USP Pending Monograph
Draft 1—For Public Comment
BRIEFING
Aripiprazole. A new USP Pending Monograph for this drug
substance is proposed based on validated methods. The
isocratic liquid chromatographic procedure in the Assay is
based on analyses performed with a YMC-Pack C8 brand of
L7 column in which aripiprazole elutes at about 6 min. The
gradient elution liquid chromatographic procedure in the
test for Organic Impurities is based on analyses performed
with a YMC-Pack C8 brand of L7 column in which
aripiprazole elutes at about 12 min.
Description and Solubility: A white to off-white, crystalline
powder. Freely soluble in methylene chloride; sparingly
soluble in toluene; insoluble in methanol and in water.
(SM4: H. Ramanathan, R. Ravichandran.)
Correspondence Number—C84352
Add the following:
.
Aripiprazole
c
Draft 1
Aripiprazole / 1
Suitability requirements
Tailing factor: NMT 1.5 for the aripiprazole peak, System suitability solution
Resolution: NLT 4.0 between the aripiprazole related
compound B and aripiprazole peaks, System suitability
solution
Relative standard deviation: NMT 2.0%, Standard
solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of aripiprazole (C23H27Cl2N3O2) in
the portion of the sample taken:
Result = (rU/rS) × (CS/CU) × 100
rU
rS
CS
= peak response from the Sample solution
= peak response from the Standard solution
= concentration of USP Aripiprazole RS in the
Standard solution (mg/mL)
CU
= concentration of Aripiprazole in the Sample
solution (mg/mL)
Acceptance criteria: 98.0%–102.0% on the dried basis
IMPURITIES
• RESIDUE ON IGNITION 〈281〉: NMT 0.1%
• HEAVY METALS, Method II 〈231〉: NMT 20 µg/g
• ORGANIC IMPURITIES
Solution A: 1.7 g/L of dibasic potassium phosphate in
water. Adjust with phosphoric acid (5 in 100) to a pH of
4.4.
Solution B: Acetonitrile
Diluent: Acetonitrile and methanol (50:50)
Mobile phase: See Table 1.
Table 1
C23H27Cl2N3O2
448.39
2(1H)-Quinolinone, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-;
7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4dihydrocarbostyril [129722-12-9].
DEFINITION
Aripiprazole contains NLT 98.0% and NMT 102.0% of
aripiprazole (C23H27Cl2N3O2), calculated on the dried basis.
IDENTIFICATION
• A. INFRARED ABSORPTION 〈197K〉
• B. The retention time of the major peak of the Sample
solution corresponds to that of the Standard solution, as
obtained in the Assay.
ASSAY
• PROCEDURE
Buffer: 2.8 g/L of sodium sulfate in water
Mobile phase: Acetonitrile, methanol, Buffer, and glacial
acetic acid (35:15:50:1)
Diluent: Acetonitrile and methanol (50:50)
System suitability solution: 0.1 mg/mL of USP
Aripiprazole RS and 0.05 mg/mL of USP Aripiprazole Related Compound B RS, in Diluent
Standard solution: 0.1 mg/mL of USP Aripiprazole RS in
Diluent
Sample solution: 0.1 mg/mL of Aripiprazole in Diluent
Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 254 nm
Column: 4.6-mm × 25-cm; 5-µm packing L7
Flow rate: 1 mL/min
Injection volume: 15 µL
Column temperature: 35°
Run time: Two times the retention time of aripiprazole
System suitability
Samples: System suitability solution and Standard solution
[NOTE—The relative retention times for aripiprazole related compound B and aripiprazole are 0.67 and 1.0,
respectively.]
Time
(min)
0
2.0
22.0
25.0
25.1
35.0
Solution A
(%)
70
70
30
30
70
70
Solution B
(%)
30
30
70
70
30
30
System suitability solution: 0.1 mg/mL each of USP
Aripiprazole RS, USP Aripiprazole Related Compound B RS,
and USP Aripiprazole Related Compound C RS, in Diluent
Standard solution: 0.4 µg/mL of USP Aripiprazole RS in
Diluent
Sample solution: 0.4 mg/mL of Aripiprazole in Diluent
Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 254 nm
Column: 4.6-mm × 25-cm; 5-µm packing L7
Flow rate: 1 mL/min
Injection volume: 15 µL
System suitability
Samples: System suitability solution and Standard solution
Suitability requirements
Tailing factor: NMT 1.5 for the aripiprazole peak,
System suitability solution
Resolution: NLT 1.5 between the aripiprazole related
compound B and aripiprazole related compound C
peaks, System suitability solution
Relative standard deviation: NMT 10.0%, Standard
solution
Analysis
Samples: Standard solution and Sample solution
[NOTE—Ignore the sharp artifact peak at the retention
time of 1.7.]
Calculate the percentage of each impurity in the portion
of Aripiprazole taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
This monograph has been developed under USP‘s Pending Monographs Guideline and is not a USP–NF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.
USP Pending Monograph
Draft 1—For Public Comment
2 / Aripiprazole
rU
= peak response of each impurity from the
Sample solution
rS
= peak response of aripiprazole from the
Standard solution
CS
= concentration of USP Aripiprazole RS in the
Standard solution (mg/mL)
CU
= concentration of Aripiprazole in the Sample
solution (mg/mL)
F
= relative response factor (see Table 2)
Acceptance criteria: See Table 2.
Table 2
Name
Aripiprazole quinoline
impuritya
Aripiprazole related
compound B
Aripiprazole related
compound C
Aripiprazole
Diquinoline butanediol
impurityb
Chlorobutoxyquinoline
impurityc
Relative
Retention
Time
Relative
Response
Factor
Acceptance
Criteria,
NMT (%)
0.33
0.77
0.10
0.46
0.78
0.20
0.52
1.0
0.56
1.0
0.10
—
1.07
1.1
0.10
1.23
1.0
0.10
Table 2 (Continued)
Name
Any other individual
impurity
Total impurities
Relative
Retention
Time
Relative
Response
Factor
—
—
—
—
Acceptance
Criteria,
NMT (%)
0.10
0.50
7-Hydroxy-3,4-dihydroquinolin-2(1H)-one.
1-(2,3-Dichlorophenyl)piperazine.
c 7-(4-Chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one.
a
b
SPECIFIC TESTS
• LOSS ON DRYING 〈731〉
Analysis: Dry at 105° for 3 h.
Acceptance criteria: NMT 0.5%
ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in tight containers, and
store at room temperature.
• USP REFERENCE STANDARDS 〈11〉
USP Aripiprazole RS
USP Aripiprazole Related Compound B RS
7-(4-Hydroxy-butoxy)-3,4-dihydroquinolin-2(1H)-one.
C13H17NO3
235.29
USP Aripiprazole Related Compound C RS
1-(2,3-Dichlorophenyl)piperazine hydrochloride.
C10H12Cl2N2 · HCl 267.58b(1-Jul-2012)
7-Hydroxy-3,4-dihydroquinolin-2(1H)-one.
b 1-(2,3-Dichlorophenyl)piperazine.
c 7-(4-Chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one.
a
This monograph has been developed under USP‘s Pending Monographs Guideline and is not a USP–NF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.