Midodrine Hydrochloride 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

Midodrine Hydrochloride Tablets contain NLT 90.0% and NMT 105.0% of the labeled amount of Midodrine Hydrochloride (C₁₂H₁₈N₂O₄ · HCl).

2 IDENTIFICATION

2.1 A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

Sample specimen: Weigh a quantity, from finely powdered Tablets (NLT 20), equivalent to 15 mg of midodrine hydrochloride, into a 50-mL disposable centrifuge tube. Add 20 mL of water, and stir for 2 min using a vortex mixer. Pass the mixture through filter paper into a 50-mL beaker, and boil it until about 2 mL of the solution is left. Evaporate the final solution in an oven at 105° for 1 h.

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

3 ASSAY

3.1 Procedure

Buffer: 13.6 g/L of monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 4.00 ± 0.05.

Mobile phase: Acetonitrile and Buffer (3:22)

Standard solution: 0.05 mg/mL of USP Midodrine Hydrochloride RS in Mobile phase

Sample solution: 0.05 mg/mL of midodrine hydrochloride in Mobile phase from NLT 5 Tablets (for 10-mg Tablet strength) or NLT 10 Tablets (for 5-mg and 2.5-mg Tablet strength). Initially add Mobile phase up to 80% of the volume of the flask. Sonicate for 10 min, stir for 15 min, and then dilute to volume, mix, and let stand for 10 min. Pass through a suitable PVDF filter of 0.45-µm pore size, and discard the first 5 mL.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 290 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L1
• Flow rate: 1.0 mL/min
• Injection size: 20 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Column efficiency: NLT 3000 theoretical plates
• 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 midodrine hydrochloride (C₁₂H₁₈N₂O₄ · HCl) in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from the Standard solution

Cₛ = concentration of the Standard solution (mg/mL)

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

Acceptance criteria: 90.0%–105.0%

4 PERFORMANCE TESTS

Change to read:

4.1 Dissolution 〈711〉

4.1.1 Test 1

Medium: 0.1 N hydrochloric acid; 900 mL, deaerated

Apparatus 2: 50 rpm

Time: 15 min

Buffer: Proceed as directed in the Assay.

Mobile phase: Acetonitrile and Buffer (3:17)

Standard solution: L/900 mg/mL of USP Midodrine Hydrochloride RS in Medium, where L is the label claim in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 45-µm pore size.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 290 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L1
• Flow rate: 1.0 mL/min
• Injection size: 50 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Column efficiency: NLT 2000 theoretical plates
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of midodrine hydrochloride dissolved:

Result = (rᵤ/rₛ) × (Cₛ/L) × V × 100

rᵤ = peak area from the Sample solution

rₛ = peak area from the Standard solution

Cₛ = concentration of the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amount of midodrine hydrochloride is dissolved.

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

Medium: 0.1 N hydrochloric acid; 500 mL

Apparatus 2: 50 rpm

Time: 15 min

Buffer: Dissolve 13.6 g of monobasic potassium phosphate in 1000 mL of water. Adjust with 50% (v/v) of phosphoric acid in water to a pH of 4.0.

Mobile phase: Acetonitrile and Buffer (15:85)

Standard solution: (L/500) mg/mL of USP Midodrine Hydrochloride RS in Medium, where L is the label claim in mg/Tablet. Sonicate to dissolve if necessary.

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

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 290 nm
• Column: 4.6-mm × 15-cm; 5-µm packing L1
• Flow rate: 1.0 mL/min
• Injection volume: 50 µL
• Run time: NLT 2.1 times the retention time of midodrine

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 midodrine hydrochloride (C₁₂H₁₈N₂O₄ · HCl) dissolved:

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

rᵤ = peak response of midodrine from the Sample solution

rₛ = peak response of midodrine from the Standard solution

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

V = volume of Medium, 500 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of midodrine hydrochloride (C₁₂H₁₈N₂O₄ · HCl) is dissolved.

4.2 Uniformity of Dosage Units 〈905〉

Meet the requirements

5 IMPURITIES

Organic Impurities

5.1 Procedure

Buffer and Mobile phase: Proceed as directed in the Assay.

Standard stock solution 1: 25 µg/mL of USP Midodrine Hydrochloride RS in Mobile phase

Standard stock solution 2: 25 µg/mL of USP Midodrine Related Compound A RS in Mobile phase

Standard solution: 1.25 µg/mL each of USP Midodrine Hydrochloride RS and USP Midodrine Related Compound A RS in Mobile phase from Standard stock solution 1 and Standard stock solution 2

Sample solution: 0.25 mg/mL in Mobile phase from NLT 5 Tablets (for 10-mg Tablet strength) and NLT 10 Tablets (for 5-mg and 2.5-mg Tablet strength). Initially add Mobile phase to about 80% of the volume of the flask. Sonicate for 10 min, stir for 15 min, and then dilute to volume. Pass through a suitable PVDF filter of 0.45-µm pore size, and discard the first 5 mL.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Proceed as directed in the Assay except for the following:
• Injection volume: 40 µL

System suitability

• Sample: Standard solution
• [Note-The relative retention times for midodrine related compound A and midodrine hydrochloride are 0.83 and 1, respectively.]
• Suitability requirements
• Resolution: NLT 2.0 between midodrine hydrochloride and midodrine related compound A
• Column efficiency: NLT 2000 theoretical plates for the midodrine peak
• Tailing factor: NMT 2.0 for the midodrine peak
• Relative standard deviation: NMT 2.0% for the midodrine peak

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of midodrine related compound A in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of midodrine related compound A from the Sample solution

rₛ = peak response of midodrine related compound A from the Standard solution

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

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

Calculate the percentage of any other unknown impurity in the portion of Tablets taken:

Result = (rᵤ/rₛ) × (Cₛ/Cᵤ) × 100

rᵤ = peak response of any other unknown impurity from the Sample solution

rₛ = peak response of midodrine from the Standard solution

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

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

Acceptance criteria

Individual impurities: NMT 0.5% of midodrine related compound A; NMT 0.2% of any other individual impurity

Total impurities: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

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

USP Reference Standards 〈11〉

USP Midodrine Hydrochloride RS

USP Midodrine Related Compound A RS

2-Amino-1-(2,5-Dimethoxyphenyl)ethanol.

C₁₀H₁₅NO₃ 197.23