Pramipexole Dihydrochloride Monohydrate CAS 191217-81-9 Assay 98.0~102.0%

C10H17N3S·2HCl·H2O 302.26
(S)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate [191217-81-9].
DEFINITION
Pramipexole Dihydrochloride contains NLT 98.0% and NMT 102.0% of C10H19Cl2N3S, calculated on the anhydrous basis.
IDENTIFICATION
• A. Infrared Absorption <197A> or <197M>
Wave number range: <197A>, 3800 cm-1 to 650 cm-1; <197M>, 4000 cm-1 to 600 cm-1
• B. The retention time of the major peak in the Sample solution corresponds to that of pramipexole (S-enantiomer) in the System suitability solution in the test for Enantiomeric Purity.
• C. Identification Tests-General, Chloride <191>
Sample: 1 mg/mL of Pramipexole Dihydrochloride in water
Acceptance criteria: Meets the requirements of the silver nitrate precipitate test
ASSAY
• 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 (1:1)
Diluent: Acetonitrile and Solution A (1:4)
Mobile phase: See the gradient table below.
Time (min) Solution A (%) Solution B (%)
0 60 40
15 20 80
15.1 60 40
20 60 40
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
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 size: 5 µL
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
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of C10H19Cl2N3S in the portion of Pramipexole Dihydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Pramipexole Dihydrochloride RS in the Standard solution (mg/mL)
CU = concentration of the Sample solution (mg/mL)
Mr1 = molecular weight of pramipexole dihydrochloride, 284.26
Mr2 = molecular weight of pramipexole dihydrochloride monohydrate, 302.26
Acceptance criteria: 98.0%–102.0% on the anhydrous basis
IMPURITIES
Inorganic Impurities
• Residue on Ignition <281>: NMT 0.10%
• Heavy Metals, Method I <231>
Standard solution: Standard Lead Solution, 10 ppm
Sample solution: Ash 2 g of Pramipexole Dihydrochloride until an almost dry, carbonized mass is obtained. Cool the residue, add 2.0 mL of concentrated nitric acid and 5 drops of concentrated sulfuric acid, and carefully allow the fumes to evolve. Ignite at 500-600 until the carbon is completely burned off. Cool the residue, add 4 mL of 6 M hydrochloric acid, cover the crucible, and digest on a boiling water bath for 15 min. Evaporate to dryness. Add one drop of concentrated hydrochloric acid and 10 mL of hot water, and digest for a further 2 min on the boiling water bath. Add 6 M ammonia solution dropwise until the solution is weakly alkaline, and adjust with 1 M acetic acid to a pH of 3.0–4.0. Filter the solution into a 25-mL volumetric flask, and dilute with water to 25 mL by washing the crucible and the filter.
Acceptance criteria: NMT 10 ppm
Organic Impurities
• Procedure
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
System suitability
Samples: System suitability solution and Standard solution
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
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of any individual impurity in the portion of Pramipexole Dihydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU = peak response of each impurity from the Sample solution
rS = peak response of pramipexole from the Standard solution
CS = concentration of USP Pramipexole Dihydrochloride RS in the Standard solution (mg/mL)
CU = concentration of pramipexole dihydrochloride monohydrate in the Sample solution (mg/mL)
Mr1 = molecular weight of pramipexole dihydrochloride, 284.26
Mr2 = molecular weight of pramipexole dihydrochloride monohydrate, 302.26
Acceptance criteria
Individual impurities: See Impurity Table 1.
Total impurities: NMT 0.5%
Impurity Table 1
Name Relative Retention Time Acceptance Criteria, NMT (%)
Pramipexole propionamidea 0.5 0.15
Pramipexole related compound Ab 0.7 0.15
Pramipexole 1.0 —
N-Propylpramipexolec 1.4 0.15
Pramipexole dimerd 1.7 0.15
Any other unidentified individual impurity — 0.10
a (S)-N-(2-Amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide.
b (S)-4,5,6,7-Tetrahydrobenzothiazole-2,6-diamine.
c (S)-2,6-Dipropylamino-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).
SPECIFIC TESTS
• Water Determination, Method I <921>: NLT 4.5% and NMT 6.5%
• Enantiomeric Purity
Mobile phase: n-Hexane, dehydrated alcohol, and diethylamine (850:150:1)
System suitability stock solution: 1 mg/mL each of USP Pramipexole Dihydrochloride RS and USP Pramipexole Related Compound D RS in dehydrated alcohol
System suitability solution: 0.01 mg/mL each of USP Pramipexole Dihydrochloride RS and USP Pramipexole Related Compound D RS from System suitability stock solution in Mobile phase
Standard stock solution: 2.0 mg/mL of USP Pramipexole Related Compound D RS in dehydrated alcohol
Standard solution: 1.5 µg/mL of USP Pramipexole Related Compound D RS in Mobile phase
Sample solution: 0.3 mg/mL, prepared by dissolving a suitable weighed quantity of Pramipexole Dihydrochloride in 25% of a flask volume of dehydrated alcohol and diluting with Mobile phase to volume
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
Sample size: 75 µL
System suitability
Samples: 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, System suitability solution
Tailing factor: NMT 2.4 for pramipexole, System suitability solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of pramipexole related compound D in the portion of Pramipexole Dihydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU = peak response of pramipexole related compound D from the Sample solution
rS = peak response of pramipexole related compound D from the Standard solution
CS = concentration of pramipexole related compound D in the Standard solution (mg/mL)
CU = concentration of the Sample solution (mg/mL)
Acceptance criteria: NMT 1.0% of pramipexole related compound D
• Limit of Palladium
[Note-Perform this test if palladium is a known inorganic impurity. ]
Diluent: 0.1 M hydrochloric acid
Standard solution: 40 µg/L of palladium in Diluent, from commercially available palladium standard solution for atomic absorption/inductively coupled plasma. [Note—Freshly prepare this solution as required on the day of use. ]
Sample solution: To 0.5 g of Pramipexole Dihydrochloride in a 50-mL volumetric flask add 5.00 mL of 1 M hydrochloric acid, and dissolve with heating. Cool to room temperature, and dilute with water to volume.
Spectrometric conditions
(See Spectrophotometry and Light-Scattering 851).
Mode: Atomic absorption spectrophotometry
Analytical wavelength: Palladium emission line at 247.6 nm
Lamp: Hollow cathode
Atomization source: Graphite furnace. [Note—Follow the manufacturer’s recommended programming sequence. ]
Sample size: 20 µL
Blank: Diluent
System suitability
Sample: Standard solution
Suitability requirements
Absorbance: NLT 0.034
Analysis
Samples: Standard solution and Sample solution
Determine the concentration of palladium in the Sample solution by the standard addition method.
Acceptance criteria: NMT 5 ppm
ADDITIONAL REQUIREMENTS
• Packaging and Storage: Preserve in well-closed containers, protected from moisture and light.
• USP Reference Standards 11
USP Pramipexole Dihydrochloride RS Click to View Structure
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.
C10H17N3S 211.33