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 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.
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.
;)
