Diphenhydramine Citrate and Ibuprofen 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

Diphenhydramine Citrate and Ibuprofen Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of diphenhydramine citrate (C₁₇H₂₁NO · C₆H₈O₇) and ibuprofen (C₁₃H₁₈O₂)

2 IDENTIFICATION

A. The retention times of the diphenhydramine and ibuprofen peaks from the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 PROCEDURE

Buffer A: 6.9 g/L of monobasic sodium phosphate in water

Buffer B: 6.9 g/L of monobasic sodium phosphate in water. Adjust with triethylamine to a pH of 7.2.

Mobile phase: Acetonitrile, triethylamine, glacial acetic acid, and Buffer A (45:0.2:0.2:55)

Diluent: Acetonitrile and Buffer B (3:2)

Standard solution: 1.1 mg/mL of USP Diphenhydramine Citrate RS and 5.7 mg/mL of USP Ibuprofen RS in Diluent. [NOTE-Sonicate as necessary.)

Sample solution: Transfer 10 Tablets into a suitable volumetric flask, add 350 mL of Diluent, and shake with a rotary shaker for 20 min.

Sonicate for 20 min with intermediate shaking to obtain a solution containing about 1.1 mg/mL of diphenhydramine citrate and 5.7 mg/mL of ibuprofen. Centrifuge an aliquot at 4000 rpm for 10 min, and use the supernatant. [NOTE-Do not dilute to volume.]

3.1.1 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: 1.2 mL/min

Injection size: 20 µL

Run time: 1.3 times the retention time of ibuprofen

3.1.2 System suitability

Sample: Standard solution

3.1.3 Suitability requirements

Tailing factor: NMT 2.0 for both diphenhydramine and ibuprofen

Relative standard deviation: NMT 2.0% for both diphenhydramine and ibuprofen

3.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of diphenhydramine citrate (C₁₇H₂₁NO · C₆H₈O₇) and ibuprofen (C₁₃H₁₈O₂) in the portion of Tablets taken: 

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

r_U = peak response of the corresponding analyte from the Sample solution

r_S = peak response of the corresponding analyte from the Standard solution

C_S = concentration of the appropriate USP Reference Standard in the Standard solution (mg/mL)

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

Acceptance criteria: 90.0%-110.0% for both diphenhydramine citrate and ibuprofen

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

Medium: pH 6.5 phosphate buffer (Transfer 250 mL of 0.2 M monobasic potassium phosphate and 58 mL of 0.2 M sodium hydroxide to a 1000-mL volumetric flask, and dilute with water to volume.); 900 mL, deaerated

Apparatus 2: 50 rpm

Time: 30 min

Buffer solution: 6.9 g/L of sodium dihydrogen phosphate monohydrate in water

Ibuprofen standard stock solution: 1.1 mg/ml. of USP Ibuprofen RS in acetonitrile

Diphenhydramine citrate standard stock solution: 1.1 mg/mL of USP Diphenhydramine Citrate RS in water

Standard solution: Transfer 5 mL of the Ibuprofen standard stock solution and 1 mL of Diphenhydramine citrate standard stock solution to a 25-mL volumetric flask, and dilute with Medium to volume.

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

Mobile phase: Acetonitrile, triethylamine, glacial acetic acid, and Buffer solution (45:0.2:0.2:55)

4.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1.2 mL/min

Injection size: 20 µL

4.1.2 System suitability

Sample: Standard solution

4.1.3 Suitability requirements

Tailing factor: NMT 2.0 for both diphenhydramine and ibuprofen

Relative standard deviation: NMT 2.0% for both diphenhydramine and ibuprofen

4.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of diphenhydramine and ibuprofen dissolved:

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

r_U = peak response of ibuprofen or diphenhydramine from the Sample solution

r_S = peak response of ibuprofen or diphenhydramine from the Standard solution s

C_S = concentration of ibuprofen or diphenhydramine in the Standard solution

L = label claim for ibuprofen or diphenhydramine (mg/Tablet)

V = volume of Medium, 900 mL

Tolerances: NLT 80% (Q) of the labeled amounts of diphenhydramine and ibuprofen are dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

5.1 ORGANIC IMPURITIES

Buffer A: 1 mL of phosphoric acid in 1 L of water. Adjust with triethylamine to a pH of 3.2.

Buffer B: 1 mL of phosphoric acid and 1.0 g of monobasic potassium phosphate in 1 L of water. Adjust with triethylamine to a pH of 3.7.

Solution A: Acetonitrile and Buffer A (1:4)

Solution B: Acetonitrile and Buffer B (1:1)

Mobile phase: See Table 1.

Table 1

Standard solution: 0.004 mg/mL of USP Diphenhydramine Citrate RS and 0.02 mg/mL of USP Ibuprofen RS in Solution B

System suitability solution: 0.004 mg/mL of USP Diphenhydramine Related Compound A RS, 0.8 mg/mL of USP Diphenhydramine Citrate RS, and 4 mg/mL of USP Ibuprofen RS in Solution B

Sample solution: Transfer an amount of powder from ground Tablets (NLT 20) to a suitable volumetric flask. Add 70% of the flask volume of Solution B, sonicate for 20 min and dilute with Solution B to volume to obtain a solution containing about 0.8 mg/mL of diphenhydramine citrate and 4 mg/mL of ibuprofen. Centrifuge an aliquot at 4000 rpm for 10 min, and use the supernatant.

5.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1 mL/min

Injection size: 10 µL

5.1.2 System suitability

Samples: Standard solution and System suitability solution

5.1.3 Suitability requirements

Resolution: NLT 0.8 between diphenhydramine and diphenhydramine related compound A, System suitability solution

Tailing factor: NMT 2.0 for both diphenhydramine and ibuprofen, Standard solution

Relative standard deviation: NMT 5.0% for both diphenhydramine and ibuprofen, Standard solution

5.1.4 Analysis

Samples: Standard solution and Sample solution

Identify the ibuprofen and diphenhydramine impurities using the relative retention times given in Table 2. Calculate the percentage of each diphenhydramine impurity and unspecified impurities in the portion of Tablets taken:

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of diphenhydramine from the Standard solution s

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

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

F = relative response factor (see Table 2)

Calculate the percentage of the ibuprofen related impurity in the portion of Tablets taken:

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

r_U = peak response of the ibuprofen related impurity from the Sample solution

r_S = peak response of ibuprofen from the Standard solution

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

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

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2.

Table 2

^a 2-(Diphenylmethoxy)-N-methylethanamine.

^b Process impurity provided for information only; the content is not calculated and not reported.

^c 2-p-Tolylpropanoic acid.

^d (Bromomethylene)dibenzene.

^e 2-(4-Isobutylphenyl) propanamide.

^f 2-(4-Isopropylphenyl)propanoic acid.

^g 2-(4-Propylphenyl)propanoic acid.

^h 2-(3-Isobutylphenyl)propanoic acid.

ⁱ 2-(4-Butylphenyl)propanoic acid.

^j Exclude peaks that elute before 4 min or after 80 min.

^k Total impurities excludes ibuprofen related compound C.

5.2 LIMIT OF IBUPROFEN RELATED COMPOUND C

Buffer: 10 g/L of chloroacetic acid in water. Adjust with ammonium hydroxide to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (3:2)

Internal standard solution: 0.35 mg/mL of valerophenone in Mobile phase

Standard stock solution: 0.6 mg/mL of USP Ibuprofen Related Compound C RS in acetonitrile

Standard solution: 0.012 mg/mL of USP Ibuprofen Related Compound C. RS in Internal standard solution; prepared by diluting 2 mL of Standard stock solution with Internal standard solution to 100 mL

Sample solution: Transfer an amount of powder equivalent to 1200 mg of ibuprofen from ground Tablets (NLT 20) to a suitable volumetric flask. Add 100 mL of Internal standard solution, and sonicate for 20 min to obtain a solution containing about 12 mg/mL of ibuprofen. Pass through a suitable filter, and use the filtrate. [NOTE-Do not dilute to volume.]

5.2.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 2 mL/min

Injection size: 5 µL

5.2.2 System suitability

Sample: Standard solution

[NOTE-The relative retention times for valerophenone and ibuprofen related compound C are 0.86 and 1.0, respectively.]

5.2.3 Suitability requirements

Tailing factor: NMT 2.5 for both valerophenone and ibuprofen related compound C

Relative standard deviation: NMT 2.0%

Resolution: NLT 2.5 between the valerophenone and ibuprofen related compound C peaks

5.2.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ibuprofen related compound C (C₁₂H₁₆O) in the portion of Tablets taken:

                Result = (R_U/R_S) x (C_S/C_U) × 100

R_U = peak area ratio of ibuprofen related compound C to valerophenone from the Sample solution

R_S = peak area ratio of ibuprofen related compound C to valerophenone from the Standard solution

C_S = concentration of USP Ibuprofen Related Compound C. RS in the Standard solution (mg/mL)

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

Acceptance criteria: NMT 0.1% of ibuprofen related compound C

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers. Store at controlled room temperature.

USP REFERENCE STANDARDS (11)

USP Diphenhydramine Citrate RS

USP Diphenhydramine Related Compound A RS

2-(Diphenylmethoxy)-N-methylethanamine hydrochloride.

C₁₆H₁₉NO · HCI               277.79

USP Ibuprofen RS

USP Ibuprofen Related Compound C RS

4-Isobutylacetophenone.

C₁₂H₁₆O           176.25