Electron Beam Radiation as a Safe Method for the Sterilization of Aceclofenac and Diclofenac-The Usefulness of EPR and 1H-NMR Methods in Determination of Molecular Structure and Dynamics.

Diclofenac (DC) [2-(2,6-Dichloroanilino)phenyl]acetic acid,) and aceclofenac (AC) 2-[2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxyacetic acid in substantia were subjected to ionizing radiation in the form of a beam of high-energy electrons from an accelerator in a standard sterilization dose of 25 kGy and higher radiation doses (50-400 kGy). We characterized non-irradiated and irradiated samples of DC and AC by using the following methods: organoleptic analysis (color, form), spectroscopic (IR, NMR, EPR), chromatographic (HPLC), and others (microscopic analysis, capillary melting point measurement, differential scanning calorimetry (DSC)). It was found that a absorbed dose of 50 kGy causes a change in the color of AC and DC from white to cream-like, which deepens with increasing radiation dose. No significant changes in the FT-IR spectra were observed, while no additional peaks were observed in the chromatograms, indicating emerging radio-degradation products (25 kGy). The melting point determined by the capillary method was 153.0 °C for AC and 291.0 °C for DC. After irradiation with the dose of 25 kGy for AC, it did not change, for DC it decreased by 0.5 °C, while for the dose of 400 kGy it was 151.0 °C and 286.0 °C for AC and DC, respectively. Both NSAIDs exhibit high radiation stability for typical sterilization doses of 25-50 kGy and are likely to be sterilized with radiation at a dose of 25 kGy. The influence of irradiation on changes in molecular dynamics and structure has been observed by 1H-NMR and EPR studies. This study aimed to determine the radiation stability of DC and AC by spectrophotometric, thermal and chromatographic methods. A standard dose of irradiation (25 kGy) was used to confirm the possibility of using this dose to obtain a sterile form of both NSAIDs. Higher doses of radiation (50-400 kGy) have been performed to explain the changes in DC and AC after sterilization.

Toward Safe Pharmacotherapy: The Interplay between Meropenem and Parenteral Nutrition Admixtures.

Simultaneous administration of parenteral nutrition (PN) admixtures with intravenous antibiotics is a common clinical problem. Coadministration of drugs incompatible with PN admixture may affect its stability, especially in the context of lipid droplet size, which is a crucial parameter for patient safety. In the present study, we investigate the in vitro compatibility of meropenem (Meropenem 1000, MPM) with five commercial PN admixtures used worldwide: Kabiven, Olimel N9E, Nutriflex Lipid Special, Nutriflex Omega Special, and SmofKabiven. The appropriate volumetric ratios, reflecting their clinical practice ratios, were used to prepare the MPM-PN admixture samples. Physicochemical properties of MPM-PN admixtures samples were determined upon preparation and after four hours of storage. The pH changes for all MPM-PN admixtures samples did not exceed the assumed level of acceptability and ranged from 6.41 to 7.42. After four hours of storage, the osmolarity changes were ±3%, except MPM-Olimel N9E samples, for which differences from 7% to 11% were observed. The adopted level of acceptability of changes in zeta potential after four hours of storage (±3 mV) was met for MPM-Kabiven, MPM-Nutriflex Lipid Special, and MPM-Nutriflex Omega Special. The mean droplet diameter for all samples was below 500 nm. However, only in the case of Nutriflex Lipid Special and Nutriflex Omega Special, the addition of MPM did not cause the formation of the second fraction of lipid droplets. The coadministration of MPM via Y-site with Kabiven, Olimel N9E, and Smofkabiven should be avoided due to osmolarity fluctuations (MPM-Olimel), significant differences in zeta potential (MPM-Olimel, MPM-Smofkabiven), and the presence of the second fraction of lipid droplets >1000 nm (MPM-Kabiven, MPM-Olimel, and MPM-Smofkabiven). The assumed acceptance criteria for MPM compatibility of MPM with PN admixtures were met only for Nutriflex Lipid Special and Nutriflex Omega Special in 1:1, 2:1, and 4:1 volume ratios.

Compatibility of intravenous metronidazole with some all-in-one parenteral nutrition regimens.

OBJECTIVES: Supplementation of parenteral nutrition (PN) admixtures with other parenteral drugs may be desired especially in the case of polypharmacy and limited vascular access. Metronidazole (MTZ) is administered in surgical and critically ill patients often requiring concomitant nutritional therapy in the form of parenteral nutrition. The aim of the study was to evaluate the possibility of the concomitant administration of MTZ with PN admixtures from one container. METHODS: MTZ (1500 mg) was combined with six different PN admixtures and stored for 7 days before the simulation of administration. The mean droplet size (MDS) of the lipid emulsion, zeta potential, color, and pH of the tested samples were determined every 24 h. The content of MTZ was determined by the high-performance liquid chromatography method within the same time frames. RESULTS: PN admixtures supplemented with MTZ were characterized by a pH range from 6.19 to 6.38 and zeta potential range from -21.6 mV to -8.8 mV. For all samples the pharmacopeial criteria for intravenously administered emulsions were met: The visual inspection showed no sign of emulsion destabilization or precipitation, and the MDS was <500 nm. The MTZ content remained >90% of the initial value throughout the whole study period. CONCLUSIONS: Results showed the physicochemical compatibility and stability of PN admixtures supplemented with MTZ at the dose of 1500 mg. Such formulations can be stored at a temperature of 5°C for up to 7 d before administration to the patient.

Kinetics of omeprazole degradation in solid state.

The influence of temperature and relative air humidity on the stability of omeprazole (OME) in solid state was studied. Changes in the concentration were monitored by HPLC with UV detection. The method was validated; its selectivity, range of linearity, precision, limit of detection (LOD) and limit of quantification (LOQ) were established. The linearity was satisfactory (r = 0.9998) in the concentration range from 0.5 to 14.0 mg/mL for a LiChrospher 100 RP-18 column (5 microm particle size, 100 mm x 4 mm, Merck, Darmstadt, Germany) and the mobile phase of methanol : 100 mM ammonium acetate (60:40 v/v). Degradation was conducted in solid phase at increased temperature (313 K to 393 K) and in the air humidity varying from 25% to 90% RH. The kinetic and thermodynamic parameters of OME decomposition in solid phase were determined.

Quality assessment of morphine hydrochloride solutions.

The therapeutic substances in solution prepared in pharmaceutical laboratories (prescribed drugs) must preserve their activity. Therefore, they must be stable throughout the period of storage in home conditions. The maintenance of stability is particularly difficult for morphine hydrochloride solutions administered orally to cancer patients at the last stage of the disease being at home. This study, aiming at the assessment of stability of morphine hydrochloride solutions, was performed on samples of 0.5% water solutions of the drug alone, 0.25% and 0.5% solutions of the drug in water with chloroform as well as injection solutions (Morphinum hydrochloricum, 20 mg, Polfa Warsaw). All the samples were kept at 20 degrees C for six months. Throughout this time observations were made to detect changes in their appearence and pH values. Their qualitative composition was determined by TLC and the content of morphine was checked by UV spectrophotometry in an environment of 0.1 mol/l of hydrochloric acid at 285 nm. Results of the kinetic study permitted drawing conclusions as to the mechanism of the decomposition of morphine hydrochloride in the solutions studied - according to a simple first order reaction and determination of the rate constants (k, s(-1)) of the process. Results of the chromatographic and spectrophotometric study did not show differences in the stability of water and chloroform/water solutions of morphine hydrochloride studied after 4 weeks and 6 months. After that time the decrease of morphine content was 10 and 25%, respectively.

Methods for the assessment of quality and stability of azidocillin.

UV and VIS spectrophotometric methods, after previous chromatographic separation (TLC/UV) and iodometric methods were adapted for the determination of azidocillin in presence of its breakdown products. These methods were applied for kinetic measurement of changes in the azidocillin concentration with time in water solutions and solid state. Using thin layer chromatography several decomposition products of azidocillin were detected.

Effect of gamma-irradiation on cladribine and cladribine-containing biodegradable copolymers.

The aims of this study were to assess the effects of sterilization with gamma-irradiation on (i). bulk cladribine and (ii). cladribine-containing biodegradable copolymers. The stability of cladribine upon irradiation was confirmed by TLC, HPLC, UV, IR, DSC, rentgenography and electron microscopy. The stability of copolymers containing cladribine upon irradiation was assessed by IR, DSC and EPR. In vitro kinetics of nucleoside release from the copolymers before and after irradiation were compared, and only slight changes were found. Results of our study indicate that gamma-irradiation can be safely applied for the sterilization of cladribine or cladribine-containing copolymers for medical purposes.

In vitro release of cytotoxic nucleoside analogs from lactide-caprolactone and lactide-glycolide copolymers.

The aims of our study were to assess the release of cytotoxic nucleoside analogs 5-fluorouracil and 2-chloro-2'-deoxyadenosine from different lactide-glycolide or lactide-caprolactone biodegradable copolymers and the effects of sterilization on this release. The polymers were sterilized either with ethylene oxide at 37 degrees C, or with gamma radiation (15 kGy, 20 kGy, or 25 kGy). The kinetics of nucleoside release from the copolymers were measured over 50 days. Four copolymers exhibited relatively constant release of nucleosides in micromolar concentrations during the entire observation period. Sterilization with either ethylene oxide or gamma radiation only slightly influenced nucleoside release. Further development of these copolymers as an intracerebral nucleoside delivery system for local treatment of brain tumors is indicated.

Sterility and antibacterial activity of some antibiotics sterilized by irradiation.

Sterility and antibacterial activity of several antibiotics (including some penicillins and their salts, gramicidin and neomycin) subjected to sterilization by irradiation has been studied. The compounds in solid phase have been exposed to gamma irradiation in air atmosphere at room temperature, with a dose of 25 kGy, and afterwards they have been subjected to tests recommended by FP V (volume I, 1990) checking their sterility and activity. The results have shown that the majority of initial compounds have been to a slight degree contaminated by bacteria from the genera Bacillus and Micrococcus, the number of bacteria did not exceed 10(2) CFU, and fungi up to 10 CFU in 1 g of the compound. All compounds subjected to sterilization with a dose of 25 kGy were sterile and preserved the activity required by FP V. The decrease in activity observed for some compounds was always within the limits of FP specification. The results have proved that the penicillins analysed, gramicidin and neomycin can be sterilized by irradiation with a dose of 25 kGy, without any detrimental effect on their properties and antibacterial activity.