Clomipramine Hydrochloride

(kloe mip' ra meen hye'' droe klor' ide).

C19H23ClN2·HCl

351.31
5H-Dibenz[b,f]azepine-5-propanamine, 3-chloro-10,11-dihydro-N,N-dimethyl-, monohydrochloride.
3-Chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride

[17321-77-6].

» Clomipramine Hydrochloride contains not less than 98.0 percent and not more than 102.0 percent of C19H23ClN2·HCl, calculated on the dried basis.

Packaging and storage— Preserve in well-closed containers.

USP Reference standards

—

USP Clomipramine Hydrochloride RS

USP Desipramine Hydrochloride RS

USP Imipramine Hydrochloride RS

Identification—

A: Infrared Absorption

197K

B: Ultraviolet Absorption

197U

—

Solution:

100 µg per mL.

Medium:

0.1 N hydrochloric acid.

Absorptivities at the wavelength of maximum absorbance, calculated on the dried basis, do not differ by more than 1.0%.

791

between 3.5 and 5.0, in a solution having a concentration of about 100 mg per mL.

Loss on drying

731

— Dry it at 105

for 2 hours: it loses not more than 1.0% of its weight.

Residue on ignition

281

not more than 0.1%.

Heavy metals, Method II

231

0.01%.

Chromatographic purity—

Test 1—

Sodium 1-heptanesulfonate solution, System suitability solution, and Chromatographic system— Proceed as directed in the Assay.

Mobile phase— Transfer 20.0 mL of Sodium 1-heptanesulfonate solution, 2.0 mL of triethylamine, and 500 mL of water to a suitable container, mix, adjust with phosphoric acid to a pH of 3.2 ± 0.1, and dilute with water to 625 mL. Transfer to a 1-liter volumetric flask, dilute with acetonitrile to volume, mix, filter, and degas. Make adjustments if necessary (see System Suitability under Chromatography

621

Test solution— Transfer about 100 mg of Clomipramine Hydrochloride, accurately weighed, to a 50-mL volumetric flask, dissolve in and dilute with methanol to volume, and mix.

Procedure— Inject a volume (about 5 µL) of the Test solution into the chromatograph, record the chromatogram, and measure all of the peak responses. Calculate the percentage of each impurity in the portion of Clomipramine Hydrochloride taken by the formula:

100(ri / rs)

in which ri is the peak response for each impurity; and rs is the sum of the responses of all the peaks.

Test 2—

Sodium 1-heptanesulfonate solution, Mobile phase, System suitability solution, and Chromatographic system— Proceed as directed in the Assay.

Test solution— Prepare as directed for Test 1.

Procedure— Inject a volume (about 10 µL) of the Test solution into the chromatograph, record the chromatogram, and measure all of the peak responses. Calculate the percentage of each impurity in the portion of Clomipramine Hydrochloride taken by the formula:

100(ri / rs)

in which ri is the peak response for each impurity; and rs is the sum of the responses of all the peaks. Not more than 0.5% of any individual impurity is found; and not more than 2.0% of total impurities is found, the results for Test 1 and Test 2 being considered.

Assay—

Sodium 1-heptanesulfonate solution— Transfer about 5.5 g of sodium 1-heptanesulfonate, accurately weighed, to a 100-mL volumetric flask, dissolve in 50.0 mL of water, and dilute with glacial acetic acid to volume.

Mobile phase— Transfer 20.0 mL of Sodium 1-heptanesulfonate solution and 2.0 mL of triethylamine to a 500-mL volumetric flask, and dilute with water to volume. Transfer this solution to a 1-L volumetric flask, adjust with phosphoric acid to a pH of 3.2 ± 0.1, dilute with acetonitrile to volume, mix, filter, and degas. Make adjustments if necessary (see System Suitability under Chromatography

621

System suitability solution— Transfer about 7.0 mg of USP Desipramine Hydrochloride RS and 10.0 mg of USP Imipramine Hydrochloride RS, both accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with methanol to volume, and mix.

Standard preparation— Dissolve an accurately weighed quantity of USP Clomipramine Hydrochloride RS in methanol, and dilute quantitatively, and stepwise if necessary, with methanol to obtain a solution having a known concentration of about 0.8 mg per mL. Transfer 10.0 mL of this solution to a 25-mL volumetric flask, dilute with methanol to volume, and mix.

Assay preparation— Transfer about 80 mg of Clomipramine Hydrochloride, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with methanol to volume, and mix. Transfer 10.0 mL of this solution to a 25-mL volumetric flask, dilute with methanol to volume, and mix.

Chromatographic system (see Chromatography

621

)— The liquid chromatograph is equipped with a 254-nm detector and a 3.9-mm × 30-cm column that contains packing L1. The flow rate is about 1.0 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the relative retention times are about 0.85 for desipramine and 1.0 for imipramine; the resolution, R, between desipramine and imipramine is not less than 0.5; and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 10 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 C19H23ClN2·HCl in the portion of Clomipramine Hydrochloride taken by the formula:

250C(rU / rS)

in which C is the concentration, in mg per mL, of USP Clomipramine Hydrochloride RS in the Standard preparation; and rU and rS are the 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	Ravi Ravichandran, Ph.D. Principal Scientific Liaison 1-301-816-8330	(SM42010) Monographs - Small Molecules 4
Reference Standards	RS Technical Services 1-301-816-8129 rstech@usp.org

USP35–NF30 Page 2722

Pharmacopeial Forum: Volume No. 27(3) Page 2529