Tiagabine 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

Tiagabine Hydrochloride contains NLT 97.5% and NMT 102.5% of tiagabine hydrochloride (C₂₀H₂₅NO₂S₂ · HCl), calculated on the anhydrous basis.

2 IDENTIFICATION

A. SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉 , Infrared Spectroscopy: 197K

Sample: Transfer about 5 mg of Tiagabine Hydrochloride to a test tube. Add 4 mL of 2-propanol, and sonicate to dissolve, if necessary. Evaporate the solvent under inert atmosphere at 50°, using a nitrogen evaporator, for 2 h.

Analysis: The IR spectrum of the Sample corresponds to that of a similarly prepared USP Tiagabine Hydrochloride RS. Acceptance criteria: Meets the requirements

B. 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

Solution A: 1.38 g/L of monobasic sodium phosphate. Adjust with phosphoric acid to a pH of 2.0. Mobile phase: Acetonitrile and Solution A (35:65)

Diluent: Methanol and water (50:50)

Internal standard solution: 0.4 mg/mL of butylparaben in Diluent

Standard stock solution: 1 mg/mL of USP Tiagabine Hy drochloride RS in Diluent

Standard solution: 0.1 mg/mL of USP Tiagabine Hydrochloride RS and 0.04 mg/mL of butylparaben in Diluent prepared as follows. Transfer suitable volumes of the Standard stock solution and Internal standard solution into a suitable volumetric flask and dilute with Diluent to volume.

Sample stock solution: 1 mg/mL of Tiagabine Hydrochloride in Diluent

Sample solution: 0.1 mg/mL of Tiagabine Hydrochloride and 0.04 mg/mL of butylparaben in Diluent prepared as follows. Transfer suitable volumes of the Sample stock solution and Internal standard solution into a suitable volumetric flask and dilute with Diluent to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 3.5 times the retention time of tiagabine

System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 5.5 between tiagabine and butylparaben

Relative standard deviation: NMT 1.5% for the peak response ratios

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tiagabine hydrochloride (C₂₀H₂₅NO₂S₂ · HCl) in the portion of Tiagabine Hydrochloride taken:

Result = (R_U/R_S) × (C_S/C_U) × 100

R_U = peak area ratio of tiagabine hydrochloride to the internal standard from the Sample solution

R_S = peak area ratio of tiagabine hydrochloride to the internal standard from the Standard solution

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

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

Acceptance criteria: 97.5%–102.5% on the anhydrous basis

4 IMPURITIES

RESIDUE ON IGNITION 〈281〉: NMT 0.2%

LIMIT OF (S)-(+) ISOMER

Mobile phase: n-Hexane, isopropyl alcohol, alcohol, and trifluoroacetic acid (80: 14: 6: 0.5). [NOTE—Increase or decrease the percentage of n- hexane or alcohol, but keep the percentage of isopropyl alcohol constant. Make other adjustments, if necessary (see Chromatography

〈 621〉, System Suitability).]

Standard solution: 0.1 mg/mL of USP Racemic Tiagabine Hydrochloride Mixture RS prepared as follows. Transfer a suitable quantity of USP Racemic Tiagabine Hydrochloride Mixture RS into a suitable volumetric flask, dissolve in a few drops of methanol, and dilute with isopropyl alcohol to volume.

Sample solution: 2 mg/mL of Tiagabine Hydrochloride prepared as follows. Transfer a suitable quantity of Tiagabine Hydrochloride in a suitable volumetric flask, dissolve in a few drops of methanol, and dilute with isopropyl alcohol to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm × 25-cm; 10-µm packing L40

Flow rate: 0.8 mL/min

Injection volume: 10 µL

Run time: NLT 1.5 times the retention of the (R)-(−) isomer

System suitability

Sample: Standard solution

[NOTE—The relative retention times of the (S)-(+) isomer and the (R)-(−) isomer are about 0.76 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between the (S)-(+) and (R)-(−) isomers

Analysis

Sample: Sample solution

Calculate the percentage of the (S)-(+) isomer in the portion of Tiagabine Hydrochloride taken:

Result = (r_U/r_T) × 100

r_U = peak response of the (S)-(+) isomer from the Sample solution

r_T = sum of the peak responses of the (S)-(+) isomer and (R)-(−) isomer from the Sample solution

Acceptance criteria: NMT 0.5%

ORGANIC IMPURITIES

Solution A: Water adjusted with phosphoric acid to a pH of 2.3 Solution B: Acetonitrile

Mobile phase: See Table 1.

Table 1

Standard stock solution: 1 mg/mL of USP Tiagabine Hydrochloride RS in water

Standard solution: 0.001 mg/mL of USP Tiagabine Hy drochloride RS in water from the Standard stock solution System suitability stock solution: 1 mg/mL of USP Tiagabine Related Compound A RS in water

System suitability solution: 0.1 mg/mL each of USP Tiagabine Hy drochloride RS and USP Tiagabine Related Compound A RS in water prepared from Standard stock solution and System suitability stock solution

Sample solution: 1 mg/mL of Tiagabine Hydrochloride in water

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Samples: Standard solution and System suitability solution

Suitability requirements

Resolution: NLT 9.0 between tiagabine hydrochloride and tiagabine related compound A, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Sample: Sample solution

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

Result = (r_U/r_T) × (1/F) × 100

r_U = peak response of each impurity from the Sample solution

r_T = sum of all the peak responses, excluding the solvent peaks, from the Sample solution

F = relative response factor for each impurity (see Table 2)

Acceptance criteria: See Table 2.

Table 2

^a (3R)-1-[3,4-Dihydroxy-4,4-bis(3-methylthiophen-2-yl)butyl]piperidine-3-carboxylic acid.

^b (R)-1-[4,4-Bis(3-methylthiophen-2-yl)-3-oxobutyl]piperidine-3-carboxylic acid.

^c (R,ZE)-1-[4-(3-Methylthiophen-2-yl)-4-(thiophen-2-yl)but-3-en-1-yl]piperidine-3-carboxylic acid.

^d (R)-1-[4-(x-Methylthiophen-2-yl)-4-(y-methylthiophen-2-yl)but-3-en-1-yl]piperidine-3-carboxylic acid; where possible, x,y combinations include (3,4), (4,3), (4,4), (5,5), (4,5), (5,4), (3,5), and (5,3).

^e Methyl (R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-en-1-yl]piperidine-3-carboxylate.

^f 4,4-Bis(3-methylthiophen-2-yl)but-3-en-1-ol.

^g Bis(3-methylthiophen-2-yl)methanone.

^h 4,4-Bis(3-methylthiophen-2-yl)but-3-en-1-yl methanesulfonate.

ⁱ 2,2-Bis(3-methylthiophen-2-yl)tetrahydrofuran.

5 SPECIFIC TESTS

WATER DETERMINATION 〈921〉 , Method I: NMT 6.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers. Store at a temperature not higher than 30°. Change to read:

USP REFERENCE STANDARDS 〈11〉

USP Racemic Tiagabine Hydrochloride Mixture RS

(S)-(+),(R)-(−)-1-[4,4-Bis(3-methyl-2-thienyl)-3 butenyl]nipecotic acid, hydrochloride. C₂₀H₂₅NO₂S₂ · HCl    412.00

USP Tiagabine Hydrochloride RS

(ERR 1-Nov-2021)

USP Tiagabine Related Compound A RS

(R)-Ethyl-1-[4,4-bis(3-methy-2-thienyl)-3-butenyl]-3-piperidinecarboxylate, hydrochloride. C₂₂H₂₉NO₂S₂ · HCl    440.06