Radiopharmaceutical is any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a medicinal purpose (Ph.Eur.).
Pharmacists prepare and control radiopharmaceuticals on the departments of nuclear chemistry. Preparation of radiopharmaceuticals and their control have to be performed under all safety protocol concerning the work with radioactive material.
Radiopharmaceuticals have to fulfill all requirements as any other drug, moreover thanks to the presence of the radioactive element, there have to undergo more test to chracterize specific properties of radioactive labelled substances. All requirements are included in valid European Pharmacopoeia.
Every radiopharmaceutical pharmacopoeia monograph includes: definition of radiopharmaceutical, synonym, dosage form, pharmaceutical ingredients (additives) and the percentage of declared activity of radionuclide in stated chemical form at the date and hour stated on the label.
Tests:
1.
Production
2.
Characters – description of a dosage form and characteristics of radionuclide (halflife and type of emitting radiation)
3.
Identification (tests) a.
Identification of radionuclide by recording the gamma, beta or RTG spectrum or by drawing the attenuation curve b.
Identification of radionuclide by the result of the test for radionuclidic purity c.
Identification of radionuclide by the result of the test for radiochemical purity
4.
Tests (of purity) a.
pH b.
Sterility c.
Chemical purity (ex: Sn, Cd, Cu, Fe, Al, residual solvents) d.
Radionuclidic purity i.
Identification of radionuclide with beta decay by measuring of attenuation curve ii.
Identification of radionuclide with beta decay by measuring beta spectrums iii.
Identification of radionuclide in radiopharmaceutical by activity decrease e.
Radiochemical purity (paper chromatography, thin-layer chromatography, electrophoresis, size-exclusion chromatography, gaz chromatography or liquid chromatography) f.
Radioactivity (measurement of the radioactivity using suitable counting equipment by comparison with a standard) g.
Storage h.
Labelling

99m
99m
Technetium (
99m
Tc) colloidal sulphur injection is a sterile, apyrogenic colloidal dispersion of sulphur, the micelles of which are labelled with technetium-99m. It may be stabilised with a colloid-protecting substance based on gelatin. It is prepared from sodium pertechnetate (
99m
Tc) injection (fission or non-fission) using suitable sterile, apyrogenic ingredients and calculating the ratio of radionuclidic impurities with reference to the date and hour of administration.
The injection contains not less than 90.0 % and not more than 110.0 % of the declared technetium-99m radioactivity at the date and hour stated on the label. Not less than 92 % of the radioactivity corresponds to technetium-99m in colloidal form. The pH of the injection may be adjusted by the addition of a suitable buffer solution, such as an acetate, phosphate, or citrate. The injection contains a variable amount of colloidal sulphur, according to the method of preparation.
Sodium pertechnetate Tc-99m reacts with sulfur produced from sodium thiosulfate at acid condition.
Chenmicals:
Sodium thiosulfate (SL1) Na
2
S
2
O
3
.5H
2
O M r
= 248.17
Concentrated hydrochlorid acid 35 % (SL1) HCl M r
= 36.46 ρ = 1.18
Gelatin (SL1)
Sodium acetate (SL1) CH
3
COOH.
3
H
2
O M r
= 136.08
Aqua ad injectabilia (SL1)
Sodium chloride (SL1)
Solutions:
They are made by dissolving the substances in Aqua ad injectabilia and they are sterilized by the filtration on membrane filter.
Solution of sodium thiosulfate V = 50.00 ml, w = 3.00 %
Solution of HCl V = 50.00 ml, c = 1.0 mol/l
Solution of gelatin V = 50.00 ml, w = 1.00 %
Solution of sodium acetate V = 50.00 ml, c = 1.0 mol/l
Material:
Sterile syringes, sterile needles, sterile vial 10.0 ml
Procedure:
Inject 1.0 ml of eluted sodium pertechnetate Tc-99m with activity of 10.0 MBq from Mo-Tc generator in sterile vial. Stirring, inject immediately with the syringe 0.5 ml 3.00 % solution of sodium thiosulfate, 0.8 ml 1.00 % solution of gelatin and 1.0 ml HCl (c = 1.0 mol/l).
Transfer the reaction vial to the lead shielded boiling water bath (100 degrees) and heat for 5 minutes. At the end of heating, remove the reaction vial and place it into a lead pig to cool for
3 minutes. Add 2.0 ml of acetate buffer and check the pH of the solution. Label the preparation and write the activity of preparation.
The colloidal solution is a clear to opalescent, colourless to yellowish liquid. pH 4.0 – 7.0

Radiochemical purity:
Control of radiochemical purity : RADIOCHROMATOGRAPHY
Examine by ascending paper chromatography.
Apply to the Whatman 3 paper strip 5 μl of the injection (1 drop). After drying, develop immediately over a path of 10 cm to 15 cm with 9 g/l solution of sodium chloride. Allow the paper to dry. Determine the distribution of radioactivity using suitable detector. Technetium-
99m in colloidal form remains at the starting-point and pertechnetate ion migrate with an R f
of
0.6. There may be other impurities of R f
0.8 to 0.9. The radioactivity corresponding to technetium-99m in colloidal form represents not less than 92 % of the total radioactivity of the chromatogram.
The kits assigned to the production of radiopharmaceutical preparations were applied because of simplification and standardization of preparations labeled by short-life radionuclides, which are prepared directly in departments of nuclear medicine.
Industry-made kits for radiopharmaceuticals preparation contains, in lyophilized and sterile form, all non-radioactive compounds. After the addition of radionuclide, they create with that radionuclide the radiopharmaceutical with required content and quality.
Kit for the preparation of radiopharmaceutical labeled with
99m
Tc contains particular complex-forming agent – ligand, reducing reagent for the reduction of pertechnetate ion to lower oxidation degree. Also, it contains another substances which ensure izoacidity, izotonity and stability. During the preparation of kit, the solution of substance assigned to label by radionuclide, is mixed with the acid solution of stannous ions in required ratio. The pH 5-7 is achieved by the addition of diluted solution NaOH. The mixture of solutions is pipetted into vials, then lyophilized and the vials are enclosed in the atmosphere of nitrogen.
In the department of nuclear medicine, the radiopharmaceutical preparation is produced after the addition of the solution containing the radionuclide. After the purity controls, this preparation is applied to a patient.
99m
99m
Technetium (
99m
Tc) medronate injection is a sterile solution which may be prepared by mixing solutions of sodium methylenediphosphonate and stannous salt with sodium pertechnetate injection (Na
99m
TcO
4
) (fission or non-fission). The injection contains a variable quantityof tin (Sn) no exceeding 3mg/ml, it may contain antimicrobial preservatives, antioxidants, stabilisers and buffers. The injection contains not less than 95 % and not more than 110.0 % of the declared technetium-99m radioactivity at the date and hour stated on the label. Radioactivity present as chemical forms other than technetium-99m medronate complex is not greater than 5.0 % of the total radioactivity.

It is prepared from sodium pertechnetate (
99m
Tc) injection }fission or non-fission) using suitable sterile ingredients and calculating the ration of radionuclidic impurities with reference to the date and hour of administration.
Preparation:
With a sterile syringe, aseptically obtain 5 ml, (of required activity) of a suitable, oxidant-free, sterile non-pyrogenic sodium pertechnetate. Sodium pertechnetate may be diluted to obtain required activity by physiological solution. Aseptically add the sodium pertechnetate Tc 99m solution to the vial. Swirl the vial until the lyophylizate dissolve and let stand for 10 minutes.Record the date and time of preparation on pressure-sensitive label.
Affix pressure-sensitive label to shield. Examine vial contents. If the solution is not clear and free of particulate matter and discoloration on visual inspection, it should not be used. The presence of oxidants is not allowed because the creation of complex depends on the presence of Sn
2+
. pH of the solution is 3.5-7.5
Radiochemical purity: Examine by thin layer chromatography using silica gel as the coating substance on a glass-fibre sheet. Use plates such that during development, the mobile phase migrates 10 cm to 15 cm in about 10 min. Determine hydrolysed technetium and technetium in colloidal form by test (a) and pertechnetate ion by test (b). Plate is warming up for 10 minuts at 110 o
C. a)
Apply to the plate (2,4 x 15 cm) 5 μl to 10 μl of the injection. Develop immediately over a path of 10 cm to 15 cm using a 136 g/l solution of sodium acetate. Allow the plate to dry in air. Determine the distribution of radioactivity using a suitable detector.
Hydrolysed technetium and technetium in colloidal form remain at the starting point.
Technetium medronate complex and pertechnetate ion migrate near to the solvent front. b)
Apply to the plate (2,4 x 15 cm) 5 μl to 10 μl of the injection and dry quickly. Develop over a path of 10 cm to 15 cm using methyl ethyl ketone. Allow the plate to dry in air.
Determine the distribution of radioactivity using a suitable detector. Pertechnetate ion migrates near to the solvent front. Technetium medronate complex and technetium in colloidal form remain at the starting-point.
The percentage of radioactivity corresponding to pertechnetate ion in the chromatogram obtained in test (b) is not greater than 2.0 % and the sum of the percentages of radioactivity corresponding in the chromatogram (a) and test (b) (including pertechnetate ion) is not greater than 5.0 %.
Detection: Place dried chromatogram into detector. Move by 0.5 cm and measure the counts along all chromatogram. Add together the counts for all cm contributing to the particular peak and calculate the percentage of total radioactivity under each peak from formula:
%peak = 100 x sum of counts for the peak
sum of all counts