Pharmaceutical point of view on parenteral nutrition.

Parenteral nutrition--a form of administering nutrients, electrolytes, trace elements, vitamins, and water--is a widely used mode of therapy applied in many diseases, in patients of different ages both at home and in hospital. The success of nutritional therapy depends chiefly on proper determination of the patient's energetic and electrolytic needs as well as preparation and administration of a safe nutritional mixture. As a parenterally administered drug, it is expected to be microbiologically and physicochemically stable, with all of the components compatible with each other. It is very difficult to obtain a stable nutritional mixture due to the fact that it is a complex, two-phase drug. Also, the risk of incompatibility between mixture components and packaging should be taken into consideration and possibly eliminated. Since parenteral nutrition is a part of therapy, simultaneous use of drugs may cause pharmacokinetic and pharmacodynamic interactions as well as those with the pharmaceutical phase. The aim of this paper is to discuss such aspects of parenteral nutrition as mixture stability, methodology, and methods for determining the stability of nutritional mixtures and drugs added to them.

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.

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.