Imipramine Pamoate Capsules

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

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

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1 DEFINITION

Imipramine Pamoate Capsules contain imipramine pamoate [(C₁₉H₂₄N₂)₂ . C₂₃H₁₆O₆] equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of imipramine hydrochloride (C₁₉H₂₄N₂ . HCl).

2 IDENTIFICATION

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

B. The UV spectrum of the imipramine peak of the Sample solution corresponds to that of the System suitability solution, as obtained in the test for Organic Impurities.

3 ASSAY

Change to read:

4 PROCEDURE

Buffer: 5.2 g/L of dibasic potassium phosphate in water

Solution A: Acetonitrile (ERR 1-May-2019) and Buffer (15:85). Adjust with phosphoric acid to a pH of 8.0.

Solution B: Acetonitrile (ERR 1-May-2019) and Buffer (38:62). Adjust with phosphoric acid to a pH of 8.0.

Mobile phase: See Table 1.

Table 1

Diluent: Acetonitrile (ERR 1-May-2019) and water (75:25)

Standard stock solution: 0.75 mg/mL of USP Imipramine Pamoate RS in Diluent

Standard solution: 0.23 mg/mL of USP Imipramine Pamoate RS (equivalent to 0.15 mg/mL of imipramine hydrochloride) from the Standard stock solution in Solution A. Pass a portion through a suitable filter of 0.45-µm pore size. Use the filtrate.

Sample stock solution: Transfer the contents of Capsules (NLT 5) into a suitable volumetric flask, and add the corresponding Capsule shells. Add 10% of the final flask volume of acetonitrile, and sonicate for 10 min with intermittent shaking. Add 80% of the final flask volume of Diluent, and sonicate for 15 min with intermittent shaking. Allow to cool to room temperature, and dilute with Diluent to volume. Allow to stand for 5 min.

Sample solution: Nominally 0.23 mg/mL of imipramine pamoate (equivalent to 0.15 mg/mL of imipramine hydrochloride) from the Sample stock solution in Solution A. Pass a portion through a suitable filter of 0.45-µm pore size. Use the filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 269 nm

Column: 4.6-mm × 15-cm; 5-µm packing L1

Autosampler temperature: 10°

Flow rate: 1.5 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

[Note—The relative retention times for pamoic acid and imipramine are 0.3 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between pamoic acid and imipramine

Tailing factor: NMT 2.0 for imipramine

Relative standard deviation: NMT 2.0% for imipramine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of imipramine hydrochloride (C₁₉H₂₄N₂ . HCl) in the portion of Imipramine Pamoate Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × [M × (M_r1/M_r2)] × 100

r_U = peak area of imipramine from the Sample solution

r_S = peak area of imipramine from the Standard solution

C_S = concentration of USP Imipramine Pamoate RS in the Standard solution (mg/mL)

C_U = equivalent concentration of imipramine hydrochloride in the Sample solution (mg/mL)

M = number of moles of imipramine hydrochloride equivalent to each mole of imipramine pamoate, 2

M_r1 = molecular weight of imipramine hydrochloride, 316.87

M_r2 = molecular weight of imipramine pamoate, 949.18

Acceptance criteria: 90.0%-110.0%

5 PERFORMANCE TESTS

5.1 DISSOLUTION 〈711〉

Test 1

Tier 1

Medium 1: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 100 rpm

Times: 30 and 90 min

Tier 2

Medium 2: 0.1 N hydrochloric acid with 0.3% purified pepsin; 900 mL

Apparatus 1: 100 rpm

Times: 30 and 90 min

Buffer: 4.4 g/L of dibasic potassium phosphate in water

Mobile phase: Acetonitrile, triethylamine, and Buffer (400:5:600). Adjust with phosphoric acid to a pH of 8.0.

Diluent A: Acetonitrile and water (75:25)

Diluent B: 20.4 g/L of monobasic potassium phosphate and 3 g/L of sodium hydroxide. Adjust with 1 N sodium hydroxide or 1 N phosphoric acid to a pH of 7.4.

Standard stock solution: 0.63 mg/mL of USP Imipramine Pamoate RS in Diluent A

Standard solution: 0.038 mg/mL of USP Imipramine Pamoate RS from the Standard stock solution prepared as follows. Transfer a suitable volume of the Standard stock solution to an appropriate flask that already contains 60% of the final flask volume of Diluent B and 30% of the final flask volume of Medium. Dilute with Diluent B to volume.

Sample stock solution: Centrifuge a portion of the solution under test. Use the supernatant. Replace the portion of solution removed from the vessel with the same volume of fresh Medium 1 or Medium 2 at 37°. [NOTE-The use of a centrifuge speed of 5000 rpm for 10 min may be suitable.]

Sample solution: Nominally equivalent to about 0.025 mg/mL of imipramine hydrochloride prepared from the Sample stock solution in Diluent B in a suitable volumetric flask

Dissolution procedure: Perform the test using the conditions under Tier 1. In the presence of cross-linking, repeat the test with a new set of Capsules using the conditions under Tier 2.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 252 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 1.2 mL/min

Injection volume: 50 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of imipramine hydrochloride (C₁₉H₂₄N₂ . HCl) dissolved at each time point (i):

Result_i = (r_i/r_S) x C_S x [M x (M_r1/M_r2)] x D x V x (1/L) x 100

r_i = peak area of imipramine from the Sample solution at each time point

r_S = peak area of imipramine from the Standard solution

C_S = concentration of USP Imipramine Pamoate RS in the Standard solution (mg/mL)

M = number of moles of imipramine hydrochloride equivalent to each mole of imipramine pamoate, 2

M_r1 = molecular weight of imipramine hydrochloride, 316.87

M_r2 = molecular weight of imipramine pamoate, 949.18

D = dilution factor of the Sample solution

V = volume of Medium 1 or Medium 2, 900 mL

L = label claim (mg/Capsule)

Tolerances: See Table 2.

Table 2

The percentage of imipramine pamoate dissolved equivalent to the labeled amount of imipramine hydrochloride (C₁₉H₂₄N₂ . HCl) dissolved at the times specied conforms to Dissolution (711), Acceptance Table 1.

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

Medium: 0.1 N hydrochloric acid; 900 mL

Apparatus 1: 100 rpm

Times: 30 and 150 min

Standard solution: A solution containing USP Imipramine Pamoate RS at the concentrations listed in Table 3 prepared as follows. Transfer a suitable quantity of USP Imipramine Pamoate RS to an appropriate volumetric flask. Add 5% of the final flask volume of methanol and sonicate for 5 min. Add 75% of the final flask volume of Medium that has been heated to NLT 60° and stir for 30 min. Allow to cool to room temperature. Dilute with Medium to volume and mix. Pass through a suitable filter and use the filtrate.

Table 3

Sample solution: Pass a portion of the solution under test through a suitable filter. Use the filtrate.

Instrumental conditions

Mode: UV-Vis

Wavelength: 251 nm

Cell: 0.2 cm

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of imipramine hydrochloride (C₁₉H₂₄N₂ . HCl) dissolved at each time point (i):

Result_i = (A_i/A_S) x C_S x [M x (M_r1/M_r2)] x V x (1/L) x 100

A_i = absorbance of imipramine from the Sample solution at each time point

A_S = absorbance of imipramine from the Standard solution

C_S = concentration of USP Imipramine Pamoate RS in the Standard solution (mg/mL)

M = number of moles of imipramine hydrochloride equivalent to each mole of imipramine pamoate, 2

M_r1 = molecular weight of imipramine hydrochloride, 316.87

M_r2 = molecular weight of imipramine pamoate, 949.18

V = volume of Medium, 900 mL

L = label claim (mg/Capsule)

Tolerances: See Table 4.

Table 4

The percentage of imipramine pamoate dissolved equivalent to the labeled amount of imipramine hydrochloride (C19H24N2 HCI) dissolved at the times specified conforms to Dissolution (711), Acceptance Table 1.

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

6 IMPURITIES

Change to read:

6.1 ORGANIC IMPURITIES

Protect solutions containing imipramine from light.

Buffer: 5.2 g/L of dibasic potassium phosphate in water

Solution A: Acetonitrile (ERR 1-May-2019) and Buffer (3:100). Adjust with phosphoric acid to a pH of 7.2.

Solution B: Methanol and acetonitrile (ERR 1-May-2019) (70:30)

Mobile phase: See Table 5.

Table 5

System suitability solution: 1.5 mg/mL of USP Imipramine Pamoate RS (equivalent to 1 mg/mL of imipramine hydrochloride), and 0.001 mg/mL each of USP Desipramine Hydrochloride RS and USP Depramine RS in Solution B. Pass a portion through a suitable membrane filter of 0.2-µm pore size, and use the filtrate.

Standard solution: 0.015 mg/mL of USP Imipramine Pamoate RS (equivalent to 0.010 mg/mL of imipramine hydrochloride) in Solution B.

Pass a portion through a suitable membrane filter of 0.2-µm pore size, and use the filtrate.

Sample solution: Nominally 1.5 mg/mL of imipramine pamoate (equivalent to 1.0 mg/mL of imipramine hydrochloride) from NLT 20 Capsules prepared as follows. Transfer a portion of the contents of the Capsules equivalent to 50 mg of imipramine hydrochloride to a 50-mL volumetric flask. Add 30 mL of Solution B, and sonicate for 10 min in a cool water bath with intermittent shaking. Dilute with Solution B to volume. Pass a portion through a suitable membrane filter of 0.2-µm pore size, and use the filtrate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm. For Identification test B, a diode-array detector may be used in the wavelength range of 200-300 nm.

Column: 4.6-mm × 15-cm; 3.5-µm packing L1

Temperatures

Autosampler: 10°

Column: 45°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

[NOTE-See Table 6 for relative retention times.]

Suitability requirements

Resolution: NLT 2.0 between the desipramine and depramine peaks; NLT 2.0 between the depramine and imipramine peaks, System suitability solution

Tailing factor: NMT 1.5, Standard solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

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

Result = (r_U/r_S) x (C_S/C_U) x [M x (M_r1/M_r2) x (1/F) x 100

r_U = peak response of each imipramine impurity from the Sample solution

r_S = peak response of imipramine from the Standard solution

C_S = concentration of USP Imipramine Pamoate RS in the Standard solution (mg/mL)

C_U = equivalent concentration of imipramine hydrochloride in the Sample solution (mg/mL)

M = number of moles of imipramine hydrochloride equivalent to each mole of imipramine pamoate, 2

M_r1 = molecular weight of imipramine hydrochloride, 316.87

M_r2 = molecular weight of imipramine pamoate, 949.18

F = relative response factor (see Table 6)

Acceptance criteria: See Table 6. Disregard any degradation product peaks less than 0.02%.

Table 6

^a Included for identification only. This peak is due to the pamoate counterion; hence it is not an impurity.

^b 10,11-Dihydro-5H-dibenzo[b,f]azepine.

7 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers. Store at controlled room temperature.

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

USP REFERENCE STANDARDS (11)

USP Depramine RS

3-(5H-Dibenzo[b, fazepin-5-yl)-N,N-dimethylpropan-1-amine.

C₁₉H₂₂N₂  278.39

USP Desipramine Hydrochloride RS

USP Imipramine Pamoate RS