Research of interaction between metronidazole tablets and metal salts `in vitro`

Introduction: Along with the efficacy and safety of drugs, the interaction of drugs with each other and with other accompanying substances is important, too. There are no data about the interaction or influence of antacids and other drugs with polyvalent cations on the metronidazole bioavailability. The purpose of this research was the studying of the metronidazole release kinetics from the tablets in an environment that simulates stomach conditions with the addition of metal salts, which are part of the widespread drugs. The research was conducted to assess the impact of possible interactions between the active substance and polyvalent metal cations on their bioavailability and efficacy.Material and Methods: Metronidazole tablets were chosen as research object. 0.1 N HCl solution with addition of metal salts was chosen as medium dissolution. The `PharmaTest-DT70` Device with basket, the `Evolution 60S` Spectrophotometer as well as the `AB 204 S/A METTLER TOLEDO` analytical balances were used in the study.Results: Research of chemical interaction between metronidazole and metal salts, which are part of the widespread drugs, in the experiment `in vitro` was carried out. Metal salts don`t influence the metronidazole release from the tablets, as evidenced by dissolution profiles and similarity factors for each of the cases.Conclusions: The chemical interactions between the chosen medicines were not observed in the `in vitro` experiment. Thus, separate intake of metronidazole with other drugs, containing metal cations, is important for further research in the `in vivo` experiment

The influence excipients on the dissolution profiles of nifedipine tablets

PURPOSE: Study of dissolution profiles of nifedipine tablets from different manufacturers to further assess of their equivalence in vitro, as well as study of the dependence of the dissolution profile on the adjuvants composition.MATERIAL AND METHODS: 3 buffer media with pH 1.2 (hydrochloric acid buffer); 4.5 (acetate buffer); 6.8 (phosphate buffer) was used. The absorptions were observed at 343.RESULTS: The dissolution profiles of nifedipine tablets from different manufacturers have been studied and have been founded that the percentage of nifedipine release from the sample B is higher than from `Corinfar`, and the percentage of nifedipine release from `Corinfar` is higher than from the sample A. Adjuvants composition of nifedipine tablets have been studied. It is founded that the inclusion of surfactants, solubilizers and emulsifiers into tablets contribute to increasing of active substance release from the dosage form.CONCLUSIONS: Found that the introduction of surfactants into tablets, solubilizers and emulsifiers help to increase the release of active substance from the dosage form

Development of methods for identification and quantitative determination of Analben in tablets

PURPOSE: Analben has been created by the researchers of the National University of Pharmacy and recommended in the solid dosage form as a promising non-narcotic analgesic and anti-inflammatory drug. The aim of the work is to develop physico-chemical and chemical methods of identification and quantitative determination of the active pharmaceutical ingredient in Analben tablets.MATERIALS AND METHODS: As the object of research a pilot batch of tablets `Analben, 1 mg` produced by the pharmaceutical firm `Neopharm` together with the company `Zdorovie` was selected. Analytical studies were performed by the methods of spectrophotometry, thin-layer chromatography and chemical reactions.RESULTS AND CONCLUSIONS: As the result of the work performed, the spectral characteristics of the analben substance in various solvents have been studied, the optimal conditions for determining related impurities have been selected using the method of thin-layer chromatography. The pectrophotometric method for quantitative determination of Analben in the tablets under study has been developed; the solvent, concentration and wavelength have been chosen. The validation characteristics of the quantitative determination method have been studied and it has been determined that linearity is observed in the range of concentrations from 0.16 μg/ml to 0.24 μg/ml (±20%), the systematic error of the method (0.33%) is practically insignificant, the relative confidence interval for the value Z (0.62%) is less than the critical value for convergence of results (1.66%)

Synthesis of novel substituted 4-phenyl-5-phenoxymethyl-3-mercapto-1,2,4-triazole (4 H) derivatives as potential anti-ulcer agents

In this work, the series of new 4-phenyl-5-4-(R)-phenoxymethyl-1,2,4-triazole-3-ylthio-1-(R1)-acetophenones have been synthesized by alkylation of correspondent 4-phenyl-5-phenoxymethyl-3-mercapto-1,2,4-triazoles (4H) with the α-chloroacetophenones. The structure of the synthesized substances has been proven by NMR spectra. High possibility of anti-ulcer and anti-helicobacter activity was determined by the PASS program. Molecular docking and anti-ulcer screening of new 1,2,4-triazole(4H) derivatives on the acute alcohol-prednisolone model NSAID-induced ulcers in rats has been performed

Docking studies and biological evaluation of anti-cancer activity of new 1,2,4 - trіаzоle(4h)derivatives

In the present work, 25 of novel 1,2,4-triazole(4H) derivatives were evaluated for their anti-tumor activity through docking studies and antitumor screening in vitro. The target protein structures of 1YS1, 1FM6, 1BXL were docked with new 1,2,4-triazole(4H) derivatives provided excellent results. In vitro anticancer activity of the compounds was tested by the National Cancer Institute and some of them have revealed the anticancer activity on leukemia, melanoma, lung, ovarian cancers cell lines. Among tested compounds three samples (3,8,16) showed high antitumor activity level and their in-depth preclinical studies are in progress.N-isopropylanilides of 4-benzyl-5-(4-brom)phenoxymethyl-1,2,4-triazolyl-3yl-merkapto-acetic acid 8 was found to be the most active candidate

Development and validation of tetracycline hydrochloride assay procedure by spectrophotometry in compounded ointment

AIM: Tetracycline hydrochloride is one of the most popular antibiotics, which are used in the manufac­turing of finished pharmaceutical products and compounded medicines. The aim of our work is develop­ment and validation of the assay method for tetracycline hydrochloride determination in the combined compounded ointment.MATERIALS AND METHODS: The assay is proposed to be carried out by spectrophotometric method.RESULTS AND CONCLUSIONS: A spectrophotometric method for tetracycline hydrochloride determi­nation in compounded ointment was developed. For this method the following validation characteristics were studied: stability, selectivity, repeatability, precision, accuracy, reproducibility. We found that all met­rological characteristics are not higher than the validation criteria. Stability of test solutions was observed for 60 minutes, which allows using this method for tetracycline hydrochloride quantitative determination in studied ointment

SIMULTANEOUS DETERMINATION OF BENZYDAMINE HYDROCHLORIDE, METHYLPARABEN AND PEPPERMINT OIL IN A SPRAY DOSAGE FORM BY GAS CHROMATOGRAPHY

Objective: To develop and validate an analytical procedure for simultaneous determination of benzydamine hydrochloride, methylparaben and peppermint oil in a spray dosage form by gas chromatography method (GC). Methods: The analytical method was conducted on Agilent 7890 gas chromatograph, equipped with HP-5 capillary column with helium as a mobile phase, split/splitless injector and flame ionization detector and an auto injector. Validation parameters, such as selectivity, linearity, precision, accuracy and, robustness were estimated. Results: A method for simultaneous determination of benzydamine hydrochloride, methylparaben and peppermint oil in a spray dosage form by GC was developed. The retention time of menthol (marker substance of peppermint oil) methylparaben and benzydamine hydrochloride, was 5.0, 9.2, and 19.4 respectively. Relative standard deviation (RSD)% for precision was 0.24, 0.13 and 0.12 respectively. The linearity of the method for given analytes was estimated in a concentration range of 80-120% to a nominal concentration with the respective correlation coefficients of more than 0.999. Accuracy of the method was within 98-102% for all analytes. Conclusion: The developed analytical procedure meets the acceptance criteria of validation parameters and can be used in quality control laboratories for determination of benzydamine hydrochloride, methylparaben and peppermint oil in a spray dosage form

A New Method for Studying the Kinetics of the Release of Poorly Soluble API from Solid Oral Dosage Forms on the Example of Quertin®

In this paper, it is proposed to consider a new method developed for studying the kinetics of release of substances that are poorly soluble in aqueous media on the example of quercetin. The study object was the drug containing plant bioactive components – Quertin® chewable tablets, 40 mg, 3 blisters, 10 pcs – produced by PJSC SIC “Borshchahivskiy CPP”. An Agilent 1290 Infinity II LC System liquid chromatograph with an Agilent 6530 mass selective detector (Agilent Technologies) was used for the analysis. Solubility profiles were studied in accordance with the requirements of the Biopharmaceutical Classification System (BCS). The solubility limit of the substance in the media studied has been determined. A method for the quantitative determination of quercetin in test media in the range of specified concentrations with high sensitivity and selectivity has been developed. The dissolution of Quertin® chewable tablets in 3 different aqueous dissolution media with pH 1.2, pH 4.5 and pH 6.8 was studied, the dissolution profiles were compared, and the f2 factor was calculated. This factor is a criterion for evaluating the study by comparing dissolution kinetics with in vivo results. The results obtained indicate that the approach proposed to studying the kinetics of the release of substances that are sparingly soluble in aqueous solutions allows us to correctly assess the release of such substances in accordance with the requirements of the BCS. The method developed has been validated

Синтез, протимікробна активність та докінгові дослідження 6-(1H-бензімідазол-2- іл)-5-метилтієно[2,3-d]піримідин-4(3H)-онів з ацетамідними та 1,2,4-оксадіазол-5- ілметильними замісниками

Aim. To synthesize, study the antimicrobial activity and suggest antimicrobial activity mechanism for the novel derivatives of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one. Results and discussion. As the result of the targeted modification of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]-pyrimidin-4(3H)-one in position 3 with acetamide and 1,2,4-oxadiazol-5-ylmethyl substituents, the compounds, which demonstrated better antimicrobial activity in the agar well diffusion assay than the reference drug Streptomycin, were obtained. To elucidate the mechanism of action of the novel compounds, the docking studies were con-ducted to the active site of the 16S subunit of ribosomal RNA, the proven target for aminoglycoside antibiotics, as well as tRNA (Guanine37-N1)-methyltransferase (TrmD), which inhibitors were considered as a new potential class of antibiotics. Experimental part. By the interaction of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one with a series of N-arylchloroacetamides and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles in DMF in the presence of K2CO3 the target compounds were obtained. The antimicrobial activity was assessed by the agar well diffusion method. The concentration of microbial cells was determined by the McFarland standard; the value was 107 cells in 1 mL of the media. The 18 – 24 hour culture of microorganisms was used for tests. For the bacteria cultivation, Müller-Hinton agar was used, Sabouraud agar was applied for C. albicans cultivation. The compounds were tested as the DMSO solution with the concentration of 100 µg/mL; the volume of the solution was 0.3 mL, the same volume was used for Streptomycin (the concentration 30 µg/mL). The docking studies were performed using Autodock Vina. Crystallographic data for the complexes of Streptomycin with the 16S subunit of ribosomal RNA (1NTB) and its active site, as well as for tRNA (Guanine37-N1)-methyltransferase (EC 2.1.1.228; TrmD) (5ZHN) and its active site were obtained from the Protein Data Bank.Conclusions. It has been determined that 2-[6-(1H-benzimidazol-2-yl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3(4H)-yl]-N-[4-(ethoxy)phenyl]acetamide, which is the most active as an antimicrobial agent among the compounds tested, also shows the best binding activity towards the active site of tRNA (guanine37-N1)-methyltransferase.Мета. Синтезувати й дослідити протимікробну активність нових похідних 6-(1H-бензімідазол-2-іл)-5-метилтієно[2,3-d]піримідин-4(3H)-онів та запропонувати механізм протимікробної активності.Результати та їх обговорення. У результаті цілеспрямованої модифікації положення 3 6-(1H-бензімідазол-2-іл)-5-метилтієно[2,3-d]піримідин-4(3H)-ону ацетамідним та 1,2,4-оксадіазол-5-ілметильним замісниками було одержано сполуки з визначеною методом дифузії в агар протимікробною активністю, що є більшою за активність препарату порівняння Стрептоміцину. З метою з’ясування механізму дії синтезованих сполук було проведено докінгові дослідження щодо активного сайту субодиниці 16S рибосомальної РНК, яка є підтвердженою мішенню для аміноглікозидних антибіотиків, а також тРНК (Гуанін-37-N1)-метилтрансферази (TrmD), інгібітори якої розглядаються як новий потенційний клас антибіотиків. Експериментальна частина. Шляхом взаємодії 6-(1H-бензімідазол-2-іл)-5-метилтієно[2,3-d]піримідин-4(3H)-ону з рядом N-арилхлороацетамідів та 3-арил-5-(хлорометил)-1,2,4-оксадіазолів в умовах ДМФА-K2CO3 було одержано цільові сполуки. Антимікробну активність визначали методом дифузії в агар. Концентрацію мікробних клітин визначали за МакФарландом; мікробне навантаження склало 107 мікробних одиниць в 1 мл середовища. Для тестів використовували 18 – 24 годинну культуру мікроорганізмів. Для культивування бактерій використовували агар Мюллера-Гінтона; для культивування C. albicans використовували агар Сабуро. Сполуки вводили методом дифузії в агар (лунками) у вигляді розчину у ДМСО в концентрації 100 мкг/мл в об’ємі 0,3 мл; аналогічний об’єм використовували для Стрептоміцину (конц. 30 мкг/мл). Докінгові дослідження проводили за допомогою програми Autodock Vina. Кристалографічні дані для комплексів стрептоміцину з 16S субодиницею рибосомальної РНК (1NTB) та її активного сайту і для тРНК (Гуанін-37-N1)-метилтрансферази (EC 2.1.1.228; TrmD) (5ZHN) та її активного сайту було отримано з Protein Data Bank.Висновки. Виявлено, що сполука 2-[6-(1H-бензімідазол-2-іл)-5-метил-4-оксотієно[2,3-d]піримідин-3(4H)-іл]-N-[4-(етокси)феніл]ацетамід, яка характеризується найбільшою протимікробною активністю, у докінгових розрахунках є також найбільш ефективним інгібітором тРНК (Гуанін-37-N1)-метилтрансферази

Obtaining the Enoxaparin Sodium Substance Equivalent to the Original Clexane® and Lovenox®. The Selection of Technological Parameters and Optimization of the “Greenness” of the Purification Stage

The aim of the study was to adjust and optimize the purification stage of crude enoxaparin sodium to obtain a substance equivalent to the original drugs Clexane® and Lovenox® according to the criteria specified by the FDA. The purification stage involves the reprecipitation of crude enoxaparin in methanol. Determining the ratio of solvents required for the reprecipitation is important for studying the correlation between the experimental conditions of the technological process and the structural characteristics of enoxaparin samples. In the study, the method of purification of enoxaparin sodium described in the patent was assessed, and the following variations of the MeOH:H2O solvent ratio were selected – 4:1; 2:1; 1:1. The obtained samples of enoxaparin sodium were analyzed according to the in-house specification developed on the basis of the pharmacopoeial monograph, as well as by non-pharmacopoeial methods, such as two-dimensional NMR spectroscopy (HSQC) and size exclusion chromatography (SEC) for detailed characterization of the molecule. Strategies of greening of the enoxaparin sodium purification stage by reducing the E-factor were also considered in the study. Considering the principles of “green” chemistry, the method of purification of crude enoxaparin sodium was optimized by the solvent regeneration. It was experimentally possible to demonstrate the effect of the solvent ratio at the stage of purification of crude enoxaparin on the composition, as well as on the number and distribution of oligosaccharide fractions in the molecule. Based on the results of the study, it can be concluded that the ratio of MeOH:H2O=1:1 allows obtaining samples that are closest to Clexane® and Lovenox® in terms of the molecular weight distribution profile and the composition profile. The E-factor was also reduced from 14 to 5.25 by solvent regeneration