Pharmaceutical Chemistry Journal (v.44, #5)

Modeling complexes of substrates with cytochrome P450 2C9 by A. A. Pogrebnoi; M. A. Grishina; V. A. Potemkin; D. A. Sysakov (237-240).
Complexes of 16 substrates with 2C9 isoform of Cytochrome P450 complex taken from the PDB database have been modeled using 3D-QSAR algorithm CiS. The arrangement of substrate molecules and the orientation of their reaction centers with respect to the heme in modeled complexes have been analyzed. The orientation of substrate molecules in the model complexes explains the experimentally observed metabolic reactions. The results show that the CiS algorithm is capable of predicting the metabolic pathways of the modeled complexes.
Keywords: docking; modeling; complex; substrate; P450; 2C9; 1R90

Synthesis and pharmacological activity of 1-dialkyl(alkyl)aminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazoles by V. A. Anisimova; A. A. Spasov; I. E. Tolpygin; M. V. Chernikov; D. S. Yakovlev; I. I. Goryagin; N. A. Gurova; O. A. Salaznikova; L. V. Naumenko; V. A. Kosolapov; L. V. Eltsova; N. A. Kolobrodova (241-244).
In continuation of the investigation of 1-dialkylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazoles demonstrating serotoninergic activity, several new substances of this class with 4-substituted piperazines and piperidines as amine moieties were synthesized and tested pharmacologically in vitro. All substances were investigated for antiserotoninergic, antiplatelet, haemorheological, antiarrhythmic, and antioxidant activity.
Keywords: synthesis; 2,3-dihydroimidazo[1,2-a]benzimidazoles; antiserotonin activity; heamorheological properties; antiarrhythmic activity; antiplatelet activity

A series of 2-acetyl-5-hydroxy-5-methyl-3-phenyl-1-cyclohexanone and alkyl-4-hydroxy-4-methyl-2-oxo6-phenylcyclohexane-1-carboxylates have been obtained via interaction of benzalacetone with various acetoacetates and acetylacetone in an ethanol solution of potassium hydroxide. The antimicrobial activity of the synthesized compounds has been studied.
Keywords: cyclohexanone; cyclohexanecarboxylates; antimicrobial activity; β-cycloketoles; alkyl-2oxocyclohexanecarboxylates

Synthesis and antimicrobial activity of geminal bis-hydroperoxides by V. I. Tropina; O. V. Krivykh; N. P. Sadchikova; A. O. Terent’ev; I. B. Krylov (248-250).
A series of six new geminal bis-hydroperoxides were synthesized based on cyclic ketones. Experiments in vitro show that the synthesized compounds exhibit pronounced antimicrobial properties that are comparable with the effect of some antiseptics and, to a lesser extent, antibiotics. Tests on B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, and A. niger showed that bis-hydroperoxides were similar to hydrogen peroxide with respect to both the spectrum of action and the MIC level (0.1, 1.0, and 10 mg/mL), which is evidence for a similar mechanism of antimicrobial action.
Keywords: peroxides; geminal bis-hydroperoxides; antimicrobial activity

Synthesis and antimicrobial activity of new mono-and biquaternized dipyridylethanes and dipyridylethylenes by N. V. El’chishcheva; Yu. V. Shklyaev; Zh. A. Vnutskikh; T. F. Odegova; Yu. S. Chekryshkin; S. S. Dubrovina (251-253).
A series of mono-and biquaternized derivatives of dipyridylethane and dipyridylethylenes were synthesized in order to study their antimicrobial activity (AMA) with respect to Gram-negative (E. coli) and Gram-positive (S. aureus) species. It is established that the antimicrobial activity depends on the nature of the radical on the nitrogen atom, the positions of the ethane and ethylene bridges between the rings relative to the onium nitrogen atoms, and the presence of conjugated systems between these atoms. The maximum AMA with respect to the indicated test microbe strains was observed for 1-(N-dodecylpyridin-4-yl)-2-(4-pyridyl)ethylene bromide (MIC 3.9 and 2.0 μg/mL, respectively).
Keywords: quaternization; 3-dipyridylethane; dipyridylethylenes; antimicrobial activity

Preparation of drug polymorphs (a review) by D. T. Guranda; G. N. Gil’deeva (254-260).
Data available in the literature concerning the screening and preparation of drug polymorphs are reviewed. The most effective methods used to obtain polymorphous modifications of drug substances are based on crystallization. Crystallization of polymorphs is governed by both thermodynamic and kinetic factors; therefore, the preparation of certain drug polymorphs requires strict control of the crystallization conditions. Metastable modifications of drugs can be prepared predominantly using non-equilibrium crystallization techniques.
Keywords: drug polymorphs; preparation of polymorphous modifications

Kinetics of 1-(2-phenylethyl)-4-phenylaminopiperidine acylation by propionyl chloride in nonaqueous media by U. A. Murashova; L. V. Skalkina; E. N. Glukhan; S. K. Smirnov (261-264).
The kinetics of 1-(2-phenylethyl)-4-phenylaminopiperidine acylation with propionyl chloride in nonaqueous solutions to form fentanyl hydrochloride have been studied experimentally using high-performance liquid chromatography (HPLC). It is established that the reaction is second order. The kinetics and activation parameters of the reaction have been determined.
Keywords: fentanyl; reaction kinetics; rate constant; activation energy; propionyl chloride; high-performance liquid chromatography

Biopharmaceutical study of suppositories containing nonsteroidal anti-inflammatory drugs by T. V. Orlova; T. A. Pankrusheva; A. V. Nesterova; N. D. Ogneshchikova (265-267).
The release of several nonsteroidal anti-inflammatory drugs (NSAIDs) including analgin, paracetamol, orthofen, naproxen, aspirin, and sodium salicylate from various lipophilic suppository bases has been investigated in vitro. Individual release patterns of NSAIDs from suppositories and the significant dependence of this process on the chemical nature of the base and surfactant were shown. It was found that a determining factor in the selection of a rational suppository base is the completeness of drug release from the suppositories because the correspondence of most of the studied suppositories to pharmacopoeial requirements for melting point and total deformation time did not guarantee that the drugs had high bioavailability. The optimum bases from a biopharmaceutical viewpoint for production of suppositories of the aforementioned NSAIDs were found. The results can be used by scientific and commercial laboratories for the creation of the optimum base for production of suppositories and other NSAID medicinal forms and for the development of a common approach to evaluating the quality of suppositories.
Keywords: biopharmaceutical investigation; suppositories; nonsteroidal anti-inflammatory drugs; surfactants

The process of tablet-coating material drag-out in apparatuses of various design including drum-type and pseudo-fluidized-bed reactors has been studied experimentally. The influence of the main parameters of the process on the drag-out value was determined. An equation describing the process kinetics and estimating the level of drag-out was obtained.
Keywords: tablets; fluidized bed; drum-type reactor; drag-out of coating material

Synthesis and physicochemical evaluation of a new carrier based on an interpolyelectrolyte complex formed by Eudragit® EPO and Carbomer 940 by R. I. Mustafin; T. V. Kabanova; E. R. Zhdanova; A. V. Bukhovets; V. R. Garipova; Sh. F. Nasibullin; V. A. Kemenova (271-273).
The formation of interpolyelectrolyte complexes (IPEC) between Eudragit® EPO (EPO) and Carbomer 940 (C940) was investigated with a view to their use in peroral controlled-release drug delivery systems. The structure of the synthesized products was investigated using FTIR spectroscopy and MT—DSC methods, which indicated that the synthesized product can be considered to be an IPEC stabilized by a cooperative system of ionic bonds. Based on results of capillary viscosimetry and elemental analysis, the IPEC prepared at pH 4.0 has a characteristic composition with a C940:EPO mole ratio of 1.75:1.
Keywords: interpolyelectrolyte complexes; Eudragit® EPO; Carbomer 940; physicochemical properties

Increasing the solubility of phenazepam by forming solid dispersions by I. I. Krasnyuk Jr.; O. V. Manakhova; R. U. Khabriev; V. A. Popkov; V. Yu. Reshetnyak; O. I. Krasnyuk (274-277).
The effect of solid dispersion (SD) formation on the solubility of phenazepam has been studied. Phenazepam and its SDs with poly(ethyleneglycol)-1500 (PEG), poly(vinylpyrrolidone)-10000 (PVP), and β-cyclodextrin were studied. The SD with PVP increases both the solubility and the dissolution rate of phenazepam. Results obtained by a complex of physical and chemical methods suggest that the improved release of phenazepam from the SD with PVP is due to solubilization, amorphization, and formation of a colloidal dispersion of the parent drug substance.
Keywords: solid dispersion; solubility; phenazepam; poly(ethyleneglycol)-1500; poly(vinylpyrrolidone)-10000; β-cyclodextrin

Developing methods for analysis of the solid dosage form (capsules) of cardiocyclide by M. S. Sergeeva; L. N. Grushevskaya; B. M. Pyatin; K. V. Alekseev; N. I. Avdyunina; E. V. Blynskaya (278-281).
We have developed methods for the pharmaceutical analysis of the new domestic antiarrhythmic drug cardiocyclide in a solid dosage form (capsules). The main pharmacopoeial quality tests were carried out. The content of impurities in capsules was determined by thin-layer chromatography. UV spectrophotometry and gradient high-performance liquid chromatography were used for simultaneous assay, purity check, and quantitative analysis of the drug. The pharmacopoeial “Dissolution” test was carried out using UV spectrophotometry.
Keywords: cardiocyclide; capsules; thin-layer chromatography; gradient high-performance liquid chromatography; UV spectrophotometry

Spectrophotometric determination of p-aminophenol in drugs using 5,7-dichloro-4,6-dinitrobenzofuroxan reagent in micellar medium by R. F. Bakeeva; T. S. Gorbunova; O. E. Vakhitova; A. I. Gaisina; L. M. Yusupova; S. Yu. Garmonov; V. F. Sopin (282-286).
A new spectrophotometric method for determining p-aminophenol in micellar aqueous dimethylsulfoxide (DMSO) media with non-ionogenic surfactant Triton X-100 that makes use of 5,7-dichloro-4,6-dinitrobenzofuroxan as an indicator has been developed. Using the proposed method, it is possible to detect an admixture of p-aminophenol in paracetamol (acetaminophen) in such media on a level that is much lower than the limiting concentration. The presence of Triton X-100 in the form of micelles improves the sensitivity of spectrophotometric determination compared to that of standard techniques.
Keywords: p-aminophenol; drugs; spectrophotometry