Gadoteridol
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C17H29GdN4O7 558.70

Gadolinium, [10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetato(3-)-N1,N4,N7,N10,O1,O4,O7,O10]-.
(±)-[10-(2-Hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetato(3-)]gadolinium [120066-54-8].
» Gadoteridol contains not less than 97.0 percent and not more than 101.0 percent of C17H29GdN4O7, calculated on the anhydrous basis.
Packaging and storage— Preserve in tight, light-resistant containers, and store at controlled room temperature.
Identification—
B: Ultraviolet Absorption 197U—
Solution: 10 mg per mL.
Medium: water.
Water, Method I 921: not more than 15%.
Heavy metals, Method II 231: not more than 0.001%.
Limit of gadoteridol related compound A—
Buffer solution— Dissolve 0.60 g of tromethamine and 3.72 g of edetate disodium in 3 L of water, adjust with 5 N sodium hydroxide to a pH of 7.0, dilute with water to 4 L, and mix. Filter, and chill between 5 and 8.
Mobile phase— Prepare a filtered and degassed mixture of Buffer solution, acetonitrile, and tetrahydrofuran (98.8:1.0:0.2). Make adjustments if necessary (see System Suitability under Chromatography 621).
Cupric acetate solution— Transfer 3.99 g of cupric acetate and 12.11 g of tromethamine to a 2-L volumetric flask, dissolve in 1500 mL of water, adjust with glacial acetic acid to a pH of 7.0, dilute with water to volume, and mix. Filter, and chill between 5 and 8.
Standard stock solution— Dissolve an accurately weighed quantity of USP Gadoteridol Related Compound A RS in Buffer solution, and dilute quantitatively and stepwise with Buffer solution to obtain a solution having a known concentration of about 6 µg per mL.
Standard solution— Just prior to injection onto the column, dilute 1.0 mL of the Standard stock solution with 1.0 mL of Cupric acetate solution to obtain a solution having a known concentration of about 3 µg of USP Gadoteridol Related Compound A RS per mL. [note—The copper–gadoteridol related compound A complex is stable for at least 2 hours, if maintained at about 5.]
Test solution— Transfer about 30 mg of Gadoteridol, accurately weighed, to a test tube, add 1.0 mL of Buffer solution, and mix on a vortex mixer to dissolve. Add 1.0 mL of Cupric acetate solution, and mix. Immediately inject the solution into the chromatograph. [note—The copper–gadoteridol related compound A complex is stable for at least 2 hours, if maintained at about 5.]
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 280-nm detector and a 4.0-mm × 15-cm column that contains packing L21. The flow rate is about 2 mL per minute. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative retention times are about 1.0 for gadoteridol related compound A and 2.0 for copper-edetate; the resolution, R, between gadoteridol related compound A and copper-edetate is not less than 1.5; and the relative standard deviation for replicate injections is not more than 2.0%.
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. Calculate the percentage of gadoteridol related compound A in the portion of Gadoteridol taken by the formula:
100(C / W)(rU / rS)
in which C is the concentration, in mg per mL, of USP Gadoteridol Related Compound A RS in the Standard stock solution; W is the weight, in mg, of Gadoteridol taken to prepare the Test solution; and rU and rS are the gadoteridol related compound A peak responses obtained from the Test solution and the Standard solution, respectively: not more than 0.01% is found, calculated on the anhydrous basis.
Limit of free gadolinium (III)—
Buffer solution, Mobile phase, Diluent, Standard stock solution 1, Standard stock solution 2, Standard solution, and Chromatographic system— Proceed as directed for Chromatographic purity, Test 1.
Test solution— Transfer about 60 mg of Gadoteridol, accurately weighed, to a vial, add 2.0 mL of Diluent, and mix. Immediately place the vial in a bath maintained at about 5.
Procedure— Proceed as directed for Procedure under Chromatographic purity, Test 1. Calculate the percentage of free gadolinium (III) in the portion of Gadoteridol taken by the formula:
200(157.25 / 334.38)(C / W)(rU / rS)
in which 157.25 is the molecular weight of gadolinium and 334.38 is the molecular weight of gadolinium acetate; C is the concentration, in mg per mL, of gadolinium acetate, calculated on the anhydrous basis, in the Standard solution; W is the weight, in mg, of Gadoteridol taken to prepare the Test solution; and rU and rS are the free gadolinium (III) peak responses obtained from the Test solution and the Standard solution, respectively: not more than 0.01% is found.
Limit of regioisomer— Using the chromatogram of the Assay preparation as obtained in the Assay, calculate the percentage of regioisomer peak at a relative retention time of about 1.2 in relation to that of the gadoteridol peak by the formula:
100rR / (rR + rG)
in which rR and rG are the regioisomer and gadoteridol peak responses, respectively, in the Assay preparation: not more than 2.5% is found.
Chromatographic purity—
Test 1: gadolinium-containing impurities—
Buffer solution— Dissolve 10.2 g of monobasic potassium phosphate, 0.165 g of dibasic potassium phosphate, and 1.76 g of edetate disodium in 3000 mL of water, and filter.
Mobile phase— Prepare a degassed mixture of Buffer solution and acetonitrile (98:2). Make adjustments if necessary (see System Suitability under Chromatography 621).
Diluent— Transfer 3.40 g of monobasic potassium phosphate, 4.21 g of dibasic potassium phosphate, and 0.584 g of edetate disodium to a 1000-mL volumetric flask, dissolve in and dilute with water to volume, and mix.
Standard stock solution 1— Quantitatively dissolve an accurately weighed quantity of gadolinium (Gd III) acetate in water to obtain a solution having a concentration of about 0.4 mg per mL.
Standard stock solution 2— Prepare a solution of USP Gadoteridol Related Compound B RS in water to obtain a solution having a known concentration of about 0.6 mg per mL.
Standard solution— Transfer 1.0 mL of Standard stock solution 1 and 2.0 mL of Standard stock solution 2 to a 10-mL volumetric flask, and dilute with Diluent to volume. Transfer 1.0 mL of this solution to a vial, add 3.0 mL of Diluent, and mix.
Test solution— Transfer about 60 mg of Gadoteridol, accurately weighed, to a vial, add 2.0 mL of Diluent, and mix. Immediately place the vial in a bath maintained at about 5.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a fluorometric detector operating at an excitation wavelength of 275 nm and an emission wavelength of 314 nm, and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 1 mL per minute. Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the relative retention times are about 1.0 for free gadolinium (III), 1.6 for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid gadolinium sodium salt (gadoteridol related compound D), and 2.2 for gadoteridol related compound B; and the relative standard deviation for replicate injections is not more than 5.0%.
Procedure— Separately inject equal volumes (about 50 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure all of the peak responses. Allow the Test solution to elute for not less than 1.3 times the retention time of the gadoteridol peak. Calculate the percentage of gadoteridol related compound D in the portion of Gadoteridol taken by the formula:
200(C / W)(rU / rS)
in which C is the concentration, in mg per mL, of USP Gadoteridol Related Compound B RS, calculated on the anhydrous basis, in the Standard solution; W is the weight, in mg, of Gadoteridol taken to prepare the Test solution; and rU and rS are the gadoteridol related compound D peak responses obtained from the Test solution and the Standard solution, respectively. Calculate the percentage of gadoteridol related compound B in the portion of Gadoteridol taken by the formula:
200(C / W)(rU / rS)
in which C is the concentration, in mg per mL, of USP Gadoteridol Related Compound B RS, calculated on the anhydrous basis, in the Standard solution; W is the weight, in mg, of Gadoteridol taken to prepare the Test solution; and rU and rS are the gadoteridol related compound B peak responses obtained from the Test solution and Standard solution, respectively. Calculate the percentage of any other impurity in the portion of Gadoteridol taken by the formula:
200(C / W)(ri / rS)
in which ri is the peak response of any other impurity obtained from the Test solution; and rS is the peak response for gadoteridol related compound B obtained from the Standard solution: not more than 0.1% of any individual impurity is found, and not more than 0.3% of gadolinium-containing impurities is found.
test 2 (nongadolinium-containing impurities)—
50 mM Ammonium phosphate buffer— Dissolve 17.25 g of monobasic ammonium phosphate in 3000 mL of water, and filter.
pH 5.0 Buffer— Transfer 2000 mL of 50 mM Ammonium to a 2-L beaker, and adjust with ammonium hydroxide to a pH of 5.0.
pH 7.0 Buffer— Transfer 1000 mL of 50 mM Ammonium to a 1-L beaker, and adjust with ammonium hydroxide to a pH of 7.0.
Mobile phase— Prepare a filtered and degassed mixture of pH 5.0 buffer and acetonitrile (87:13). Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard solution— Dissolve an accurately weighed quantity of USP Gadoteridol Related Compound C RS in pH 7.0 Buffer to obtain a solution having a known concentration of about 5 µg per mL.
System suitability solution— Prepare a solution in pH 7.0 buffer containing about 2 mg of USP Gadoteridol RS and 0.002 mg of USP Gadoteridol Related Compound C RS per mL.
Test solution— Transfer about 50 mg of Gadoteridol to a 25-mL volumetric flask, dissolve in and dilute with pH 7.0 Buffer to volume, and mix.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 220-nm detector and a 4.6-mm × 25-cm column that contains packing L18. The flow rate is about 1 mL per minute. Chromatograph the System suitability solution, and record the responses as directed for Procedure: the relative retention times are about 1.0 for gadoteridol, 1.2 for 1,4,7,10-tetraaza-1,4,7-tris-(carboxymethyl)-11-oxo-bicyclo [8.2.2] tetradecanium chloride (gadoteridol related compound F), 1.5 for 1,4,7,10-tetraaza-13-oxo-bicyclo [8.2.1] tridecane-4,7-diacetic acid (gadoteridol related compound E), and 1.7 for gadoteridol related compound C; and the resolution, R, between gadoteridol and gadoteridol related compound C is not less than 5. Chromatograph the Standard solution as directed for Procedure: the relative standard deviation for replicate injections is not more than 4.0%.
Procedure— Separately inject equal volumes (about 20 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. Allow the Test solution to elute for not less than twice the retention time of the gadoteridol peak. Calculate the percentage of gadoteridol related compound C in the portion of Gadoteridol taken by the formula:
2.5(C / W)(rU / rS)
in which C is the concentration, in µg per mL, of USP Gadoteridol Related Compound C RS in the Standard solution; W is the weight, in mg, of Gadoteridol taken to prepare the Test solution; and rU and rS are the peak responses for gadoteridol related compound C obtained from the Test solution and Standard solution, respectively. Calculate the percentages of gadoteridol related compound F and gadoteridol related compound E in the portion of Gadoteridol taken by the formula:
2.5(1 / F)(C / W)(ri / rS)
in which F is the relative response factor for gadoteridol related compound F (0.68) or for gadoteridol related compound E (1.7); ri is the peak response for gadoteridol related compound E or gadoteridol related compound F in the Test solution; and C, W, and rS are as defined above. Calculate the percentage of any other impurity in the portion of Gadoteridol taken by the formula:
2.5(C / W)(ri / rS)
in which ri is the response of any other impurity in the chromatogram of the Test solution; and C, W, and rS are as defined above: not more than 0.1% of any other impurity is found, and the total of nongadolinium-containing impurities is not more than 0.3%, calculated on the anhydrous basis.
Other requirements— Where the label states that Gadoteridol is sterile, it meets the requirements for Sterility Tests 71 and Bacterial endotoxins under Gadoteridol Injection. Where the label states that Gadoteridol must be subjected to further processing during the preparation of injectable dosage form, it meets the requirements for Bacterial endotoxins under Gadoteridol Injection.
Assay—
Buffer solution— Dissolve 10.2 g of monobasic potassium phosphate and 0.165 g of dibasic potassium phosphate in 3 L of water, and filter.
Mobile phase— Prepare a filtered and degassed mixture of Buffer solution and acetonitrile (98:2). Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard preparation— Dissolve an accurately weighed quantity of USP Gadoteridol RS in Buffer solution to obtain a solution having a known concentration of about 0.6 mg per mL.
Assay preparation— Transfer about 60 mg of Gadoteridol, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with Buffer solution to volume, and mix.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a fluorometric detector operating at an excitation wavelength of 275 nm and an emission wavelength of 314 nm, and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 1 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the resolution, R, between the gadoteridol peak and the peak with a relative retention time of about 1.2 is not less than 1.2; and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 50 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the responses for the major peaks. Calculate the quantity, in mg, of C17H29GdN4O7 in the portion of Gadoteridol taken by the formula:
100C(rU / rS)
in which C is the concentration of USP Gadoteridol RS, in mg per mL, in the Standard preparation; and rU and rS are the gadoteridol peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Ian DeVeau, Ph.D.
Director, Veterinary Drugs and Radiopharmaceuticals
1-301-816-8178		 (RMI05) Radiopharmaceuticals and Medical Imaging Agents 05
Reference Standards Lili Wang, Technical Services Scientist
1-301-816-8129
RSTech@usp.org
USP32–NF27 Page 2471
Pharmacopeial Forum: Volume No. 29(6) Page 1890
Chromatographic Column—
Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.