Haloperidol

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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C₂₁H₂₃CIFNO₂ 375.87 (USP 1-May-2021)

1-Butanone, 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-;

4-[4-(p-Chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone;

4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one. (USP 1-May-2021)

CAS RN^®: 52-86-8; UNII: J6292F8L3D.

1 DEFINITION

Haloperidol contains NLT 98.0% and NMT 102.0% of haloperidol (C₂₁H₂₃CIFNO₂), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K or 197A (USP 1-May-2021)

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the test for Organic Impurities.

3 ASSAY

Change to read:

3.1 PROCEDURE

Protect solutions containing haloperidol from light.

Solution A: 6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 4.0.

Solution B: Methanol

Mobile phase: See Table 1.

Table 1

Diluent: Methanol

System suitability solution: 0.2 mg/mL of USP Haloperidol RS and 0.02 mg/mL of USP Haloperidol Related Compound B RS in Diluent

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

Sample solution: 0.2 mg/mL of Haloperidol in Diluent

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 247 nm

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

Flow rate: 0.8 mL/min

Injection volume: 10 µL

3.3 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for haloperidol related compound B and haloperidol are 0.85 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.5 between the haloperidol related compound B and haloperidol peaks, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 0.73%, Standard solution

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of haloperidol (C₂₁H₂₃CIFNO₂) in the portion of Haloperidol taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of haloperidol from the Sample solution

r_S = peak response of haloperidol from the Standard solution

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

C_U = concentration of Haloperidol in the Sample solution (mg/mL) (USP 1-May-2021)

Acceptance criteria: 98.0%-102.0% on the dried basis

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

NMT 0.1%

Change to read:

4.2 ORGANIC IMPURITIES

Prepare the solutions immediately before use, and protect solutions containing haloperidol (USP 1-May-2021) from light.

Solution A: 17 g/L of tetrabutylammonium hydrogen sulfate in water (USP 1-May-2021)

Solution B: Acetonitrile

Mobile phase: See Table 2.

Table 2 (USP 1-May-2021)

System suitability solution: 10 mg/mL of USP Haloperidol RS and 20 µg/mL each of USP Haloperidol Related Compound A RS and USP Haloperidol Related Compound B RS in methanol. [NOTE-Haloperidol related compound A is used for identification purposes only.]

Sensitivity solution: 5 µg/mL of USP Haloperidol RS in methanol (USP 1-May-2021)

Standard solution: 0.01 mg/mL (USP 1-May-2021) of USP Haloperidol RS in methanol

Sample solution: 10 mg/mL of Haloperidol in methanol

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 10-cm; 3-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution, Sensitivity solution, and Standard solution

[NOTE-The relative retention times for the peaks are given in Table 3.1 (USP 1-MAY-2021)

Suitability requirements

Resolution: NLT 3.0 between haloperidol related compound B and haloperidol, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution (USP 1-May-2021)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of any individual impurity in the portion of Haloperidol taken:

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

r_U = peak response of an individual impurity from the Sample solution

r_S = peak response of haloperidol from the Standard solution

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

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

F = relative response factor (see Table 3) (USP 1-May-2021)

Acceptance criteria: See Table 3. The reporting threshold is 0.05%.

Table 3 (USP 1-May-2021)

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry a sample under vacuum at 60° for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in tight, light-resistant containers. Store at room temperature.

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Haloperidol RS

USP Haloperidol Related Compound A RS

4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-1-{4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]phenyl}butan-1-one; also known as (USP 1-May-2021) 4,4'-Bis[4-p-chlorophenyl)-4-hydroxypiperidino]butyrophenone.

C₃₂H₃₆CI₂N₂O₃ 567.55(USP 1-May-2021)

USP Haloperidol Related Compound B RS

4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(2-fluorophenyl)butan-1-one.

C₂₁H₂₃CIFNO₂ 375.87(USP 1-May-2021)