The influence of radiation sterilization on thiamphenicol.

The effect of ionising radiation, applied in the form of an electron beam, in the doses of 25, 100 and 400 kGy on the physical and chemical properties of thiamphenicol in solid phase has been studied by organoleptic analysis (form, colour, smell, solubility, clarity) and spectroscopic methods (UV, IR, EPR), chromatography (TLC), SEM observations, X-ray diffraction, polarimetry and thermal method (DSC). The above-discussed results have proved that on irradiation with a dose of 25 kGy no significant changes appear in thiamphenicol, apart from the formation of free radicals of the lifetime of over 352 days. On irradiation with much higher doses (100 and 400 kGy) no changes were observed in the IR spectra but the UV line intensities slightly increased at lambda(max)=266 and 273 nm, the colour of the powder changed, the radiolysis products appeared as detected by TLC, changes were also observed in the XRD, SEM pictures, the melting point values (DSC) and optical rotation. On the basis of DSC results a linear relation was found between the irradiation dose and the decrease in the melting point and increase in the enthalpy of melting, characterised by high correlation coefficients of r=0.9839 and 0.9622, respectively. Moreover, a linear relation was established between the optical rotation angle and the irradiation dose, alpha(D) ( degrees )=f(dose), characterised by the correlation coefficient r=0.9874. The results obtained indicate that thiamphenicol can be safely subjected to radiation sterilization by the standard dose of 25 kGy.

Radiochemical stability of fluconazole in the solid state.

The effect of ionizing radiation in doses between 20 and 200 kGy on physicochemical properties of fluconazole (alpha-(2,4-diflurophenyl)-alpha-(1H-triazol-1-methyl)-1H-1,2,4-triazole-1-ethanol) in the solid state was examined. A number of qualitative and quantitative methods such as scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), ultraviolet (UV) and infrared (IR) spectroscopy, thin layer chromatography (TLC) and high pressure liquid chromatography (HPLC) and organoleptic analysis were used to determine and analyse any changes resulting from irradiation. A change in colour from white to cream was observed at even smallest dose (20 kGy) and as the dose increased the colour deepened from salmon pink to orange at the highest dose of 200 kGy. The UV method showed an increase in absorbance at lambda(max) and an appearance of an additional band in the range 280-310 nm for irradiated samples. These changes were associated with the appearance of one to two decomposition products observed by TLC. Depending on the dose of radiation, the HPLC method detected between 2 and 3 radiolysis products and the decreasing fluconazole content from 0.48 to 7.12%. The remaining analytical methods (SEM, IR and NMR) did not provide any conclusive information in respect of radiological stability of fluconazole. The results indicate that fluconazole is a compound of low radiological stability and should not be sterilized using gamma, beta or E-beam radiation.

Ruthenium-catalyzed deaminative redistribution of primary and secondary amines.

A ruthenium-hydride complex, [Ru(H)(Cl)(CO)(PCy3)2], was found to be active in the highly selective redistribution of primary and secondary amines bearing an α-hydrogen atom. This new deaminative coupling of amines enables the highly selective synthesis of secondary amines from primary amines and of tertiary amines from secondary amines with the evolution of ammonia. A preliminary mechanistic view of this novel reaction based on catalytic experiments using NMR methods confirms the synthetic observations.

Tetra-functional double-decker silsesquioxanes as anchors for reactive functional groups and potential synthons for hybrid materials.

A series of double-decker silsesquioxane derivatives with four reactive functional groups were designed, efficiently synthesized, and characterized. These novel inorganic-organic hybrids show highly attractive features for applications as building blocks with Si-O-Si rigid cores (good thermal properties) with four reactive moieties, which can be functionalized in further processes.

Microwave-assisted one-pot synthesis of new ionic iridium complexes of [Ir(bzq)2(N

Iridium C,N-cyclometalated complexes with an ionic structure are considered to be promising candidates for application in host/guest solid-state phosphorescent single-layer devices because the employment of such dopants offers the possibility of reducing their concentration in organic matrices as well as allows obtaining organic light emitting devices (OLEDs) with interesting emission parameters. We report herein a methodology enabling the synthesis of cyclometalated ionic iridium(iii) complexes of the type [Ir(C^N)2(N^N)]+A- according to a three-component one-pot strategy involving the acceleration of the reaction via microwave irradiation. The developed protocol allowed efficient synthesis of a series of new cationic iridium(iii) coordination derivatives, which were isolated and spectroscopically characterized, while the structures of two of them were determined by the X-ray method. Moreover, the iridium(iii) derivatives were subjected to the cyclic voltammetry studies in order to determine the energies of the HOMO and LUMO levels as well as to estimate their electrochemical properties and to predict some electronic properties. Additionally, the ONIOM calculation scheme that was used to predict HOMO-LUMO gaps for the studied Ir(iii) complexes showed a good correlation between the experimental and calculated values. In order to determine the influence of the structure and nature of the ancillary ligand on the location of the maximum emission band, the photophysical properties of the synthesized iridium complexes were characterized. Finally, the selected compounds were used as emitters for the construction of polymer light emitting diodes (PLEDs) based on a poly(N-vinylcarbazole)/2-(4-tert-butylphenyl)-5-(4-biphenyl)-1,3,4-oxadiazole (PVK/PBD) matrix. The highest luminance, above 10 000 cd m-2, was recorded for the device containing only 1.0 wt% of [Ir(bzq)2(1,10-phenanthroline)]+PF6- in the PVK/PBD. The fabricated PLEDs exhibit current efficiency in the range of 1.0 to 2.2 cd A-1.

Synthesis of a new class of silsesquioxanes with alkynyl and germyl functionality.

Although there are a variety of functional compounds in the vast family of silsesquioxanes (POSS), the number of protocols describing specific monosubstituted silsesquioxanes is limited. There are even fewer reports on alkynyl and/or germyl functionalities appearing together with the POSS compounds. Here, a series of novel kinds of cubic monosubstituted POSS bearing alkynyl and germyl functionality in one molecule are reported. These compounds were synthesized by effective germylative coupling of terminal alkynes with vinylgermanes in the presence of a Ru-H complex. The structures of the products were determined. Moreover, stoichiometric reactions of a complex possessing Ru-Ge were also performed to propose the general mechanistic scheme of this reaction.

A highly selective synthesis of new alkenylsilsesquioxanes by hydrosilylation of alkynes.

Hydrosilylation of a wide group of mono- and disubstituted (symmetrical and nonsymmetrical) alkynes with 1-dimethylsiloxy-3,5,7,9,11,13,15-heptaisobutylpentacyclo-[9.5.1.13,9.15,15.17,13]octasiloxane ((HSiMe2O)(i-Bu)7Si8O12, 1) in the presence of Karstedt's catalyst (Pt2(dvs)3) has been performed for the first time. A series of new 1,2-(E)-disubstituted and 1,1,2-(E)-trisubstituted ethenes with a silsesquioxane moiety were selectively afforded and fully characterized. On the basis of nuclear magnetic resonance (NMR) and infrared spectroscopy (in situ FT-IR and/or FT-IR), the influence of alkyne structure and reaction conditions on the stereoselectivity as well as on the progress of triple bond hydrosilylation catalyzed by Pt2(dvs)3 was explained. The results of the studies clearly indicated for which reagents the developed procedures lead to alkenylsilsesquioxanes with almost stoichiometric yields in short time, and for which other catalytic systems or methods should be considered.

Free radicals in irradiated drugs: an EPR study.

Exposure of dry powder forms of the drugs nitrendipine, nifedipine, felodipine, and nimodipine to gamma-radiation results in the formation of free radicals detected by electron paramagnetic resonance (EPR) spectroscopy. The four structurally related drugs show qualitatively identical EPR spectral features in terms of g-values, the qualitative descriptive parameter. These radicals are very stable, surviving long periods of time in excess of 9 months and possibly beyond conventional shelf-life of the drugs. The residual radical population is high enough to be detectable after long storage. Administration of such radiation-treated drugs may present patients with quantities of free radicals and possibilities of secondary cell damage.

The effect of ionizing radiation on some derivatives of 1,4-dihydropyridine in the solid state.

The effect of gamma and beta radiation in doses between 10 and 100 kGy on physico-chemical properties of four derivatives of 1,4-dihydropyridine (nifedipine, nitrendipine, felodipine and nimodipine) in the solid state was analysed. A number of qualitative and quantitative methods such as UV, IR, TLC, GLC, DSC, EPR as well as organoleptic and gravimetric analysis were used to determine and analyse any changes resulting from irradiation. In order to determine the effectiveness of sterilization with ionizing radiation of doses from 10 to 25 kGy, various microbiological tests were used. It was established that only doses 10-20 kGy of both kinds of radiation ensure total sterilization without any degradation of physico-chemical properties of the compounds studied. For the doses 50-100 kGy a decrease in the content of the compounds, appearance of the products of their decomposition and changes in the melting point and IR spectra appeared. Felodipine (with chlorophenyl substituent) was found to be much more sensitive to ionising radiation than nifedipine, nitrendipine and nimodipine (all with nitrophenyl substituent).

Aminopropylsilane treatment for the surface of porous glasses suitable for enzyme immobilisation.

During silylation of porous glass with 3-aminopropyltriethoxysilane, the properties of the carrier affected the concentration of bound amino groups, the formation of aminopolysiloxane mono- or multilayer on the surface, and the hydrolytic stability of the layer formed. The influence of the carrier depended on the specific surface area and the size of pores. In contrast to silylation performed in organic solvents, in aqueous solutions a monolayer of aminopolysiloxane of high hydrolytic stability was formed on the surface of porous glass. Tetraethoxysilane modification of porous glass prior to silylation with aminosilane yields carriers of increased hydrolytic stability. Glucoamylase immobilised on carriers, that were modified in aqueous solutions, exhibit higher enzymatic activity.

Photochemical decomposition of phenazone derivatives. Part 7: Mechanism of decomposition in aqueous solutions.

Kinetic studies, supplemented by the isolation and identification of the products of decomposition, have proved the process of photochemical decomposition of phenazone derivatives to be a complex reaction, involving several successive parallel reactions, one of which is predominant depending on the concentration of the solution and the atmosphere above it. In an oxygen-free atmosphere and at low concentrations (10(-4) mol/dm3) decomposition is almost wholly the result of second photolysis of zero order to aziridine derivative----aniline----isonitrile. At higher concentrations (10(-3)-10(-2) mol/dm3), the contribution from the reaction of water photoaddition to the double bond C3-C4 increases. Whereas at concentrations of order greater than or equal to 10(-2) mol/dm3, photoisomerization to imidazole derivatives is predominant. In air, one onserves additionally a second reaction of photooxidation to 4-hydroxy-phenazone----1-acetylo-1-methyl-2-phenyl-hydrazine, a reaction of photodemethylation at N2 with simultaneous oxidation to the 4-ketoderivative, and reactions of hydrolysis characteristic for the individual derivatives. The principal primary photolytic reaction for the group of compounds studied consists in cleavage of the N1-N2 bond of the pyrazoline ring.

Photochemical decomposition of phenazone derivatives. Part 6: Effect of substituents on mass fragmentation and photochemical stability.

Mass spectra (EI) of phenazone, aminophenazone, 4-aminophenazone, noramidopyrine, isopropyl-aminophenazone, niphenazone, propylphenazone and morazone are obtained. The fragmentation pathways are discussed and the mechanisms of spectrometric fragmentation, as well as their similarities and differences within the group under investigation, are determined. A Hammett relationship is found to hold between the intensity of certain ions and the type of substituent on the C-4 positions. Certain similarities are established between photochemical decomposition and spectroscopic fragmentation, and it is suggested that MS may prove useful when making predictions concerning the photochemical stability of phenazone derivatives.

Photochemical decomposition of phenazone derivatives. Part 5(1): Isolation and identification of decomposition products in aqueous solution.

From aqueous solutions of phenazone, aminophenazone, propyphenazone, nifenazone, morazone, noramidopyrine, 4-aminophenazone and isopropylaminophenazone, UV irradiated at lambda = 254 nm in oxygen free atmosphere as well as in the presence of air, 24 decomposition products were isolated and identified as derivatives of pyrazoline, pyrazolidinone, imidazoline, hydantoin, aziridine, phenylhydrazine and aniline.

Kinetics of drug decomposition. Part 69: Effect of excipients on the thermal decomposition of the mixture of aminophenazone allobarbital and adiphenine hydrochloride in the solid.

By the method of accelerated testing at elevated temperature, the thermal decomposition rate of the mixture of aminophenazone (AP), allobarbital (AB) and adiphenine hydrochloride (AD) and its individual components in the presence of the excipients starch (potato), agar, talcum, kaolin and magnesium stearate is studied. The individual and joint effect of the excipients on the components of the mixture AP + AB + AD as well as on the mixture as a whole is determined and compared. The theoretically predicted stability of the components is discussed and compared with the results of "self-life" tests in the presence and absence of the excipients.

Evaluation of nifedipine preparations by chromatographic-spectrophotometric methods.

The content of nifedipine in 10 currently available preparations (tablets, capsules, dragees and drops) was analyzed. In the qualitative analysis, a TLC method was employed, whereas in the quantitative analysis, a chromatographic-spectrophotometric method developed in our laboratory (TLC-UV), a TLC-UV method according to USP XXI, and the method of gas chromatography coupled with mass spectrometry (GC-MS) were employed. For all the preparations under study, the presence of at least one decomposition product as well as a decrease in the content of active component, in most cases proportional to the storage time, were observed. However, in none of the preparations pyridine nitro derivative decomposition products were found, but in each the presence of nitroso derivative was reported. As a result, it was stated that about a half of the preparations studied do not meet the requirements of USP XXI as for as the content of the active substance is concerned, which suggests that the expiration date is shorter by 6 to 12 months.

[Analysis of the products of drug decomposition. XLII. Determining the levels of vitamin K in pharmaceutical preparations in the presence of decomposition products]. / Analiza produktów rozkladu leków. XLII. Oznaczanie witamin K w preparatach farmaceutycznych w obecnosci produktów rozkladu.

Chromatographic-spectrophotometric methods for the determination of vitamins K1, K3 and K4 in pharmaceuticals (tablets, dragees, injection solutions) in the presence of decomposition products have been elaborated. The TLC method on Kieselgel HF 254 (Merck) was applied to separation of the active substances from decomposition products, using the following solvent systems: benzene--ethyl acetate (9:1) for vitamin K1, cyclohexane--chloroform--metanol--acetic acid (2:15:3:1) for vitamin K3, and benzene--acetone (9:1) for vitamin K4. After elution from the plates, vitamin K1 was determined in ethanol at lambda = 251 nm, vitamin K3 in water at lambda = 234 nm and vitamin K4 in methanol at lambda = 225 nm. Maximum sensitivity of the elaborated methods came up to 7 X 10(-5) g, and standard deviations of single determinations ranged from 1.99% to 3.70%.

[Analysis of 5-pyrazolinone derivatives in pharmaceutical products. I. Spectrophotometric analysis of two-component drugs containing propyphenazone]. / Oznaczanie pochodnych 5-pirazolinonu w preparatach farmaceutycznych. I. Spektrofotometryczne oznaczanie leków dwuskladnikowych z propyfenazonem.

Two new methods for the determination of active components in the preparations Gardan P (propyphenazone + noramidopyrine) and Pabialgin P (propyphenazone + allobarbital) have been elaborated. The first one is a direct spectrophotometric method based on measurements of absorption at two wave lengths; at lambda = 218 and 270 nm for Pabialgin P, and at lambda = 232 and 260 nm for Gardan P. The second method, the chromatographic-spectrophotometric method has been based on separation of individual components by thin-layer chromatography followed by their spectrophotometric determination. The results obtained by the above two methods were compared with the results given by the titrimetric method according to the producer's standard. Statistic analysis by the Student's and F-Snecodor's tests has shown that all these methods are equally precise but differ in accuracy, sensitivity and selectivity. The spectrophotometric determination of allobarbital has proved to show the highest accuracy (Wz = 1.4), while the acidimetric determination of propyphenazone in the non-aqueous medium has appeared least accurate (Wz = 3.7). Sensitivity of the tested methods was found to range from 3 x 10(-4) g/cm3 for the titrimetric methods to 6 x 10(-6) g/cm3 for direct spectrophotometric measurements. In respect of selectivity, only the chromatographic-spectrophotometric method has proved to be enough selective and to give quite correct results.

[Infrared spectrophotometry in quantitative drug analysis. II. Assay of some steroids]. / Zastosowanie spektrofotometrii w podczerwieni w ilosciowej analizie leków. II. Oznaczanie niektórych pochodnych sterydowych.

PIP: Infrared spectrometry was applied to the determination of mestranol, chlormadinone, estradiol benzoate, progesterone, testosterone propionate, and methyltestosterone. Except for mestranol, all of the steroids were determined in the range of 1656-1735 cm (-1) on the ground of the absorption of the carbonyl groups. Mestranol can be determined at 3308 cm (-1) (ethyl group variations) or at 1502 cm (-1) (variations of the aromatic ring system). The asorption band 1495 cm (-1) has been shown to be suitable for assaying estradiol benzoate. A relative error of .58% to 3.26% has been charged for the methods used. Methyltestosterone and progesterone can also be assayed by using the absorption bands reflecting the vibrations of the methyl groups, at 1361 cm (-1) and 1380 cm (-1). However, the assays at the latter wave lengths are found to be less accurate, with relative error at 3.49% and 4.41% and precision error at 1.19% and 1.39%, respectively. All measurements were performed in a medium of highly purified chloroform.^ieng

The effect of gamma-radiation on nitroimidazole derivatives.

The effect of gamma irradiation, in doses from 10 to 50 kGy on physical and chemical properties of metronidazole, ornidazole and tynidazole in solid state has been studied. Results of the measurements by the UV, IR, TLC, EPR, DSC methods revealed the presence of free radicals, products of decomposition, an increase in the melting point and a decrease or increase in the content of the substance studied. Microbiological assays proved that sterilization of the compounds studied was effective even with the smallest irradiation dose applied. The maximum tolerated dose and the safe sterilisation dose were determined.

Identification of radiolysis products of solid thiamphenicol.

Spectroscopic and chromatographic methods (HPLC, HPLC-MS, NMR) were used to observe, separate and identify products of radiolysis of thiamphenicol (TF), irradiated in the solid state at room temperature and atmospheric pressure with an electron beam from a linear accelerator to doses between 25 and 800 kGy. Nine products of radiolysis of thiamphenicol were identified, among them were TF amine, dichloroacetic acid, 4-methylsulfonylbenzoic acid, demono- and dedichloroderivative of TF, 2,2-dichloro-N-{3-hydroxy-1-[4-(methylsulfonyl)phenyl]-1-oxopropan-2-yl}acetamide and 3-({1,3-dihydroxy-1-[4-(methylsulfonyl)phenyl]propan-2-yl}amino)-3-oxopropanoic acid. The process of radiodegradation of TF was proposed as consisting of several parallel primary reactions (dehalogenation, oxidation of the OH group at C(1), hydrolysis of the amide bond, a rapture of the C(2)-C(3) bond of propan-1-ol) and secondary reactions (carboxylation and oxidation). The use of high doses, well above the sterilization dose of 25 kGy, allowed observation of changes of TF content as a function of radiation dose, calculation of radiolytic yield (G(-TF)) and kinetic parameters of the degradation reaction. It was found that the standard sterilizing dose lowers the content of TF by only 0.1% and the radiolytic efficacy of the process of radiodegradation is 0.76 molecules/100eV. Further increase in the dose lowers the content of TF to 92.1% for 800 kGy dose and leads to an increase in the value of G(-TF). It was also found that the summative process of radiodegradation of TF exposed to a beam of electrons of 10 kGy/s follows the first order reaction kinetics with a degradation constant of k=0.001s(-1). On the basis of the experiments conducted it can be stated that the radiolysis of TF in the presence of an E-beam, in substantia, follows multidirectional course in the same way as radiolysis of chloramphenicol. TF exposed to the standard sterilizing dose of 25 kGy degrades only by 0.1%, the amount acceptable by the ICH, and forms only one product of radiolysis (TF amine) and therefore we conclude that it can be sterilized by ionizing radiation under the conditions described above.