. Mode: Revision Bulletin Official April 1, 2013 Cetirizine 1 Cetirizine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets Column: 30 LC Detector: UV 230 nm Column: 4.6-mm 15-cm; 3.5-µm packing L1 Temperatures Autosampler: 5 DEFINITION Flow rate: 1mL/min Cetirizine Hydrochloride and Pseudoephedrine Hydrochlo- ride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of cetirizine hydro- Sample: Standard chloride (C 21H 25ClN 2O 3 2HCl) and pseudoephedrine hy- drochloride (C 10H 15NO HCl). Column efficiency: NLT 3000 theoretical plates Tailing factor: NMT 1.5 IDENTIFICATION Relative standard deviation: NMT 2.0% A. The retention times of the major peaks of the Sample correspond to those of the Standard, as obtained in the Assay. Samples: Standard and Sample Calculate the percentage of cetirizine hydrochloride (C 21H 25ClN 2O 3 2HCl) in the portion of Tablets taken: ASSAY CETIRIZINE HYDROCHLORIDE Result = (r U/r S) (C S/C U) 100 Buffer: 3.5 g/l of monobasic ammonium phosphate and 1.0 g/l of tetrabutylammonium bisulfate in water. r U = peak response of cetirizine from the Sample Adjust with phosphoric acid to a ph of 2.5. Diluent: Methanol and Buffer (2:3) r S = peak response of cetirizine from the Standard Solution A: Acetonitrile, methanol, and Buffer (9:2:29) Solution B: Acetonitrile C S = concentration of USP Cetirizine Hydrochloride Mobile phase: See Table 1. RS in the Standard C U = nominal concentration of cetirizine Table 1 hydrochloride in the Sample Time Solution A Solution B Acceptance criteria: 90.0% 110.0% (min) (%) (%) PSEUDOEPHEDRINE HYDROCHLORIDE 0 100 0 Buffer: 0.8 g/l of ammonium acetate in water. To 1 L 27.0 100 0 of the add 1.0 ml of triethylamine. Adjust 30.0 0 100 30.1 100 0 35.0 100 0 Standard stock : 0.5 mg/ml of USP Cetirizine Hydrochloride RS in Diluent. [NOTE Sonicate to dissolve.] Standard : 0.025 mg/ml of USP Cetirizine Hy- drochloride RS in Diluent from the Standard stock Sample : 0.025 mg/ml of cetirizine hydrochlo- ride (from NMT 10 finely powdered Tablets) prepared as follows. Dissolve the Tablets first in methanol, using 22.5% of the final flask volume. Sonicate for NLT 20 min with vigorous swirling every 5 min. To the add a volume of Buffer equal to 26% of the final flask volume. Allow the to equilibrate to room tem- perature. Dilute with Diluent to volume. Pass a portion through a membrane filter of 0.45-µm pore size. with glacial acetic acid to a ph of 4.5. Mobile phase: Acetonitrile and Buffer (3:7) Standard : 0.5 mg/ml of USP Pseudoephedrine Hydrochloride RS in Mobile phase. [NOTE Sonicate to dissolve.] Sample stock : 2.4 mg/ml of pseudoephedrine hydrochloride (from 5 finely powdered Tablets) prepared as follows. Dissolve the crushed Tablets first in acetonitrile, using 24% of the final flask volume. Sonicate for NLT 15 min. To the add a volume of Buffer equal to 56% of the final flask volume. Sonicate for NLT 15 min. Shake the flask for NLT 10 min. Allow the to equilibrate to room temperature. Dilute with Mobile phase to volume. Centrifuge a portion for 15 min to obtain a clear supernatant. Sample : 0.5 mg/ml of pseudoephedrine hy- drochloride in Mobile phase from the Sample stock. Pass the through a membrane filter of 0.45-µm pore size. Detector: UV 254 nm Column: 4.6-mm 15-cm; 5-µm packing L9 Flow rate: 1.5 ml/min Run time: 2 times the retention time of pseudoephedrine
2 Cetirizine Official April 1, 2013 Calculate the percentage of cetirizine hydrochloride Sample: Standard dissolved: Column efficiency: NLT 1000 theoretical plates Result = (r U/r S) (C S/L) V 100 Tailing factor: NMT 2.0 Relative standard deviation: NMT 2.0% r U = peak response of cetirizine from the Sample Samples: Standard and Sample r S = peak response of cetirizine from the Standard Calculate the percentage of pseudoephedrine hydro- chloride (C 10H 15NO HCl) in the portion of Tablets C S = concentration of cetirizine hydrochloride in taken: the Standard L = label claim for cetirizine hydrochloride Result = (r U/r S) (C S/C U) 100 V = volume of Medium, 500 ml r U = peak response of pseudoephedrine from the Calculate the percentage of pseudoephedrine Sample hydrochloride dissolved at each time point: r S = peak response of pseudoephedrine from the Standard Q 30 = (r U/r S) (C S/L) V 100 Hydrochloride RS in the Standard Q 1 = (Q 30 5/500) + [(r U/r S) (C S/L) 495 100] C U = nominal concentration of pseudoephedrine hydrochloride in the Sample Q 2 = (Q 30 5/500) + (Q 1 5/495) + [(r U/r S) (C S/L) 490 100] Acceptance criteria: 90.0% 110.0% PERFORMANCE TESTS Q 6 = (Q 30 5/500) + (Q 1 5/495) + (Q 2 5/490) + [(r U/r S) (C S/L) 485 100] Change to read: r U = peak response of pseudoephedrine from the DISSOLUTION 711 Sample.Test r S = peak response of pseudoephedrine from the 1 (RB 1-Apr-2013) Medium: 0.1 N hydrochloric acid; 500 ml, deaerated Standard Apparatus 1: 100 rpm C S = concentration of pseudoephedrine Time: 30 min for cetirizine hydrochloride and 30 min hydrochloride in the Standard (used only for adjustments in the calculations); 1, 2, and 6 h for pseudoephedrine hydrochloride L = label claim for pseudoephedrine hydrochloride Buffer: 0.77 g/l of ammonium acetate in water. To 1 L of the add 1.0 ml of triethylamine. Adjust V = initial volume of Medium, 500 ml with glacial acetic acid to a ph of 4.5 ± 0.05..Tolerances Mobile phase: Acetonitrile and Buffer (3:7) Cetirizine hydrochloride: NLT 80% (Q) of the la- Standard stock : 0.5 mg/ml of USP Cein 30 min beled amount of cetirizine hydrochloride is dissolved tirizine Hydrochloride RS in water Standard : 0.24 mg/ml of USP Pseudoe- Pseudoephedrine hydrochloride (C 10H 15NO HCl): phedrine Hydrochloride RS and 0.01 mg/ml of USP See Table 2. Cetirizine Hydrochloride RS in Medium from the Standard stock Table 2 Sample : At the times specified, withdraw Time Amount 5 ml of the under test, and pass through a (h) Dissolved suitable filter of 0.45-µm pore size, discarding the first few ml. 1 30% 50% 2 50% 70% 6 NLT 80% Detector: UV, 230 nm for cetirizine hydrochloride, The percentages of the labeled amount of pseudoe- 254 nm for pseudoephedrine hydrochloride phedrine hydrochloride dissolved at the times speci- Column: 4.6-mm 15-cm; 5-µm packing L9 fied conform to Acceptance Table 2 in 711. Flow rate: 1.5 ml/min Test 2: If the product complies with this test, the label- ing indicates that it meets USP Dis Test 2. Run time: 2 times the retention time of Medium: 0.1 N HCl; 500 ml pseudoephedrine Apparatus 1: 100 rpm Time: 30 min for cetirizine hydrochloride and 30 min- Sample: Standard utes (used only for adjustments in the calculations); 1, 2, 4 and 8 h for pseudoephedrine hydrochloride Tailing factor: NMT 2.0 for both cetirizine and Buffer: 6.8 g/l of sodium acetate and 16.2 g/l of sopseudoephedrine dium 1-octanesulfonate Relative standard deviation: NMT 2.0% for both Mobile phase: Methanol and Buffer (50:50). Adjust cetirizine and pseudoephedrine with glacial acetic acid to a ph of 5.5. Standard : 0.01 mg/ml of USP Cetirizine Hydrochloride RS and 0.24 mg/ml of USP Pseudoephedrine Hydrochloride RS in Medium
Official April 1, 2013 Cetirizine 3 Sample : Pass a 5-mL portion of the C i = concentration of pseudoephedrine under test through a suitable filter of 0.45-µm pore hydrochloride in the portion of sample size. withdrawn at time point (i) V = volume of the Medium (500 ml) V S = volume of the Sample withdrawn from the Medium (ml) Detector: UV 242 nm L = label claim for pseudoephedrine hydrochloride Column: 4.6-mm 10-cm; 5-µm packing L1 Column temperature: 35 Tolerances Flow rate: 2 ml/min Cetirizine hydrochloride: NLT 75% (Q) of the la- Injection volume: 100 µl beled amount of cetirizine hydrochloride (C 21H 25ClN 2O 3 2HCl) is dissolved. [NOTE The relative retention times for pseudoephed- Pseudoephedrine hydrochloride (C 10H 15NO HCl): rine and cetirizine are 1.0 and 2.9, respectively.] See Table 3. Sample: Standard Table 3 Column efficiency: NLT 2000 theoretical plates for both pseudoephedrine and cetirizine Time point Time Amount Tailing factor: NMT 2.0 for both pseudoephedrine (i) (h) Dissolved and cetirizine 1 0.5 Relative standard deviation: NMT 2.0% for both 2 1 30% 50% pseudoephedrine and cetirizine 3 2 50% 70% 4 4 70% 90% Samples: Standard and Sample Calculate the percentage of the labeled amount of cetirizine 5 8 NLT 80% hydrochloride (C 21H 25ClN 2O 3 2HCl) dissolved: The percentages of the labeled amount of pseudoephedrine hydrochloride dissolved at the times speci- U/r S) (C S/L) V 100 Result = (r fied conform to Acceptance Table 2 in 711. (RB 1-Aprr 2013) U = peak response of cetirizine from the Sample UNIFORMITY OF DOSAGE UNITS 905 : Meet the r S = peak response of cetirizine from the Standard requirements IMPURITIES C S = concentration of USP Cetirizine Hydrochloride CETIRIZINE HYDROCHLORIDE RELATED COMPOUNDS RS in the Standard Buffer, Diluent, Solution A, and Solution B: Proceed L = label claim as directed in the Assay for Cetirizine hydrochloride. V = volume of Medium, 500 ml Mobile phase: See Table 4. Calculate the concentration (C i) of pseudoephedrine hydrochloride (C 10H 15NO HCl) in the sample withdrawn from the vessel at each time point (i) Table 4 shown in Table 3: Time Solution A Solution B Result i = (r U/r S) C S (min) (%) (%) 0 100 0 r U = peak response of pseudoephedrine from the 27 100 0 Sample 45 60 40 r S = peak response of pseudoephedrine from the 65 60 40 Standard 65.1 100 0 75 100 0 Hydrochloride RS in the Standard Standard stock : 0.5 mg/ml of USP Cetirizine Calculate the percentage of the labeled amounts (Q i) Hydrochloride RS in Diluent. [NOTE Sonicate to of pseudoephedrine hydrochloride (C 10H 15NO HCl) dissolve.] dissolved at each time point (i) shown in Table 3: Standard : 1 µg/ml of USP Cetirizine Hydrochloride Result 1 = C 1 V (1/L) 100 RS in Diluent from the Standard stock Sample stock : 0.5 mg/ml of cetirizine hydrochloride (from NMT 10 finely powdered Tablets) prepared Result 2 = {[C 2 (V V s)] + (C 1 V s)} (1/L) 100 as follows. Dissolve the Tablets first in methanol, using 70% of the final flask volume. Sonicate for 15 min, and then shake for 15 min. Allow the to Result 3 = {[C 3 [V (2 V S)]] + [(C 2 + C 1) V S]} (1/L) cool to room temperature, and dilute with methanol to 100 volume. Centrifuge a portion for 10 min. Sample : 0.2 mg/ml of cetirizine hydrochloride in Buffer from the Sample stock. Pass a por- Result 4 = {[C 4 [V (3 V S)]] + [(C 3 + C 2 + C 1) V S]} (1/L) 100 tion through a suitable membrane filter of 0.45-µm pore size. Result 5 = {[C 5 [V (4 V S)]] + [(C 4 + C 3 + C 2 + C 1) V S]} (1/L) 100
4 Cetirizine Official April 1, 2013 Standard stock : 0.48 mg/ml of USP Pseudoe- Detector: UV 230 nm phedrine Hydrochloride RS in Diluent Column: 4.6-mm 15-cm; 3.5-µm packing L1 Standard : 4.8 µg/ml of USP Pseudoephedrine Temperatures Hydrochloride RS in Diluent from the Standard stock Column: 30 Autosampler: 5 stock : 49 µg/ml of ephe- Flow rate: 1 ml/min drine in Diluent from USP Ephedrine Sulfate RS : 1.96 µg/ml of ephedrine and 0.46 mg/ml of USP Pseudoephedrine Hydrochlo- Sample: Standard ride RS in Standard stock from the System suita- bility stock and the Standard stock, Column efficiency: NLT 1300 theoretical plates respectively Tailing factor: NMT 2.0 Sample stock : 2.4 mg/ml of pseudoephed- Relative standard deviation: NMT 5.0% rine hydrochloride (from NMT 25 finely powdered Tab- lets) prepared as follows. Dissolve the Tablets first in Samples: Standard and Sample methanol, using 75% of the final flask volume. Soni- Calculate the percentage of each impurity in the por- cate for NLT 15 min, and then shake for 15 min. Allow tion of Tablets taken: the to cool to room temperature, and dilute with methanol to volume. Centrifuge a portion for 10 Result = (r U/r S) (C S/C U) (1/F) 100 min. Sample : 0.48 mg/ml of pseudoephedrine hyr U = peak response of the individual impurity from drochloride in Diluent from the Sample stock. the Sample Pass a portion through a suitable membrane filter of r S = peak response of cetirizine from the Standard 0.45-µm pore size. C S = concentration of USP Cetirizine Hydrochloride RS in the Standard C U = nominal concentration of cetirizine Detector: UV 212 nm hydrochloride in the Sample Column: 4.6-mm 25-cm; 4-µm packing L11 Column temperature: 40 F = relative response factor (see Table 5) Flow rate: 1 ml/min Acceptance criteria: See Table 5. Injection volume: 30 µl [NOTE Disregard any peak less than 0.05% of the main peak.] Samples: Standard and Table 5 Re: NLT 1.3 between ephedrine and pseu- Relative Relative Acceptance doephedrine, Retention Response Criteria, Tailing factor: NMT 1.5, Standard Name Time Factor NMT (%) Relative standard deviation: NMT 3.0%, Standard Cetirizineethanol 0.54 1.4 0.3 a. Chlorobenzhydryl piperazine (CBHP) b. 0.57 1.5 0.3 Samples: Standard and Sample Cetirizine 1.0 Calculate the percentage of each impurity in the por- Cetirizine acetic acid 1.30 1.1 0.3 tion of Tablets taken: Cetirizine N-Oxide 1.47 1.2 0.3 Result = (r d. U/r S) (C S/C U) (1/F) 100 Any unspecified deg- radation product 1.0 0.2 r U = peak response of the individual impurity from Total impurities 0.8 the Sample r a. 2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]ethanol. S = peak response of pseudoephedrine from the 1-[(4-Chlorophenyl)phenylmethyl]piperazine. Standard b. c. 2-[4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl]acetic acid. 2-[4-[(4-Chlorophenyl)phenylmethyl]-1-oxide-1-piperazinyl]ethoxy]acetic Hydrochloride RS in the Standard d. acid. C U = nominal concentration of pseudoephedrine PSEUDOEPHEDRINE HYDROCHLORIDE RELATED COMPOUNDS Buffer: 11.2 g/l of sodium perchlorate monohydrate in hydrochloride in the Sample water. Adjust with hydrochloric acid to a ph of 2.7. Solution A: Methanol and Buffer (3:17) F = relative response factor (see Table 7) Solution B: Methanol and Buffer (1:1) Acceptance criteria: See Table 7. Diluent: Solution A [NOTE Disregard any peak less than 0.05% of the Mobile phase: See Table 6. main peak.] Table 6 Time Solution A Solution B (min) (%) (%) 0 100 0 10 100 0 35 28 72
Official April 1, 2013 Cetirizine 5.. Table 7 ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in well-closed con- Relative Relative Acceptance tainers. Store at controlled room temperature. Retention Response Criteria, Name Time Factor NMT (%) Ephedrine, b a. 0.95 Add the following: Pseudoephedrine 1.0 Methcathinone 1.1 1.1 0.2. LABELING: When more than one Dis test is given, the labeling states the Dis test used only if c. Any unspecified deg- Test 1 is not used. (RB 1-Apr-2013) radation product 1.0 0.2 USP REFERENCE STANDARDS 11 Total pseudoephed- USP Cetirizine Hydrochloride RS rine related impuri- USP Ephedrine Sulfate RS ties 0.5 USP Pseudoephedrine Hydrochloride RS a. [R-(R*,S*)]-α-[1-(Methylamino)ethyl]-benzenemethanol. b. For system suitability and identification purposes only. c. 2-Methylamino-1-phenylpropan-1-one. Sum of cetirizine and pseudoephedrine related impurities: NMT 1.0%