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USP 40 Official Monographs / Ropinirole 6073

Suitability requirements Table 5 (Continued)

Resolution: NLT 2.0 between ropinirole related com- Relative Relative Acceptance
pound B and ropinirole, System suitability solution Retention Response Criteria,
Relative standard deviation: NMT 10% for Name Time Factor NMT (%)
ropinirole related compound B, Standard solution
Signal-to-noise ratio: NLT 10 for ropinirole, Sensitiv- Any individual
ity solution unspecified
Analysis degradation product 1.0 0.2
Samples: Standard solution and Sample solution Total degradation

Calculate the percentage of ropinirole related com- products 1.5
pound B in the portion of Tablets taken: a 4-[2-(Propylamino)ethyl]indolin-2-one.
.

b 4-[2-(Dipropylamino)ethyl]-1-(hydroxymethyl)indolin-2-one.

Result = (rU/rS) (CS/CU) (Mr1/Mr2) 100

.

c N-[2-(2-Oxoindolin-4-yl)ethyl]-N-propylpropan-1-amine
. oxide.
d 4-[2-(Dipropylamino)ethyl]-3-({4-[2-(dipropylamino)ethyl]-2-oxo-2,3-

rU = peak response of ropinirole related compound

.

dihydro-1H-indol-3-yl}methyl)-2,3-dihydro-1H-indol-2-one.
B from the Sample solution e (Z)-4-[2-(Dipropylamino)ethyl]-3-propylideneindolin-2-one.
.

rS = peak response of ropinirole related compound f Process impurity included in the table for identification only. Process im-
.

B from the Standard solution purities are controlled in the drug substance and are not to be reported
or included in the total impurities for the drug product.
CS = concentration of USP Ropinirole Related
Compound B RS in the Standard solution ADDITIONAL REQUIREMENTS
(g/mL) PACKAGING AND STORAGE: Preserve in well-closed contain-
CU = nominal concentration of ropinirole related ers. Store at controlled room temperature.
compound B free base in the Sample solution USP REFERENCE STANDARDS 11
(g/mL) USP Ropinirole Hydrochloride RS
Mr1 = molecular weight of ropinirole related USP Ropinirole Related Compound B RS
compound B free base, 274.36 4-[2-(Dipropylamino)ethyl]indoline-2,3-dione
Mr2 = molecular weight of ropinirole related hydrochloride.
compound B hydrochloride, 310.82 C16H22N2O2 HCl 310.82
Calculate the percentage of each degradation product
in the portion of Tablets taken:
Result = (rU/F)/[(rU/F) + rR] 100 .

rU = peak response of each degradation product Ropinirole Hydrochloride

from the Sample solution
F = relative response factor for the corresponding
degradation product from Table 5
rR = peak response of ropinirole from the Sample

USP Monographs
solution
Acceptance criteria: See Table 5. Disregard peaks less
than 0.05%.
C16H24N2O HCl 296.84
Table 5 2H-Indol-2-one, 4-[2-(dipropylamino)ethyl]-1,3-dihydro-,
monohydrochloride;
Relative Relative Acceptance
4-[2-(Dipropylamino)ethyl]-2-indolinone monohydrochloride
Retention Response Criteria,
[91374-20-8].
Name Time Factor NMT (%)
Ropinirole DEFINITION
monopropyla . 0.42 1.0 0.5 Ropinirole Hydrochloride contains NLT 98.0% and NMT
Ropinirole related 102.0% of ropinirole hydrochloride (C16H24N2O HCl), cal-
culated on the anhydrous and solvent-free basis.
compound B 0.89 0.5
Ropinirole
IDENTIFICATION
N-hydroxymethylb 0.94 0.71 0.5
.

A. INFRARED ABSORPTION 197K

Ropinirole 1.00 B. The retention time of the major peak of the Sample
Ropinirole N-oxidec . 1.31 1.0 0.5 solution corresponds to that of the Standard solution, as
Ropinirole methylene obtained in the Assay.
dimerd . 1.82 1.0 0.5 C. IDENTIFICATION TESTSGENERAL, Chloride 191
Propylidene Sample: 20 mg/mL
Acceptance criteria: Meets the requirements for the sil-
ropinirolee,f 1.96 2.0
ver nitrate precipitate test
. . .

a 4-[2-(Propylamino)ethyl]indolin-2-one.
.

b 4-[2-(Dipropylamino)ethyl]-1-(hydroxymethyl)indolin-2-one.
.

ASSAY
c N-[2-(2-Oxoindolin-4-yl)ethyl]-N-propylpropan-1-amine
. oxide. PROCEDURE
d 4-[2-(Dipropylamino)ethyl]-3-({4-[2-(dipropylamino)ethyl]-2-oxo-2,3-
.

Buffer: 1.88 g of sodium 1-hexanesulfonate and 1 g of

dihydro-1H-indol-3-yl}methyl)-2,3-dihydro-1H-indol-2-one.
e (Z)-4-[2-(Dipropylamino)ethyl]-3-propylideneindolin-2-one.
phosphoric acid in 1 L of water. Adjust with dilute tri-
.

f Process impurity included in the table for identification only. Process im-
ethylamine solution (1 mL/10 mL) to a pH of 6.5.
.

purities are controlled in the drug substance and are not to be reported Diluent: Acetonitrile and water (20:80)
or included in the total impurities for the drug product. Mobile phase: Acetonitrile and Buffer (20:80)
Standard solution: 0.1 mg/mL of USP Ropinirole Hy-
drochloride RS in Diluent. Sonication may be used to
aid dissolution.

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6074 Ropinirole / Official Monographs USP 40

Sample solution: 0.1 mg/mL of Ropinirole Hydrochlo- the residue, and evaporate to dryness. Add 1 mL of 2 M
ride in Diluent. Sonication may be used to aid hydrochloric acid and, if necessary, dissolve the residue
dissolution. with gentle heating. When cool, transfer the contents
Chromatographic system to a 50-mL beaker. Wash the crucible twice with 1-mL
(See Chromatography 621, System Suitability.) aliquots of water, and add the washings to the beaker.
Mode: LC Pass the solution through a membrane filter of 2-m
Detector: UV 215 nm pore size into a centrifuge tube.
Column: 4.6-mm 25-cm; 5-m packing L7 Analysis: To the filtered Standard solution and Sample
Column temperature: 30 solution add 1 mL of Solution A, 0.2 mL of Solution B,
Flow rate: 1.0 mL/min and 2 mL of Buffer. Cap the centrifuge tubes securely,
Injection volume: 10 L and incubate at 37 for 2 h. Pass the Sample solution
Run time: 2.5 times the retention time of ropinirole and Standard solution through a membrane filter of
System suitability 2-m pore size, wash the membrane with 2-mL aliquots
Sample: Standard solution of water, and allow the membrane to dry.
Suitability requirements Acceptance criteria: The intensity of the spot due to
Tailing factor: NMT 1.6 the sample is not more intense than the spot due to
Relative standard deviation: NMT 1.5% the standard (10 ppm).
Analysis ORGANIC IMPURITIES, PROCEDURE 1
Samples: Standard solution and Sample solution If methylene ropinirole and propylidene ropinirole are
Calculate the percentage of ropinirole hydrochloride known process impurities, Organic Impurities, Procedure
(C16H24N2O HCl) in the portion of Ropinirole Hydro- 2 is recommended. If ropinirole indole derivative and
chloride taken: ropinirole oxime are known process impurities, Organic
Impurities, Procedure 3 is recommended.
Result = (rU/rS) (CS/CU) 100 Buffer and Diluent: Proceed as directed in the Assay.
Solution A: Acetonitrile and Buffer (15:85)
rU = peak response from the Sample solution Solution B: Acetonitrile and water (60:40)
rS = peak response from the Standard solution Mobile phase: See Table 1.
CS = concentration of the Standard solution
(mg/mL)
Table 1
CU = concentration of the Sample solution (mg/mL)
Acceptance criteria: 98.0%102.0% on the anhydrous Time Solution A Solution B
and solvent-free basis (min) (%) (%)
0 100 0
IMPURITIES
5 100 0
RESIDUE ON IGNITION 281: NMT 0.1%
30 60 40
50 60 40
Delete the following:
55 100 0
USP Monographs

HEAVY METALS, Method II 231: NMT 10 ppm (Official 1-

.
65 100 0
Jan-2018)
System suitability solution: 1 mg/mL of USP Ropinirole
LIMIT OF Pd Hydrochloride RS and 1.5 g/mL of USP Ropinirole Re-
[NOTEPerform this test if Pd is a known inorganic lated Compound B RS in Diluent
impurity.] Sample solution: 1 mg/mL of Ropinirole Hydrochloride
Solution A: Dissolve 2.4 g of sodium hydroxide in in Diluent
20 mL of water, and dilute with glycerol to 100 mL. Chromatographic system
Solution B: 40 mg/mL of thioacetamide in water. (See Chromatography 621, System Suitability.)
[NOTEThe solution may be filtered if necessary.] Mode: LC
Buffer: Carefully add 27 mL of hydrochloric acid to Detector: UV 215 nm
25 g of ammonium acetate, and dilute with water to Column: 4.6-mm 25-cm; 5-m packing L7
100 mL. Column temperature: 30
Pd standard solution: 10 ppm of Pd from commer- Flow rate: 1 mL/min
cially available ICP grade 1000 ppm Pd stock solution Injection volume: 10 L
Standard solution: Pipet 1.0 mL of Pd standard solution System suitability
into a platinum crucible, and gently evaporate to dry- Sample: System suitability solution
ness. Moisten the residue with 0.5 mL of sulfuric acid, Suitability requirements
and heat with a Bunsen burner until fumes are no Resolution: NLT 1.5 between ropinirole and
longer emitted. Place the crucible in a muffle furnace at ropinirole related compound B
700, and heat for 5 additional min. Cool, add 5 mL of Tailing factor: NMT 2.0 for the ropinirole peak
hydrochloric acid to the residue, and evaporate to dry- Relative standard deviation: NMT 2.0% for the
ness. Add 1 mL of 2 M hydrochloric acid and, if neces- ropinirole peak
sary, dissolve the residue with gentle heating. When Analysis
cool, transfer the contents to a 50-mL beaker. Wash the Sample: Sample solution
crucible twice with 1-mL aliquots of water, and add the Calculate the percentage of any individual impurity in
washings to the beaker. Pass the solution through a the portion of Ropinirole Hydrochloride taken:
membrane filter of 2-m pore size into a centrifuge
tube. Result = (rU/rT) (1/F) 100
Sample solution: Transfer 1 g of Ropinirole Hydrochlo-
ride to a platinum crucible, and heat over a Bunsen rU = peak response of each individual impurity
burner until the material is completely carbonized. from the Sample solution
Moisten the contents with 0.5 mL of sulfuric acid, and rT = sum of responses of all the peaks from the
heat over a Bunsen burner until fumes are no longer Sample solution
emitted. Place the crucible in a muffle furnace at 700, F = relative response factor (see Table 2)
and heat until all the organic material has been de- Acceptance criteria: See Table 2.
stroyed. When cool, add 5 mL of hydrochloric acid to

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USP 40 Official Monographs / Ropinirole 6075

Table 2 Analysis
Relative Relative Acceptance
Samples: Standard solution and Sample solution
Retention Response Criteria,
Calculate the percentage of ropinirole related com-
Name Time Factor NMT (%)
pound B in the portion of Ropinirole Hydrochloride
taken:
Open ring nitro
derivativea . 0.39 0.72 0.15 Result = (rU/rS) (CS/CU) 100
Monopropyl
ropiniroleb . 0.58 1.1 0.15 rU = peak response of ropinirole related compound
N-hydroxyropinirolec 0.84 0.65 0.15 B from the Sample solution
rS = peak response of USP Ropinirole Related
.

Ropinirole related
compound B 0.97 0.66 0.15 Compound B RS from the Standard solution
Ropinirole 1.0
CS = concentration of USP Ropinirole Related
Compound B RS in the Standard solution
Any individual (mg/mL)

unknown impurity 1.0 0.10 CU = concentration of the Sample solution (mg/mL)
Total impuritiesd . 1.0 Calculate the percentage of any other individual impurity
a 2-{2-[2-(Dipropylamino)ethyl]-6-nitrophenyl}acetic
. acid. in the portion of Ropinirole Hydrochloride taken:
b 4-[2-(Propylamino)ethyl]indolin-2-one.

Result = (rU/rT) 100

.

c 4-[2-(Dipropylamino)ethyl]-1-hydroxyindolin-2-one.
.

d Includes impurities greater than or equal to 0.05%.

rU = peak response of each individual impurity
.

ORGANIC IMPURITIES, PROCEDURE 2 from the Sample solution

Solution A: 3.85 g/L of ammonium acetate. Adjust with rT = sum of the responses of all the peaks from the
phosphoric acid to a pH of 2.5. Sample solution
Solution B: Acetonitrile and methanol (70:30) Acceptance criteria: See Table 4.
Diluent: Solution A and Solution B (84:16)
Mobile phase: See Table 3.
Table 4

Table 3 Relative Acceptance

Retention Criteria,
Time Solution A Solution B Name Time NMT (%)
(min) (%) (%) Monopropyl ropinirolea . 0.37 0.2
0 84 16 Ropinirole related compound Ab . 0.70
16 84 16 Ropinirole related compound B 0.85 0.3
36 20 80 Ropinirole 1.0
37 84 16 Methylene ropinirolec . 1.39 0.2

USP Monographs
51 84 16 Ropinirole isohexyl analogd . 1.64 0.3
System suitability solution: 0.05 mg/mL each of USP Propylidene ropinirolee . 1.70 0.2
Ropinirole Hydrochloride RS, USP Ropinirole Related Any individual unspecified impurity 0.10
Compound A RS, and USP Ropinirole Related Com- Total impurities 1.0
pound B RS in Diluent a 4-[2-(Propylamino)ethyl]indolin-2-one.

Standard solution: 3 g/mL of USP Ropinirole Related

.

b Only used for system suitability and peak identification. This impurity is
Compound B RS in Diluent
.

not to be reported and not to be included in total impurities.

Sample solution: 1 mg/mL of Ropinirole Hydrochloride c 4-[2-(Dipropylamino)ethyl]-3-methyleneindolin-2-one.
.

in Diluent d 4-[2-(2-Methylpentylamino)ethyl]indolin-2-one.
.

Chromatographic system e (Z)-4-[2-(Dipropylamino)ethyl]-3-propylideneindolin-2-one.

.

(See Chromatography 621, System Suitability.)

Mode: LC ORGANIC IMPURITIES, PROCEDURE 3
Detector: UV 250 nm Solution A: Dissolve 3.95 g of ammonium bicarbonate
Column: 4.6-mm 25-cm; 5-m packing L7 in 990 mL of water. Add 4 mL of 25% ammonia, and
Column temperature: 40 dilute with water to 1000 mL. The pH is 9.29.3.
Flow rate: 1 mL/min Solution B: Acetonitrile
Injection volume: 10 L Diluent: Acetonitrile and water (32:68)
System suitability Mobile phase: See Table 5.
Samples: System suitability solution and Standard
solution Table 5
Suitability requirements Time Solution A Solution B
Resolution: NLT 2.0 between ropinirole related com- (min) (%) (%)
pound A and ropinirole related compound B; NLT 3.0
0 68 32
between ropinirole related compound B and
ropinirole, System suitability solution 12 68 32
Tailing factor: NMT 1.5 for ropinirole, System suita- 28 20 80
bility solution 34 20 80
Relative standard deviation: NMT 5.0% for the 34.1 68 32
ropinirole related compound B peak, Standard 40 68 32
solution
System suitability solution: 1 mg/mL of USP Ropinirole
Hydrochloride RS and 0.01 mg/mL of USP Ropinirole
Related Compound B RS in Diluent
Standard solution: 1.2 g/mL of USP Ropinirole Hydro-
chloride RS in Diluent

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6076 Ropinirole / Official Monographs USP 40

Sample solution: 1.2 mg/mL of Ropinirole Hydrochlo-

ride in Diluent
.

Chromatographic system Ropivacaine Hydrochloride

(See Chromatography 621, System Suitability.)
Mode: LC
Detector: UV 220 nm
Column: 3.9-mm 15-cm; 5-m packing L1
Flow rate: 1 mL/min
Injection volume: 20 L
System suitability
Samples: System suitability solution and Standard C17H26N2O HCl H2O 328.88
solution (S)-()-1-Propylpiperidine-2-carboxylic acid (2,6-
Suitability requirements dimethylphenyl)amide hydrochloride monohydrate;
Resolution: NLT 1.5 between ropinirole and (S)-()-1-Propyl-2,6-pipecoloxylidine hydrochloride mono-
ropinirole related compound B, System suitability hydrate [132112-35-7].
solution
Tailing factor: 0.81.5 for ropinirole, Standard DEFINITION
solution Ropivacaine Hydrochloride contains NLT 98.5% and NMT
Relative standard deviation: NMT 5.0% for 101.0% of C17H26N2O HCl, calculated on the anhydrous
ropinirole, Standard solution basis.
Analysis
Samples: Standard solution and Sample solution IDENTIFICATION
Calculate the percentage of any individual impurity in A. INFRARED ABSORPTION 197K
the portion of Ropinirole Hydrochloride taken: B. IDENTIFICATION TESTSGENERAL, Chloride 191
Sample solution: 10 mg/mL
Result = (rU/rS) (CS/CU) (1/F) 100
ASSAY
rU = peak response from the Sample solution PROCEDURE
rS = peak response from the Standard solution Sample solution: Dissolve 1000 mg of Ropivacaine Hy-
CS = concentration of the Standard solution drochloride in 10 mL of water and 40 mL of alcohol.
(mg/mL) Add 1.0 mL of 1 N hydrochloric acid.
CU = concentration of the Sample solution (mg/mL) Analysis: Titrate with 1 N sodium hydroxide VS. Two
F = relative response factor (see Table 6) equivalence points are obtained; the difference in titrant
Acceptance criteria: See Table 6. volume corresponds to the amount of ropivacaine hy-
drochloride (see Titrimetry 541). Each mL of 1 N so-
Table 6
dium hydroxide is equivalent to 310.9 mg of anhydrous
ropivacaine hydrochloride (C17H26N2O HCl).
Relative Relative Acceptance Acceptance criteria: 98.5%101.0% on the anhydrous
USP Monographs

Retention Response Criteria, basis

Name Time Factor NMT (%)
Ropinirole oximea 0.69 1.0 0.15 IMPURITIES
Inorganic Impurities
.

Ropinirole 1.0
Ropinirole related
compound B 1.2 1.0 0.15 Delete the following:
Ropinirole indole
derivativeb 2.0 4.0 0.10 HEAVY METALS 231
.

pH 3.5 acetate buffer and Standard lead solution:

.

Any individual
unspecified impurity

0.10 Prepare as directed under Heavy Metals 231.
Total impurities 0.50
Dilute lead standard solution: Dilute 10.0 mL of the
a 4-[2-(Dipropylamino)ethyl]-3-(hydroxyimino)indolin-2-one.
Standard lead solution with water to 100 mL. Each mL
.

b N,N-Dipropyl-N-(2-indol-4-ylethyl)amine.
of Dilute lead standard solution contains the equivalent
.

of 1 g of lead.
SPECIFIC TESTS 0.25 M Sodium sulfide solution: Dissolve 6.0 g of so-
WATER DETERMINATION, Method Ic 921: NMT 0.5% dium sulfide in 40 g of glycerol, then dilute with water
to 100 mL. Filter using a cotton pad, and store in a
ADDITIONAL REQUIREMENTS glass container protected from light.
PACKAGING AND STORAGE: Preserve in well-closed contain- Sample stock solution: Prepare as directed under
ers, and store at room temperature. Heavy Metals 231, Method II, using 3.974.00 g of
LABELING: The label states with which Organic Impurities Ropivacaine Hydrochloride.
procedure the article complies if Organic Impurities, Proce- Standard solution: Combine 10.0 mL of the Dilute lead
dure 1 is not used. standard solution with 2 mL of the Sample stock solution
USP REFERENCE STANDARDS 11 and 2 mL of pH 3.5 acetate buffer.
USP Ropinirole Hydrochloride RS Sample solution: Combine 12 mL of the Sample stock
USP Ropinirole Related Compound A RS solution with 2 mL of pH 3.5 acetate buffer.
4-(2-Hydroxyethyl)indolin-2-one. Blank: Combine 10 mL of water, 2 mL of pH 3.5 acetate
C10H11NO2 177.20 buffer, and 2 mL of the Sample stock solution.
USP Ropinirole Related Compound B RS Analysis: Transfer the Blank to a color-comparison tube.
4-[2-(Dipropylamino)ethyl]indoline-2,3-dione Transfer the Standard solution and the Sample solution to
hydrochloride. individual color-comparison tubes each containing 1
C16H22N2O2 HCl 310.82 drop of 0.25 M sodium sulfide solution. After 1 min,
compare the colors, viewing downward over a white
surface.
Acceptance criteria: The Standard solution shows a
slight brown color compared to the Blank. The Sample

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