UDC 615.072

Кotova E.E., Kotov A.G.

State Enterprise «Ukrainian Scientific Pharmacopoeial Center for Quality of Medicines», Kharkiv

Pharmacopoeial reference standards as part of the herbal drug standardization in Ukraine

The analysis of approaches to classification, features of use and introduction various types of reference standards in monographs on herbal drugs (HDs) and herbal drug preparations (HDPs) in the European Pharmacopoeia (Ph. Eur.) and the State Pharmacopoeia of Ukraine (SPU) has been conducted. As in the Ph. Eur., and in the SPU, pharmacopoeial reference standards are used to control the quality of HDs and HDPs which can be divided into the following categories: Herbal drug reference standards (HDRS) – reference standards of HD; Herbal drug preparation reference standards (HDPRS) – reference standards of HDPs; Chemical reference standards (CRS). One of the main features of the use standards is guarantee a qualitative and/or quantitative determination of the specific components of the chain HDs → HDPs → finished HDPs. It is shown that the SPU approaches to the introduction of reference standards in the national monographs and national parts of monographs on herbal drugs are simultaneously harmonized with Ph. Eur. approaches and economically justified for national needs.

Keywords: Pharmacopoeial reference standard, European Pharmacopoeia, the State Pharmacopoeia of Ukraine, monographs on herbal drugs, herbal drug reference standards, herbal drug preparation reference standards, chemical reference standards.


UDC 615.07: 615.457.1: 617.741-004.1

Sidenko L.M., Nazarova O.S.

State Enterprise «State Scientific Center for Drugs and Medical Products», Kharkiv

Development of methods for the quantitative determination azapentaсenе in eye drops anticataract action

A method for the quantitative determination of sodium azapentaсenе polysulphonates in eye drops using the method of absorption spectrophotometry in the ultraviolet region at a wavelength of 293 nm. In accordance with the method developed by the absorbance of the test solution was measured spectrophotometrically at a wavelength of 293 nm in a cuvette with a layer thickness of 10 mm, using a water solution compensation. According to the requirements of the application range SFU proposed technique should be from 80 % to 120 % of the nominal content. As a result of analysis of model compounds and their statistical processing it found that the method of analysis has sufficient convergence (found value relative confidence value of the interval Z (Δz(%) = 0.54 % is less than the critical value for the convergence of the results (1.6 %)) and accuracy (the criterion insignificance systematic method error — systematic method error (0.44 %) and almost statistically insignificant) in the whole concentration range. Calculation of the linear dependence of the parameters carried out by least squares. The high value of the correlation coefficient (= 0.99983) meets the acceptability criteria (= 0.99810) and confirmed the linearity relationship between the taken («true»), and found azapentatsene amount in the range from 80 % to 120 %. The relative confidence interval of five parallel measurements (Δz = 0.82 %) when checking intermediate precision quantification azapentatsene satisfies the eligibility criteria (≤ 1.6 %) (at B = 5 %). When checking the stability of the solutions of the relative value of the confidence interval of successive measurements of the optical density of the solution and the WS azapentatsene (Δt = 0.0015) test solution (Δt = 0.0017) meets the criterion of acceptability (Δt ≤ max= 0.51 %) (at B = 5 %), that is, solutions are stable for at least 5 hours. Predicted complete uncertainty analysis results (As,%) is 1.15 %, which does not exceed the maximum permissible uncertainty analysis (≤ 1.6 %), i.e. the methodology will give correct results in other laboratories in terms of «quantitative determination». The studies found matching techniques eligibility criteria for the content of tolerance of ± 5 % on to validated characteristics: specificity, linearity, precision (convergence) is correct, the application range and intermediate precision. It is experimentally proved that this method can be reproduced correctly, and is suitable for the quality control of the eye drops at various stages of its life cycle.

Keywords: azapentaсenе, absorption spectrophotometric method, validation, standardization, eye drops.


UDC 547.792:543.544.5.068.7:[615.31:615.213]

Kucherenko L.I., Nimenko A.R., Vashchenko E.V., Vashchenko V.V. NVT «Farmatron», Ukraine

Zaporozhye State Medical University, Ukraine

For joint definitions of carbamazepine and thiotriazolin in model mixture by HPLC. Message 2: selection phase for the joint determination of carbamazepine and thiotriazoline in the model mix HPLC (gradient elution)

Epilepsy ⎯ a chronic pathology that is a violation of all the indicators of CNS. Memory, thinking, emotional sphere suffer from it. Among the various forms and CNS pathologies, it is one of the leading.

The primary objective of anticonvulsants is permanent suppression of epileptic discharges that disrupt the work of integration of the brain. Among the various antiepileptic drugs one of the most active and well proven in practice are carbamazepine.

Carbamazepine has positive effects in various forms of seizures, as the easiest (no change of consciousness) and complex (combined with violation of consciousness), indicating its effectiveness both in symptomatic and cryptogenic epilepsy. Carbamazepine advantage is its direct effect in the localization of foci of excitation in the temporal region, which often leads to defects in the mental sphere. Carbamazepine prevents or reduces the frequency of seizures, EEG normalizes patients. There is evidence of efficacy at hyperkinesia of different origin. Noted the selective inhibition of carbamazepine pentilentetrazol clonic seizures. Along with anticonvulsant activity it has psychotropic properties such as antidepressant. A positive aspect of the use of antioxidants in epilepsy is their ability to increase resistance to hypoxia of the brain (seizures), activate plastic processes in the central nervous system (convulsions cause apoptosis) strengthen the integrative mechanisms of the brain.

Therefore, the use of medicines with significant antioxidant capacity can be considered logical and reasonable to deal with painful conditions, and therefore may be promising in the joint application with carbamazepine in the treatment of neuropathic pain. This drug is adequate antioxidant thiotriasolin ⎯ highly effective drug with a broad spectrum of activity that has antioxidant, antiischemic, membrane, immunomodulatory, antiarrhythmic, anti-inflammatory, antiviral and stimulating cell regeneration activity. He gives expressed normalizing effect on pathobiochemical processes in the brain (intensification of oxidative production of energy in neurons, reducing the formation of singlet oxygen, reactivation of the antioxidant system and enhance adaptation processes of neurons in hypoxia) has cerebroprotective action in terms of CNS pathology, shows neuroprotective, antioxidant, antiischemic action. Adding carbamazepine to thiotriazoline enables to reduce its side effects by reducing the dose of anticonvulsants and provide high therapeutic effect. The aim of our research is to develop methods and selection of items for the joint determination of carbamazepine and thiotriazoline in a model mixture by high performance liquid chromatography (HPLC) using gradient-elution pair. To develop best practices for standardizing artificial mixtures based on carbamazepine and thiotriazolin gradient was used ⎯ even elution. To do this in the laboratory at the Department of Pharmaceutical Chemistry ZSMU model was made mixture of active ingredients in the optimal ratio of 1.5:1. Further research was carried out selection eluent containing methanol (MeOH), trifluoroacetic acid (TFA), 0.01 M solution tetrabutylammonium hydrosulfatum (TBAHS) in various proportions and combinations.

Based on previous studies it was found that the simultaneous determination of carbamazepine with thiotriazolin complicated by the following factors: the difference in solubility and chromatographic big difference in their mobility (low-carbamazepine and strongly polar thiotriazoline). In isocratic elution was unable to successfully pick up the condition of simultaneous determination of these substances, which thiotriazoline amount of maintenance would significantly different from a dead volume of the column. To address this issue we used gradient elution with the necessary conditions for it. Thus it can be argued that an even gradient elution ion can simultaneously identify the active ingredients of the model mix, carbamazepine and thiotriazoline, making it possible to simultaneously identify both identify and quantify by HPLC.

Keywords: carbamazepine, thiotriasolin, model mix, high performance liquid chromatography, gradient elution.


UDC 615.276:615.454].001.53

Lyapunov O.M., Bezuglaya O.P., Lyapunov M.O.

State Scientific Institution «Institute for Single Crystals» of National Academy of Sciences of Ukraine, Kharkiv, Ukraine

Investigation of meloxicam release from semisolid preparations in tests in vitro by the dialysis method through the semipermeable membrane

Meloxicam properties (particles size distribution and solubility in water and mixed solvents water-ethanol), which can be important for meloxicam release from semisolid preparations have been studied. It is shown that the particle size of the meloxicam in the alcohol suspensions reduces during dispergation; effectiveness of diminution increases with increasing rotor speed. Meloxicam solubility in water and mixed solvents ethanol – water (25:75) and ethanol – water (40:60) in comparison with system N-methylpyrrolidone (N-МP) – ethanol – water (15:25:60) at 25 оС temperature, depending on tromethamol content and pH value of solutions, has been studied. According to the degree of meloxicam salt with tromethamol solubility increasing the solvents are represented in the following order: water < ethanol 25 % < ethanol 40 % < N-МP – ethanol – water. The meloxicam solubility spikes when the pH of solutions increases, beginning with the definite pH value, characteristic for each solvent. It is possible to adjust meloxicam disperse state and meloxicam proportion in gels in the form of solution and suspension by the pH value and composition of mixed solvents varying. Taking into account the solubility data of meloxicam, Meloxicam gel 1 % on the carbomer basis has been produced, in which 60 % of active substance is in the form of dispersed phase of suspension, 40 % in the form of solution. For this gel in comparison with Amelotex® gel 1 %, some physical and chemical properties have been studied, which can be important for the meloxicam rate and degree of release through semipermeable membrane. It has been demonstrated that both gels are characterized by the comparable rheological properties, similar microviscosity and polarity of the dispersed media and almost identical kinetics of water absorption in tests in vitro, these facts confirm comparability of their osmotic activity. The meloxicam release from the above mentioned gels in tests in vitro by the dialysis method through the semipermeable membrane has been studied. It has been established that the quantity of meloxicam release from Amelotex® gel 1 % is nearly in 2.5 times bigger in comparison with Meloxicam gel 1 %, in which meloxicam content in the form of solution is also in 2.5 times less. The results of investigation have shown that it is only meloxicam in the form of true solution, not suspension that is released from the gels through the semipermeable membrane. It has been shown that during 8 hours, Amelotex® gel 1 % releases meloxicam in 57 times more than Mataren® Plus cream, containing 3 % meloxicam in the form of suspension. For topical treatment of osteoarthritis and other diseases, where meloxicam release and its transdermal penetration is required, it is rational to use semisolid preparations containing dissolved meloxicam.

Keywords: meloxicam, solubility, solvent, solution, suspension, release.


UDC 615.453.6:615.22

Sidenko L.М., Nazarova О.S., Kazarinov М.О.

State Enterprise «State Scientific Centre for Drugs and Medical Product», Kharkіv

Choosing the best moisturizer in the development of composition and technology of tablets candesartan cilexetil by wet granulation — stage pharmaceutical development

The research results obtained during the development of composition and technology of candesartan cileksetil tablets using a wet granulation method. In accordance with the pharmaceutical development of the algorithm defined critical characteristics of candesartan, which may affect the quality of the drug, and are considered in the development of the drug in accordance with the requirements for solid dosage forms. The influence of the type and concentration of binder and other auxiliary agents on the physico-chemical, pharmacotechnological properties of the tablet mass and indicators of the quality of the finished tablets.

It is found that when used as a humidifier 10 % hydroxypropylcellulose solution obtained tablets did not correspond to a reference drug Atacand, tablets of 8 mg (firm AstraZeneca, Sweden), disintegration index whose value is 1 min. Reducing the concentration of hydroxypropyl humidifier to 5 % is irrational, since the disintegration of the resulting tablets have changed insignificantly, which led to a large variation in the resistance to crushing. Upon receipt of the finished product using a 15 % solution of HPMC tablets of all pharmaco-technological characteristics consistent with the requirements the reference product and the State Pharmacopoeia of Ukraine, but the kinetics of dissolution satisfy the eligibility criteria only in two environments: at pH 1.2 and pH 6.8. When used as a humidifier 5 % corn starch paste obtained tablets of pharmaco-technological parameters — disintegration, friability, crush resistance, uniformity of dosage units correspond to reference product and State Pharmacopoeia of Ukraine requirements. Comparison of dissolution profiles developed and reference formulation showed that over 15 minutes more than 85 % of active ingredient passed into the media at pH 1.2 and buffer medium of pH 6.8 buffer and in pH 4.5 medium similarity factor f2 = 67 i.e. satisfies the eligibility criteria (≥ 50 %). The studies selected optimal humidifier 5 % corn starch paste. The optimum amount of auxiliary agents for drug stability. Designed with candesartan tablets are equivalent to a reference drug Atacand, tablets of 8 mg (manufactured by AstraZeneca, Sweden) on the functional characteristics.

Keywords: candesartan cilexetil, pharmaco-technological research, humidifier, level of quality, tablets.


UDC 615.212:615.276:615.217-092.9

Trutaev S.I., Shtrygol’ S.Yu., Kovalova I.O., Shtrygol’ Yu.Yu.

National University of Pharmacy, Kharkiv, Ukraine

An experimental study of «Dolosan Forte®» tablets analgesic, anti-inflammatory and antispasmodic activity

Analgesic, anti-inflammatory and antispasmodic activity of new medicine — tablets «Dolosan Forte®», containing zirilon (2,4-dichlorobenzoic acid potassium salt), pitofenone hydrochloride, fenpiverinium bromide, has been studied experimentally. Effective doses for analgesic and anti-inflammatory activity were determined in animals and amounted to 5 mg/kg for mice and 2.3 mg/kg for rats, achieving an efficacy level of 35-40 %. Antispasmodic activity of the tablets «Dolosan Forte®» and the reference drug «Spazmalgon®» tablets was about the same level (73 % for the former) in animals with the increased tone of the intestine, but the studied medicine did not influence on the intestinal motility in intact animals, in contradistinction to the reference drug, which decreased normal peristalsis. The significant biliary spasmodic effect was manifested in the normalization of bile release to the intact animals value under the condition of the increased tone of the biliary ways. Thus, the new original medicine «Dolosan Forte®» shows high efficacy in doses lower than the reference drug «Spazmalgon®».

Keywords: zirilon, analgesic action, anti-inflammatory drugs, antispasmodic activity, animals.


UDC 615.322

Filenko S.V., Litvinenko V.I.

To discuss the proposals of appropriate rules for storage of medicinal plants

For the production of original new modern complex of herbal medicines need new kinds of medicinal plants. Due to the fact that the quality of herbal remedies is directly dependent on the quality of raw materials on which they are made, high quality raw materials should be standard. MH Quality — the main criterion in the production of herbal remedies, in turn, depends on primary key primary production: growing, harvesting (collecting), drying, storage. Therefore, each step in the production of medicinal plants collected in the wild on cultivated in order to ensure its quality and use in the creation of the drug should be standardized according to the rules GACP. One of the stages of production of high quality raw materials are appropriate rules for storage. Overview available scientific and reference data storage of medicinal plants in Ukraine. Developed by «Manual of storage of medicinal plants» which harmonized with the modern requirements of production of medicinal plants of good quality.

Keywords: medicinal herbs, quality, standardization, storage.


UDC 543.421/424:547.856'872/874

Kryvoshey О.V.

Zaporozhye State Medical University, Ukraine

UV-spectral study of the condensed triazinoquinazoline derivatives

It is the common knowledge, that evaluation of relationships between UV-spectra characteristics, structure and biological activity is quite reasonable for the purposeful search of bioactive compounds with specified pharmacological action. In spite of the potential of [1,2,4]triazino[4,3-c]quinazoline derivatives as promising bioactive compounds, their electronic spectra has not been studied. Present manuscript aimed to the estimation of relationships of molecular structure with the nature of their UV-spectra and identifying spectral patterns of pharmacophore that determines the pharmacological activity of the substances. Mentioned information is certainly a contribution to the development of the theory of the purposeful synthesis of organic compounds. Object of research: benzyl 2-(3-oxo-3,4-dihydro-2H-[1,2,4] triazino[4,3-c]quinazolin-4-yl)acetate (substance I) and N-benzyl 2-(3-oxo-3,4-dihydro-2H-[1,2,4]triazino[4,3-c]quinazolin- 4-yl)acetamide (substance II). The purity and authenticity of the studied compounds were estimated by thin-layer chromatography according to recommendations of the State Pharmacopoeia of Ukraine. Elemental analysis of compounds was performed on EL cube instrument (Elementar Analysensysteme GmbH, Germany). UV-spectra were registered on scanning spectrophotometer Optizen POP (Mecasys Co. Ltd., Korea). Water, 95 % ethanol, 0.1 M hydrochloric acid, 0.1 M solution sodium hydroxide were used as a solvents. All reagents and chemicals used were of analytical grade. The UV-spectra of benzyl 2-(3-oxo-3,4-dihydro-2H-[1,2,4] triazino[4,3-c]quinazolin-4-yl)acetate (substance I) and N-benzyl 2-(3-oxo-3,4-dihydro-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl) acetamide (substance II) in solvents with different polarity (water, 95 % ethanol, 0.1 M hydrochloric acid, 0.1 M solution sodium hydroxide) have been studied. It has been showed that UV-spectra of studied compounds in used solvents are characterized by UV three absorption bands with maximums in the range of 191-217 nm, 274-284 nm and 330-346 nm (substance I) and in the range of 192-215 nm, 274-285 nm and 327-348 nm (substance ІІ). Considering the features of absorption spectra patterns in solvents with different polarity, it was found, that the first two bands of both compounds caused by π → π* transition of electrons in condensed triazinoquinazoline system. Mentioned bands may be classified as 1Lа-band (the 1st – absorption band) and 1Lb-band (the 2nd – absorption band). The third bands, depending on the solvent are characterized by maximums in the range of 330-346 nm (substance I) and 327-348 nm (substance ІІ), and caused by p-π-conjugation of condensed triazinоquinazolinе structure. It has been found, the main chromophore, the structure of which allows to establish the relationship between the electronic nature of the absorption spectra and their nature.

Keywords: triazinoquinazoline derivatives, ultraviolet spectra, electron transitions, absorption bands.


UDC 615.22:615.456.5


Goy A.M., Voskoboynicova G.L., Gapon N.V.

Farmak JSC, Kyiv

Conceptual approaches to determination of methodology of project management of modern pharmaceutical production of parenteral medicinal forms on the basis of recombinant proteins

Actuality of application of innovative approaches of project management is reflected in complex combination with the classic methods of design of technological processes for industrial introduction of hi-tech preparations on the basis of recombinant proteins. It is reasonable conceptual approaches to the project management of modern pharmaceutical production of parenterally medical forms on the basis of recombinant proteins. Certainly pharmaceutical acceptable methods of project management of modern pharmaceutical production of parenteral medical forms and transfer of technological process of industrial production of preparations for parenterally introduction on the basis of recombinant proteins. On the basis of marketing analysis and analysis of the systems of objects of guard right and intellectual property of patents of EP, WO on the preparations-analogues of Human Insulin, preparations of Insulin of urgent and prolonged action, got on the basis of recombinant proteins, technological processes and pharmaceutical formulation, composition and technology of injection forms, adaptations for parenterally introduction we selected effective technologies and the most influential factors of process of receipt parenteral preparation of Insulin are certain on the basis of recombinant proteins and was built diagram of quality pharmaceutical product dependence from efficiency application risk management and monitoring critical parameter of technological process on the stage of pharmaceutical development and introduction in industrial manufacturing.

Keywords: hi-tech pharmaceutical preparations on the basis of recombinant proteins, project management, design, riskmanagement, monitoring of critical parameters, technological process, industrial production.