part of Empetrum nigrum. All individual compounds (1-3) were found and isolated from Empetrum nigrum for the first time. Future assessment of the isolated compounds biological activity is presumed.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"80-86"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42680539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-50-61
Yu. A. Polkovnikova , N. Kovaleva
Introduction. Microencapsulation is one of the promising areas for obtaining new dosage forms. The peculiarity of microencapsulated forms is that the substance is protected from the effects of various environmental factors that can cause their destruction (acidity of gastric juice, the effect of food, joint intake of other drugs, diseases of the gastrointestinal tract, etc.). This method is used for various groups of drugs, such as antibiotics, nootropics, vitamins, probiotics, anticonvulsants, enzymes. Particular attention should be paid to antibacterial drugs, since the possibility of microencapsulation solves one of the most important problems in antibiotic therapy – the resistance of microorganisms.Text. The purpose of the review is to analyze modern research in the field of microencapsulation, to study trends and directions for the creation of microcapsules with high activity and bioavailability and with minimal side effects. The article provides brief information and main conclusions on the development of techniques and selection of conditions for microencapsulation of individual medicinal substances, on the study of polymers of various natures for use as carriers, on the methods of forming double shells of microcapsules, and also investigated the efficiency of microencapsulation of biologically active substances, such as antibacterial preparations, substances of plant and animal origin and preparations from various pharmacological groups. Variants of microencapsulation techniques for specific compounds that are suitable for substances similar in composition and action, as well as methods for creating microcapsules with double shells for compounds insoluble in water, are presented.Conclusion. The article shows the achievements and prospects of using microencapsulation of medicinal substances and their advantages over standard dosage forms. The active introduction of the developed methods into production will allow the creation of new dosage forms with known medicinal substances that have a prolonged effect, which will reduce the frequency of use of the drug, as well as retain their activity under the influence of negative factors of the internal environment of the body. Also, in the form of microcapsules, the substances are more active in comparison with non-encapsulated substances.
{"title":"Modern Research in the Field of Microencapsulation (Review)","authors":"Yu. A. Polkovnikova , N. Kovaleva","doi":"10.33380/2305-2066-2021-10-2-50-61","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-50-61","url":null,"abstract":"Introduction. Microencapsulation is one of the promising areas for obtaining new dosage forms. The peculiarity of microencapsulated forms is that the substance is protected from the effects of various environmental factors that can cause their destruction (acidity of gastric juice, the effect of food, joint intake of other drugs, diseases of the gastrointestinal tract, etc.). This method is used for various groups of drugs, such as antibiotics, nootropics, vitamins, probiotics, anticonvulsants, enzymes. Particular attention should be paid to antibacterial drugs, since the possibility of microencapsulation solves one of the most important problems in antibiotic therapy – the resistance of microorganisms.Text. The purpose of the review is to analyze modern research in the field of microencapsulation, to study trends and directions for the creation of microcapsules with high activity and bioavailability and with minimal side effects. The article provides brief information and main conclusions on the development of techniques and selection of conditions for microencapsulation of individual medicinal substances, on the study of polymers of various natures for use as carriers, on the methods of forming double shells of microcapsules, and also investigated the efficiency of microencapsulation of biologically active substances, such as antibacterial preparations, substances of plant and animal origin and preparations from various pharmacological groups. Variants of microencapsulation techniques for specific compounds that are suitable for substances similar in composition and action, as well as methods for creating microcapsules with double shells for compounds insoluble in water, are presented.Conclusion. The article shows the achievements and prospects of using microencapsulation of medicinal substances and their advantages over standard dosage forms. The active introduction of the developed methods into production will allow the creation of new dosage forms with known medicinal substances that have a prolonged effect, which will reduce the frequency of use of the drug, as well as retain their activity under the influence of negative factors of the internal environment of the body. Also, in the form of microcapsules, the substances are more active in comparison with non-encapsulated substances.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"50-61"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49281033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-120-127
A. V. Aleshina, T. N. Komarov, O. A. Archakova, D. S. Shchelgacheva, N. S. Bagaeva, V. V. Davydanova, A. Y. Savchenko, I. Shohin
Introduction. Tranexamic acid is one of the most common drugs used to stop bleeding after trauma, in surgery and gynecology. The most common analytical method for the determination of this compound is reversed-phase high-performance liquid chromatography (HPLC). However, this compound belongs to the group of so-called poorly retained compounds due to its chemical structure. It is necessary to develop an analytical method that will allow the determination of tranexamic acid in human blood plasma with the least time, resource costs and without the use of specialized columns. Aim. The aim of this study is to develop a method for tranexamic acid in human plasma by high performance liquid chromatography with tandem mass-spectrometry (HPLC-MS/MS) for pharmacokinetic studies. Materials and methods. Determination of tranexamic acid in plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation. Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification, carry-over effect and stability. Conclusion. The method of the determination of tranexamic acid in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 100.00–15000.00 ng/ml. Method could be applied to tranexamic acid determination in plasma for pharmacokinetics and bioequivalence studies.
{"title":"Определение транексамовой кислоты в плазме крови человека методом высокоэффективной жидкостной хроматографии с масс-спектрометрическим детектированием","authors":"A. V. Aleshina, T. N. Komarov, O. A. Archakova, D. S. Shchelgacheva, N. S. Bagaeva, V. V. Davydanova, A. Y. Savchenko, I. Shohin","doi":"10.33380/2305-2066-2021-10-2-120-127","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-120-127","url":null,"abstract":"Introduction. Tranexamic acid is one of the most common drugs used to stop bleeding after trauma, in surgery and gynecology. The most common analytical method for the determination of this compound is reversed-phase high-performance liquid chromatography (HPLC). However, this compound belongs to the group of so-called poorly retained compounds due to its chemical structure. It is necessary to develop an analytical method that will allow the determination of tranexamic acid in human blood plasma with the least time, resource costs and without the use of specialized columns. Aim. The aim of this study is to develop a method for tranexamic acid in human plasma by high performance liquid chromatography with tandem mass-spectrometry (HPLC-MS/MS) for pharmacokinetic studies. Materials and methods. Determination of tranexamic acid in plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation. Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification, carry-over effect and stability. Conclusion. The method of the determination of tranexamic acid in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 100.00–15000.00 ng/ml. Method could be applied to tranexamic acid determination in plasma for pharmacokinetics and bioequivalence studies.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"120-127"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69657900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-112-118
E. Stepanova, L. Makarenkova, S. Goryainov, T. Fedotcheva, N. Shimanovsky
Introduction. Gestobutanoil is a synthetic pregnane steroid with gestagenic activity. Gestobutanoil has two pharmacologically active metabolites (AMOL and megestrol acetate). This implies the need for a detailed study of the kinetics of metabolites. It is rational to combine the study of the pharmacokinetics of gestobutanoil and its metabolites (AMOL and megestrol acetate). The simultaneous determination of several analytes in the rats’ serum can be carried out using chromatography-mass-spectrometry.Aim. Development of an analytical method for the simultaneous determination of gestobutanoil and two its metabolites in a biomatrix (rat serum).Materials and methods. The following methods were used to determine gestobutanoyl and two its metabolites in a biological matrix: GC-MS, HPLCESI-MS, HPLC-ESI-MS with derivatization, HPLC-APCI-MS.Results and discussion. When working with GC-MS, the chromatographic peaks of gestobutanoyl, AMOL, and megestrol acetate were strongly blurred and superimposed on each other, which is apparently due to the thermolability of the substances. The GC-MS method was abandoned in favor of HPLC. Analytes were separated by HPLC gradient elution on a C18 column. ESI ionization did not give typical protonated ions of gestobutanoyl and AMOL, and the intense signals of their cationized ions and fragment ions, which were observed in the spectra of AMOL and gestobutanoyl, could not ensure the reproducibility of the spectra, since the conditions of their formation are not suitable for routine analysis. Derivatization of analytes to form oximes and substituted hydrazones did not give the expected reaction products for HPLC-ESI-MS. APCI made it possible to remove intense cationized ions from the spectra of gestobutanoyl and AMOL and to increase the reliability of the method. The HPLCAPCI-MS technique was reproduced on model rat blood serum.Conclusion. An HPLC-MS method was developed for the simultaneous determination of gestobutanoyl, megestrol acetate, and AMOL. The technique was tested on a model rat blood serum containing all three analytes.
{"title":"Development of Simultaneous Determination Method of a Pregnan Steroid with Gestagenic Activity – Gestobutanoil and Two its Metabolites in Rat Serum","authors":"E. Stepanova, L. Makarenkova, S. Goryainov, T. Fedotcheva, N. Shimanovsky","doi":"10.33380/2305-2066-2021-10-2-112-118","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-112-118","url":null,"abstract":"Introduction. Gestobutanoil is a synthetic pregnane steroid with gestagenic activity. Gestobutanoil has two pharmacologically active metabolites (AMOL and megestrol acetate). This implies the need for a detailed study of the kinetics of metabolites. It is rational to combine the study of the pharmacokinetics of gestobutanoil and its metabolites (AMOL and megestrol acetate). The simultaneous determination of several analytes in the rats’ serum can be carried out using chromatography-mass-spectrometry.Aim. Development of an analytical method for the simultaneous determination of gestobutanoil and two its metabolites in a biomatrix (rat serum).Materials and methods. The following methods were used to determine gestobutanoyl and two its metabolites in a biological matrix: GC-MS, HPLCESI-MS, HPLC-ESI-MS with derivatization, HPLC-APCI-MS.Results and discussion. When working with GC-MS, the chromatographic peaks of gestobutanoyl, AMOL, and megestrol acetate were strongly blurred and superimposed on each other, which is apparently due to the thermolability of the substances. The GC-MS method was abandoned in favor of HPLC. Analytes were separated by HPLC gradient elution on a C18 column. ESI ionization did not give typical protonated ions of gestobutanoyl and AMOL, and the intense signals of their cationized ions and fragment ions, which were observed in the spectra of AMOL and gestobutanoyl, could not ensure the reproducibility of the spectra, since the conditions of their formation are not suitable for routine analysis. Derivatization of analytes to form oximes and substituted hydrazones did not give the expected reaction products for HPLC-ESI-MS. APCI made it possible to remove intense cationized ions from the spectra of gestobutanoyl and AMOL and to increase the reliability of the method. The HPLCAPCI-MS technique was reproduced on model rat blood serum.Conclusion. An HPLC-MS method was developed for the simultaneous determination of gestobutanoyl, megestrol acetate, and AMOL. The technique was tested on a model rat blood serum containing all three analytes.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"112-118"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46371133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-25-31
С. Чиряпкин, П. Кодониди, Аlexey S. Chiriapkin, I. Kodonidi, Mikhail V. Larsky
Introduction. Azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide are acyclic precursors of biologically active compounds derived from 5,6,7,8-tetrahydro-3H-benzoteopheno[2,3-d]pyrimidine-4-one. Examples of these groups of compounds with different pharmacological properties are given in the literature, but their cytostatic effect is mainly described. These data and the preparative availability allow us to judge the prospects for further study and molecular design in a number of azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide. Optimization of methods for the synthesis and analysis of substances of this series and the identification of structure-activity relationship are of considerable interest for medical chemistry and pharmaceutical science. The resulting leading compounds will allow us to further develop laboratory requirements for the synthesis of an active pharmaceutical substance.Aim. To make a predict, optimize the synthesis conditions and develop a method for high performance liquid chromatography (HPLC) analysis of pharmacologically active azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.Materials and methods. The prediction of biological activity was carried out through the web resource PASS Online. The synthesis of the target azomethines was carried out by the interaction of aromatic aldehydes with 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide in an ethanol. The reaction was monitored by thin-layer chromatography (TLC). The determination of related impurities was done by HPLC. The analysis was carried out under the conditions of isocratic elution with a mobile phase of acetonitrile – water (70:30).Results and discussion. The results of the prediction of the biological activity of the constructed structures suggest the manifestation of cytostatic, antitubercular and anti-inflammatory activity characteristic of all target azomethines. The analysis of the reactivity revealed the influence of substituents of aldehydes contained in the aromatic core on the completeness of the condensation reaction. The spectral characteristics clearly confirmed the structure of the products, and the HPLC results showed the purity of the obtained substances, which is more than 95 %.Conclusion. As a result of the conducted studies, the structure of promising azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide was justified and the method of their synthesis and analysis by HPLC was optimized. In the future, the results of the research will allow us to identify the leading compounds with the specified pharmacological properties.
{"title":"Targeted Synthesis and Analysis of Biologically Active Azomethine Derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide","authors":"С. Чиряпкин, П. Кодониди, Аlexey S. Chiriapkin, I. Kodonidi, Mikhail V. Larsky","doi":"10.33380/2305-2066-2021-10-2-25-31","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-25-31","url":null,"abstract":"Introduction. Azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide are acyclic precursors of biologically active compounds derived from 5,6,7,8-tetrahydro-3H-benzoteopheno[2,3-d]pyrimidine-4-one. Examples of these groups of compounds with different pharmacological properties are given in the literature, but their cytostatic effect is mainly described. These data and the preparative availability allow us to judge the prospects for further study and molecular design in a number of azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide. Optimization of methods for the synthesis and analysis of substances of this series and the identification of structure-activity relationship are of considerable interest for medical chemistry and pharmaceutical science. The resulting leading compounds will allow us to further develop laboratory requirements for the synthesis of an active pharmaceutical substance.Aim. To make a predict, optimize the synthesis conditions and develop a method for high performance liquid chromatography (HPLC) analysis of pharmacologically active azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.Materials and methods. The prediction of biological activity was carried out through the web resource PASS Online. The synthesis of the target azomethines was carried out by the interaction of aromatic aldehydes with 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide in an ethanol. The reaction was monitored by thin-layer chromatography (TLC). The determination of related impurities was done by HPLC. The analysis was carried out under the conditions of isocratic elution with a mobile phase of acetonitrile – water (70:30).Results and discussion. The results of the prediction of the biological activity of the constructed structures suggest the manifestation of cytostatic, antitubercular and anti-inflammatory activity characteristic of all target azomethines. The analysis of the reactivity revealed the influence of substituents of aldehydes contained in the aromatic core on the completeness of the condensation reaction. The spectral characteristics clearly confirmed the structure of the products, and the HPLC results showed the purity of the obtained substances, which is more than 95 %.Conclusion. As a result of the conducted studies, the structure of promising azomethine derivatives of 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide was justified and the method of their synthesis and analysis by HPLC was optimized. In the future, the results of the research will allow us to identify the leading compounds with the specified pharmacological properties.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"25-31"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45243060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-29DOI: 10.33380/2305-2066-2021-10-2-101-105
Y. Domnina, V. V. Suslov, S. Kedik, D. A. Akhmedova, A. Malkova
Introduction. Acute toxicity of naltrexone hydrochloride nasal spray during intragastric administration to mice and local irritant effect on rabbits was studied. At all stages of the experiment, observations were made on the General condition of the animals. The state of homeostasis was evaluated using functional, hematological and morphometric methods. According to the results of research, there was no local irritant effect on the eyes of rabbits, as well as no toxic effect of high doses of the drug on animals. Introduction. Naltrexone hydrochloride in doses of 1.5– 5 mg/day has shown its effectiveness in the treatment of a number of diseases. Due to the lack of such a "low-dose" naltrexone registered on the pharmaceutical market, we have developed the composition of the nasal spray naltrexone hydrochloride. One of the stages of our research is to study the safety of the drug being developed. The first step in this direction was to study its acute toxicity and local irritant effect.Aim. Study of acute toxicity and local irritant effect of naltrexone hydrochloride nasal spray.Materials and methods. The object of the study was a nasal spray of naltrexone hydrochloride. Acute toxicity studies were performed on outbred adult mice (females). Study of local irritant effect on Soviet chinchilla rabbits (males).Results and discussion. The study of acute toxicity showed that the drug, at a dose significantly higher than the estimated maximum daily therapeutic dose for humans, did not have a significant toxic effect on the body of laboratory animals. The presence of a local irritant effect in the studied drug was not established in the framework of the experiment.Conclusion. As part of the experiment, the drug under study did not have a local irritant or toxic effect on the animal body. The results obtained allow us to continue the development and study of the nasal spray naltrexone hydrochloride.
{"title":"Study of Acute Toxicity and Irritant Effect of Nasal Spray Naltrexone Hydrochloride","authors":"Y. Domnina, V. V. Suslov, S. Kedik, D. A. Akhmedova, A. Malkova","doi":"10.33380/2305-2066-2021-10-2-101-105","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-2-101-105","url":null,"abstract":"Introduction. Acute toxicity of naltrexone hydrochloride nasal spray during intragastric administration to mice and local irritant effect on rabbits was studied. At all stages of the experiment, observations were made on the General condition of the animals. The state of homeostasis was evaluated using functional, hematological and morphometric methods. According to the results of research, there was no local irritant effect on the eyes of rabbits, as well as no toxic effect of high doses of the drug on animals. Introduction. Naltrexone hydrochloride in doses of 1.5– 5 mg/day has shown its effectiveness in the treatment of a number of diseases. Due to the lack of such a \"low-dose\" naltrexone registered on the pharmaceutical market, we have developed the composition of the nasal spray naltrexone hydrochloride. One of the stages of our research is to study the safety of the drug being developed. The first step in this direction was to study its acute toxicity and local irritant effect.Aim. Study of acute toxicity and local irritant effect of naltrexone hydrochloride nasal spray.Materials and methods. The object of the study was a nasal spray of naltrexone hydrochloride. Acute toxicity studies were performed on outbred adult mice (females). Study of local irritant effect on Soviet chinchilla rabbits (males).Results and discussion. The study of acute toxicity showed that the drug, at a dose significantly higher than the estimated maximum daily therapeutic dose for humans, did not have a significant toxic effect on the body of laboratory animals. The presence of a local irritant effect in the studied drug was not established in the framework of the experiment.Conclusion. As part of the experiment, the drug under study did not have a local irritant or toxic effect on the animal body. The results obtained allow us to continue the development and study of the nasal spray naltrexone hydrochloride.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":"10 1","pages":"101-105"},"PeriodicalIF":0.0,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45275211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-02-25DOI: 10.33380/2305-2066-2021-10-1-120-128
T. N. Komarov, I. Shohin, M. Tokareva, O. A. Archakova, D. Bogdanova, A. V. Aleshina, N. S. Bagaeva, V. V. Davydanova
Introduction. Currently, physicochemical methods of quantification are actively used to determine the content of drugs in biological fluids. High-performance liquid chromatography with various detection methods is particularly widespread. One of the most difficult practical tasks is the chromatographic separation of so-called poorly retained compounds – drug substances poorly retained on the chromatographic column. Valganciclovir and Ganciclovir are among such substances. Aim. The aim of this study is to develop a method for valganciclovir and ganciclovir in human plasma by high performance liquid chromatography with tandem mass-spectrometry (HPLC-MS/MS) for pharmacokinetic studies.Materials and methods. Determination of valganciclovir and ganciclovir in plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation.Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification, carry-over and stability.Conclusion. The method of the determination of valganciclovir and ganciclovir in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 5.00–1000.00 ng/ml for valganciclovir and 50.00–10000.00 ng/ml for ganciclovir. Method could be applied to valganciclovir and ganciclovir determination in plasma for PK and BE studies.
{"title":"Development and Validation of Valganciclovir and its Active Metabolite Ganciclovir Determination in Human Plasma by HPLC-MS/MS Method","authors":"T. N. Komarov, I. Shohin, M. Tokareva, O. A. Archakova, D. Bogdanova, A. V. Aleshina, N. S. Bagaeva, V. V. Davydanova","doi":"10.33380/2305-2066-2021-10-1-120-128","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-1-120-128","url":null,"abstract":"Introduction. Currently, physicochemical methods of quantification are actively used to determine the content of drugs in biological fluids. High-performance liquid chromatography with various detection methods is particularly widespread. One of the most difficult practical tasks is the chromatographic separation of so-called poorly retained compounds – drug substances poorly retained on the chromatographic column. Valganciclovir and Ganciclovir are among such substances. Aim. The aim of this study is to develop a method for valganciclovir and ganciclovir in human plasma by high performance liquid chromatography with tandem mass-spectrometry (HPLC-MS/MS) for pharmacokinetic studies.Materials and methods. Determination of valganciclovir and ganciclovir in plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation.Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification, carry-over and stability.Conclusion. The method of the determination of valganciclovir and ganciclovir in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 5.00–1000.00 ng/ml for valganciclovir and 50.00–10000.00 ng/ml for ganciclovir. Method could be applied to valganciclovir and ganciclovir determination in plasma for PK and BE studies.","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43439983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-02-25DOI: 10.33380/2305-2066-2021-10-1-74-81
L. N. Nikiforov, S. Krivoshchekov, N. Kolomiets, T. V. Kadyrova, N. V. Isaikina, N. Abramets, E. Bezverkhniaia, M. Belousov
Introduction. Lemna minor L. (duckweed) refers to the duckweed subfamily (Lemnaceae S. F. Gray) and widely distributed in ponds of Russia. Literature data confirm the possibility of harvesting significant volumes of this raw material in natural habitat and grown in aquaculture. The process of biosynthetic accumulation in duckweed fronds provides a variety of compounds with a wide spectrum of biological activity. Therefore, the use of raw materials Lemna minor L. is promising for the development of drugs and parapharmaceutical products. Thus, it is an urgent task to quantify active components of duckweed and standardize (determination of criteria for identification, quality and safety) plant material.Aim. Establish macro- and microscopic characteristics of raw materials and develop methods for the quantitative determination of the main groups of biologically active substances (BAS) for standardization of raw duckweed.Materials and methods. Samples of duckweed was collected in natural habitats of Western Siberia. Macro- and microscopic assay, HPLC, UV-spectrometry were used in research process.Results and discussion. Were established the criteria for identification of duckweed fronds by studying external (macroscopic) and microscopic features of raw material Lemna minor L. Was developed and validated the procedure of the quantitative determination of phenolcarboxylic acids in raw material Lemna minor L.Conclusion. The study of external (macroscopic) and microscopic features provided the criteria for identification of the raw material Lemna minor L. The technique for the quantitative analysis of polysaccharides using gravimetry does not need validation, because is a direct method of substance measurement. Was validated quantification method of phenolcarboxylic acids (in terms of chlorogenic acid) by criteria of linearity, repeatability, in-laboratory precision and accuracy. Was established quality criteria for identification and quantitative assay, which can be used in the draft for normative documents for medicinal plant raw material of Lemna minor L. «Duckweed fronds».
介绍Lemna minor L.（浮萍）是指浮萍亚科（Lemnaceae S.F.Gray），广泛分布于俄罗斯的池塘中。文献数据证实了在自然栖息地和水产养殖中收获大量这种原材料的可能性。浮萍叶片的生物合成积累过程提供了多种具有广泛生物活性的化合物。因此，利用小柠檬为原料开发药物及制剂是很有前景的。因此，对浮萍的活性成分进行量化并对植物材料进行标准化（鉴定、质量和安全标准的确定）是一项紧迫的任务。目标建立原料的宏观和微观特征，制定主要生物活性物质组分的定量测定方法，用于生浮萍的标准化。材料和方法。浮萍的样本是在西伯利亚西部的自然栖息地采集的。研究过程中采用了宏观和微观分析法、高效液相色谱法、紫外光谱法。结果和讨论。通过对小柠檬原料的外观（宏观）和微观特征的研究，建立了浮萍叶的鉴定标准。开发并验证了小柠檬原料中酚羧酸的定量测定方法。结论。对小柠檬原料的外部（宏观）和微观特征的研究为鉴定小柠檬原料提供了标准。使用重量法定量分析多糖的技术不需要验证，因为这是一种直接的物质测量方法。通过线性、重复性、实验室精密度和准确度标准验证了酚羧酸（以绿原酸计）的定量方法。建立了鉴定和定量分析的质量标准，可用于小柠檬药用植物原料《浮萍叶》的规范性文件草案。
{"title":"Development of Parameters for Standardization of Duckweed (Lemna Minor L.) Raw Material","authors":"L. N. Nikiforov, S. Krivoshchekov, N. Kolomiets, T. V. Kadyrova, N. V. Isaikina, N. Abramets, E. Bezverkhniaia, M. Belousov","doi":"10.33380/2305-2066-2021-10-1-74-81","DOIUrl":"https://doi.org/10.33380/2305-2066-2021-10-1-74-81","url":null,"abstract":"Introduction. Lemna minor L. (duckweed) refers to the duckweed subfamily (Lemnaceae S. F. Gray) and widely distributed in ponds of Russia. Literature data confirm the possibility of harvesting significant volumes of this raw material in natural habitat and grown in aquaculture. The process of biosynthetic accumulation in duckweed fronds provides a variety of compounds with a wide spectrum of biological activity. Therefore, the use of raw materials Lemna minor L. is promising for the development of drugs and parapharmaceutical products. Thus, it is an urgent task to quantify active components of duckweed and standardize (determination of criteria for identification, quality and safety) plant material.Aim. Establish macro- and microscopic characteristics of raw materials and develop methods for the quantitative determination of the main groups of biologically active substances (BAS) for standardization of raw duckweed.Materials and methods. Samples of duckweed was collected in natural habitats of Western Siberia. Macro- and microscopic assay, HPLC, UV-spectrometry were used in research process.Results and discussion. Were established the criteria for identification of duckweed fronds by studying external (macroscopic) and microscopic features of raw material Lemna minor L. Was developed and validated the procedure of the quantitative determination of phenolcarboxylic acids in raw material Lemna minor L.Conclusion. The study of external (macroscopic) and microscopic features provided the criteria for identification of the raw material Lemna minor L. The technique for the quantitative analysis of polysaccharides using gravimetry does not need validation, because is a direct method of substance measurement. Was validated quantification method of phenolcarboxylic acids (in terms of chlorogenic acid) by criteria of linearity, repeatability, in-laboratory precision and accuracy. Was established quality criteria for identification and quantitative assay, which can be used in the draft for normative documents for medicinal plant raw material of Lemna minor L. «Duckweed fronds».","PeriodicalId":36465,"journal":{"name":"Drug Development and Registration","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45699955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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