http://www.revistadechimie.ro REV.CHIM.(Bucharest)♦68♦No. 4 ♦2017 666 Fast Method for the Determination of Residual Solvents in Radiopharmaceutical Products MIRELA MIHON 1,2 *, CATALIN STELIAN TUTA 2 , ALINA CATRINEL ION 1 , DANA NICULAE 2 , VASILE LAVRIC 1 1 University Politehnica of Bucharest, 313 Splaiul Independentei,060042, Bucharest, Romania 2 National Institute for Physics and Nuclear Engineering Horia Hulubei, 30 Reactorului Str., 077125, Magurele, Ilfov, Romania The aim of this work was the development and validation of a fast analytical method to determine the residual solvents content in radiopharmaceuticals such as: 18 F-Fluorodeoxyglucose ( 18 F-FDG), 18 F- Fluoroestradiol ( 18 F-FES), 18 F-Fluorothymidine ( 18 F-FLT), 18 F-Fluoromisonidazole ( 18 F-FMISO). Radiopharmaceuticals are radioactive preparations for medical purposes used in nuclear medicine as tracers in diagnostic imaging and treatment of certain diseases. Positron Emission Tomography (PET) is a medical imaging technique that consists in introducing into the body of a small amount of a biologically active chemical compound labelled with a short lived positron-emitting radioisotope ( 18 F, 11 C, 68 Ga). Residual solvents are critical impurities in radiopharmaceuticals that can affect labelling, stability and physicochemical properties of drugs. Therefore, the determination of these solvents is essential for quality control of radiopharmaceuticals. Validation of the control method for residual solvents by gas chromatography is referred by the European Pharmacopoeia using a special injection technique (head space). The parameters of the method, which comply with International Conference on Harmonization guidelines, are: accuracy, precision, linearity, limit of detection, limit of quantification and robustness. The proposed method (direct gas chromatography injection) proved to be linear, precise, accurate and robust. Good linearity was achieved for all the solvents and correlation coefficients (R 2 ) for each residual solvent were found more than 0.99. Keywords: residual solvent, ethanol, gas chromatography, radiopharmaceuticals, validation Radiopharmaceuticals are radioactive compounds used for diagnosis and therapy of human diseases. Radiopharmaceuticals formulated as liquid solutions are sterile, isotonic and pyrogen free. Even some solvents are required in the production process (acetonitrile, methanol), final product purification (ethanol), cleaning the synthesis module (acetone, 2-propanol) and cannot be excluded from the fabrication process [1], the content of solvents in the final product must not exceed the limits required by the pharmaceutical regulation. The quality parameters of any radiopharmaceuticals are very important, as in all pharmaceutical industry, so the qualitative and quantitative determination of residual solvent impurities in the final products is essential. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the European Pharmacopoeia (Eur.Ph.) provide limits of residual solvents [2]. Because the Positron Emission Tomography (PET) requires the injection of radiopharmaceutical solution, the Eur.Ph requirements recommend appropriate limits for any toxic potential ingredients. The content of residual solvent in radiopharmaceuticals is analysed by using headspace gas chromatography (HS-GC), in accordance with the recommendations of Eur.Ph. [3]. Residual solvents are critical impurities in radiopharmaceuticals because of the side biological effects that can affect the efficacy of the labelling and physicochemical properties of drugs. The amount of the solvent in the radiopharmaceutical must be safe from a toxicological point of view. Class 1 solvents are known for human carcinogens or environmental hazards. Class 2 solvents (acetonitrile and methanol) are suspected of other significant but reversible toxicities, below certain limits. ICH guideline Q3C lists acetone and ethanol as a Class 3 * email: mirela.mihon@nipne.ro; Tel: + 40723871076 solvents and their presence in radiopharmaceuticals may be regarded as being of low risk to human health. Ethanol is used as a scavenger in radiopharmaceuticals preparation, being demonstrated its presence is improving the stability, the FDG stability increase with the use of ethanol up to 10% [4]. The ethanol concentration is considered within the tolerance for injectable solution [5]. Currently, the allowed dose of ethanol is 0.5%, if considered as residual solvent. Analytical methods for the determination of residual solvent in pharmaceuticals are based on gas chromatography: static headspace [6], purge and trap [7], headspace- programmed temperature vaporization and gas chromatography/mass spectrometry [8]. Also, headspace – solid phase microextraction (HS-SPME) and spray dried dispersion [9, 10] has been proposed for determination of solvents in the pharmaceutical preparation. Only few reports concerning methods of determination of residual solvents in radiopharmaceuticals have been published both direct injection and headspace technique [11, 12]. One of the most important aspects of working with radiopharmaceuticals emitting positrons is the short time, about 30 minutes, which can be spent on quality control testing. The analytical test should be fast and effective, since the radioisotope has a short half-life (109.8 min for 18 F). Channing et al. described the analysis of ethanol, acetone and acetonitrile with a lower resolution of ethanol and acetonitrile for concentrations of ethanol up to 10 % [13]. This work is devoted to the development and validation of an improved analytical method to quantify the residual levels of methanol, acetonitrile, acetone, ethanol and 2- propanol in radiopharmaceutical preparations such as 18 F FDG, 18 F FMISO, 18 F FLT and 18 F FES. Gas chromatography