Fluorodopa F 18 Injection
» Fluorodopa F 18 Injection is a sterile aqueous solution, suitable for intravenous administration of 6-[18F]fluorolevodopa in which a portion of the molecules are labeled with radioactive 18F (see Radiopharmaceuticals for Positron Emission TomographyCompounding 823). It contains not less than 90.0 percent and not more than 110.0 percent of the labeled amount of 18F expressed in MBq (or mCi) per mL at the time indicated in the labeling. It may contain suitable preservatives and/or stabilizing agents.
Mobile phase, Standard solution, Test solution, and Chromatographic system Proceed as directed in the test for Radiochemical purity.
Procedure Separately inject equal volumes (about 50 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the concentration of l-fluorodopa found, in mg per mL, in the Injection by the formula:
C(rU / rS)in which C is the concentration of the Standard solution; and rU and rS are the peak responses of the Test solution and the Standard solution, respectively. Determine the concentration of fluorodopa F 18, in mCi per mL, as directed in the Assay for radioactivity. Calculate the Specific activity by dividing the result from the Assay (in mCi per mL) by the concentration (in mg per mL): it is not less than 0.463 mCi per mg of l-fluorodopa (3.7 × 103 MBq [100 mCi] per mmol).
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 Labeling under Injections 1: the time and date of calibration; the amount of 18F as fluorodopa expressed as total MBq (or 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 CautionRadioactive Material. The labeling indicates that in making dosage calculations, correction is to be made for radioactive decay. The radioactive half-life of 18F is 109.7 minutes. The label also includes the statement Do not use if cloudy or if it contains particulate matter.
USP Reference standards 11
USP Endotoxin RS
Radionuclidic identification (see Radioactivity 821)
A: Its half-life, determined using a suitable detector system, is between 105 and 115 minutes.
B: Radiochemical identityThe retention time of the major peak in the chromatogram of the Test solution corresponds to that in the chromatogram of the Standard solution, as obtained in the test for Radiochemical purity.
Bacterial endotoxins 85: not more than 175/V USP Endotoxin Unit per mL of Injection, in which V is the maximum administered total dose, in mL, at the expiration time.
pH 791: between 4.0 and 5.5.
Mobile phase Prepare a filtered and degassed mixture of 0.1% acetic acid and methanol (97:3).
Standard solution Dissolve an accurately weighed quantity of USP l-Fluorodopa RS in 10 mmol of pH 4.5 sodium acetate buffer, and dilute quantitatively, and stepwise if necessary, with the same buffer to obtain a solution having a known concentration of about 0.1 mg per mL.
Test solution Use the Injection diluted with water such that it provides a count rate of about 5 × 105 counts per minute.
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a 4.6-mm × 30-cm column that contains packing L1, a radioactivity detector, and a variable wavelength UV detector operating in the range of 260 to 290 nm. The flow rate is about 0.8 mL per minute. Chromatograph the Test solution, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 2.0%.
Procedure Prepare a mixture of the Test solution and the Standard solution and inject about 50 µL into the chromatograph, record the chromatograms, and measure the areas for both the radioactive and nonradioactive peaks. The ratio and injected volume may be adjusted to obtain suitable detection system sensitivity. The radioactivity of the major peak is not less than 90% of the total radioactivity measured, and no individual radiochemical impurity is more than 2%. The retention time of the major peak in the chromatogram of the Test solution corresponds to that in the chromatogram of the Standard solution. [noteThe typical retention time for fluorodopa is about 6 minutes. Retention times are very sensitive to the pH of the solvent. ]
Radionuclidic purity Using a suitable gamma-ray spectrometer (see Selection of a Counting Assembly under Radioactivity 821), count an appropriate aliquot of Injection for a period of time sufficient to obtain a gamma spectrum. The resultant gamma spectrum should be analyzed for the presence of identifiable photopeaks which are not characteristic of F 18 emissions. Not less than 99.5% of the gamma emissions should correspond to the 0.511 MeV, 1.022 MeV, or Compton scatter peaks of F 18, with no individual impurity peaks present above 0.1%.
Chemical purity The methods and limits described in this section relate to potential impurities associated with commonly used methods of synthesis for Fluorodopa F 18 Injection. If methods of synthesis are used that may result in different impurities, the presence of unlabeled ingredients, reagents, and by-products specific to the process must be controlled and then potential for physiological or pharmacological effects must be considered.
limit of organotin (to be determined if tin-containing starting materials or reagents are used in the synthesis)
Mobile phase Prepare a filtered and degassed 5 µmol solution of morin in a mixture of toluene, acetic acid, methanol, and acetonitrile (91:5:2:2).
Standard solution Prepare a mixture of 10 mmol each of dimethyltin dibromide and trimethyltin bromide in alcohol.
Test solution Use the Injection.
Chromatographic system (see Chromatography 621) The liquid chromatograph is equipped with a fluorescence detector (excitation at 420 nm and detection at 500 nm) and a 4.6-mm × 25-cm column that contains packing L32. The flow rate is about 1 mL per minute.
Procedure Separately inject equal volumes (about 50 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. The volume of Injection in the Standard solution and the Test solution may be adjusted to obtain suitable detection system sensitivity. Calculate the concentration, in µg per mL, of dimethyltin and trimethyltin in the portion of Injection taken by the formula:
C(rU / rS)in which C is the concentration, in µg per mL, of the relevant organotin compound in the Standard solution; and rU and rS are the peak responses obtained from the Test solution and the Standard solution, respectively: not more than 0.5 µg per mL of dimethyltin and trimethyltin is found.
limit of mercury (to be determined if mercury-containing starting materials or reagents are used in the synthesis) [CautionBecause of the toxic nature of mercury vapor, great care must be taken to avoid inhaling it. A bypass has been included in the system, therefore, either to vent the mercury vapor into an exhaust hood or to pass the vapor through some absorbing media such as a solution containing equal volumes of 0.1 M potassium permanganate and dilute sulfuric acid (1 in 10). ]
Apparatus Use a flameless atomic absorption spectrophotometer for measuring radiation at 253.7 nm emitted by mercury vapor.
Stannous chloride suspension Add 25 g of stannous chloride to 250 mL of 0.5 N sulfuric acid. This mixture is a suspension and is to be stirred continuously during use.
Sodium chloridehydroxylamine hydrochloride solution Dissolve 12 g of sodium chloride and 12 g of hydroxylamine hydrochloride in water, dilute with water to 100 mL, and mix.
Mercury stock solution Dissolve 135.4 mg of mercuric chloride, accurately weighed, in 75 mL of water. Add 10 mL of nitric acid, dilute with water to 100.0 mL, and mix. Each mL of this solution contains 1 mg of mercury.
Mercury standard solution Before using, make successive dilutions of the Mercury stock solution with water to obtain a Mercury standard solution containing 0.1 µg per mL.
Calibration To six 300-mL glass-stoppered bottles, transfer, respectively, 0-, 0.5-, 1.0-, 2.0-, 5.0-, and 10.0-mL aliquots of the Mercury standard solution containing 0 µg to 1.0 µg of mercury. To each bottle add water to make 100 mL, mix, and add 5 mL of sulfuric acid and 2.5 mL of nitric acid. Add 15 mL of potassium permanganate solution (1 in 20). Allow to stand for 15 minutes. Add 8 mL of potassium persulfate solution (1 in 20), and heat in a water bath at 95 for 2 hours. Cool, and add 6 mL of Sodium chloridehydroxylamine hydrochloride solution to reduce the excess permanganate. When the solution has been decolorized, wait for 30 seconds and add 5 mL of Stannous chloride suspension. Immediately attach the flask to the aeration apparatus to form a closed system. Allow the sample to stand without manual agitation. The circulating pump, previously adjusted to a rate of 1 L per minute, is allowed to run continuously. The absorbance will increase and reach a maximum within 30 seconds. As soon as the recorder pen levels off, in about 1 minute, open the bypass valve and continue the aeration until the absorbance returns to its minimum value. Close the bypass valve, remove the stopper and frit from the bottle, and continue the aeration. Plot a standard curve of the peak height versus micrograms of mercury.
Test preparation Transfer 1.0 mL of Injection to a 300-mL glass-stoppered bottle, and proceed as directed under Calibration, beginning with To each bottle add water. Measure the absorbance of the solution, and determine the quantity, in µg, of mercury in the Test preparation from the standard curve: not more than 0.5 µg is found.
Mobile phase Prepare a filtered and degassed mixture of 100 mmol of monobasic potassium phosphate and 2 mmol of cupric sulfate (1:1). Adjust to a pH of 4.6. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard solution Use the Standard solution as directed under Radiochemical purity.
Test solution Use the Injection.
Chromatographic system (see Chromatography 621) The liquid chromatograph as directed under Radiochemical purity is equipped with a 4.6-mm × 25-cm column that contains packing L32. The flow rate is about 1 mL per minute. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the capacity factors, k¢ , for the d- and l-isomers are not less than 2.1 and 7.3, respectively.
Procedure Prepare a mixture of the Test solution and the Standard solution, and inject about 50 µL into the chromatograph, record the chromatograms, and measure the areas for both the radioactive and nonradioactive peaks. The ratio and injected volume may be adjusted to obtain suitable detection system sensitivity. The radioactivity of the l-isomer is not less than 95%.
Other requirements It meets the requirements under Injections 1, except that the Injection may be distributed or dispensed prior to completion of the test for Sterility 71; the latter being started within 24 hours of final manufacture, and except that it is not subject to the recommendation on Volume in Container.
Assay for radioactivity Using a suitable calibrated system as directed under Radioactivity 821, determine the radioactivity, in MBq (or mCi) per mL, of Injection.
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USP35NF30 Page 3234Pharmacopeial Forum: Volume No. 30(2) Page 486