Barbara Marciniec

DSC study of radiostability of 1,4-dihydropyridine derivatives

The effect of sterilisation by irradiation has been studied for the seven most often used in medicine derivatives of 1,4-dihydropyridine (nifedipine, nisoldipine, nicardipine, nitrendipine, nimodipine, felodipine and amlodipine). The sterilisation was performed for the compounds in the solid phase with an electron beam of the energy 10 MeV, at room temperature, using the irradiation doses from 20 to 400 kGy. The effects of the irradiation were studied by the methods SEM, DSC, XRD and TLC. The sterilisation with doses 20-100 kGy was found to cause no changes in the physico-chemical properties of the compounds, while the irradiation with higher doses (200-400 kGy) was found to induce changes in the colour, DSC spectrum and TLC picture. As follows from the TLC results, the main product of radiolysis of the compounds studied was a pyridine nitrozoderivative, which indicates the same mechanism of decomposition as in the process of photodegradation. The results prove that the 1,4-dihydropyridine derivatives being highly sensitive to visible and UV radiation are generally resistant to ionising radiation and thus can be subjected to sterilisation by irradiation.

Analytical Study of β-Irradiated Antibiotics in the Solid State

This paper reports results of the study on the influence of β-irradiation on the physical and chemical properties of selected salts of β-lactam antibiotics in solid state (sodium salt: ampicillin, azlocillin, benzylpenicillin, carbenicillin and piperacillin; potassium salt of benzylpenicillin, ampicillin anhydricum, ampicillin trihydricum, amoxicillin trihydricum and bacampicillin hydrochloride). The source of irradiation was a linear accelerator of electrons, and the irradiation effects were checked on the basis of the following: determination of mass, melting point and water contrent, and spectrophotometric (UV, IR) chromatographic and thermal (DTG, DSC) studies.

Evaluation of radiostability of some steroid derivatives

The effect of ionising radiation (15-100 kGy) on the physico-chemical properties of 6 steroid derivatives in solid state (Hydrocortisone, Hydrocortisone acetate, Prednisolone, Prednisolone acetate, Dexamethasone and Fludrocortisone acetate) was studied by differential scanning calorimetry (DSC), differential thermal analysis (DTA), scanning electron microscopy (SEM), UV spectrophotometry, high-performance liquid chromatography (HPLC), X-ray powder diffraction and polarimetry. DSC and DTA results revealed that the irradiated compounds undergo phase transitions at lower temperatures, show lower melting points and lower enthalpy of the melting process their non-irradiated analogues. The results of HPLC measurements proved a loss in the active substance content after irradiation ranging from 0.5 to 2.88%. No significant effect of irradiation was detected by the UV spectrophotometry or polarimetry in the course of the UV spectrum, absorbancy or optical rotation, as well as in the SEM photographs and X-ray patterns. For some compounds studied a correlation was found between the irradiation dose and the shifts in DSC curves and the loss of content determined by the HPLC method. Similar, but not so much pronounced relations were established in or earlier studies of the derivatives of nitroimidazole and 1,4-dihydropyridine. In general the results have shown relatively high radiochemical stability of the compounds studied and have proved that the DSC method is a sensitive detector of irradiation-caused changes in drugs in solid phase.

Influence of ionising irradiation on clotrimazole in the solid state

The effect of ionising irradiation on the antifungal drug clotrimazole has been studied. The compound was subjected to ionisation irradiation in the form of high-energy electron beam (25-800 kGy) from an accelerator. Before and after the irradiation the compound was subjected to the EPR, TLC, HPLC and HPLC-MS analysis. After irradiation with doses 400-800 kGy the colour of the substance was changed from white to cream. Four products of radiolysis appeared in the HPLC chromatogram at 7.7, 4.2, 6.4 and 14.6 min and the active ingredient content decreased to 96.5%. The irradiation with a dose of 25 kGy resulted in the appearance of trace amounts of the product at 7.7 min and free radicals (2.54 x 10(14)spins/g). On the basis of the HPLC-MS data, the main product of radiolysis (t(R)=7.7 min) is 1-(9-phenylfluoren-9-yl)-imidazole. Besides traces of (2-chlorophenyl)-diphenylmethanol, other impurities listed in the European Pharmacopoeia (European Pharmacopea, 5th edition, Council of Europe, Strasbourg, France, 2004.) have not been detected. Clotrimazole has been found to show relatively high resistance to ionising irradiation (greater than fluconazole) and probably will be suitable for radiation sterilisation but with doses lower than 25 kGy.

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.

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.

Identification of Radiodegradation Products of Acebutolol and Alprenolol by HPLC/MS/MS.

Two therapeutically active compounds from the group of β-blockers, acebutolol (AC) and alprenolol (AL), in solid form were subjected to ionizing radiation emitted by a beam of high energy electrons from an accelerator with a standard sterilization dose of 25 kGy and in higher doses of 50-400 kGy. The effects of irradiation were detected by chromatographic methods (TLC, HPLC) and a hyphenated method (HPLC/MS/MS). No significant changes in the physicochemical properties of both compounds studied irradiated with 25 kGy were noted, but upon irradiation with the highest dose (400 kGy) the loss of AC and AL content determined by HPLC was 2.79 and 9.12%, respectively. The product of AC decomposition and the two products of AL decomposition were separated and identified by HPLC/MS/MS. It has been established that radiodegradation of AC and AL takes place by oxidation, leading to formation of the products of radiolysis, most probably alcohol derivatives of the β-blockers studied. The additional product that appears on radiodegradation of AL is probably formed as a result of two simultaneous reactions: oxidation and CH2 group elimination.

Analysis of Drug Impurities

Although the development of trace analysis is considered to have begun with studies related to the determination of trace elements, from the pharmaceutical point of view, the beginning of this field of science should be sought in the analysis of drugs and especially in the search for active compounds in different types of pharmaceutical decoctions, tinctures, and macerations. Isolation of opium and later morphine from poppy juice, or isolation of quinine from cinchona tree bark, were nothing other than preparation and concentration of a sample before performing trace analysis [1–3].

Spectroscopic analysis of pindolol irradiated in the solid state

AbstractPindolol ((2RS)-(1-(1H-indol-4-iloxy)-3- [(1-metyloetylo)amino]-2-propanol) in substantia was exposed to ionising radiation emitted by high energy electrons from an accelerator, in the standard sterilisation dose of 25 kGy and in higher doses from the range 50–400 kGy. The effects of irradiation were checked by spectrometric methods (UV, MS, FT-IR, EPR) and hyphenated methods (HPLC-MS) and the results were referred to those obtained for non-irradiated sample. EPR results indicated the presence of free radicals in irradiated samples, in the amount of 1.36 × 1016 spin g−1 for 25 kGy and 3.70×1016 spin g−1 for 400 kGy. The loss of pindolol content determined by HPLC was 1.34% after irradiation with 400 kGy, while the radiolytic yield of the total radiolysis for this dose of irradiation was 2.69×107 mol J−1. By means of HPLC-MS it was possible to separate and identify one product of radiolytic decomposition, which probably is 2-((R)-3-(1H-indol-4-yloxy)-2-hydroxypropylamino)propan-1-ol formed upon oxidation.In the range of sterilisation doses (25–50 kGy), pindolol was found to show high radiochemical stability and would probably be safely sterilised by the standard dose of 25 kGy.

The effect of ionizing radiation on metoprolol

The influence of ionising radiation on physico-chemical properties of metoprolol tartrate (MT) in solid phase was studied. The compound was irradiated by radiation produced by a beam of high-energy electrons in an accelerator, in doses from 25 to 400 kGy, and the possible changes in the samples were detected by organoleptic analysis (colour, forms, clarity), chromatographic and spectrometric methods. Already at the standard sterilisation dose of 25 kGy, the presence of free radicals (0.3764 × 1016 spin/g) and a decrease in the melting point by 1°C were noted. At higher doses of irradiation products of radiolysis appeared (100 kGy) and the colour was changed from white to pale cream (200 kGy). Our observation was that with increasing mass loss of MT after irradiation with 100, 200 and 400 kGy, the concentration of free radicals increased from 1.0330 to 1.6869 × 1016 spin/g. The radiolytic yield of total radiolysis was 4.54 × 107 mol/J for 100 kGy, 7.42 × 107 mol/J for 200 kGy and 4.74 × 107 mol/J for 400 kGy. No significant changes were observed in the character of FT–IR spectra, but in UV an increase in intensity of the band at the analytical wavelength was noted. As follows from the results MT shows high radiochemical stability for the typical sterilisation doses 25–50 kGy, and will probably be able to be sterilised by radiation in the dose of 25 kGy.