Fludeoxyglucose F18Injection
»Fludeoxyglucose F18Injection is a sterile,aqueous solution,suitable for intravenous administration,of 2-deoxy-2-[18F]fluoro-D-glucose in which a portion of the molecules are labeled with radioactive 18F(see Radiopharmaceuticals for Positron Emission Tomography—Compounding á823ñ).It contains not less than 90.0percent and not more than 110.0percent of the labeled amount of 18Fexpressed in MBq (mCi)per mLat the time indicated in the labeling.It may contain suitable preservatives and/or stabilizing agents.
Specific activity: no carrier added.
Packaging and storage— Preserve in single-dose or multiple-dose containers that are adequately shielded.
Labeling— Label it to include the following,in addition to the information specified for Labelingunder Injection á1ñ:the time and date of calibration;the amount of 18Fas fludeoxyglucose expressed as total MBq (mCi)per mL,at time of calibration;the expiration time and date;the name and quantity of any added preservative or stabilizer;and the statement “Caution—Radioactive Material.”The labeling indicates,that in making dosage calculations,correction is to be made for radioactive decay.The radioactive half-life of 18Fis 109.7minutes.The label indicates “Do not use if cloudy or if it contains particulate matter.”
Identification—
A: Radionuclidic identity—Its half-life,determined using a suitable detector system (see Radioactivity á821ñ),is between 105and 115minutes.
B: Radiochemical identity—The RFvalue of Fludeoxyglucose F18in the chromatogram of the Test solutioncorresponds to that in the chromatogram of the Standard solution,as obtained in the Radiochemical puritytest.
Bacterial endotoxins á85ñ(see Sterilization and Sterility Assuranceunder Radiopharmaceuticals for Positron Emission Tomography—Compounding á823ñ)— It contains not more than 175/VUSP Endotoxin Unit per mLof the Injection,in which Vis the maximum administered total dose,in mL,at the expiration time.
pHá791ñ: between 4.5and 7.5.
Radiochemical purity—
Standard solution— Dissolve 10mg of USP Fludeoxyglucose RSin 100mg of acetonitrile and water (95:5).(The USP Fludeoxyglucose RSthat is specified in this test is nonradioactive 2-deoxy-2-fluoro-D-glucose [molecular weight 182.15].)
Test solution— Use the Injection.
Procedure— Apply a volume of Injection,appropriately diluted such that it provides a count rate suitable for the radioactivity detection system being utilized,to an activated silica gel thin-layer chromatographic plate (see Chromatography á621ñ).Apply about 10µg of the Standard solutionto the same chromatographic plate.Develop the chromatogram in a solvent system consisting of a mixture of acetonitrile and water (95:5)until the solvent has moved about three-fourths of the length of the plate.Remove the plate,and allow the chromatogram to dry.Determine the radioactivity distribution by scanning the chromatogram with a suitable collimated radiation detector.Determine the location of the Fludeoxyglucose by spraying the developed chromatographic plate with 2Nsulfuric acid and heating the plate at 110for 10minutes:the RFvalue of Fludeoxyglucose F18(determined by radiochromatogram scanning)corresponds to that of the Standard solution(about 0.4);the radioactivity of Fludeoxyglucose F18is not less than 90%of the total radioactivity.
Radionuclidic purity— Using a suitable gamma-ray spectrometer (see Selection of a Counting Assemblyunder Radioactivity á821ñ),count an appropriate aliquot of the Injection for a period of time sufficient to collect a gamma spectrum.The resultant gamma spectrum should be analyzed for the presence of identifiable photopeaks which are not characteristic of 18Femissions.Not less than 99.5%of the observed gamma emissions should correspond to the 0.511MeV,1.022MeV,or Compton scatter peaks of 18F.
Chemical purity— [NOTE—The methods and limits described in this section relate to potential impurities associated with the acid-hydrolysis method of synthesis for the Injection.Specific examples include aminopolyether (KryptofixR)and 2-chloro-2-deoxy-D-glucose.If methods of synthesis that may result in different impurities are used,the presence of unlabeled ingredients,reagents,and by-products specific to the process must be controlled,and their potential for physiological or pharmacological effects must be considered (see Radiopharmaceuticals for Positron Emission Tomography—Compounding á823ñ).Any ingredients with toxic potential must be within appropriate limits,and conformance with these limits is to be demonstrated by the use of one or more validated limit tests.]
LIMIT OF AMINOPOLYETHER— [NOTE—This test must be performed for Fludeoxyglucose F18produced by any route of synthesis that uses this reagent.]
Absorbent: 0.25-mm layer of chromatographic silica gel.1
Test solution: Use the Injection.
Standard solution— Dissolve an accurately weighed quantity of USP Fludeoxyglucose Related Compound A RSin saline TSto obtain a solution having a known concentration of 50µg per mL.
Application volume: about 1µL.
Developing solvent system: a mixture of methanol and 30%ammonium hydroxide (9:1).
Procedure— Proceed as directed for Thin-Layer Chromatographyunder Chromatography á621ñ.Place the plate in a chamber containing iodine crystals.Develop the plate until a spot is visible on the chromatogram of the Standard solution:the size and intensity of the spot obtained from the Test solutiondoes not exceed that obtained from the Standard solution.
LIMIT OF2-CHLORO-2-DEOXY-D-GLUCOSE— [NOTE—This test is performed when the nucleophilic synthesis includes hydrolysis with hydrochloric acid or the use of anionic exchange resins in the chloride form to trap fluoride 18Freleased from the target prior to its use in the synthesis of Fludeoxyglucose F18.]
Mobile phase— Dissolve about 16g of 50%sodium hydroxide solution in 1000mLof water,filter,and degas by sparging with helium.
System suitability solution— Dissolve accurately weighed quantities of USP Fludeoxyglucose RSand USP Fludeoxyglucose Related Compound B RSin Mobile phaseto obtain a solution having known concentrations of 1.0mg per mLand 0.1mg per mL,respectively.
Standard solution— Dissolve an accurately weighed quantity of USP Fludeoxyglucose Related Compound B RSin water to obtain a solution having a known concentration of 0.1mg per mL.
Test solution— Use the Injection.
Chromatographic system(see Chromatography á621ñ)— The liquid chromatograph is equipped with a pulsed amperometric detector and a 4.0-mm ×25-cm column that contains 10-µm packing L46.The flow rate is adjusted to about 0.5mLper minute.Chromatograph the Standard solutionand the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between fludeoxyglucose and fludeoxyglucose related compound Bis not less than 1.5;and the relative standard deviation for replicate injections is not more than 5%.
Procedure— Separately inject equal volumes (about 100µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the areas for the major peaks.Calculate the quantity,in mg,of 2-chloro-2-deoxy-D-glucose in each mLof the Injection taken by the formula:
C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Fludeoxyglucose Related Compound B RSin the Standard solution;and rUand rSare the 2-chloro-2-deoxy-D-glucose peak areas obtained from the Test solutionand the Standard solution,respectively:not more than 1mg is found in the total volume of the batch of Injection produced.
Residual solvents—
Standard solutions— Prepare separate aqueous solutions of ether,acetonitrile,and dehydrated alcohol having known concentrations of 0.1%,0.01%,and 0.1%,respectively.
Test solutions— Use the Injection.
Chromatographic system(see Chromatography á621ñ)— The gas chromatograph is equipped with a flame-ionization detector,a splitless injector system,and a 0.53-mm ×30-m fused-silica column coated with a 0.25-µm,chemically cross-linked G16stationary phase.The carrier gas is helium,flowing at a rate of 10mLper minute.(Nitrogen may be used as a makeup gas.)The chromatograph is programmed as follows.Initially the temperature is maintained at 40for 2minutes,then the temperature is increased at a rate of 20per minute to 130,and maintained at 130for 5.5minutes.The injection port and detector temperatures are maintained at 250and 300,respectively.Inject the Standard solutions,and record the identity peak responses as directed for Procedure:the resolution,R,between any two components is not less than 1.0;and the relative standard deviation for replicate injections is not more than 5%.
Procedure— Separately inject equal volumes (about 1µL)of the Standard solutionsand the Test solutioninto the chromatograph,record the chromatograms,and measure the peak responses.Calculate the percentage of acetonitrile,ether,and alcohol in the Injection by the formula:
C(ri/rS),
in which Cis the percentage of the relevant analyte in the Standard solution;and riand rSare the peak responses of the relevant analyte obtained from the Test solution,if any,and the Standard solution,respectively:not more than 0.04%of acetonitrile is found;not more than 0.5%of ether is found;and not more than 0.5%of alcohol is found.
Other requirements— It meets the requirements under Injections á1ñ,except that the Injection may be distributed or dispensed prior to completion of the test for Sterility á71ñ,the latter test being started within 24hours of final manufacture,and except that it is not subject to the recommendation of Volume in Container.
Assay for radioactivity— Using a suitable calibrated system as directed under Radioactivity á821ñ,determine the radioactivity in MBq (or mCi)per mL,of the Injection.
1  Available from Alltech Associates,Inc.,2051Waukegan Rd.,Deerfield,IL60015as Machery Nagel SILG/UV2544×8cm,Alltech catalog No.805021.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(RMI)Radiopharmaceuticals and Medical Imaging Agents
USP28–NF23Page 846
Pharmacopeial Forum:Volume No.27(2)Page 2145
Phone Number:1-301-816-8305