Pramipexole Dihydrochloride

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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C₁₀H₁₇N₃S · 2HCl · H₂O     302.26

Benzothiazole-2,6-diamine, 4,5,6,7-tetrahydro-N6-propyl-, dihydrochloride, monohydrate, (S)-;

(S)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate CAS RN®: 191217-81-9; UNII: 3D867NP06J. Change to read:

1 DEFINITION

Pramipexole Dihydrochloride is a monohydrate and contains NLT 98.0% and NMT 102.0% of pramipexole dihydrochloride (C₁₀H₁₇N₃S · 2HCl _{(USP 1-Dec-2022)} ), calculated on the anhydrous basis.

2 IDENTIFICATION

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

Wavelength ranges

For 197A: 3800 cm−1 to 650 cm−1

For 197M: 4000 cm−1 to 600 cm−1

Acceptance criteria: Meets the requirements

B. The retention time of the major peak of the Sample solution corresponds to the pramipexole (S-enantiomer) peak of the System suitability solution in the test for Limit of Pramipexole Related Compound D.

C. Identification Tests—General 〈191〉, Chemical Identification Tests, Chloride

Sample: 1 mg/mL of Pramipexole Dihydrochloride in water

Acceptance criteria: Meets the requirements of test A

3 ASSAY

Change to read:

Procedure

Solution A: Dissolve 9.1 g of potassium dihydrogen phosphate and 5.0 g of sodium 1-octanesulfonate monohydrate in 1 L of water. Adjust with phosphoric acid to a pH of 3.0.

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

Diluent: Acetonitrile and Solution A (20:80)

Mobile phase: See Table 1.

Table 1

System suitability solution: 1.5 mg/mL of USP Pramipexole Dihydrochloride RS and 0.8 mg/mL of USP Pramipexole Related Compound A RS in Diluent

Standard solution: 1.5 mg/mL of USP Pramipexole Dihydrochloride RS in Diluent

Sample solution: 1.5 mg/mL of Pramipexole Dihydrochloride in Diluent

3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 264 nm

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

Column temperature: 40 ± 5°

Flow rate: 1.5 mL/min

Injection volume: 5 µL

3.2 System suitability

Samples: System suitability solution and Standard solution

[Note—The relative retention times for pramipexole related compound A and pramipexole are about 0.7 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 6.0 between pramipexole related compound A and pramipexole, System suitability solution

Tailing factor: NMT 2.0 for pramipexole, System suitability solution

Relative standard deviation: NMT 1.0%, Standard solution

3.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of pramipexole dihydrochloride (C₁₀H₁₇N₃S· 2HCl _{(USP 1-Dec-2022)} ) in the portion of Pramipexole

Dihydrochloride taken:

Result = (r_U /r_S ) × (C_S /C_U ) × (M_r1 /M_r2 ) × 100

r_U = peak response of the Sample solution

r_S = peak response of the Standard solution

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

C_U = concentration of Pramipexole Dihydrochloride (as monohydrate) in the Sample solution (mg/mL)

M_r1 = molecular weight of pramipexole dihydrochloride, 284.24

M_r2 = molecular weight of pramipexole dihydrochloride monohydrate, 302.26

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

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.10%

Change to read:

4.1 Limit of Pramipexole Related Compound D

Mobile phase: n-Hexane, dehydrated alcohol, and diethylamine (850:150:1)

System suitability stock solution: 1 mg/mL (USP 1-Dec-2022) of USP Pramipexole Dihydrochloride RS and 1.3 mg/mL of (USP 1-Dec-2022) USP Pramipexole Related Compound D RS in dehydrated alcohol

System suitability solution: 0.01 mg/mL (USP 1-Dec-2022) of USP Pramipexole Dihydrochloride RS and 0.013 mg/mL of (USP 1-Dec-2022) USP Pramipexole Related Compound D RS from the System suitability stock solution in Mobile phase

Standard stock solution: 2.7 (USP 1-Dec-2022) mg/mL of USP Pramipexole Related Compound D RS in dehydrated alcohol

Standard solution: 2.0 (USP 1-Dec-2022) µg/mL of USP Pramipexole Related Compound D RS in Mobile phase from the Standard stock solution

Sample solution: 0.3 mg/mL of Pramipexole Dihydrochloride prepared as follows. Transfer a suitable weighed quantity of Pramipexole Dihydrochloride into a suitable ask, dissolve in 25% of the ask volume of dehydrated alcohol, and dilute with Mobile phase to volume.

4.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm × 25-cm; 10-µm packing L51

Flow rate: 1.5 mL/min

Injection volume: 75 µL

4.1.2 System suitability

Sample: System suitability solution

[Note—The relative retention times for pramipexole related compound D (R-enantiomer) and pramipexole (S-enantiomer) are 0.5 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 5.0 between pramipexole related compound D and pramipexole

Tailing factor: NMT 2.4 for pramipexole

4.1.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of pramipexole related compound D in the portion of Pramipexole Dihydrochloride taken:

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

r_U = peak response of pramipexole related compound D from the Sample solution

r_S = peak response of pramipexole related compound D from the Standard solution

C_S = concentration of USP Pramipexole Related Compound D RS in the Standard solution (mg/mL)

C_U = concentration of Pramipexole Dihydrochloride (as monohydrate) in the Sample solution (mg/mL)

Acceptance criteria: NMT 1.0% of pramipexole related compound D

4.2 Organic Impurities

Solution A, Solution B, Diluent, Mobile phase, and Chromatographic system: Proceed as directed in the Assay.

System suitability solution: 7.5 µg/mL of USP Pramipexole Dihydrochloride RS and 3 µg/mL of USP Pramipexole Related Compound A RS in Diluent

Standard solution: 1.5 µg/mL of USP Pramipexole Dihydrochloride RS in Diluent

Sample solution: 1.5 mg/mL of Pramipexole Dihydrochloride in Diluent

4.2.1 System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 6.0 between pramipexole related compound A and pramipexole, System suitability solution

Tailing factor: NMT 2.0 for pramipexole, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

4.2.2 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Pramipexole Dihydrochloride taken:

Result = (r_U /r_S ) × (C_S /C_U ) × (1/F) × (M_r1 /M_r2 ) × 100

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

r_S = peak response of pramipexole from the Standard solution

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

C_U = concentration of Pramipexole Dihydrochloride (as monohydrate) in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

M_r1 = molecular weight of pramipexole dihydrochloride, 284.24

M_r2 = molecular weight of pramipexole dihydrochloride monohydrate, 302.26

Acceptance criteria: See Table 2. Disregard any peak less than 0.05%.

Table 2

^a Relative response factor is relative to pramipexole dihydrochloride.

^b (S)-N-(2-Amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide.

^c (S)-2,6-Di(propylamino)-4,5,6,7-tetrahydrobenzothiazole.

^d N6,N6′-[2-Methylpentane-1,3-diyl]bis(4,5,6,7-tetrahydrobenzothiazole-2,6-diamine). This is a dimer of pramipexole (a mixture of four possible isomers).

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I: NLT 4.5% and NMT 7.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, protected from moisture and light.

Change to read:

USP Reference Standards 〈11〉

USP Pramipexole Dihydrochloride RS

[Note—Supplied in monohydrate form.]

USP Pramipexole Related Compound A RS

(S)-4,5,6,7-Tetrahydrobenzothiazole-2,6-diamine.

C₇H₁₁N₃S     169.25

USP Pramipexole Related Compound D RS

(R)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride.

C₁₀H₁₇N₃S · 2HCl    284.25 (USP 1-Dec-2022)