Haloperidol Tablets

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

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

DOWNLOAD PDF HERE

1 DEFINITION

Haloperidol Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of haloperidol (C₂₁H₂₃CIFNO₂).

2 IDENTIFICATION

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

Add the following:

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay (USP 1-May-2021)

3 ASSAY

Change to read:

3.1 PROCEDURE

Buffer: Dissolve 6.8 g of monobasic potassium phosphate in 1 L of water (USP 1-May-2021)

Mobile phase: Methanol and Buffer (USP 1-May-2021) (60:40). Adjust with 1 N sodium hydroxide or phosphoric acid to a pH of 4.0.

Standard solution: 0.1 mg/mL of USP Haloperidol RS in Mobile phase

Sample solution: Nominally 0.1 mg/mL of haloperidol from Tablets (USP 1-May-2021) prepared as follows. Transfer an equivalent of about 10 mg of haloperidol from finely powdered Tablets (NLT 20) to a 100-mL volumetric flask. Add 60 mL of Mobile phase, sonicate with occasional shaking for 30 min. Dilute with Mobile phase to volume. Pass the solution through a filter of suitable pore size, discarding the first 1 mL of the filtrate. (USP 1-May-2021)

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification B, use a diode array detector in the range of 200-400 nm. (USP 1-May-2021)

Column: 4.6-mm × 25-cm; 5-µm (USP 1-May-2021) packing L1

Column temperature: 30° (USP 1-May-2021)

Flow rate: 1 mL/min

Injection volume: 15 µL

Run time: NLT 2 times the retention time of haloperidol (USP 1-May-2021)

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0% (USP 1-May-2021)

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of haloperidol (C₂₁H₂₃CIFNO₂) in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of the Sample solution

r_S = peak response of the Standard solution

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

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

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711)

Medium: Simulated gastric fluid TS without enzyme; 900 mL

Apparatus 1: 100 rpm

Time: 60 min

Buffer and (USP 1-May-2021) Mobile phase: Prepare as directed in the Assay.

Standard solution: A known concentration of USP Haloperidol RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium, if necessary, to a concentration that is similar to that of the Standard solution.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; 5-µm (USP 1-May-2021) packing L1

Column temperature: 30° (USP 1-May-2021)

Flow rate: 1 mL/min

Injection volume: 50 µL

Run time: NLT 2 times the retention time of haloperidol (USP 1-May-2021)

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of haloperidol (C₂₁H₂₃CIFNO₂) dissolved:

Result = (r_U/r_S) x (C_S/L) x V x 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

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

L = label claim (mg/Tablet)

V = volume of Medium (900 mL) (USP 1-May-2021)

Tolerances: NLT 80% (Q) of the labeled amount of haloperidol (C₂₁H₂₃CIFNO₂) is dissolved.

Change to read:

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

(USP 1-May-2021)

5 IMPURITIES

Add the following:

ORGANIC IMPURITIES

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

Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Diluent: Solution A and Solution B (50:50)

System suitability solution: 1 mg/mL of USP Haloperidol RS, 0.02 mg/mL of USP Haloperidol Related Compound A RS, and 0.003 mg/mL of USP Haloperidol Related Compound B RS in Diluent

Sensitivity solution: 0.001 mg/mL of USP Haloperidol RS in Diluent

Standard solution: 0.002 mg/mL of USP Haloperidol RS in Diluent

Sample solution: Nominally 1.0 mg/mL of haloperidol in Diluent prepared as follows. Transfer Tablets (NLT 20) to a suitable volumetric flask. Add 50%-75% of the flask volume of Diluent and sonicate for NLT 15 min. Then stir for about 15 min. Allow the solution to cool.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm x 10-cm; 3.5-µm packing L1

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

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

[NOTE-See Table 2 for the relative retention times. The peak eluting at a relative retention time of 1.37 is cis-haloperidol-N-oxide. Its IUPAC name is 4-[cis-4-(4-chlorophenyl)-4-hydroxy-1-oxido-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone.]

Suitability requirements

Peak-to-valley ratio: NLT 50 for the ratio of the height of the haloperidol related compound B peak to the height of the valley between the haloperidol related compound B and haloperidol peaks, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each degradation product in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of each degradation product from the Sample solution

r_S = peak response from the Standard solution

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

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

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

^a Process impurity controlled in drug substance and not included in the total degradation products.

^b 4-(4-Chlorophenyl)piperidin-4-ol.

^c 4-[4-(4-Chlorophenyl)-4-hydroxy-1-oxido-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone.

^d 4-Chloro-1-(4-fluorophenyl)butan-1-one.

6 ADDITIONAL REQUIREMENTS

Change to read:

6.1 PACKAGING AND STORAGE

Preserve in tight, light-resistant containers. Store at controlled room temperature. (USP 1-May-2021)

Change to read:

6.2 USP REFERENCE STANDARDS (11)

USP Haloperidol RS

USP Haloperidol Related Compound A RS

4,4'-Bis[4-p-chlorophenyl)-4-hydroxypiperidino]butyrophenone.

C₃₂H₃₆CI₂N₂O₃ 567.56

USP Haloperidol Related Compound B RS

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

C₂₁H₂₃CIFNO₂ 375.86(USP 1-May-2021)