Fluorodeoxyglucose (18F) Injection
Fludeoxyglucose (18F) injection.
18
F-FDG injection.
Fluorodeoxyglucose (18F) Injection contains not less than 90.0 per cent and not more than 110.0 per cent of the
stated amount of Fluorine-18 radioactivity at the date and time stated on the label; Fluorine-18 in the form of 2[18F]Fluoro-2-deoxy-D-glucose and 2-[18F]Fluoro-2-deoxy-D-mannose is not less than 95.0 per cent of the total
radioactivity; 2-[18F]Fluoro-2-deoxy-D-mannose is not more than 10.0 per cent of the total radioactivity due to 2[18F]Fluoro-2-deoxy-D-glucose and 2-[18F]Fluoro-2-deoxy-D-mannose and 2-Fluoro-2-deoxy-D-glucose is not
more than 0.5 mg per maximum recommended dose, in milliliters.
Category. Diagnostic
Description. A clear, colourless or a very slightly yellow solution. Fluorine-18 has a half -life of 109.8 minutes.
Fluorodeoxyglucose (18F) Injection is a sterile solution consisting of 2-[18F] Fluoro-2-deoxy-D-glucopyranose (2[18F]Fluoro-2-deoxy-D-glucose) prepared by nucleophilic substitution. It may also contain 2-[18F]Fluoro-2-deoxy-Dmannose.
Radionuclide Production. The radionuclide Fluorine-18 is most commonly produced by proton irradiation of water
enriched in oxygen-18
Radiochemical Synthesis
2-[18F]Fluoro-2-deoxy-D-glucose is mostly prepared by phase transfer catalysed nucleophilic substitution of 1,3,4,6tetra-O-acetyl-2-O-triFluoromethanesulphonyl-β-D-mannopyranose (tetraacetylmannose triflate) with [ 18F]Fluoride.
Generally, [18F] Fluoride is adsorbed on an anion-exchange resin and eluted with a solution of potassium carbonate,
evaporated to dryness. Addition of a phase-transfer catalyst, such as an aminopolyether or a tetra-alkyl ammonium
salt in dry acetonitrile, may be used to enhance the nucleophilicity of the [ 18F] Fluoride so that it reacts easily with
the tetraacetylmannose triflate at elevated temperature. A variation of the method uses solid-phase-catalysed
nucleophilic substitution on derivatised anion-exchange resin, for example, derivatised with 4-(4-methylpiperidin-1yl)pyridine.
Hydrolysis under either alkaline or acidic conditions yields 2-[18F] Fluoro-2-deoxy-D-glucose. Depending on the
conditions of hydrolysis, variable amounts of 2-chloro-2-deoxy-D-glucose and/or 2-[18F] Fluoro-2-deoxy-Dmannose may be formed as a by-product.
The preparation can be purified by serial chromatography on combinations of ion-retardation resin, ion-exchange
resin, alumina and octadecylsilyl derivatised silica gel.
Half-life and nature of radiation of Fluorine-18 complies with the table of physical characteristics of radionuclides
stated under Radiopharmaceutical Preparations.
Identification
A. Colourless or slightly yellow solution free from particulate matter when observed visually behind leaded glass
under adequate light. The test must be completed before release of the drug product.
B. Complies with test A given under Radionuclidic purity.
C. Radionuclide identity: The half-life determined by measuring the radioactivity decay of the sample over a 10
minutes period, is between 105 and 115 minutes. The test must be completed before release of the product.
D. In the test A for Radiochemical purity, the principal peak in the chromatogram obtained with the test solution
corresponds to the peak in the chromatogram obtained with reference solution (a).
Radiochemical Identity. Determine by thin layer chromatography (2.4.17), using silica gel G coated plates.
Mobile phase. A mixture of 95 volumes of acetonitrile and 5 volumes of water.
Test solution. The injection under examination.
Reference solution. A solution of Fluorodeoxyglucose (19F) RS in water.
The retention factor (Rf) value of test solution corresponds (e.g., < +10%) to the Rf value (about 0.4) of the reference
solution when both are chromatographed together side by side on the same thin layer chromatography (TLC) silica
gel strip and scanned using a radiochromatographic TLC scanner. The Rf of the reference Fluorodeoxyglucose (19F)
is identified by treatment with appropriate reagent. The test must be completed before release of the drug product.
Tests
pH (2.4.24). 4.5 to 8.5.
NOTE- Particular tests for chemical impurities may be omitted if the substances mentioned are not used or cannot
be formed in the production process.
2-Fluoro-2-deoxy-D-glucose and Fluorodeoxyglucose impurity A. Determine by liquid chromatography (2.4.14).
Test solution. The injection under examination.
Reference solution (a). Dissolve 1.0 mg of 2-Fluoro-2-deoxy-D-glucose RS in water and dilute to 2.0 ml with water.
Dilute 1.0 ml of the solution to a volume equivalent to the maximum recommended dose in milliliters (V) with
water.
Reference solution (b). Dissolve 1.0 mg of 2-chloro-2-deoxy-D-glucose RS (Fluorodeoxyglucose impurity A RS) in
water and dilute to 2.0 ml with water. Dilute 1.0 ml of the solution to a volume equivalent to the maximum
recommended dose in milliliters with water.
Reference solution (c). Dissolve 1.0 mg of 2-Fluoro-2-deoxy-D-mannose RS in water and dilute to 2.0 ml with
water. Mix 0.5 ml of this solution with 0.5 ml of reference solution (a).
Chromatographic system
— a stainless steel column 25 cm × 4.0 mm, packed with strong anion exchange resin (10 µm),
— column temperature. 20° to 25°,
— mobile phase. 0.4 per cent w/v solution of sodium hydroxide in carbon dioxide-free water,
— flow rate. 1 ml per minute,
— pulse amperometric detector (carbohydrate detector) and radioactivity detector connected in series,
— injection volume. 20 µl.
Inject reference solution (c). The test is not valid unless the resolution between the peaks due to 2-Fluoro-2-deoxyD-mannose and 2-Fluoro-2-deoxy-D-glucose is not less than 1.5 and signal to noise ratio for the peak due to 2Fluoro-2-deoxy-D-glucose is not less than 10. The relative retention time, with reference to 2-Fluoro-2-deoxy-Dglucose (retention time about 12 min), for 2-Fluoro-2-deoxy-D-mannose is about 0.9 and for Fluorodeoxyglucose
impurity A is about 1.1.
Inject the test solution, reference solution (a) and (b). Run the chromatogram for twice the retention time of the
principal peak. In the chromatogram obtained with the test solution using carbohydrate detector the area due to 2Fluoro-2-deoxy-D-glucose is not more than the area of the corresponding peak in the chromatogram obtained with
reference solution (a) (0.5 mg/V) and the area due to Fluorodeoxyglucose impurity A is not more than the area of the
corresponding peak in the chromatogram obtained with reference solution (b) (0.5 mg/V).
Fluorodeoxyglucose impurity B or aminopolyether. Determine by thin-layer chromatography (2.4.17), silica gel
G coated plates.
Mobile phase. A mixture of 90 volumes of methanol and 10 volumes of 30 per cent ammonium hydroxide.
Test solution. The injection under examination.
Reference solution (a). Water.
Reference solution (b). A 0.22 per cent w/v solution of aminopolyether RS (Fluorodeoxyglucose impurity B RS) in
water. Dilute 1 ml of the solution to appropriate volume equivalent to the maximum recommended dose in
milliliters (V) with water.
Apply to the plate 2.5 µl of each solution and 2.5 µl of the test solution and reference solution (b) at the same place.
Visually compare the spots 1 minute after application. The spots due to the successive application of the test solution
and reference solution (b) is similar in appearance to the spot due to reference solution (b), characterised by a
number of concentric circles; the darker innermost circle (of intensity proportional to the concentration of
Fluorodeoxyglucose impurity B) may be surrounded by a bluish-black ring, outside of which is a lighter circle
surrounded by a peripheral dark edge. The spot due to reference solution (a) has a more diffuse inner circle, which is
brownish-pink and without a distinct margin between it and the surrounding lighter zone. The spot due to reference
solution (b) is clearly different from the spot due to reference solution (a).
The central portion of the spot due to the test solution is less intense than that of the spot due to reference
solution (b) (2.2 mg/V). The test must be completed before release of drug product.
Fluorodeoxyglucose impurity C or tetrabutylammonium hydroxide. Determine by liquid chromatography
(2.4.14).
Test solution. The injection under examination
Reference solution (a). A 0.27 per cent w/v solution of tetrabutylammonium hydroxide RS (Fluorodeoxyglucose
impurity C RS) in water. Dilute 1.0 ml of this solution to appropriate volume equivalent to the maximum
recommended dose in milliliters (V) with water.
Reference solution (b). A 0.26 per cent w/v solution of tetrabutylammonium hydroxide RS in water. Dilute 1 ml of
this solution to 25 ml with water.
Chromatographic system
- a stainless steel column 10 cm × 4.6 mm, packed with octadecylsilane bonded to porous silica (3 µm),
- column temperature 20 to 25°,
- mobile phase: 25 volumes of a 0.095 per cent w/v solution of toluenesulphonic acid and 75 volumes of
acetonitrile,
- flow rate. 0.6 ml per minute,
- spectrophotometer set at 254 nm,
- injection volume. 20 µl.
Inject reference solution (b). The test is not valid unless the signal-to-noise ratio for the principle peak is not less
than 10 and the symmetry factor is not more than 1.8.
Inject the test solution and reference solution (a). Run the chromatogram for twice the retention time of
tetrabutylammonium ions. In the chromatogram obtained with the test solution, the area of the peak due
to Fluorodeoxyglucose impurity C is not more than the area of the corresponding peak in the chromatogram
obtained with reference solution (a) (2.75 mg/V).
Fluorodeoxyglucose Impurity D or 4-(4-methylpiperidin-1-yl) pyridine. Measure the absorbance of the injection
under examination and the reference solution, [prepared by dissolving 20.0 mg of 4-(4-methylpiperidin-1yl)pyridine (Fluorodeoxyglucose impurity D), dissolve in sufficient water to produce 100.0 ml. Dilute 0.1 ml of the
solution to a volume equivalent to maximum recommended dose in milliliters with water] at the maximum of about
263 nm (2.4.7).
The absorbance of the injection under examination is not more than that of the reference solution (0.02 mg/V).
Other tests. Complies with the tests stated under Radiopharmaceuticals Preparation. The preparation may be
released for use before completion of the tests.
Radioactivity assay. Use of suitably calibrated system to determine the total radioactivity of the
Fluorodeoxyglucose (18F) Injection in megabecquerals (or millicuries) and the radioactivity concentration in
MBq/ml or mCi/ml. The test must be completed before release of drug product.
Radionuclidic purity
Either tests A or B may be applied. The test must be completed before release of the preparation.
A. Determine by gamma-ray spectrometry using Sodium Iodide (Thallium) detector or Semiconductor detector. The
only spectrum is concordant with that of gamma photons have energy of 0.511 MeV and, depending on the
measurement geometry, a sum peak of 1.022 MeV may be observed.
B. Determine by gamma-ray spectrometry. The half-life is between 105 min and 115 min determined with a gamma
ray counter, by not less than three measurements of the radioactivity of a sample in the same geometrical conditions
within a suitable period of decay time (for example, three readings at 10 minute intervals over 30 minutes) is
between 105 and 115 minutes.
Radiochemical purity
The test must be completed before release of the product.
A. Determine by liquid chromatography (2.4.14) as described in the test for 2-Fluoro-2-deoxy-D-glucose and
Fluorodeoxyglucose impurity A.
If necessary, dilute the test solution with water to obtain a radioactivity concentration suitable for the radioactivity
detector.
Inject the test solution and reference solutions (a) and (c). The relative retention time with reference to 2-[18F]
Fluoro-2-deoxy-D-glucose for 2-[18F] Fluoro-2-deoxy-D-mannose is about 0.9. Partially and fully acetylated
derivatives of both compounds hydrolyse under the chromatographic conditions and therefore elute as 2-[18F]
Fluoro-2-deoxy-D-glucose and 2-[18F] Fluoro-2-deoxy-D-mannose. Locate the peaks due to 2-[18F] Fluoro-2-deoxyD-glucose and 2-[18F] Fluoro-2-deoxy-D-mannose using the chromatograms obtained with the carbohydrate detector
and reference solutions (a) and (c). Fluorine-18 in the form of 2-[18F] Fluoro-2-deoxy-D-glucose and 2-[18F] Fluoro2-deoxy-D-mannose not less than 95.0 per cent of the total radioactivity; 2-[18F]Fluoro-2-deoxy-D-mannose is not
more than 10 per cent of the total radioactivity due to 2-[18F]Fluoro-2-deoxy-D-glucose and 2-[18F]Fluoro-2-deoxyD-mannose.
B. Determine by thin-layer chromatography (2.4.17), using silica gel as stationary phase.
Mobile phase. A mixture of 5 volumes of water and 95 volumes of acetonitrile.
Test solution. The injection under examination.
Reference solution. Dissolve, with gentle heating, 30 mg of 1, 2, 3, 4-tetra-O-acetyl-β-D-glucopyranose RS and
20 mg of glucose in 1 ml of water.
Apply to the plate 2 to 10 µl of each solution. Allow the mobile phase plate to rise 8 cm. After development, dry the
plate in air for 15 minutes, then immerse the plate in a 7.5 per cent w/v solution of sulphuric acid in methanol and
dry with a heat gun or at 150° until the appearance of dark spots in the chromatogram obtained with the reference
solution.
Retardation factors for [18F] Fluoride is about 0; for 2-[18F]Fluoro-2-deoxy-D-glucose and 2-[18F]Fluoro-2-deoxyD-mannose is about 0.45; for partially or fully acetylated derivatives of 2-[18F]Fluoro-2-deoxy-D-glucose and 2[18F]Fluoro-2-deoxy-D-mannose have a Rf of about 0.8 to 0.95.
Apply to the plate reference solution. The test is not valid unless the chromatogram shows 2 clearly separated spots.
Fluorine-18 in the form of 2-[18F]Fluoro-2-deoxy-D-glucose and 2-[18F]Fluoro-2-deoxy-D-mannose not less than
95 per cent of the total radioactivity, Fluorine-18 in the form of Fluoride and partially or fully acetylated derivatives
of 2-[18F]Fluoro-2-deoxy-D-glucose and 2-[18F]Fluoro-2-deoxy-D-mannose not more than 5 per cent of the total
radioactivity.
Validation to be done periodically if following the TLC procedure (Test B) for Radiochemical purity
Apply to the plate 2 µl of each reference solution (a) and test solution. Develop over a path of 8 cm using a mixture
of 5 volumes of water R and 95 volumes of acetonitrile R. Allow the plate to dry in air for 15 min. Immerse the
plate in a 7.5 per cent w/v solution of sulphuric acid in methanol and dry with a hot air gun or at 150° until the
appearance of dark spots in the chromatogram obtained with the reference solution. The Rf of the reference solution
and the test solution should be similar.
Residual solvents. Estimated by gas chromatography. Not more than 0.04 per cent acetonitrile, 0.5 per cent
dehydrated ethanol, 0.5 per cent ether and 0.5% acetone. The reference standards for comparison are made with
these solvents in water at the percentages specified. The injection may be released for use before completion of the
test.
Bacterial endotoxins (2.2.3). Not more than 175/V IU/ml, V being the maximum recommended dose in milliliters.
The test must be completed before release of the preparation.
Sterility (2.2.11). Complies with the test for sterility. The test must be initiated within 24 hours however, the
preparation may be released for use before completion of test.
Membrane filter integrity test. This test must be completed before release of the drug product. The bubble point
test may be used or any alternate test assuring the integrity of the membrane filter may be reported.
Storage. Store in sterile and endotoxin free containers either as single-dose or multiple-doses. The containers should
be adequately shielded for radiation safety.
Labelling. The label states (1) the maximum recommended dose, in milliliters (2) the amount of 18FDG expressed in
megabecquerels (microcuries or millicuries) per ml at the time of calibration (3) use within specified period (4) the
statement “ Caution- Radioactive Material” and “do not use if cloudy or if it contains particulate matter” (5) in
making dosage calculations, correction is to be made for radioactive decay.