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.

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.

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).

Glass transition of gluten. 2: The effect of lipids and emulsifiers.

The effects of lipids and emulsifiers on the glass transition temperature (Tg) of gluten have been studied as a function of water content, using differential scanning calorimetry, dynamic mechanical thermal analysis, a three point bend test and pulsed nuclear magnetic resonance. Lipids and emulsifiers were found to have little or no effect on Tg, with the exception of the lower molecular weight caproic and hydroxycaproic acids, which had a plasticizing effect. In the case of hydroxycaproic acid this was found to be in accordance with the Couchman-Karasz equation. The magnitude of the drop in modulus at Tg was increased in the presence of these additives at low water contents. The effect of lipids and emulsifiers on the Tg of gluten and their compatibility with gluten appears to depend both on their hydrophobicity and on their molecular weight.

Glass transition of gluten. 1: Gluten and gluten-sugar mixtures.

The glass transition in hydrated wheat gluten has been studied using dynamic mechanical thermal analysis, differential scanning calorimetry, pulsed nuclear magnetic resonance and a three point bend test. The results for gluten alone are in good agreement with results obtained by other workers for gluten and glutenin. In contrast to their effect on the Tg of amylopectin, a gluten:sugar ratio of 10:1 (where the sugar is amorphous fructose, sucrose or glucose) has little effect on the glass transition temperature, as a function of water content. A sample containing gluten and fructose in the ratio 2:1 showed plasticization due to the sugar.

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.