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Citalopram Hydrobromide
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C20H21FN2O·HBr 405.30

5-Isobenzofurancarbonitrile, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-, monohydrobromide.

1-[3-(Dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile monohydrobromide [59729-32-7].
» Citalopram Hydrobromide contains not less than 98.0 percent and not more than 102.0 percent of C20H21FN2O·HBr, calculated on the anhydrous basis.
Packaging and storage— Preserve in well-closed containers, and store at controlled room temperature.
Labeling— If a test for Related compounds other than Test 1 is used, then the labeling states with which Related compounds test the article complies.
Completeness of solution— The absorbance at 410 nm of a 2.5% w/v solution, in 96% alcohol, against a sample solvent in a 1-cm quartz cell is not more than 0.040.
Change to read:
Identification—
B: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.
C: A solution of 10 mg per mL meets the requirement of the silver nitrate precipitate test1S (USP31) for Bromide 191.
Specific rotation 781S: between –0.2 and +0.2 at 20.
Test solution: 25 mg per mL, in methanol.
pH 791: between 5.5 and 6.5, in a solution (0.5 in 100).
Water, Method I 921: not more than 0.5%, using about 250 mg of sample.
Residue on ignition 281: not more than 0.1%. The sample is moistened with 2 mL of nitric acid and 5 drops of sulfuric acid.
Related compounds—
note—On the basis of the synthetic route used, perform either Test 1 or Test 2. However, if the chloro and bromo analogs are potential related compounds in the synthetic route used, Test 2 is recommended.
test 1—
Buffer, Mobile phase, Diluent, and Chromatographic system— Proceed as directed in the Assay. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard solution— Use the Standard preparation, prepared as directed in the Assay.
Working standard solution— Dilute the Standard solution with Mobile phase, quantitatively and stepwise if necessary, to obtain a solution having a concentration of 0.625 µg per mL of citalopram hydrobromide.
System suitability solution— Dissolve an accurately weighed quantity of USP Citalopram Hydrobromide RS and USP Citalopram Related Compound D RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.001 mg per mL.
Sensitivity solution— Dilute 5.0 mL of the Working standard solution with Diluent to 50 mL to obtain a solution having 0.0625 µg of citalopram hydrobromide per mL.
Test solution— Use the Assay preparation.
Chromatographic system (see Chromatography 621)— Inject the Diluent as directed for Procedure to verify that there are no interfering peaks. Chromatograph the Sensitivity solution, and record the peak responses as directed for Procedure: the signal-to-noise ratio is at least 3. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the resolution, R, between citalopram related compound D and citalopram is not less than 1.8; the tailing factor for the citalopram hydrobromide peak is not less than 0.8 and not more than 1.5; and the relative standard deviation for replicate injections, based on the citalopram peak, is not more than 5%.
note—For the purpose of identification, the approximate relative retention times are 0.90 for citalopram related compound D and 1.0 for citalopram hydrobromide.
Procedure— Separately inject equal volumes (about 20 µL) of the Working standard solution and the Test solution into the chromatograph, record the chromatograms for about 40 minutes, and measure the responses for the major peaks. Calculate the percentage of related compounds in the portion of Citalopram Hydrobromide taken by the formula:
100(CS / CT)(ri / rS)(324.39/405.30)(1/F)
in which CS and CT are the concentrations, in mg per mL, of Citalopram Hydrobromide in the Working standard solution and the Test solution, respectively; ri is the peak response for each impurity obtained from the Test solution; rS is the peak response for the citalopram peak, obtained from the Working standard solution; 324.39 and 405.30 are the molecular weights for citalopram and citalopram hydrobromide, respectively; and F is the relative response factor for each impurity relative to citalopram (free base), as presented in Table 1.
Table 1
Related Compound Relative Retention Time Relative Response Factor (F) Limit (%)
1-(3-Dimethylaminopropyl)-1-(4¢-fluorophenyl)-5-(4-dimethylaminobutyryl)-1,3-dihydrobenzofuran 0.13 0.34 NMT* 0.1
Citalopram related compound A 0.18 0.77 NMT 0.1
4-[4-Dimethylamino-1-(4¢-fluorophenyl)-1-hydroxy-1-butyl]-3hydroxymethyl benzonitrile 0.26 0.99 NMT 0.1
Citalopram related compound B 0.40 0.98 NMT 0.1
Citalopram related compound C 0.67 0.69 NMT 0.1
Citalopram related compound D 0.90 1.04 NMT 0.1
Citalopram hydrobromide 1.0 1.0 —
Citalopram related compound E 1.29 0.91 NMT 0.1
Individual unknown impurity — 1.0 NMT 0.1 each
Total impurities — — NMT 0.5
*  NMT = not more than.
test 2—
Buffer— Dissolve about 2.7 g of monobasic potassium phosphate in 1000 mL of water, add 1 mL of N,N-dimethyloctylamine, stir, and adjust with phosphoric acid to a pH of 3.0.
Diluent— Prepare a mixture of Buffer and acetonitrile (70:30).
Solution A— Prepare a mixture of Buffer, methanol, and tetrahydrofuran (70:24:6).
Solution B— Prepare a mixture of acetonitrile and Buffer (80:20).
Mobile phase— Use variable mixtures of Solution A and Solution B as directed in Table 2 for Chromatographic system. Make adjustments if necessary (see System Suitability under Chromatography 621).
Standard solution— Dissolve accurately weighed quantities of USP Citalopram Hydrobromide RS, USP Citalopram Related Compound A RS, USP Citalopram Related Compound C RS, USP Citalopram Related Compound D RS, USP Citalopram Related Compound G RS, and USP Citalopram Related Compound H RS in Diluent to obtain a final solution having a concentration of 1.5 µg per mL of each compound.
Test solution— Dissolve an accurately weighed quantity of Citalopram Hydrobromide in a suitable volume of Diluent to obtain a solution having a final concentration of 1.5 mg per mL of citalopram hydrobromide.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 224-nm detector and a 4.6-mm × 25-cm column that contains 5-µm packing L1. The flow rate is about 0.8 mL per minute. The column temperature is maintained at 40. The chromatograph is programmed as shown in Table 2.
Table 2
Time
(minutes)		 Solution A
(%)		 Solution B
(%)		 Elution
0–18 100 0 isocratic
18–40 100®10 0®90 linear gradient
40–45 10 90 isocratic
45–46 10®100 90®10 linear gradient
46–55 100 0 re-equilibration
Chromatograph the Standard solution, and record the peak responses as directed for Procedure: the resolution, R, between citalopram and citalopram related compound D is not less than 2.0, and that between citalopram related compound G and citalopram related compound H is not less than 4.0; and the relative standard deviation for the citalopram peak in replicate injections is not more than 2.0%.
note—For the purpose of identification, the approximate relative retention times of citalopram related compounds are provided in Table 3.
Table 3
Related Compound Relative
Retention
Time		 Limit (%)
Citalopram related compound A 0.40 NMT* 0.10
Citalopram related compound C 0.88 NMT 0.10
Citalopram 1.0 —
Citalopram related compound D 1.09 NMT 0.10
Citalopram related compound G 2.20 NMT 0.10
Citalopram related compound H 2.30 NMT 0.10
Individual unspecified impurity — NMT 0.10
Total specified and unspecified impurities — NMT 0.50
*  NMT = not more than.
Procedure— Inject equal volumes (about 10 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure all the peak responses. Calculate the percentage of each citalopram related compound in the portion of Citalopram Hydrobromide taken by the formula:
100(CS / CT)(ri / rS)
in which CS is the concentration, in mg per mL, of each citalopram related compound in the Standard solution; CT is the concentration of citalopram hydrobromide in the Test solution; ri is the peak area of each impurity obtained from the Test solution; rS is the peak area of each corresponding impurity obtained from the Standard solution.
(Official until July 1, 2008)
Assay—
Buffer— In a 1-L volumetric flask, dissolve about 1 g of sodium acetate in 800 mL of water, and add 6 mL of triethylamine. Adjust with acetic acid to a pH of 4.6, and dilute with water to volume.
Mobile phase— Prepare a filtered and degassed mixture of Buffer and acetonitrile (80:20). The apparent pH is 5.0 ± 0.1. Make adjustments if necessary (see System Suitability under Chromatography 621).
Diluent— Prepare a mixture of methanol and water (1:1).
Standard preparation— Dissolve an accurately weighed quantity of USP Citalopram Hydrobromide RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about 0.625 mg per mL.
Assay preparation— Transfer about 62.5 mg of Citalopram Hydrobromide, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with Diluent to volume, and mix to obtain a solution containing 0.625 mg per mL.
Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a 239-nm detector and a 150-mm × 4.6-mm column that contains 5-µm packing L7. The flow rate is about 1 mL per minute. The column temperature is maintained at 50. Inject the Diluent to verify that there are no interfering peaks. Inject the Standard preparation, and record the peak responses as directed for Procedure: the column efficiency is not less than 3000 theoretical plates; the tailing factor is not more than 3.0; and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 20 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms for about 30 minutes, and measure the responses for the major peaks. Calculate the quantity, in percentage of C20H21FN2O·HBr, in the portion of Citalopram Hydrobromide taken by the formula:
100(CS / CU)(rU / rS)
in which CS and CU are the concentrations, in mg per mL, of the Standard preparation and the Assay preparation, respectively; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information— Staff Liaison : Ravi Ravichandran, Ph.D., Senior Scientist
Expert Committee : (MDPP05) Monograph Development-Psychiatrics and Psychoactives
USP31–NF26 Page 1778
USP31–NF26 Supplement : No. 1 Page 3626
Pharmacopeial Forum : Volume No. 33(2) Page 214
Phone Number : 1-301-816-8330