DOMPERIDONE

Calculate the percentage of domperidone (C22H24ClN5O2) in the Sample solution: Result = (rU/rS) (CS/CU) 100 rU = response from the Sample solution rS = response from the Standard solution CS = concentration of the Standard solution CU = concentration of the Sample solution Acceptance criteria: 98.0%102.0% on the dried basis

C22H24ClN5O2

425.91

2H-Benzimidazol-2-one, 5-chloro-1-[1-[3-(2,3-dihydro2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3- IMPURITIES RESIDUE ON IGNITION <281>: NMT 0.1% dihydro-; ELEMENTAL IMPURITIES <232>: Proceed as directed 5-Chloro-1-[1-[3-(2-oxo-1-benzimidazolinyl)propyl]-4in the chapter. piperidyl]-2-benzimidazolinone [57808-66-9]. RESIDUAL SOLVENTS <467>: Proceed as directed in the chapter. Domperidone is a slightly white to almost white, ORGANIC IMPURITIES powder. It is very slightly soluble in water; sparingly Standard solution: USP Domperidone CRM and soluble in dimethylformamide; slightly soluble in all appropriate USP Impurity RSs, at methanol; and very slightly soluble in alcohol. concentrations corresponding to the Acceptance criteria of the impurity, in an appropriate diluent Performance-Based Monograph Sample solution: Domperidone in an appropriate (Contains tests, procedures, and acceptance criteria diluent for the material under test. It also includes the Analytical system: Use a procedure validated as criteria-based procedures necessary to demonstrate described in MC general chapter Assessing that an Acceptable Procedure is equivalent to the Validation Parameters for Reference and Reference Procedures.) Acceptable Procedures <10>. System performance requirements DEFINITION Precision: Meets the requirements Domperidone contains NLT 98.0% and NMT 102.0% Accuracy: Meets the requirements of domperidone (C22H24ClN5O2), calculated on the Ruggedness: Meets the requirements dried basis. Specificity: Meets the requirements Analysis IDENTIFICATION Samples: Standard solution and Sample solution A. INFRARED ABSORPTION <197K> Calculate the percentage of each impurity in the Sample solution: ASSAY PROCEDURE Result = (rU/rS) (CS/CU) 100 Standard solution: USP Domperidone CRM in an appropriate diluent rU = response of each impurity from the Sample solution: Domperidone in an appropriate Sample solution diluent r = response of each USP Impurity RS from S Analytical system: Use a procedure validated as the Standard solution. [NOTEIf no USP described in MC general chapter Assessing Impurity RSs are available, use the Validation Parameters for Reference and response of domperidone.] Acceptable Procedures <10>. CS = concentration of standard material in the System performance requirements Standard solution Precision: Meets the requirements C = concentration of Domperidone in the U Accuracy: Meets the requirements Sample solution Specificity: Meets the requirements Acceptance criteria Range: Meets the requirements Any individual impurity: NMT 0.10% Analysis Total impurities: NMT 2.0% Samples: Standard solution and Sample solution

SPECIFIC TESTS LOSS ON DRYING <731> Analysis: Dry a sample at 105 to constant weight. Acceptance criteria: NMT 0.5% ADDITIONAL REQUIREMENTS REFERENCE STANDARDS <11> USP Domperidone CRM USP Domperidone Impurity A RS 5-Choloro-1-(piperidin-4-yl)-1,3-dihydro-2Hbenzimidazol-2-one. USP Domperidone Impurity B RS 4-(5-Choloro-2-oxo-2,3-dihydro-1H-benzimidazol1-yl)-1-formylpiperidine. USP Domperidone Impurity C RS cis-4-(5-Choloro-2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)-1-[3-(2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)propyl]piperidine 1-oxide. USP Domperidone Impurity D RS 5-Choloro-3-[3-(2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)propyl]-1-[1-[3-(2-oxo-2,3dihydro-1H-benzimidazol-1-yl) propyl] piperidin-4yl]- 1,3-dihydro-2H-benzimidazol-2-one. USP Domperidone Impurity E RS 1-[3-[4-(5-Choloro-2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)piperidin-1-yl]propyl]-3-[3-(2oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]-1,3dihydro-2H-benzimidazol-2-one. USP Domperidone Impurity F RS 1,3-bis[3-[4-(5-Choloro-2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)piperidin-1-yl]propyl]-1,3dihydro-2H-benzimidazol-2-one. USP Domperidone Impurity G RS 1-[1-[3-(p-Fluorobenzoyl)propyl]-1,2,3,6tetrahydro-4-pyridyl]-2-benzimidazolinone.

Time (min) 0 30 35 45 47 50

Table 1 Solution A (%) 60 45 30 30 60 60

Solution B (%) 40 55 70 70 40 40

REFERENCE PROCEDURES (This section provides detailed descriptions of procedures that may be used for the evaluation of the material under test. These procedures have been fully validated, and the data is available on the MC website.) ASSAY PROCEDURE Solution A: 10 mM ammonium acetate in water. Adjust with ammonium hydroxide solution to a pH of 7.0. Solution B: Methanol and acetonitrile (1:1) Mobile phase: See Table 1.

System suitability solution: 0.5 g/mL each of USP Domperidone CRM and USP Domperidone Impurity B RS and USP Domperidone Impurity C RS in methanol Standard solution: 0.2 mg/mL of USP Domperidone CRM in methanol Sample solution: 0.2 mg/mL of Domperidone in methanol Chromatographic system (See Chromatography <621>, System Suitability.) Mode: LC Detector: PDA (scan 200700 nm). [NOTE Calculations should be based on the chromatograms collected at 285 nm.] [NOTETo confirm the absence of co-eluting known and unknown impurity peaks, substitute the Detector under Reference Procedures, Impurities.] Column: 4.6-mm 25-cm; 5-m packing L1 (similar to Thermo Hypersil BDS) Flow rate: 1 mL/min Column oven temperature: 30 Autosampler temperature: 5 Injection volume: 20 L System suitability Samples: System suitability solution and Standard solution Suitability requirements Resolution: NLT 1.5 between the impurity C and impurity B peaks, System suitability solution Relative standard deviation: NMT 1.0% for the domperidone peak, Standard solution Analysis Samples: Standard solution and Sample solution Calculate the percentage of domperidone (C22H24ClN5O2) in the portion of the sample taken: Result = (rU/rS) (CS/CU) 100 rU = peak response of domperidone from the Sample solution

rS CS

CU

= peak response of domperidone from the Standard solution = concentration of USP Domperidone CRM in the Standard solution. [NOTEThe potency of the Reference Material is included in this term.] = concentration of Domperidone in the Sample solution

Result = (rU/rS) (CS/CU) 100 rU rS CS = peak response of each impurity from the Sample solution = peak response of each impurity from the Standard solution. = concentration of each impurity in the Standard solution. [NOTEThe potency of the Reference Material is included in this term.] = concentration of Domperidone in the Sample solution

IMPURITIES ORGANIC IMPURITIES Solution A, Solution B, Mobile phase, Standard solution, and Chromatographic system: Proceed as directed in Reference Procedures, Assay. System suitability solution: Proceed as directed in the Standard solution under Reference Procedures, Assay. Standard solution: 0.5 g/mL each of USP Domperidone CRM, USP Domperidone Impurity A RS, USP Domperidone Impurity B RS, USP Domperidone Impurity C RS, USP Domperidone Impurity D RS, USP Domperidone Impurity F RS, and USP Domperidone Impurity G RS in methanol Sample solution: 0.5 mg/mL of Domperidone in methanol Detector: PDA and MS PDA wavelengths: 200700 nm. [NOTE Calculations should be made at an isobestic point of the drug substance and impurity spectra or at 285 nm if an isobestic point is not available.] MS source: ES scan (+ and ) MS conditions Source temperature: 80 Desolvation temperature: 450 System suitability Samples: Standard solution and System suitability solution Suitability requirements Resolution: NLT 1.5 between the impurity C and impurity B peaks, Standard solution Relative standard deviation: NMT 1.0% for the domperidone peak, System suitability solution Analysis Samples: Standard solution and Sample solution Calculate the percentage of each impurity in the portion of domperidone taken. [NOTEWhere an impurity other than those included in the Standard solution is found in the Sample solution, the peak response and concentration of domperidone in the Standard solution is used for the calculation.]

CU