Clomipramine Hydrochloride Capsules

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

1 DEFINITION

Clomipramine Hydrochloride Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl).

2 IDENTIFICATION

A. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Change to read

3.1.1 Procedure

Solution A: Add 2.5 mL of acetic acid to 1 L of water. Adjust with ammonia water, stronger to a pH of 7.5.

Solution B: Acetonitrile, methanol, and tetrahydrofuran, stabilizer-free (80:15:5)

Mobile phase: See Table 1.

Diluent: Solution A and acetonitrile (50:50)

System suitability solution: 0.2 mg/mL of USP Clomipramine Hydrochloride RS and 0.005 mg/mL of USP Clomipramine Related Compound A RS in Diluent

Standard solution: 0.2 mg/mL of USP Clomipramine Hydrochloride RS in Diluent

Sample solution: Nominally 0.2 mg/mL of clomipramine hydrochloride from Capsules in Diluent prepared as follows. Transfer a sufficient portion of the contents of Capsules (NLT 20) to a suitable volumetric flask. Add 60% of the final flask volume of Diluent. Shake by mechanical means for about 30 min. Dilute with Diluent to volume. Centrifuge to obtain a clear supernatant and use the clear supernatant. [NOTE-The use of a centrifuge speed of 3000 rpm for 10 min may be suitable.]

Chromatographic system

• (See Chromatography (621), System Suitability.)
• Mode: LC
• Detector: UV 254 nm
• Column: 2.1-mm × 10-cm; 1.7-µm packing L1
• Column temperature: 30°
• Flow rate: 0.3 mL/min
• Injection volume: 2 µL

System suitability

• Samples: System suitability solution and Standard solution
• [Note-See Table 2 for relative retention times.]
• Suitability requirements
• Resolution: NLT 2.0 between clomipramine and clomipramine related compound A, System suitability solution
• Relative standard deviation: NMT 1.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) in the portion of Capsules taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Clomipramine Hydrochloride RS in the Standard solution (mg/mL)

C_u = nominal concentration of clomipramine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 Change to read

4.1.1 Dissolution 〈711〉

4.1.1.1 Test 1

Medium: 0.1 N hydrochloric acid; 500 mL

Apparatus 2: 50 rpm. With suitable sinkers, if needed.

Time: 30 min

Standard solution: USP Clomipramine Hydrochloride RS in Medium

Sample solution: Pass the solution under test through a suitablelter and use the ltrate. Dilute with Medium, if necessary, to a concentration that is similar to the Standard solution.

Instrumental conditions

• (See Ultraviolet-Visible Spectroscopy <857> .)
• Mode: UV
• Analytical wavelength: 252 nm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of clomipramine hydrochloride (C, HCIN, HCI) dissolved: 

Result = (A_u/A_s) × C_s × D × V × (1/L) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of USP Clomipramine Hydrochloride RS in the Standard solution (mg/mL)

D = dilution factor for the Sample solution

V = volume of Medium, 500 mL

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) is dissolved.

4.1.1.2 Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 0.01 N hydrochloric acid: 500 mL

Apparatus 2: 75 rpm with sinkers

Time: 15 min

Solution A: 55 g/L of sodium 1-heptanesulfonate in solution prepared as follows. Transfer a suitable amount of sodium 1-heptanesulfonate to an appropriate volumetric flask. Add 50% of the flask volume of water and dilute with glacial acetic acid to volume.

Solution B: To an appropriate volumetric flask, add 4% of the flask volume of Solution A and 0.4% of the flask volume of triethylamine. Dilute with water to volume.

Mobile phase: To an appropriate volumetric flask, add 50% of the flask volume of Solution B. Adjust the resulting solution with phosphoric acid to a pH of 3.2. Dilute with acetonitrile to volume.

Standard stock solution: 0.5 mg/mL of USP Clomipramine Hydrochloride RS in Medium, Sonication may be used to promote dissolution.

Standard solution: (L/500) mg/ml. of USP Clomipramine Hydrochloride RS from the Standard stock solution in Medium, where L is the label claim in mg/Capsule

Sample solution: Pass a portion of the solution under test through a suitable filter and discard NLT the first 5 mL of filtrate.

Chromatographic system

• (See Chromatography (621), System Suitability.)
• Mode: LC
• Detector: UV 254 nm
• Column: 4.6-mm x 25-cm; 5-µm packing 11
• Column temperature: 35"
• Flow rate: 1.5 mL/min
• Injection volume: 10 µL
• Run time: NLT 1.4 times the retention time of clomipramine

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: 0.8-2.0
• Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) dissolved:

Result =  (r_u/r_s) x C_s x V x (1/L) x 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Clomipramine Hydrochloride RS in the Standard solution (mg/mL) C

V = volume of the Medium, 500 mL

L = label claim of clomipramine hydrochloride (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) is dissolved.

4.1.1.3 Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: 0.1 N hydrochloric acid; 500 mL

Apparatus 2: 50 rpm

Time: 20 min

Standard solution: 0.025 mg/mL of USP Clomipramine Hydrochloride RS in Medium. Sonicate to dissolve, if necessary. [NOTE-The Standard solution may be stable for 17 h at room temperature.]

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained. Dilute the filtrate with Medium to a concentration similar to that of the Standard solution. [NOTE-The Sample solution may be stable for 17 h at room temperature.]

Capsule shell solution: Transfer a suitable number of empty capsule shells separately into each of 500 ml. of Medium. Start the dissolution test following the same conditions as the intact Capsules. At the specified time point, pass a portion of the solution under test through a suitable filter of 0.45-um pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained. Dilute the filtrate with Medium in a manner consistent with the Sample solution preparation.

Instrumental conditions

• (See Ultraviolet-Visible Spectroscopy (857).)
• Mode: UV
• Analytical wavelength: 252 nm
• Blank: Medium

Analysis

Samples: Standard solution, Sample solution, and Capsule shell solution Calculate the percentage of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) dissolved:

Result = {[A_u-(A_cs/N)]/A_s} x C_s x D x V x (1/L) x 100

A_u = absorbance from the Sample solution

A_cs = absorbance from the Capsule shell solution

N = number of capsule shells used to prepare the Capsule shell solution

A_s = absorbance from the Standard solution

C_s = concentration of USP Clomipramine Hydrochloride RS in the Standard solution (mg/mL) 

D = dilution factor for the Sample solution

V = volume of Medium, 500 mL

L = label claim (mg/Capsule)

Tolerances: NLT 80% (Q) of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) is is dissolved. 

4.1.2 UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

4.1.2.1 Procedure for content uniformity

Standard solution: 30 µg/mL of USP Clomipramine Hydrochloride RS in methanol

Sample stock solution: Transfer the contents of 1 Capsule to a 100-mL volumetric flask with the aid of methanol. Add about 75 mL of methanol, shake by mechanical means for 1 h, and dilute with methanol to volume.

Sample solution: Nominally 30 µg/mL of clomipramine hydrochloride from the Sample stock solution in methanol

Instrumental conditions

• (See Ultraviolet-Visible Spectroscopy (857),)
• Mode: UV
• Analytical wavelength: 252 nm
• Cell: 1 cm
• Blank: Methanol

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of clomipramine hydrochloride (C₁₉H₂₃ClN₂·HCl) in the Capsule taken:

Result = (A_u/A_s) x (C_s/C_u) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of USP Clomipramine Hydrochloride RS in the Standard solution (µg/mL)

C_u = nominal concentration of clomipramine hydrochloride in the Sample solution (µg/mL)

5 IMPURITIES

5.1 Organic Impurities

Solution A, Solution B, Mobile phase, Diluent, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 0.5 mg/mL of USP Clomipramine Hydrochloride RS and 0.0025 mg/mL of USP Clomipramine Related Compound A RS in Diluent

Standard solution: 0.0025 mg/mL each of USP Clomipramine Hydrochloride RS. USP Clomipramine Related Compound C. RS, and USP Imipramine Hydrochloride RS in Diluent

Sample solution: Nominally 0.5 mg/mL of clomipramine hydrochloride from Capsules in Diluent prepared as follows. Transfer a sufficient portion of the contents of Capsules (NLT 20) to a suitable volumetric flask. Add 60% of the final flask volume of Diluent. Shake by mechanical means for about 30 min. Dilute with Diluent to volume. Centrifuge to obtain a clear supernatant and use the clear supernatant. [NOTE-The use of a centrifuge speed of 3000 rpm for 10 min may be suitable.]

System suitability

• Samples: System suitability solution and Standard solution
• [NOTE-See Table 2 for relative retention times.]
• Suitability requirements
• Resolution: NLT 2.0 between clomipramine and clomipramine related compound A, System suitability solution
• Relative standard deviation: NMT 5.0% for all standard peaks, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each specified impurity in the portion of Capsules taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of each specified impurity from the Sample solution

r_s = peak response of the corresponding USP Reference Standard from the Standard solution

C_s = concentration of the corresponding USP Reference Standard in the Standard solution (mg/mL)

C_u = nominal concentration of clomipramine hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of each unspecified impurity:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of each unspecified impurity from the Sample solution

r_s = peak response of clomipramine from the Standard solution

C_s = concentration of USP Clomipramine Hydrochloride RS in the Standard solution (mg/mL)

C_u = nominal concentration of clomipramine hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: See Table 2. The reporting threshold is 0.03%.

a Process impurity included in the table for identification only. Process impurities are controlled in the drug substance, and are not to be reported or included in the total impurities for the drug product.
b 3-(3,7-Dichloro-10,11-dihydro-5H-dibenzo[b, flazepin-5-yl)-N,N-dimethylpropan-1-amine hydrochloride.
c 3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepine.

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

Preserve in tight, light-resistant containers. Protect from moisture. Store at controlled room temperature.

6.2 Labeling

The labeling states the Dissolution test used only if Test 1 is not used.

6.3 USP Reference Standards 〈11〉

USP Clomipramine Hydrochloride RS

USP Clomipramine Related Compound A RS

N¹-[3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl]-N¹,N³,N³-trimethylpropane-1,3-diamine dihydrochloride.

C₂₃H₃₂ClN₃·2HCl     458.90

USP Clomipramine Related Compound C RS

3-(3-Chloro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine hydrochloride, monohydrate.

C₁₉H₂₁ClN₂.HCl.H₂O    367.31

USP Imipramine Hydrochloride RS