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DOMPERIDONE

C22H24ClN5O2 425.91

2H-Benzimidazol-2-one, 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro-;

5-Chloro-1-[1-[3-(2-oxo-1-benzimidazolinyl)propyl]-4-piperidyl]-2-benzimidazolinone [57808-66-9].

Domperidone is a slightly white to almost white,powder. It is very slightly soluble in water; sparinglysoluble in dimethylformamide; slightly soluble inmethanol; and very slightly soluble in alcohol.

Performance-Based Monograph(Contains tests, procedures, and acceptance criteria

for the material under test. It also includes thecriteria-based procedures necessary to demonstratethat an Acceptable Procedureis equivalent to theReference Procedures.)

DEFINITIONDomperidone contains NLT 98.0% and NMT 102.0%

of domperidone (C22H24ClN5O2), calculated on thedried basis.

IDENTIFICATION

A. INFRARED ABSORPTION

ASSAY

PROCEDUREStandard solution: USP Domperidone CRM in an

appropriate diluentSample solution: Domperidone in an appropriate

diluentAnalytical system: Use a procedure validated as

described in MCgeneral chapterAssessingValidation Parameters for Reference and

Acceptable Procedures.System performance requirementsPrecision:Meets the requirementsAccuracy:Meets the requirementsSpecificity: Meets the requirementsRange: Meets the requirements

AnalysisSamples:Standard solutionand Sample solution

Calculate the percentage of domperidone(C22H24ClN5O2) in the Sample solution:

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

rU = response from the Sample solutionrS

= response from the Standard solutionCS = concentration of the Standard solutionCU = concentration of the Sample solution

Acceptance criteria: 98.0%102.0% on the driedbasis

IMPURITIES

RESIDUE ON IGNITION:NMT 0.1%

ELEMENTAL IMPURITIES : Proceed as directedin the chapter.

RESIDUAL SOLVENTS :Proceed as directed inthe chapter.

ORGANIC IMPURITIESStandard solution: USP Domperidone CRM and

all appropriate USP Impurity RSs, atconcentrations corresponding to the Acceptancecriteriaof the impurity, in an appropriate diluent

Sample solution: Domperidone in an appropriatediluent

Analytical system: Use a procedure validated asdescribed in MCgeneral chapterAssessingValidation Parameters for Reference andAcceptable Procedures.System performance requirementsPrecision:Meets the requirementsAccuracy:Meets the requirementsRuggedness: Meets the requirements

Specificity: Meets the requirementsAnalysis

Samples:Standard solutionand Sample solutionCalculate the percentage of each impurity in theSample solution:

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

rU = response of each impurity from theSample solution

rS = response of each USP Impurity RS fromthe Standard solution. [NOTEIf no USPImpurity RSs are available, use the

response of domperidone.]CS = concentration of standard material in the

Standard solutionCU = concentration of Domperidone in the

Sample solutionAcceptance criteria

Any individual impurity: NMT 0.10%Total impurities: NMT 2.0%

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SPECIFIC TESTS

LOSS ON DRYING Analysis: Dry a sample at 105 to constant weight.Acceptance criteria: NMT 0.5%

ADDITIONAL REQUIREMENTS REFERENCE STANDARDS

USP Domperidone CRMUSP Domperidone Impurity A RS

5-Choloro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one.

USP Domperidone Impurity B RS4-(5-Choloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-formylpiperidine.

USP Domperidone Impurity C RScis-4-(5-Choloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]piperidine 1-oxide.

USP Domperidone Impurity D RS

5-Choloro-3-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]-1-[1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) propyl] piperidin-4-yl]- 1,3-dihydro-2H-benzimidazol-2-one.

USP Domperidone Impurity E RS1-[3-[4-(5-Choloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]propyl]-3-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]-1,3-dihydro-2H-benzimidazol-2-one.

USP Domperidone Impurity F RS1,3-bis[3-[4-(5-Choloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]propyl]-1,3-dihydro-2H-benzimidazol-2-one.

USP Domperidone Impurity G RS1-[1-[3-(p-Fluorobenzoyl)propyl]-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone.

REFERENCE PROCEDURES(This section provides detailed descriptions of

procedures that may be used for the evaluation ofthe material under test. These procedures have beenfully validated, and the data is available on the MCwebsite.)

ASSAY

PROCEDURESolution A: 10 mM ammonium acetate in water.Adjust with ammonium hydroxide solution to a pHof 7.0.

Solution B: Methanol and acetonitrile (1:1)Mobile phase: See Table 1.

Table 1Time(min)

Solution A(%)

Solution B(%)

0 60 40

30 45 55

35 30 70

45 30 70

47 60 40

50 60 40

System suitability solution: 0.5 g/mL each ofUSP Domperidone CRM and USP DomperidoneImpurity B RS and USP Domperidone Impurity CRS in methanol

Standard solution: 0.2 mg/mL of USPDomperidone CRM in methanol

Sample solution: 0.2 mg/mL of Domperidone inmethanol

Chromatographic system(See Chromatography , System Suitability.)Mode: LCDetector: PDA (scan 200700 nm). [NOTECalculations should be based on thechromatograms collected at 285 nm.][NOTETo confirm the absence of co-elutingknown and unknown impurity peaks, substitutethe DetectorunderReference Procedures,Impurities.]

Column: 4.6-mm 25-cm; 5-m packing L1(similar to Thermo Hypersil BDS)

Flow rate: 1 mL/minColumn oven temperature: 30Autosampler temperature: 5Injection volume: 20 L

System suitabilitySamples:System suitability solutionand Standardsolution

Suitability requirementsResolution: NLT 1.5 between the impurity Cand impurity B peaks, System suitabilitysolution

Relative standard deviation: NMT 1.0% for thedomperidone peak, Standard solution

AnalysisSamples:Standard solutionand Sample solutionCalculate the percentage of domperidone(C22H24ClN5O2) in the portion of the sample taken:

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

rU = peak response of domperidone from theSample solution

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rS = peak response of domperidone from theStandard solution

CS = concentration of USP Domperidone CRMin the Standard solution. [NOTEThepotency of the Reference Material isincluded in this term.]

CU

= concentration of Domperidone in theSample solution

IMPURITIES

ORGANIC IMPURITIESSolution A, Solution B, Mobile phase, Standard

solution, and Chromatographic system:Proceed as directed in Reference Procedures,Assay.

System suitability solution: Proceed as directedin the Standard solutionunderReferenceProcedures, Assay.

Standard solution: 0.5 g/mL each of USPDomperidone CRM, USP Domperidone Impurity A

RS, USP Domperidone Impurity B RS, USPDomperidone Impurity C RS, USP DomperidoneImpurity D RS, USP Domperidone Impurity F RS,and USP Domperidone Impurity G RS in methanol

Sample solution: 0.5 mg/mL of Domperidone inmethanolDetector: PDA and MS

PDA wavelengths: 200700 nm. [NOTECalculations should be made at an isobesticpoint of the drug substance and impurityspectra or at 285 nm if an isobestic point is notavailable.]MS source: ES scan (+ and )

MS conditionsSource temperature: 80Desolvation temperature: 450

System suitabilitySamples:Standard solutionand System suitabilitysolution

Suitability requirementsResolution: NLT 1.5 between the impurity C

and impurity B peaks, Standard solutionRelative standard deviation: NMT 1.0% for the

domperidone peak, System suitability solutionAnalysisSamples:Standard solutionand Sample solution

Calculate the percentage of each impurity in theportion of domperidone taken. [NOTEWhere animpurity other than those included in the Standardsolutionis found in the Sample solution, the peakresponse and concentration of domperidone inthe Standard solutionis used for the calculation.]

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

rU = peak response of each impurity from theSample solution

rS = peak response of each impurity from theStandard solution.

CS

= concentration of each impurity in theStandard solution. [NOTEThe potencyof the Reference Material is included inthis term.]

CU = concentration of Domperidone in theSample solution