Methylphenidate 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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1 DEFINITION

Methylphenidate Hydrochloride contains NLT 98.0% and NMT 102.0% of methylphenidate hydrochloride (C₁₄H₁₉NO₂ · HCl), calculated on the dried basis.

2 IDENTIFICATION

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

B. Identification Tests—General 〈191〉, Chemical Identification Tests, Chloride: Meets the requirements

C. 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

Procedure

Buffer: 2.7 g/L of monobasic potassium phosphate

Mobile phase: Methanol and Buffer (1:2). Adjust with phosphoric acid to a pH of 4.6 ± 0.1.

System suitability solution: 0.005 mg/mL of USP Methylphenidate Related Compound A RS and 0.5 mg/mL of USP Methylphenidate

Hydrochloride RS in Mobile phase

Standard solution: 0.5 mg/mL of USP Methylphenidate Hydrochloride RS in Mobile phase

Sample solution: 0.5 mg/mL of Methylphenidate Hydrochloride in Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 209 nm

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

Flow rate: 1.0 mL/min

Injection volume: 10 µL

Run time: NLT 2 times the retention time of methylphenidate

System suitability

Sample: System suitability solution

Suitability requirements

Resolution: NLT 2.5 between methylphenidate related compound A and methylphenidate

Tailing factor: NMT 3.0 for methylphenidate

Relative standard deviation: NMT 2.0% for methylphenidate

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of methylphenidate hydrochloride (C₁₄H₁₉NO₂ · HCl) in the portion of Methylphenidate Hydrochloride taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

rᵤ = peak response from the Sample solution

rₛ = peak response from the Standard solution

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

Cᵤ = concentration of Methylphenidate Hydrochloride in the Sample solution (mg/mL)

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities, Procedure 1

Buffer, Mobile phase, System suitability solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed

in the Assay.

Analysis

Sample: Sample solution

Identify each impurity using the relative retention times in Table 1.

Calculate the percentage of each impurity in the portion of Methylphenidate Hydrochloride taken:

Result = (rᵤ / rₜ) × 100

rᵤ = peak response of each impurity from the Sample solution

rₜ = sum of the responses of all impurity peaks including the methylphenidate peak from the Sample solution

Acceptance criteria: See Table 1. The reporting threshold is 0.05%.

Table 1

ᵃ (RS)-Methyl-2-phenyl-2-[(SR)-piperidin-2-yl] acetate.

Organic Impurities, Procedure 2

[Note—Perform this test only if ethylphenidate or all-rac-dimethyl 2,2′-(piperidine-1,2-diyl)bis(2-phenylacetate) is a known process impurity.]

Buffer A: 5.7 g of monobasic ammonium phosphate and 1.6 g of octanesulfonic acid sodium salt in 1 L of water

Buffer B: Add 4 mL of triethylamine to 1 L of Buffer A. Adjust with phosphoric acid to a pH of 2.9.

Solution A: Acetonitrile and Buffer B (14:86)

Solution B: Acetonitrile and Buffer A (80:20)

Mobile phase: See Table 2.

Table 2

[Note—Equilibration of the chromatographic system at the initial conditions for a minimum of 30 min is recommended before the first injection.]

System suitability solution: 0.5 mg/mL of USP Methylphenidate Hydrochloride RS and 3 µg/mL each of USP Methylphenidate Related

Compound A RS, phenylacetic acid, and USP Methylphenidate Hydrochloride Erythro Isomer Solution RS in Solution A

Standard solution: 0.5 µg/mL of USP Methylphenidate Hydrochloride RS in Solution A

Sample solution: 0.5 mg/mL of Methylphenidate Hydrochloride in Solution A. [Note—Allow the solution to stand for at least 2 h.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 3.9-mm × 15-cm; 5-µm packing L7

Column temperature: 40°

Flow rate: 2.8 mL/min

Injection volume: 10 µL

System suitability

Sample: System suitability solution

[Note—See Table 3 for the relative retention times.]

Suitability requirements

Resolution: NLT 2.7 between methylphenidate related compound A and phenylacetic acid; NLT 3.6 between phenylacetic acid and erythro

isomer

Tailing factor: NMT 2.0 for methylphenidate

Relative standard deviation: NMT 2.0% for methylphenidate; NMT 5.0% for methylphenidate related compound A, phenylacetic acid, and

Methylphenidate hydrochloride erythro isomer

Analysis

Samples: Standard solution and Sample solution

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

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (1 / F) × 100

rᵤ = peak response of each individual impurity from the Sample solution

rₛ = peak response of methylphenidate from the Standard solution

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

Cᵤ = concentration of Methylphenidate Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 3)

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

Table 3

ᵃ (RS)-Methyl-2-phenyl-2-[(SR)-piperidin-2-yl] acetate.

ᵇ Ethyl(RS)-2-phenyl-2-[(RS)-piperidin-2-yl]acetate.

ᶜ all-rac-Dimethyl 2,2′-(piperidine-1,2-diyl)bis(2-phenylacetate).

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry under vacuum at 60° for 4 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers.

Labeling: If a test for Organic Impurities other than Procedure 1 is used, then the labeling states the procedure with which the article complies.

Change to read:

USP Reference Standards 〈11〉

USP Methylphenidate Hydrochloride RS

USP Methylphenidate Hydrochloride Erythro Isomer Solution RS

This solution contains 0.5 mg/mL of methylphenidate hydrochloride erythro isomer in methanol.

USP Methylphenidate Related Compound A RS

▲(RS)-2-Phenyl-2-[(RS)-piperidin-2-yl]acetic acid hydrochloride.▲ (ERR 1-Jun-2023)

C₁₃H₁₇NO₂ · HCl 255.74