USP Pending Monograph

Draft 1For Public Comment Aripiprazole / 1

BRIEFING Suitability requirements

Tailing factor: NMT 1.5 for the aripiprazole peak, Sys-
tem suitability solution
Aripiprazole. A new USP Pending Monograph for this drug Resolution: NLT 4.0 between the aripiprazole related
substance is proposed based on validated methods. The compound B and aripiprazole peaks, System suitability
isocratic liquid chromatographic procedure in the Assay is solution
based on analyses performed with a YMC-Pack C8 brand of Relative standard deviation: NMT 2.0%, Standard
L7 column in which aripiprazole elutes at about 6 min. The solution
gradient elution liquid chromatographic procedure in the Analysis
test for Organic Impurities is based on analyses performed Samples: Standard solution and Sample solution
with a YMC-Pack C8 brand of L7 column in which Calculate the percentage of aripiprazole (C23H27Cl2N3O2) in
aripiprazole elutes at about 12 min. the portion of the sample taken:
Description and Solubility: A white to off-white, crystalline
powder. Freely soluble in methylene chloride; sparingly Result = (rU/rS) (CS/CU) 100
soluble in toluene; insoluble in methanol and in water.
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Aripiprazole RS in the
(SM4: H. Ramanathan, R. Ravichandran.) Standard solution (mg/mL)
Correspondence NumberC84352 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%
Add the following: HEAVY METALS, Method II 231: NMT 20 g/g
ORGANIC IMPURITIES
Solution A: 1.7 g/L of dibasic potassium phosphate in
Aripiprazole
.

c
water. Adjust with phosphoric acid (5 in 100) to a pH of
Draft 1 4.4.
Solution B: Acetonitrile
Diluent: Acetonitrile and methanol (50:50)
Mobile phase: See Table 1.

Table 1
Time Solution A Solution B
C23H27Cl2N3O2 448.39 (min) (%) (%)
2(1H)-Quinolinone, 7-[4-[4-(2,3-dichlorophenyl)-1-piper- 0 70 30
azinyl]butoxy]-3,4-dihydro-; 2.0 70 30
7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4- 22.0 30 70
dihydrocarbostyril [129722-12-9]. 25.0 30 70
DEFINITION 25.1 70 30
Aripiprazole contains NLT 98.0% and NMT 102.0% of 35.0 70 30
aripiprazole (C23H27Cl2N3O2), calculated on the dried basis.
System suitability solution: 0.1 mg/mL each of USP
IDENTIFICATION Aripiprazole RS, USP Aripiprazole Related Compound B RS,
A. INFRARED ABSORPTION 197K and USP Aripiprazole Related Compound C RS, in Diluent
B. The retention time of the major peak of the Sample Standard solution: 0.4 g/mL of USP Aripiprazole RS in
solution corresponds to that of the Standard solution, as Diluent
obtained in the Assay. Sample solution: 0.4 mg/mL of Aripiprazole in Diluent
Chromatographic system
ASSAY (See Chromatography 621, System Suitability.)
PROCEDURE Mode: LC
Buffer: 2.8 g/L of sodium sulfate in water Detector: UV 254 nm
Mobile phase: Acetonitrile, methanol, Buffer, and glacial Column: 4.6-mm 25-cm; 5-m packing L7
acetic acid (35:15:50:1) Flow rate: 1 mL/min
Diluent: Acetonitrile and methanol (50:50) Injection volume: 15 L
System suitability solution: 0.1 mg/mL of USP System suitability
Aripiprazole RS and 0.05 mg/mL of USP Aripiprazole Re- Samples: System suitability solution and Standard solution
lated Compound B RS, in Diluent Suitability requirements
Standard solution: 0.1 mg/mL of USP Aripiprazole RS in Tailing factor: NMT 1.5 for the aripiprazole peak,
Diluent System suitability solution
Sample solution: 0.1 mg/mL of Aripiprazole in Diluent Resolution: NLT 1.5 between the aripiprazole related
Chromatographic system compound B and aripiprazole related compound C
(See Chromatography 621, System Suitability.) peaks, System suitability solution
Mode: LC Relative standard deviation: NMT 10.0%, Standard
Detector: UV 254 nm solution
Column: 4.6-mm 25-cm; 5-m packing L7 Analysis
Flow rate: 1 mL/min Samples: Standard solution and Sample solution
Injection volume: 15 L [NOTEIgnore the sharp artifact peak at the retention
Column temperature: 35 time of 1.7.]
Run time: Two times the retention time of aripiprazole Calculate the percentage of each impurity in the portion
System suitability of Aripiprazole taken:
Samples: System suitability solution and Standard solution
[NOTEThe relative retention times for aripiprazole re- Result = (rU/rS) (CS/CU) (1/F) 100
lated compound B and aripiprazole are 0.67 and 1.0,
respectively.]

This monograph has been developed under USPs Pending Monographs Guideline and is not a USPNF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.
 USP Pending Monograph
2 / Aripiprazole Draft 1For Public Comment

rU = peak response of each impurity from the Table 2 (Continued)

Sample solution Relative Relative Acceptance
rS = peak response of aripiprazole from the Retention Response Criteria,
Standard solution Name Time Factor NMT (%)
CS = concentration of USP Aripiprazole RS in the
Standard solution (mg/mL) Any other individual

CU = concentration of Aripiprazole in the Sample impurity 0.10
solution (mg/mL) Total impurities 0.50
F = relative response factor (see Table 2) a 7-Hydroxy-3,4-dihydroquinolin-2(1H)-one.
Acceptance criteria: See Table 2. b 1-(2,3-Dichlorophenyl)piperazine.
c 7-(4-Chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one.

Table 2 SPECIFIC TESTS

Relative Relative Acceptance LOSS ON DRYING 731
Retention Response Criteria, Analysis: Dry at 105 for 3 h.
Name Time Factor NMT (%) Acceptance criteria: NMT 0.5%
Aripiprazole quinoline ADDITIONAL REQUIREMENTS
impuritya 0.33 0.77 0.10 PACKAGING AND STORAGE: Preserve in tight containers, and
Aripiprazole related store at room temperature.
compound B 0.46 0.78 0.20 USP REFERENCE STANDARDS 11
Aripiprazole related USP Aripiprazole RS
compound C 0.52 0.56 0.10 USP Aripiprazole Related Compound B RS
Aripiprazole 1.0 1.0 7-(4-Hydroxy-butoxy)-3,4-dihydroquinolin-2(1H)-one.
Diquinoline butanediol C13H17NO3 235.29
impurityb 1.07 1.1 0.10 USP Aripiprazole Related Compound C RS
Chlorobutoxyquinoline
1-(2,3-Dichlorophenyl)piperazine hydrochloride.
impurityc 1.23 1.0 0.10
C10H12Cl2N2 HCl 267.58b(1-Jul-2012)
a 7-Hydroxy-3,4-dihydroquinolin-2(1H)-one.
b 1-(2,3-Dichlorophenyl)piperazine.
c 7-(4-Chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one.

This monograph has been developed under USPs Pending Monographs Guideline and is not a USPNF monograph.
http://www.usp.org
2012 The United States Pharmacopeia. All Rights Reserved.