Dipivefrin Hydrochloride

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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C₁₉H₂₉NO₅ · HCI          387.90

Propanoic acid, 2,2-dimethyl-, 4-[1-hydroxy-2-(methylamino) ethyl]-1,2-phenylene ester, hydrochloride, (±);

(±)-3,4-Dihydroxy-a-[(methylamino) methyl benzyl alcohol 3,4-dipivalate hydrochloride CAS RN^®: 64019-93-8; UNII: 5QTH9UHV0K.

1 DEFINITION

Dipivefrin Hydrochloride contains NLT 98.5% and NMT 101.5% of dipivefrin hydrochloride (C₁₉H₂₉NO₅ · HCI), calculated on the dried basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K

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

C. IDENTIFICATION TESTS GENERAL, Chloride (191).

Sample solution: 10 mg/mL of Dipivefrin Hydrochloride

Acceptance criteria: Meets the requirements

3 ASSAY

3.1 PROCEDURE

Mobile phase: Acetonitrile, 0.014 M sodium dodecyl sulfate, and glacial acetic acid (24:15:1)

Standard solution: 5 mg/mL of USP Dipivefrin Hydrochloride RS in 0.0015 N hydrochloric acid

Sample solution: 5 mg/mL of Dipivefrin Hydrochloride in 0.0015 N hydrochloric acid

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 2 mL/min

Injection volume: 20 µL

3.1.2 System suitability

Sample: Standard solution

3.1.3 Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 0.6%

3.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of dipivefrin hydrochloride (C₁₉H₂₉NO₅ · HCI) in the portion of Dipivefrin Hydrochloride taken:

                Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response from the Sample solution r_{u} = 1

r_S = peak response from the Standard solution s

C_S = concentration of USP Dipivefrin Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Dipivefrin Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 98.5%-101.5% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281): NMT 0.3%

Change to read:

4.2 IRON (241), Procedures. Procedure 1 ▲(CN 1-JUN-2023)

Standard iron solution: Use the Standard Iron Solution prepared as directed in the chapter.

Hydroxylamine solution: 100 mg/mL of hydroxylamine hydrochloride in water

Triazine solution: 1.25 mg/mL of 2,4,6-tri-(2-pyridyl)-S-triazine in methanol

Standard solution: Into a 50-mL color-comparison tube pipet 1 mL of Standard iron solution, add 42.0 mL of water, and mix.

Sample solution: Into a 50-mL color-comparison tube add 2.0 g of Dipivefrin Hydrochloride, 43.0 mL of water, and mix.

Analysis: To each of the tubes containing the Standard solution and the Sample solution add 5.0 mL of Hydroxylamine solution and 2.0 mL of Triazine solution, and mix.

Acceptance criteria: NMT 5 ppm; the color of the solution from the Sample solution is not darker than that of the solution from the Standard solution.

4.3 LIMITS OF EPINEPHRINE AND ADRENALONE

Protect the Standard solution and the Sample solution from light.

Solution A: 0.1% (v/v) Anhydrous formic acid in water

Solution B: Acetonitrile and methanol (60:40)

Mobile phase: See Table 1. Return to the original conditions and re-equilibrate the system.

Table 1

Diluent: 0.01 M hydrochloric acid

Standard solution: 0.02 mg/mL of USP Epinephrine Bitartrate RS and 0.01 mg/mL of USP Adrenalone Hydrochloride RS in Diluent.

Sample solution 10.0 mg/mL of Dipivefrin Hydrochloride in Diluent

4.3.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 260 nm

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

Flow rate: 1 mL/min

Injection volume: 10 µL

4.3.2 System suitability

Sample: Standard solution

4.3.3 Suitability requirements

Resolution: NLT 2.0 between epinephrine and adrenalone

Relative standard deviation: NMT 5%

4.3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of epinephrine in the portion of Dipivefrin Hydrochloride taken:

                Result = (r_U/r_S) x (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of epinephrine from the Sample solution

r_S = peak response of epinephrine from the Standard solution s

C_S = concentration of USP Epinephrine Bitartrate RS in the Standard solution (mg/mL) 

C_U = concentration of Dipivefrin Hydrochloride in the Sample solution (mg/mL) 

M_r1 = molecular weight of epinephrine, 183.20

M_r2 = molecular weight of epinephrine bitartrate, 333.29

Calculate the percentage of adrenalone in the portion of Dipivefrin Hydrochloride taken:

                Result = (r_U/r_S) x (C_S/C_U) × (M_r1/M_r2) × 100

r_U = peak response of adrenalone from the Sample solution

r_S = peak response of adrenalone from the Standard solution

C_S = concentration of USP Adrenalone Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Dipivefrin Hydrochloride in the Sample solution (mg/mL)

M_r1 = molecular weight of adrenalone, 181.19

M_r2 = molecular weight of adrenalone hydrochloride, 217.65 12

Acceptance criteria: See Table 2.

Table 2

^a 4-1[-Hydroxy-2-(methylamino) ethylbenzene-1,2-diol.

^b This impurity is a racemate of epinephrine (also known as racepinephrine or [±] adrenaline).

^c 3',4'-Dihydroxy-2-(methylamino)acetophenone.

5 ORGANIC IMPURITIES

Solution A: Acetonitrile and methanol (60:40)

Solution B: 2.7 g/L of ammonium hydroxide, adjusted with 2 M acetic acid to a pH of 10.0

Mobile phase: Solution A and Solution B (55:45)

Diluent: Solution A and 0.01 M hydrochloric acid (55:45)

System suitability solution: 10 mg/mL of USP Dipivefrin Hydrochloride RS and 10 µg/mL of USP Dipivefrin Related Compound ERS in Diluent

Standard solution: 10 µg/mL each of USP Dipivefrin Hydrochloride RS and USP Dipivefrin Related Compound E RS in Diluent

Sample solution: 10 mg/mL of Dipivefrin Hydrochloride in Diluent

4.3.5 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 260 nm

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

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: 2.5 times the retention time of dipivefrin

4.3.6 System suitability

Samples: System suitability solution and Standard solution

4.3.7 Suitability requirements

Resolution: NLT 3.0 between dipivefrin and dipivefrin related compound E, System suitability solution

Relative standard deviation: NMT 5% for the dipivefrin peak, Standard solution

4.3.8 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of dipivefrin related compound E in the portion of Dipivefrin Hydrochloride taken:

                Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of dipivefrin related compound E from the Sample solution 

r_S = peak response of dipivefrin related compound E from the Standard solution 

C_S = concentration of USP Dipivefrin Related Compound E RS in the Standard solution (mg/mL)

C_U = concentration of Dipivefrin Hydrochloride in the Sample solution (mg/mL)

Calculate the percentage of any other individual impurity in the portion of Dipivefrin Hydrochloride taken:

                Result = (r_U/r_S) x (C_S/C_U) × (1/F) x 100

r_U = peak response of each impurity from the Sample solution

r_S = peak response of dipivefrin from the Standard solution

C_S = concentration of USP Dipivefrin Hydrochloride RS in the Standard solution (mg/mL)

C_U = concentration of Dipivefrin Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. Disregard any impurity peak less than 0.05%.

Table 3

^a 2-Hydroxy-5-[1-hydroxy-2-(methylamino) ethyl]phenyl pivalate.

^b 2-Hydroxy-4-[1-hydroxy-2-(methylamino)ethyl]phenyl pivalate.

^c 5-Pivaloyl racepinephrine and 4-Pivaloyl racepinephrine coelutes.

^d 4-[(Methylamino) acetyl]-1,2-phenylene dipivalate.

^e 4-(2-[Ethyl(methyl)amino]-1-hydroxyethyl)-1,2-phenylene dipivalate.

6 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry in a suitable vacuum drying tube over phosphorus pentoxide at 60° for 6 h.

Acceptance criteria: NMT 1.0%

7 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers.

USP REFERENCE STANDARDS (11).

USP Adrenalone Hydrochloride RS

3',4'-Dihydroxy-2-(methylamino)acetophenone hydrochloride.

C₉H₁₁NO₃ · HCI            217.65

USP Dipivefrin Hydrochloride RS

USP Digivefrin Related Compound ERS

4-[(Methylamino)acetyl)-1,2-phenylene dipivalate hydrochloride.

C₁₉H₂₇NO₅ · HCI              385.88

USP Epinephrine Bitartrate RS         C₉H₁₃NO₃ · H₄C₆O₆              333.29