Trandolapril and Verapamil Hydrochloride Extended-Release Tablets

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

Trandolapril and Verapamil Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) and verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The UV absorption spectra of the trandolapril and verapamil peaks of the Sample solution exhibit maxima and minima at the same wavelengths as those of the corresponding peaks from the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Buffer 1: 7 mL/L of triethylamine in water. Adjust with phosphoric acid to a pH of 3.0.

Buffer 2: 0.82 mg/mL of sodium acetate anhydrous in acetic acid

Mobile phase: Acetonitrile, methanol, and Buffer 1 (240:160:600)

Diluent 1: Methanol and water (80:20)

Diluent 2: Acetonitrile, 2-aminoheptane, and Buffer 2 (30:0.5:70). Adjust with 10 M sodium hydroxide to a pH of 5.0.

Standard solution: 20 µg/mL of USP Trandolapril RS and 24 µg/mL of USP Verapamil Hydrochloride RS in Diluent 1 prepared as follows. Add Diluent 1 to USP Trandolapril RS and USP Verapamil Hydrochloride RS to fill about 70% of the volume of the flask, sonicate to facilitate dissolution, and then dilute with Diluent 1 to volume.

Sample solution 1: Nominally 20 µg/mL of trandolapril from NLT 5 Tablets in Diluent 1 prepared as follows. Add Diluent 1 to the sample, to fill about 50% of the volume of the flask, and sonicate for 45 min with occasional swirling. Cool and dilute with Diluent 1 to volume. Pass this solution through a suitable filter of 0.45-µm pore size.

Alternatively, Sample solution 1 can be prepared as follows. Suspend NLT 20 Tablets in 950 mL of Diluent 2 taken in a 1-L volumetric flask. Stir for about 2 h with a stir bar at NLT 800 rpm until the Tablets are completely disintegrated. [Note-Ensure that the Tablets do not adhere to the bottom of the vessel.] Remove the stir bar and rinse with Diluent 2. Dilute with Diluent 2 to volume and shake thoroughly. Centrifuge a portion of the suspension for 10 min, pipet a portion of the supernatant, and pass through a suitable filter. Discard the first 5 mL of the filtrate.

Sample solution 2: Nominally 24 µg/mL of verapamil hydrochloride in Diluent 1 or Diluent 2 from Sample solution 1

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 216 nm. For Identification B, use a diode array detector in the range of UV 200–400 nm.
• Column: 4.6-mm × 15-cm; 3-µm packing L1
• Column temperature: 40°
• Flow rate: 1.3 mL/min
• Injection volume: 20 µL
• Run time: NLT 1.5 times the retention time of the trandolapril peak

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0 for both the trandolapril and verapamil peaks
• Relative standard deviation: NMT 2.0% for both the trandolapril and verapamil peaks

Analysis

Samples: Standard solution, Sample solution 1, and Sample solution 2

Calculate the percentage of the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) and verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of trandolapril from Sample solution 1 or verapamil from Sample solution 2

rₛ = peak response of trandolapril or verapamil from the Standard solution

Cₛ = concentration of USP Trandolapril RS or USP Verapamil Hydrochloride RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of trandolapril in Sample solution 1 or verapamil hydrochloride in Sample solution 2 (µg/mL)

Acceptance criteria

• Trandolapril: 90.0%–110.0%
• Verapamil hydrochloride: 90.0%–110.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉: Test 1

4.1.1 For trandolapril

Medium: Water; 500 mL

Apparatus 2: 50 rpm

Time: 60 min

Buffer 1, Chromatographic system, and System suitability: Proceed as directed in the Assay except for the following.

• Flow rate: 1 mL/min
• Injection volume: 100 µL

Mobile phase: Acetonitrile and Buffer 1 (400:600)

Standard stock solution: Prepare 0.2 mg/mL of USP Trandolapril RS as follows. Transfer USP Trandolapril RS to a suitable volumetric flask, add about 5% of the volume of the flask of acetonitrile, sonicate to dissolve, and dilute with Medium.

Standard solution: (L/500) mg/mL in Medium from the Standard stock solution, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Analysis

Calculate the percentage of the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) dissolved:

Result = (rᵤ/rₛ) × (Cₛ × V) × (1/L) × 100

rᵤ = peak response of trandolapril from the Sample solution

rₛ = peak response of trandolapril from the Standard solution

Cₛ = concentration of USP Trandolapril RS in the Standard solution (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) is dissolved. 

4.1.2 For verapamil hydrochloride

Acid stage medium: Simulated gastric fluid (without enzyme); 900 mL

Buffer stage medium: Simulated intestinal fluid (without enzyme); 900 mL

Apparatus 2: 50 rpm, with a sinker (see Dissolution (711), Apparatus, Figure 2a)

Times: 1 h in Acid stage medium; 2, 3.5, 5, and 8 h in Buffer stage medium

Mobile phase: Acetonitrile and Buffer 1 (400:600)

Buffer 1, Chromatographic system, and System suitability: Proceed as directed in the Assay except for the following.

• Detector: UV 278 nm
• Flow rate: 1 mL/min
• Injection volume: 10 µL

Standard stock solution: Prepare 1.34 mg/ml. of USP Verapamil Hydrochloride RS as follows. Transfer USP Verapamil Hydrochloride RS to a suitable volumetric flask, add about 20% of the volume of the flask of methanol, sonicate to dissolve, cool to room temperature, and dilute with water to volume.

Standard solution: (L/900) mg/mL in the respective Medium from the Standard stock solution, where L is the label claim in mg/Tablet

Sample solution: Withdraw 10 mL of solution at each time interval, and centrifuge at 2500 rpm for 5 min.

Analysis

Samples: Standard solution and Sample solutions

Place 1 Tablet in the sinker and place the sinker in the vessel. Prepare Samples as directed under Sample solutions.

Analysis

Samples: Standard solution and Sample solutions

Place 1 Tablet in the sinker and place the sinker in the vessel. Prepare Samples as directed under Sample solutions.

Calculate the percentage of the labeled amount of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) dissolved in the acid stage:

Result = (rᵤ/rₛ) × Cₛ × V × (1/L) × 100

rᵤ = peak response of verapamil from the Sample solution

rₛ = peak response of verapamil from the Standard solution

Cₛ = concentration of USP Verapamil Hydrochloride RS in the Standard solution

V = volume of Acid stage medium, 900 mL

L = label claim (mg/Tablet)

Calculate the concentration (Cᵢ) of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) in the sample withdrawn from the vessel at each buffer stage time point (i):

Resultᵢ = (rᵤ/rₛ) × Cₛ

rᵤ = peak response of verapamil from the Sample solution at each time point (i)

rₛ = peak response of verapamil from the Standard solution

Cₛ = concentration of USP Verapamil Hydrochloride RS in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − Vₛ)] + (C₁ × Vₛ)} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 × Vₛ)]} + [(C₂ + C₁) × Vₛ]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 × Vₛ)]} + [(C₃ + C₂ + C₁) × Vₛ]) × (1/L) × 100

Result₅ = ({C₅ × [V − (4 × Vₛ)]} + [(C₄ + C₃ + C₂ + C₁) × Vₛ]) × (1/L) × 100

Cᵢ = concentration of verapamil hydrochloride in the Sample solution at the specified time point (i) (mg/mL)

V = volume of Buffer stage medium, 900 mL

L = label claim (mg/Tablet)

Vₛ = volume of the Sample solution withdrawn at each time point in the buffer stage (mL)

Tolerances: See Table 1

Table 1

The percentages of the labeled amount of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.2 Dissolution 〈711〉: Test 2

[Note-If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.]

4.2.1 For trandolapril and verapamil hydrochloride (acid stage)

[Note-During analysis, place the bi-layer Tablet in the dissolution vessel such that the trandolapril layer faces the bottom of the vessel.]

Medium: Simulated gastric fluid (without enzyme); 900 mL

Apparatus 2: 50 rpm, suitable wire helix sinkers

Times

• Trandolapril: 45 min
• Verapamil hydrochloride: 1 h

Buffer: Dissolve 6.8 g of monobasic potassium phosphate and the contents from one vial of paired ion chromatography reagent into a 1-L volumetric flask. Dissolve in approximately 950 mL of water. Adjust with dilute potassium hydroxide to a pH of 6.0 and then dilute with water to volume.

Solution A: Acetonitrile and Buffer (15:85)

Solution B: Acetonitrile and Buffer (60:40)

Mobile phase: See Table 2.

Table 2

Standard stock solution: 0.56 mg/mL of USP Trandolapril RS in methanol

Standard solution 1: (L/900) mg/mL of USP Trandolapril RS in 0.1 N hydrochloric acid from the Standard stock solution, where L is the label claim in mg/Tablet. [Note-For better recoveries during analysis, suitable quantities of an excipient mixture used in the formulation are mixed with the Standard solution 1 before dilution as follows: 0.85 mg of excipient mixture per milliliter of Standard solution 1 for trandolapril/verapamil hydrochloride Tablet strength 2/180; 1.05 mg of excipient mixture per milliliter of Standard solution 1 for trandolapril/verapamil hydrochloride Tablet strengths 1/240, 2/240, and 4/240.]

Standard solution 2: (L/900) mg/mL of USP Verapamil Hydrochloride RS in 0.1 N hydrochloric acid, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size.

Chromatographic system: Procedure for trandolapril

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 210 nm
• Column: 2-mm × 30-mm; 7-µm packing L1
• Flow rate: 1 mL/min
• Injection volume: 250 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 1.5
• Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution 1 and Sample solution

Use a portion of the sample withdrawn at 45 min to analyze the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) dissolved and save the rest for analyzing verapamil hydrochloride.

Calculate the percentage of the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) dissolved:

Result = (rᵤ/rₛ) × (Cₛ × V) × (1/L) × 100

rᵤ = peak response of trandolapril from the Sample solution

rₛ = peak response of trandolapril from Standard solution 1

Cₛ = concentration of USP Trandolapril RS in Standard solution 1 (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

4.2.2 Instrumental conditions: Procedure for verapamil hydrochloride

• (See Ultraviolet-Visible Spectroscopy 〈857〉.)
• Mode: UV
• Wavelength range: 250–300 nm
• Cell: 1 cm

Analysis

Samples: Standard solution 2 and Sample solution

For the total labeled amount of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) dissolved in the acid stage, combine the results from the analysis of the sample withdrawn at 45 min and also at 1 h.

Calculate the percentage of the labeled amount of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) dissolved at each time point using a suitable multicomponent analysis software.

Tolerances

• Trandolapril: NLT 80% (Q) of the labeled amount of trandolapril (C₂₄H₃₄N₂O₅) is dissolved.
• Verapamil hydrochloride: See Table 3 at 1 h.

4.2.3 For verapamil hydrochloride (buffer stage)

Buffer stage medium: Simulated intestinal fluid TS (without enzyme); 900 mL. Adjust with 0.2 N sodium hydroxide to a pH of 7.5.

Apparatus 2: 50 rpm

Times: 2, 3.5, 5, and 8 h

Sample solutions: Pass portions of the solution under test at each time interval through a suitable filter of 0.45-µm pore size.

Instrumental conditions and Analysis: Proceed as directed under verapamil hydrochloride (acid stage).

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of verapamil hydrochloride (C₂₇H₃₈N₂O₄ · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.3 Uniformity of Dosage Units 〈905〉, Content Uniformity

Meet the requirements

5 IMPURITIES

5.1 Trandolapril Related Impurities, Procedure 1

[Note-On the basis of the type of formulation, perform either Trandolapril Related Impurities, Procedure 1 and Content of Trandolapril Related Compound E, or Trandolapril Related Impurities, Procedure 2. Trandolapril Related Impurities, Procedure 2 is recommended when the formulation is a bi-layered Tablet.]

Buffer 1: Prepare a mixture of 2.72 g/L of monobasic potassium phosphate and 3.5 g/L of sodium 1-decane sulfonate. The pH of the resulting solution is about 4.68.

Buffer 2: Prepare a mixture of 2.72 g/L of monobasic potassium phosphate and 3 g/L of sodium 1-octane sulfonate. Adjust with triethylamine to a pH of 6.6.

Diluent: Acetonitrile, methanol, and water (25:25:50)

Solution A: Acetonitrile and Buffer 1 (15:85)

Solution B: Acetonitrile, methanol, and Buffer 2 (70:7:30)

Solution C: Acetonitrile, methanol, and Buffer 2 (70:4:30)

Mobile phase: See Table 4.

Table 4

Trandolapril related compound A stock solution: 5 µg/mL of USP Trandolapril Related Compound A RS prepared as follows. Transfer USP Trandolapril Related Compound A RS to a suitable volumetric flask, add about 10% of the volume of the flask of methanol, and sonicate to dissolve. Cool and dilute with Diluent to volume.

System suitability solution: 0.125 mg/mL of USP Trandolapril RS and 0.15 µg/mL of USP Trandolapril Related Compound A RS in Diluent prepared as follows. Add about 30% of the volume of the flask of methanol to USP Trandolapril RS, and sonicate to dissolve. Cool, add appropriate quantities of Trandolapril related compound A stock solution, and dilute with Diluent to volume.

Standard solution: 1.2 µg/mL of USP Trandolapril RS in Diluent

Sample solution: Nominally 0.125 mg/mL of trandolapril in Diluent prepared as follows. Transfer an equivalent to 6.25 mg of trandolapril, from finely powdered Tablets (NLT 10), to a 50-mL volumetric flask, add 30 mL of Diluent, and sonicate for 15 min with intermittent and vigorous shaking. Cool and dilute with Diluent to volume. Centrifuge the resulting solution at 2500 rpm for 20 min, and pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 210 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Column temperature: 40°
• Flow rate: 1 mL/min
• Injection volume: 50 µL
• Run times: NLT 1.5 times the retention time of trandolapril for the Standard solution, and NLT 7.0 times for the System suitability solution and the Sample solution

System suitability

• Samples: System suitability solution and Standard solution
• Suitability requirements
• Resolution: NLT 5.0 between trandolapril and trandolapril related compound A, System suitability solution
• Tailing factor: NMT 2.0 for trandolapril, System suitability solution
• Relative standard deviation: NMT 5.0% for trandolapril, Standard solution

Analysis

Samples: Standard solution and Sample solution

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

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of trandolapril from the Standard solution

Cₛ = concentration of USP Trandolapril RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of trandolapril in the Sample solution (µg/mL)

Acceptance criteria: See Table 5.

Table 5

ᵃ This impurity is controlled using the procedure described under Content of Trandolapril Related Compound E.

ᵇ Process related impurity and is controlled in the drug substance.

ᶜ (2S,3aR,7aS)-1-[N-[(S)-1-Carboxy-3-phenylpropyl]-l-alanyl]hexahydro-2-indolinecarboxylic acid 1-isopropyl ester.

ᵈ (2S,3aR,7aS)-1-[N-[(S)-1-Carboxy-3-cyclohexylpropyl]-l-alanyl]hexahydro-2-indolinecarboxylic acid 1-ethyl ester.

ᵉ Total impurities include all process related and degradation impurities from both Trandolapril Related Impurities and Verapamil Hydrochloride Related Impurities procedures except for trandolapril related compound D and do not include the content of trandolapril related compound E.

5.2 Trandolapril Related Impurities, Procedure 2

[Note-Trandolapril Related Impurities, Procedure 2 is recommended when the formulation is a bi-layered Tablet.]

Diluent: Ethanol and water (50:50)

Solution A: Acetonitrile and isopropanol (25:75)

Solution B: Solution A, triethylamine, phosphoric acid, and water (20:0.1:0.1:80)

Solution C: Solution A, triethylamine, phosphoric acid, and water (40:0.1:0.1:60)

Mobile phase: See Table 6.

Table 6

Standard stock solution: 0.05 mg/mL each of USP Trandolapril Related Compound D RS and USP Trandolapril Related Compound E RS prepared as follows. Add about 50% of the volume of the flask of alcohol and then dilute with water to volume.

System suitability solution: 0.8 mg/mL of USP Verapamil Hydrochloride RS and 4 µg/mL each of USP Trandolapril Related Compound D RS and USP Trandolapril Related Compound E RS prepared as follows. Transfer a suitable quantity of USP Verapamil Hydrochloride RS and a suitable quantity of Standard stock solution to a suitable volumetric flask, and dilute with Diluent to volume.

Standard solution: 2 µg/mL each of USP Trandolapril Related Compound D RS and USP Trandolapril Related Compound E RS from the Standard stock solution in Diluent

Sample solution: Cut off the trandolapril layer of a sufficient number of Tablets with a tablet cutter or scalpel. Finely powder the trandolapril layer mixture using a mortar and pestle and transfer a suitable quantity of the powder to a suitable volumetric flask as described in Table 7.

Dissolve the mixture in a volume of Diluent per Table 7 and stir for about 10 min. Further sonication may be necessary for complete dissolution. Remove and rinse the stir bar with Diluent and dilute with Diluent to volume. Centrifuge the contents for about 10 min and use the supernatant. Pass through a suitable filter of 0.45-µm size.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 215 and 278 nm
• Column: 4.6-mm × 15-cm; 3-µm packing L1
• Temperatures
• Autosampler: 2°–8°
• Column: 45°
• Flow rate: 1 mL/min
• Injection volume: 100 µL
• Run time: NLT 3.0 times the retention time of trandolapril

System suitability

• Samples: System suitability solution and Standard solution
• Suitability requirements
• Resolution: NLT 2 between verapamil and trandolapril related compound E, System suitability solution
• Relative standard deviation: NMT 2.0% for both peaks, Standard solution

Analysis

Samples: Standard solution and Sample solution

Overlay the chromatograms at 215 nm and at 278 nm. Disregard any peaks detected in the chromatogram at 278 nm as verapamil related impurity peaks.

Calculate the percentage of trandolapril related compound D and trandolapril related compound E impurity in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of trandolapril related compound D or trandolapril related compound E from the Standard solution

Cₛ = concentration of USP Trandolapril Related Compound D RS or USP Trandolapril Related Compound E RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of trandolapril in the Sample solution (µg/mL)

Calculate the percentage of any unspecified impurity in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × (1/F) × 100

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

rₛ = peak response of trandolapril related compound D from the Standard solution

Cₛ = concentration of USP Trandolapril Related Compound D RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of trandolapril in the Sample solution (µg/mL)

F = relative response factor, 1.2

Acceptance criteria: See Table 8.

Table 8

ᵃ Total impurities include all process related and degradation impurities from Trandolapril Related Impurities, Procedure 2 except for trandolapril related compound D and trandolapril related compound E.

5.3 Content of Trandolapril Related Compound E

[Note-The Content of Trandolapril Related Compound E procedure is recommended when Trandolapril Related Impurities, Procedure 1 is used.]

Buffer: 2.72 g/L of monobasic potassium phosphate and 1.0 g/L of octane sulphonic acid. Adjust with 2% (v/v) phosphoric acid to a pH of 4.0.

Diluent 1: Acetonitrile and water (90:10)

Diluent 2: Acetonitrile and Buffer (20:80)

Mobile phase: See Table 9.

Table 9

Standard stock solution: 0.05 mg/mL of USP Trandolapril Related Compound E RS prepared as follows. Transfer a suitable amount of USP Trandolapril Related Compound E RS to a suitable volumetric flask and add methanol to about 5% of the total volume. Sonicate to dissolve, cool, and dilute with Diluent 2 to volume.

Standard solution: 0.5 µg/mL of USP Trandolapril Related Compound E RS in Diluent 2 from Standard stock solution

Sample stock solution: Nominally 0.3 mg/mL of trandolapril prepared as follows. Transfer a quantity nominally equivalent to 7.5 mg of trandolapril, from finely powdered Tablets (NLT 10), to a 25-mL volumetric flask, add 15 mL of Diluent 1, and sonicate for 15 min with intermittent swirling. Cool and dilute with Diluent 1 to volume.

Sample solution: Nominally 0.075 mg/mL of trandolapril in Buffer from Sample stock solution

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 210 nm
• Column: 4.0-mm × 10-cm; 3-µm packing L1
• Column temperature: 45°
• Flow rate: 1 mL/min
• Injection volume: 100 µL
• Run times: NLT 1.5 times and NLT 3.5 times the retention time of trandolapril related compound E for the Standard solution and the Sample solution, respectively

System suitability

• Sample: Standard solution
• Suitability requirements
• Relative standard deviation: NMT 5.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of trandolapril related compound E in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of trandolapril related compound E from the Sample solution

rₛ = peak response of trandolapril related compound E from the Standard solution

Cₛ = concentration of USP Trandolapril Related Compound E RS in the Standard solution (µg/mL)

Cᵤ = nominal concentration of trandolapril in the Sample solution (µg/mL)

Acceptance criteria: NMT 2.0%. Disregard peaks below 0.045%.

5.4 Verapamil Hydrochloride Related Impurities

Buffer: 6.8 g/L of monobasic potassium phosphate and 1.0 g/L of sodium 1-octane sulfonate. Adjust with phosphoric acid to a pH of 2.5.

Diluent: Acetonitrile, methanol, and water (25:25:50)

Mobile phase: Acetonitrile and Buffer (33:67)

Verapamil related compound B stock solution: 0.05 mg/mL of USP Verapamil Related Compound B RS in Diluent

System suitability solution: 1.25 mg/mL of USP Verapamil Hydrochloride RS and 5 µg/mL of USP Verapamil Related Compound B RS in Diluent. Initially add Diluent to USP Verapamil Hydrochloride RS to fill about 50% of the volume of the flask, and sonicate to dissolve. Cool and add appropriate quantities of Verapamil related compound B stock solution, then dilute with Diluent to volume.

Standard stock solution: 0.3 mg/mL of USP Verapamil Hydrochloride RS in Mobile phase. Initially add Mobile phase to about 70% of the volume of the flask, and sonicate to dissolve. Cool, and dilute with Mobile phase to volume.

Standard solution: 0.12 mg/mL of USP Verapamil Hydrochloride RS in Mobile phase from the Standard stock solution

Sample solution: Nominally 1.2 mg/mL of verapamil hydrochloride in Mobile phase prepared as follows. Transfer a quantity equivalent to 240 mg of verapamil hydrochloride, from finely powdered Tablets (NLT 10), to a 200-mL volumetric flask, add 150 mL of Mobile phase, and sonicate for 30 min with intermittent vigorous shaking. Cool, and dilute with Mobile phase to volume. Pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 278 nm
• Column: 4.0-mm × 10-cm; 3-µm packing L1
• Column temperature: 30°
• Flow rate: 1.2 mL/min
• Injection volume: 10 µL
• Run times: NLT 1.6 times the retention time of verapamil for the Standard solution, and NLT 3.0 times for the System suitability solution and the Sample solution

System suitability

• Samples: System suitability solution and Standard solution
• Suitability requirements
• Resolution: NLT 1.5 between verapamil related compound B and verapamil, System suitability 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 Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of each impurity from the Sample solution

rₛ = peak response of the verapamil from the Standard solution

Cₛ = concentration of USP Verapamil Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of verapamil hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: Disregard peaks below 0.02%.

• Any other individual unknown impurity: NMT 0.5%
• Total impurities: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Store in a well-closed container at 15°–25°.

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Trandolapril RS

USP Trandolapril Related Compound A RS

(2S,3aR,7aS)-1-[N-[(S)-1-Carboxy-3-phenylpropyl]-l-alanyl]hexahydro-2-indolinecarboxylic acid 1-methyl ester.

C₂₃H₃₂N₂O₅ 416.51

USP Trandolapril Related Compound D RS

(S)-Ethyl 2-[(3S,5aS,9aR,10aS)-3-methyl-1,4-dioxodecahydropyrazino[1,2-a]indol-2(1H)-yl)]-4-phenylbutanoate.

C₂₄H₃₂N₂O₄ 412.52

USP Trandolapril Related Compound E RS

(2S,3aR,7aS)-1-[N-[(S)-1-Carboxy-3-phenylpropyl]-l-alanyl]hexahydro-2-indolinecarboxylic acid.

C₂₂H₃₀N₂O₅ 402.48

USP Verapamil Hydrochloride RS

USP Verapamil Related Compound B RS

α-[2-[[2-(3,4-Dimethoxyphenyl)-ethyl]methylamino]ethyl]-3,4-dimethoxy-α-(1-methylethyl)-benzeneacetonitrile monohydrochloride.

C₂₆H₂₆N₂O₄ · HCl 477.05