INTERIM REVISION ANNOUNCEMENT

Transcription

1 INTERIM REVISION ANNOUNCEMENT In this section readers will find the following: The list of new USP Reference Standards that have become available The list of assays or tests that are adopted but held in abeyance pending availability of required USP Reference Standards Newly adopted (official) revisions to the USP NF that become official before the official date of the next Supplement or that were not ready for adoption by the closing date for the upcoming Supplement. (The official date for these revisions is stated on the next page.) Errata Readers should review this section to determine if they are affected by any of the changes. Symbols New. text is enclosed in symbols and set off from the current official text as shown in the following example: new text. Where the symbols appear together with no enclosed text, such as.., it means that text has been deleted and no new text was proposed to replace it. In all revisions, the closing symbol is accompanied by an identifier that indicates the issue of a given PF volume. Errata Errata are considered to be text, erroneously published in the USP NF or its Supplements, that do not accurately reflect the intended official requirements of the Council of Experts. At the end of the section in this publication is a list of errata and corrections to the USP NF. The page number indicates where the item is found in USP NF. Errata lists are updated as necessary in each and also appear on USP s website ( Errata lists will be cumulative in future Supplements, and the corrected text will appear in the next annual edition of USP NF.

2 1128 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT Cephalexin Cephalexin Capsules Cephalexin for Oral Suspension Cephalexin Tablets Cephalexin Tablets for Oral Suspension Cephalexin Hydrochloride Glacial Acetic Acid Protamine Sulfate Protamine Sulfate Injection Protamine Sulfate for Injection ERRATA LIST FOR USP 32 NF # 2010 The United States Pharmacopeial Convention All Rights Reserved.

3 Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1129 INTERIM REVISION ANNOUNCEMENT to USP 33 and to NF 28 REISSUE By authority of the United States Pharmacopeial Convention, Inc. Prepared by the Council of Experts and published by the Board of Trustees Duane M. Kirking, Pharm.D., Ph.D., Chair, USP Board of Trustees, USP Trustee At-Large Roger L. Williams, M.D., Chief Executive Officer and Chairman, USP Council of Experts Susan de Mars, J.D., Chief Documentary Standards Officer and General Counsel William F. Koch, Ph.D., FACB, Chief Standards Acquisition and Metrology Officer Released September 1, 2010 Official October 1, 2010 Inquiries regarding USP NF can be addressed to the USP Executive Secretariat, Twinbrook Parkway, Rockville, MD 20852, USA # 2010 The United States Pharmacopeial Convention All Rights Reserved.

4 1130 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] New USP Reference Standards The following USP Reference Standards, which were not available when the associated monograph was made official, have since become available. The respective official date of each USP NF standard, test, or assay requiring the use of the following USP Reference Standards is indicated in parentheses after the name of the Reference Standard. Note that the official date is six months after the notice of availability for this Reference Standard was published in PF. USP Powdered Echinacea Pallida Extract RS (February 1, 2011) USP Oleyl Oleate RS (September 1, 2010) Unavailable First-Time Official USP Reference Standards The official dates of any USP NF standards, tests, or assays requiring the use of the following new USP Reference Standards are postponed until further notice pending availability of the respective Reference Standards. This listing was updated as of June 15, Please refer to the current USP Catalog for a more upto-date availability list. The USP Catalog can be accessed on-line at USP Acarbose RS USP Acarbose System Suitability Mixture RS USP Albumin Human RS USP Alteplase RS USP Amifostine RS USP Amifostine Thiol RS USP Antithrombin III Human RS USP Aprotinin RS USP Aprotinin System Suitability RS USP Copolymer Polypropylene RS USP Diethylstilbestrol Diphosphate RS USP Eucatropine Hydrochloride RS USP Gonadorelin Hydrochloride RS USP Hemoglobin RS USP Maritime Pine Extract RS USP Menotropins RS USP Sargramostim RS USP Sincalide RS USP Valrubicin Related Compound A RS # 2010 The United States Pharmacopeial Convention All Rights Reserved.

5 . wavelength Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1131 MONOGRAPHS (USP) Cephalexin Allow the spots to dry, and place the plate in a saturated chamber containing the solvent system and lined with filter paper. Develop the chromatogram until the solvent front has moved three-fourths of the length of the plate. Remove the plate from the developing chamber, mark the solvent front, allow the plate to air-dry, and examine under short- UV light. Acceptance criteria: The R F value of the principal spot of the Sample solution corresponds to that of the Standard solution. 5 C 16H 17N 3O 4S H 2O Mobile phase: g/l of sodium-1-pentanesulfonate in a C 16H 17N 3O 4S mixture of acetonitrile, methanol, triethylamine, and water 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[(ami- (20:10:3:170), adjusted with phosphoric acid to a ph of nophenylacetyl)amino]-3-methyl-8-oxo-, monohydrate, [6R-[6α, 3.0 ± 0.1 7β (R*)]]-; 5 (6R,7R)-7-[(R)-2-Amino-2-phenylacetamido]-3-methyl-8-oxo-5- Standard stock solution: 1 mg/ml of USP Cephalexin RS in thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohy- water Standard solution: drate [ ]. 0.4 mg/ml of cephalexin in Mobile phase Anhydrous [ ]. from Standard stock solution Sample stock solution: 1 mg/ml 5 of Cephalexin in water DEFINITION Sample solution: 0.4 mg/ml of Cephalexin in Mobile phase Cephalexin has a potency of NLT 950 µg and NMT 1030 µg of C 16H 17N 3O 4S/mg, calculated on the anhydrous basis. from Sample stock solution 5 IDENTIFICATION A. INFRARED ABSORPTION 197K Delete the following: B. ULTRAVIOLET ABSORPTION 197U 5 Detector: UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity Flow rate: 1.5 ml/min Injection size: 20 µl Sample: Standard solution Sample solution: 0.02 mg/ml of Cephalexin in water Standard solution: 0.02 mg/ml of USP Cephalexin RS in Suitability requirements water 5 Absorptivity: On the anhydrous basis, at peak maxima about Relative standard deviation: NMT 2.0% 262 nm: 95.0% 104.0% of Sample solution to Standard solu- tion corrected for potency Acceptance criteria: Peak maxima and minima at the same Calculate the quantity, in µg, of C 16H 17N 3O 4S per mg of the Cephalexin taken: wavelengths 5 Result = (ru/r S) (C S/C U) P Add the following: r U = peak response from the Sample solution r S = peak response from the Standard solution 5 B. The retention time of the major peak of the Sample solu- C S = concentration of USP Cephalexin RS in the Stantion corresponds to that of the Standard solution, as obtained dard solution (mg/ml) in the Assay. 5 C U = concentration of Cephalexin in the Sample solution (mg/ml) Delete the following: P = designated content of cephalexin in USP Cephalexin RS (µg/mg) C. THIN-LAYER CHROMATOGRAPHY Acceptance criteria: µg/mg on the anhydrous basis Standard solution: 25 mg/ml of USP Cephalexin RS in water with the aid of 0.1 N hydrochloric acid IMPURITIES Sample solution: 25 mg/ml in water, with 0.1 N hydrochloric Organic Impurities acid 1 Solution A: Dissolve 1 g of sodium 1-pentanesulfonate in a (See Chromatography 621, Thin-Layer Chromatography.) mixture of 1000 ml of water and 15 ml of triethylamine. Mode: TLC Adjust with phosphoric acid to a ph of 2.5 ± 0.1. Adsorbent: 0.25-mm layer of chromatographic silica gel Solution B: Dissolve 1 g of sodium 1-pentanesulfonate in a mixture mixture of 300 ml of water and 15 ml of triethylamine. Application volume: 5 µl Adjust with phosphoric acid to a ph of 2.5 ± 0.1, and add Developing solvent system: Ethyl acetate, acetonitrile, glacial 350 ml of acetonitrile and 350 ml of methanol. acetic acid, and water (21:7:7:9)

6 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] Mobile phase: See the gradient table below. IDENTIFICATION Time Solution A Solution B Delete the following: (min) (%) (%) A. THIN-LAYER CHROMATOGRAPHY Standard solution: 3 mg/ml of USP Cephalexin RS in water Sample solution: 3 mg/ml of cephalexin from Capsules in water and filter Diluent: 18 mg/ml of monobasic potassium phosphate in (See Chromatography 621, Thin-Layer Chromatography.) water Mode: TLC Standard solutions: 0.08 mg/ml and 0.16 mg/ml of Adsorbent: 0.25-mm layer of binder-free silica gel C 16H 17N 3O 4S from USP Cephalexin RS in Diluent, taking into Application volume: 10 µl account the stated potency the USP Cephalexin RS Pre-developing solvent system: n-hexane and tetradecane Sample solution: 5 mg/ml of Cephalexin in Diluent (95:5) Ninhydrin solution: 66.7 mg/ml of ninhydrin in acetone Developing solvent system: 0.1 M citric acid, 0.1 M dibasic sodium phosphate, and Ninhydrin solution (60:40:1.5) Detector: UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity Flow rate: 1 ml/min Allow the solvent front to move the length of the plate in Injection size: 20 µl the Pre-developing solvent system, remove the plate from the chamber, and allow the solvent to evaporate. On this plate Samples: Standard solutions and Sample solution apply 10 µl each of the Sample solution and Standard solu- Plot the responses of cephalexin peaks from the Stantion. Allow the spots to dry, and develop the chromatogram dard solutions versus their concentrations, calculated on the in the Developing solvent system until the solvent front has anhydrous basis, in mg/ml, and draw a straight line moved three-fourths of the length of the plate. Remove the through the two points and zero. From the line so obplate from the developing chamber, mark the solvent front, tained and the peak responses of the Sample solution, dedry the plate for 10 min at 110, and examine the termine the concentration, I, in mg/ml, of each chromatogram. cephalexin-related substance of the Sample solution other Acceptance criteria: The R F value of the principal spot of the than the cephalexin peak. Sample solution corresponds to that of the Standard Calculate the percentage of each cephalexin-related substance: solution. 5 Result = I/C 100 Add the following: I = concentration of each cephalexin-related substance in the Sample solution as determined The retention time of the major peak of the Sample solufrom the calibration curve (mg/ml) 5 tion corresponds to that of the Standard solution, as ob- Acceptance criteria tained in the Assay. Individual impurities: NMT 1.0% of any individual 5 cephalexin-related substance Total impurities: NMT 5.0% 2: DIMETHYLANILINE 223 : Meets the requirement OPTICAL ROTATION, Specific Rotation 781S : +149 to +158 Sample solution: 5 mg/ml, in ph 4.4 neutralized phthalate buffer (See Reagents, Indicators, and Solutions Buffer Solutions) CRYSTALLINITY 695 : Meets the requirements PH 791 : , in an aqueous suspension containing 50 Mobile phase: g/l of sodium 1-pentanesulfonate in a mixture of acetonitrile, methanol, triethylamine, and water (20:10:3:170), adjusted with phosphoric acid to a ph of 3.0 ± 0.1 mg/ml 5 WATER DETERMINATION, Method I 921 : 4.0% 8.0% Standard stock solution: 1 mg/ml of USP Cephalexin RS in ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers. USP REFERENCE STANDARDS 11 USP Cephalexin RS Cephalexin Capsules DEFINITION Cephalexin Capsules contain the equivalent of NLT 90.0% and NMT 120.0% of the labeled amount of cephalexin (C 16H 17N 3O 4S). water Standard solution: 0.4 mg/ml of cephalexin in Mobile phase from Standard stock solution Sample stock solution: Equivalent 5 to 1 mg/ml of cephalexin from combined contents of NLT 20 Capsules in water. Sonicate, if necessary, to dissolve the cephalexin. Filter, if necessary, to obtain a clear solution. Sample solution: 0.4 mg/ml of cephalexin in Mobile phase from Sample stock solution 5 Detector: UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity Flow rate: 1.5 ml/min Injection size: 20 µl Sample: Standard solution 5

7 . Detector: Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1133 Suitability requirements Ninhydrin solution: 66.7 mg/ml of ninhydrin in acetone 5 Relative standard deviation: NMT 2.0% Mode: TLC Adsorbent: 0.25-mm layer of binder-free silica gel Application volume: 10 µl Calculate the percentage of C 16H 17N 3O 4S in the portion of Pre-developing solvent: n-hexane and tetradecane (95:5) Capsules taken: Developing solvent: 0.1 M citric acid, 0.1 M dibasic sodium phosphate, and Ninhydrin solution (120:80:3) Result = (ru/r S) (C S/C U) P F 100 r U response from the Sample solution Place the plate in Pre-developing solvent at a depth of 1 cm r S response from the Standard solution 5 and allow the solvent front to move the length of the plate, C S = concentration of USP Cephalexin RS in the Stan- remove the plate from the chamber, and allow the solvent dard solution (mg/ml) to evaporate. On this plate apply 10 µl each of the Sample C U = nominal concentration of cephalexin in the Sam- solution and the Standard solution. Allow the spots to dry, ple solution (mg/ml) and develop the chromatogram in the Developing solvent P = designated content of cephalexin in USP until the solvent front has moved three-fourths of the length Cephalexin RS (µg/mg) of the plate. Remove the plate from the developing cham- F = unit conversion factor, mg/µg ber, mark the solvent front, dry the plate for 10 min at Acceptance criteria: 90.0% 120.0% 110, and examine the chromatogram. Acceptance criteria: The R F value of the principal spot of the PERFORMANCE TESTS Sample solution corresponds to that of the Standard DISSOLUTION 711 solution 5 Medium: Water; 900 ml Apparatus 1: 100 rpm Add the following: Time: 30 min Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium, if necessary, to a The retention time of the major peak of the Sample solution concentration of about 20 µg/ml. corresponds to that of the Standard solution, as obtained in Standard solution: 20 µg/ml of USP Cephalexin RS in the Assay. 5 Medium Spectrometric conditions (See Spectrophotometry and Light-Scattering 851.) Mode: UV Analytical wavelength: 262 nm Tolerances: NLT 80% (Q) of the labeled amount of Mobile phase: g/l of sodium 1-pentanesulfonate in C 16H 17N 3O 4S is dissolved. acetonitrile, methanol, triethylamine, and water (20:10:3:170), UNIFORMITY OF DOSAGE UNITS 905 : Meet the requirements adjusted with phosphoric acid to a ph of 3.0 ± 0.1 Standard stock solution: 1 mg/ml of USP Cephalexin RS in water Standard solution: Mix 10.0 ml of Standard stock solution with 15.0 ml of Mobile phase. Delete the following: 5 WATER DETERMINATION, Method I 921 : NMT 10.0% 5 ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers. USP REFERENCE STANDARDS 11 USP Cephalexin RS Cephalexin for Oral Suspension DEFINITION Cephalexin for Oral Suspension is a dry mixture of Cephalexin and one or more suitable buffers, colors, diluents, and flavors. It contains the equivalent of NLT 90.0% and NMT 120.0% of the labeled amount of C 16H 17N 3O 4S per ml when constituted as directed in the labeling. IDENTIFICATION Delete the following: Sample stock solution: Nominally equivalent to 1 mg/ml of cephalexin from Oral Suspension, constituted as directed in the labeling, freshly mixed and free from air bubbles. Sonicate, if necessary, to assure complete dissolution of the cephalexin. Filter, if necessary, to obtain a clear solution. Sample solution: Mix 10.0 ml of Sample stock solution and 15.0 ml of Mobile phase. UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity Flow rate: 1.5 ml/min Injection size: 20 µl Sample: Standard solution 5 Suitability requirements 5 Relative standard deviation: NMT 2.0% Calculate the percentage of C 16H 17N 3O 4S in each ml of Oral Suspension taken: A. THIN-LAYER CHROMATOGRAPHY Standard solution: 3 mg/ml of USP Cephalexin RS in water Sample solution: 3 mg/ml of Cephalexin, from Oral Suspen- sion constituted as directed in the labeling and filtered r U r S Result = (r U/r S) (C S/C U) P F 100 = cephalexin peak response from the Sample solution = cephalexin peak response from the Standard solution

8 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] C S = concentration of USP Cephalexin RS in the Standard stock solution (mg/ml) Add the following: C U = nominal concentration of cephalexin from the Sample stock solution (mg/ml) The retention time of the major peak of the Sample solution P = designated potency of USP Cephalexin RS corresponds to that of the Standard solution, as obtained in (µg/mg) the Assay. F = unit conversion factor, mg/µg 5 Acceptance criteria: 90.0% 120.0% PERFORMANCE TESTS UNIFORMITY OF DOSAGE UNITS 905 For solid packaged in single-unit containers: meets the requirements DELIVERABLE VOLUME 698 : Meets the requirements Mobile phase: g/l of sodium 1-pentanesulfonate in a mixture of acetonitrile, methanol, triethylamine, and water (20:10:3:170). Adjust with phosphoric acid to a ph of Delete the following: 3.0 ± WATER DETERMINATION, Method I 921 : NMT 2.0% 5 PH 791 : , constituted as directed in the labeling ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers. USP REFERENCE STANDARDS 11 USP Cephalexin RS Standard stock solution: 1 mg/ml of USP Cephalexin RS in water Standard solution: 0.4 mg/ml of cephalexin in Mobile phase from Standard stock solution Sample stock solution: Equivalent 5 to 1 mg/ml of cephalexin from combined contents of powdered Tablets (NLT 20) in water. Sonicate, if necessary, to assure complete dissolution of the cephalexin. Filter, if necessary, to obtain a clear solution. Sample solution: 0.4 mg/ml of cephalexin in Mobile phase from Sample stock solution 5 Cephalexin Tablets Detector: UV 254 nm DEFINITION Column: 4.6-mm 25-cm; packing L1 of low acidity Cephalexin Tablets are prepared from Cephalexin or Cephalexin Flow rate: 1.5 ml/min Hydrochloride. They contain the equivalent of NLT 90.0% and Injection size: 20 µl NMT 120.0% of the labeled amount of cephalexin (C 16H 17N 3O 4S). Sample: Standard solution IDENTIFICATION 5 Suitability requirements 5 Delete the following: Relative standard deviation: NMT 2.0% THIN-LAYER CHROMATOGRAPHY Calculate the percentage of C 16H 17N 3O 4S in the portion of Standard solution: 3 mg/ml of USP Cephalexin RS in water Tablets taken: Sample solution: 3 mg/ml of cephalexin from powdered Tablets in water and filter Result = (ru/r S) (C S/C U) P F 100 (See Chromatography 621, Thin-Layer Chromatography.) r U = peak response from the Sample solution Mode: TLC r S = peak response from the Standard solution C 5 Adsorbent: 0.25-mm layer of binder-free silica gel S = concentration of USP Cephalexin RS in the Stan- Application volume: 10 µl dard solution (mg/ml) Pre-developing solvent system: n-hexane and tetradecane C U = nominal concentration of cephalexin in the Sam- (95:5) ple solution (mg/ml) Ninhydrin solution: 66.7 mg/ml of ninhydrin in acetone P = designated content of cephalexin in USP Developing solvent system: 0.1 M citric acid, 0.1 M dibasic Cephalexin RS (µg/mg) sodium phosphate, and Ninhydrin solution (60:40:1.5) F = unit conversion factor, mg/µg Acceptance criteria: 90.0% 120.0% Allow the solvent front to move the length of the plate in PERFORMANCE TESTS the Pre-developing solvent system, remove the plate from the DISSOLUTION 711 chamber, and allow the solvent to evaporate. On this plate, For Cephalexin apply 10 µl each of the Sample solution and Standard solu- Medium: Water; 900 ml tion. Allow the spots to dry, and develop the chromatogram Apparatus 1: Use 40-mesh cloth and 100 rpm in the Developing solvent system until solvent front has Time: 30 min moved three-fourths of the length of the plate. Remove the Sample solution: Pass a portion of the solution under test plate from the developing chamber, mark the solvent front, through a suitable filter. Dilute, if necessary, with Medium to dry the plate for 10 min at 110, and examine the a concentration that is similar to the Standard solution. chromatogram. Standard solution: 20 µg/ml of USP Cephalexin RS in Acceptance criteria: The R F value of the principal spot of the Medium Sample solution corresponds to that of the Standard Spectrometric conditions solution. 5 (See Spectrophotometry and Light-Scattering 851.)

9 . Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1135 Mode: UV Add the following: Analytical wavelength: 262 nm The retention time of the major peak of the Sample solution Tolerances: NLT 80% (Q) of the labeled amount of corresponds to that of the Standard solution, as obtained in C 16H 17N 3O 4S is dissolved. the Assay. For Cephalexin hydrochloride 5 Medium, Sample solution, Standard solution, Spectrometric conditions, and : Proceed as directed For Cephalexin. Apparatus 1: Use 10-mesh cloth and 150 rpm Time: 45 min Tolerances: NLT 75% (Q) of the labeled amount of C 16H 17N 3O 4S is dissolved. Mobile phase: g/l of sodium 1-pentanesulfonate in a UNIFORMITY OF DOSAGE UNITS 905 : Meet the requirements mixture of acetonitrile, methanol, triethylamine, and water (20:10:3:170), adjusted with phosphoric acid to a ph of 3.0 ± 0.1 Delete the following: Standard stock solution: 1 mg/ml of USP Cephalexin RS in water Standard solution: 0.4 mg/ml of cephalexin in Mobile phase WATER DETERMINATION, Method I 921 : NMT 9.0% where from Standard stock solution 5 Tablets contain Cephalexin; NMT 8.0% where Tablets contain Sample stock solution: Nominally equivalent to 1 mg/ml of Cephalexin Hydrochloride 5 cephalexin from combined contents of NLT 20 powdered Tablets for Oral Suspension in water. Pass a portion of the solu- ADDITIONAL REQUIREMENTS tion through a filter having a 1-µm or finer porosity. PACKAGING AND STORAGE: Preserve in tight containers. Sample solution: 0.4 mg/ml of cephalexin in Mobile phase LABELING: The label states whether the Tablets contain from Sample stock solution Cephalexin or Cephalexin Hydrochloride. 5 USP REFERENCE STANDARDS 11 USP Cephalexin RS Detector: UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity Flow rate: 1.5 ml/min Injection size: 20 µl Cephalexin Tablets for Oral Suspension Sample: Standard solution DEFINITION 5 Cephalexin Tablets for Oral Suspension contain NLT 90.0% and 5 Suitability requirements NMT 110.0% of the labeled amount of cephalexin 5 (C 16H 17N 3O 4S). Relative standard deviation: NMT 2.0% IDENTIFICATION Delete the following: Calculate the percentage of C 16H 17N 3O 4S in each Tablet for Oral Suspension: Result = (ru/r S) (C S/C U) P F 100 A. THIN-LAYER CHROMATOGRAPHY Standard solution: 3 mg/ml of USP Cephalexin RS in water r U = response from the Sample solution Sample solution: 3 mg/ml of cephalexin from powdered r S = response from the Standard solution C 5 Tablets for Oral Suspension in water and filter S = concentration of USP Cephalexin RS in the Sam- ple stock solution (mg/ml) (See Chromatography 621, Thin-Layer Chromatography. C U = nominal concentration of cephalexin in the Sam- Mode: TLC ple stock solution (mg/ml) Adsorbent: 0.25-mm layer of binder-free silica gel P = designated content of cephalexin in USP Application volume: 10 µl Cephalexin RS (µg/mg) Pre-developing solvent system: n-hexane and tetradecane F = unit conversion factor, mg/µg (95:5) Acceptance criteria: 90.0% 110.0% Ninhydrin solution: 66.7 mg/ml of ninhydrin in acetone PERFORMANCE TESTS Developing solvent system: 0.1 M citric acid, 0.1 M dibasic DISINTEGRATION 701 : Tablets for Oral Suspension disintegrate sodium phosphate, and Ninhydrin solution (60:40:1.5) in 3 min, using water at 20 ± 5. DISSOLUTION 711 Medium: Water; 900 ml Allow the solvent front to move the length of the plate in Apparatus 1: Use 40-mesh cloth and 100 rpm the Pre-developing solvent system, remove the plate from the Time: 30 min chamber, and allow solvent to evaporate. On this plate Sample solution: Pass a portion of the solution under test apply 10 µl each of the Standard solution and Sample soluthrough a suitable filter. Dilute with Medium, if necessary, to a tion. Allow the spots to dry, and develop the chromatogram concentration of about 20 µg/ml. in the Developing solvent system until the solvent front has Standard solution: 20 µg/ml of USP Cephalexin RS in moved three-fourths of the length of the plate. Remove the Medium plate from the developing chamber, mark the solvent front, Spectrometric conditions dry the plate for 10 min at 110, and examine the (See Spectrophotometry and Light-Scattering 851.) chromatogram. Acceptance criteria: The R F value of the principal spot of the Sample solution corresponds to that of the Standard solution. 5

10 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] Mode: UV Analytical wavelength: 262 nm Add the following: A. The retention time of the major peak of the Sample solu- Tolerances: NLT 80% (Q) of the labeled amount of tion corresponds to that of the Standard solution, as obtained C 16H 17N 3O 4S is dissolved. DISPERSION FINENESS: Place 2 Tablets for Oral Suspension in 100 in the Assay. 5 ml of water, and stir until completely dispersed. A smooth dispersion is obtained that passes through a No. 25 sieve. Delete the following: UNIFORMITY OF DOSAGE UNITS 905 : Meets the requirements B. PROCEDURE Sample solution: 0.02 mg/ml of cephalexin in water : The UV absorption spectrum of the Sample solution Delete the following: exhibits maxima and minima at the same wavelengths as that of a similar solution of USP Cephalexin RS, concomitantly WATER DETERMINATION, Method I 921 : NMT 9.0% 5 measured. 5 ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers at controlled room temperature. USP REFERENCE STANDARDS 11 USP Cephalexin RS Cephalexin Hydrochloride B. 5 IDENTIFICATION TESTS GENERAL, Chloride 191 : 10 mg/ ml meets the requirements (6R,7R)-7-[(2R)-2-Amino-2-phenylacetamido]-3-methyl-8-oxo-5-5 C 16H 17N 3O 4S HCl H 2O Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[(ami- nophenylacetyl)amino]-3-methyl-8-oxo-, monohydrochloride, monohydrate, [6R-[6α,7β (R*)]]-; Mobile phase: g/l of sodium 1-pentanesulfonate in a mixture of acetonitrile, methanol, triethylamine, and water (20:10:3:170), adjusted with phosphoric acid to a ph of 3.0 ± 0.1 thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monohydrochloride, monohydrate; Standard stock solution: 1 mg/ml of USP Cephalexin RS in 7-(D-2-Amino-2-phenylacetamido)-3-methyl-3-cephem-4-carboxwater Standard solution: ylic acid hydrochloride monohydrate [ ]. 0.4 mg/ml of cephalexin in Mobile phase from Standard stock solution Sample stock solution: DEFINITION mg/ml of Cephalexin Hydro- Cephalexin Hydrochloride contains the equivalent of NLT 800 µg chloride in water and NMT 880 µg of cephalexin (C 16H 17N 3O 4S) per mg. Sample solution: 0.4 mg/ml of cephalexin in Mobile phase from Sample stock solution IDENTIFICATION 5 Delete the following: Detector: UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity A. THIN-LAYER CHROMATOGRAPHY Flow rate: 1.5 ml/min Standard solution: 25 mg/ml of USP Cephalexin RS in water Injection size: 20 µl with the aid of 0.1 N hydrochloric acid Sample solution: 25 mg/ml in water with the aid of 0.1 N Sample: Standard solution hydrochloric acid 5 Suitability requirements (See Chromatography 621, Thin-Layer Chromatography.) 5 Mode: TLC Relative standard deviation: NMT 2.0% Adsorbent: 0.25-mm layer of chromatographic silica gel mixture Application volume: 5 µl Calculate the quantity, in µg, of C 16H 17N 3O 4S in each mg of Developing solvent system: Ethyl acetate, acetonitrile, glacial acetic acid, and water (21:7:7:9) Cephalexin Hydrochloride taken: Result = (ru/r S) (C S/C U) P r U = peak response from the Sample solution Allow the spots to dry, place the plate in a saturated chamr S = peak response from the Standard ber containing the solvent system and lined with filter pasolution C 5 S = concentration of USP Cephalexin RS in the Stanper. Develop the chromatogram until the solvent front has dard stock solution (mg/ml) moved three-fourths of the length of the plate. Remove the C U = concentration of Cephalexin Hydrochloride from plate from the developing chamber, mark the solvent front, the Sample stock solution (mg/ml) allow the plate to air-dry, and examine under short-wave- P = designated content of cephalexin in USP length UV light. Cephalexin RS (µg/mg) Acceptance criteria: The R F value of the principal spot of the Sample solution corresponds to that of the Standard solution. 5

11 Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1137 Acceptance criteria: µg/mg Total impurities: NMT 5.0% IMPURITIES 2: DIMETHYLANILINE 223 : Meets the requirement Organic Impurities 1 CRYSTALLINITY 695 : Meets the requirements Solution A: 1 g of sodium 1-pentanesulfonate in a mixture of PH 791 : , in a solution containing 10 mg/ml 1000 ml of water and 15 ml of triethylamine. Adjust with WATER DETERMINATION, Method I 921 : 3.0% 6.5% phosphoric acid to a ph of 2.5 ± 0.1. Solution B: 1 g of sodium 1-pentanesulfonate in a mixture of ADDITIONAL REQUIREMENTS 300 ml of water and 15 ml of triethylamine. Adjust with PACKAGING AND STORAGE: Preserve in tight containers. phosphoric acid to a ph of 2.5 ± 0.1, and add 350 ml of USP REFERENCE STANDARDS 11 acetonitrile and 350 ml of methanol. USP Cephalexin RS Mobile phase: See the gradient table below. (min) (%) (%) Glacial Acetic Acid Diluent: 18 mg/ml of monobasic potassium phosphate in C 2H 4O water Acetic acid [ ]. Standard solutions: 0.08 mg/ml and 0.16 mg/ml of C 16H 17N 3O 4S from USP Cephalexin RS in Diluent, taking into DEFINITION account the stated potency the USP Cephalexin RS Glacial Acetic Acid contains NLT 99.5% and NMT 100.5%, by Sample solution: 6 mg/ml of Cephalexin Hydrochloride in weight, of C 2H 4O 2. Diluent IDENTIFICATION Detector: UV 254 nm Column: 4.6-mm 25-cm; packing L1 of low acidity Flow rate: 1 ml/min IDENTIFICATION TESTS GENERAL, Acetate 191 : Meets the Injection size: 20 µl requirements Sample solution (for lanthanum nitrate test): 5 Glacial Samples: Standard solutions and Sample solution Acetic Acid and water (1:100) 5 Plot the responses of the cephalexin peaks of the Standard solutions versus their concentrations, calculated on the anhydrous basis, in mg/ml, and draw a straight line through the two points and zero. From the line so obtained and the peak responses of the Sample solution, determine the concentration, I, in mg/ml, of each cephalexin-related sub- stance from the Sample solution other than the cephalexin peak. Calculate the percentage of each cephalexin-related sub- stance represented by each peak of the Sample solution, other than the cephalexin peak. Result = (I/C) 100 Sample solution: Measure 2 ml of Glacial Acetic Acid into a glass-stoppered flask, previously tared while containing about 20 ml of water, and weigh again to obtain the weight of the substance under assay. : Add 20 ml of water, then add phenolphthalein TS. Titrate with 1 N sodium hydroxide VS. Each ml of 1 N sodium hydroxide is equivalent to mg of C 2H 4O 2. Acceptance criteria: 99.5% 100.5% I = concentration of each cephalexin-related sub- stance other than cephalexin in the Sample so- lution (mg/ml) C = concentration mg/ml of cephalexin from the Sample solution Acceptance criteria Individual impurities: NMT 1.0% of any individual cephalexin-related substance is found. IMPURITIES Inorganic Impurities LIMIT OF NONVOLATILE RESIDUE: Evaporate 20 ml in a tared dish, and dry at 105 for 1 h: the weight of the residue does not exceed 1.0 mg. HEAVY METALS 231 : NMT 5 ppm Sample solution: To the residue obtained in the test for Limit of Nonvolatile Residue add 8 ml of 0.1 N hydrochloric acid, warm gently until solution is complete, dilute with water to 100 ml, and use 20 ml. CHLORIDE AND SULFATE, Chloride 221 Sample solution: Dilute 1.0 ml with 20 ml of water. : Add 5 drops of silver nitrate TS. Acceptance criteria: No opalescence is produced. CHLORIDE AND SULFATE, Sulfate 221 Sample solution: Dilute 1.0 ml with 10 ml of water. : Add 1 ml of barium chloride TS. Acceptance criteria: No turbidity is produced. Organic Impurities : READILY OXIDIZABLE SUBSTANCES Sample solution: Dilute 2.0 ml in a glass-stoppered vessel with 10 ml of water. : Add 0.10 ml of 0.10 N potassium permanganate. Acceptance criteria: The pink color is not changed to brown within 2 h.

12 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] Spectrometric conditions CONGEALING TEMPERATURE 651 : NLT 15.6 (See Spectrophotometry and Light-Scattering 851.) Mode: UV ADDITIONAL REQUIREMENTS Wavelength range: Between 260 and 280 nm PACKAGING AND STORAGE: Preserve in tight containers, and Blank: Water store at room temperature. Acceptance criteria: The difference in absorbance between 260 and 280 nm of the Sample solution against the Blank is NMT 0.1. SULFATE Sample: 150 mg Protamine Sulfate : Dissolve the Sample in 75 ml of water, add 5 ml of 3 N hydrochloric acid, heat to boiling, and while maintaining DEFINITION at the boiling point, slowly add 10 ml of barium chloride TS. Protamine Sulfate is a purified mixture of simple protein principles Cover the vessel, and allow the mixture to stand on a steam obtained from the sperm or testes of suitable species of fish, bath for 1 h. Filter, wash the precipitate with several portions which has the property of neutralizing heparin. Each mg of of hot water, dry, and ignite to constant weight. The weight Protamine Sulfate, calculated on the dried basis, neutralizes of the barium sulfate, multiplied by , represents the NLT 100 USP Heparin Units. weight of sulfate in the portion of Protamine Sulfate taken. Acceptance criteria: 16% 22% on the dried basis ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers in a refrigerator. Sample solution A: 0.15 mg/ml of Protamine Sulfate in water Sample solution B: Dilute 2.0 ml of Sample solution A with USP REFERENCE STANDARDS 11 water to 3.0 ml. USP Heparin Sodium for Assays 5 RS Sample solution C: Dilute 1.0 ml of Sample solution A with water to 3.0 ml. Titrant: USP Heparin Sodium for Assays RS in water (about USP Heparin Units/mL) : [NOTE Titrate each Sample solution in duplicate.] Protamine Sulfate Injection Transfer a volume of the Sample solution to the analytical cell of a suitable colorimeter, and set the apparatus for measure- DEFINITION ment at a suitable wavelength (none is critical) in the visible range. Add Titrant in small volumes until there is a sharp increase in the absorbance, and note the volume of Titrant added. Perform the entire Assay in triplicate for a total of 18 determinations. Calculate the number of USP Heparin Units in the volume of Protamine Sulfate Injection is a sterile, isotonic solution of Protamine Sulfate. Titrant added at the endpoint per mg of Protamine Sulfate. Each mg of Protamine Sulfate, used in the man- Calculate the USP Heparin Units neutralized per mg of Protaufacture of the Injection, neutralizes NLT 100 USP Heparin Units, calculated on the dried basis. 5 mine Sulfate taken: It contains NLT 90.0% and NMT 120.0% of the labeled amount of protamine sulfate. Result = (V T C T)/(V S C S) IDENTIFICATION IDENTIFICATION V TESTS GENERAL, Sulfate 191 T = volume of Titrant added (ml) C T = concentration of Titrant (USP Heparin Units/mL) V S = volume of the Sample solution (ml) C S = concentration of Protamine Sulfate (mg/ml) Calculate the potency of the Protamine Sulfate as the average of the 18 values. Calculate the 3 standard deviations for the results obtained with each of the Sample solutions. Calculate the 3 standard deviations for the results obtained with each Sample solution: of the 3 independent assays. The Assay is valid if each of the 0.15 mg/ml 5 of protamine sulfate in 6 standard deviations is NMT 5% of the average result. Water for Injection from a measured volume of Injection Acceptance criteria: Each mg of Protamine Sulfate neutralizes : [NOTE Titrate the Sample solution in duplicate.] NLT 100 USP Heparin Units, on the dried Transfer the same volume of the Sample solution to the analyti- basis. 5 cal cell as used in the Assay for the drug substance. Proceed OTHER COMPONENTS as directed in the Assay under Protamine Sulfate, using the NITROGEN DETERMINATION, Method II 461 same concentration of Titrant and the same wavelength as Acceptance criteria: 22.5% 25.5% of N, on the dried basis. used in the Assay for the drug substance. The concentration of the Sample solution of the drug substance should also be 0.15 mg/ml. Perform the entire Assay in triplicate, and calculate LOSS ON DRYING 731 : Dry a sample at 105 for 3 h: it loses the average of the triplicate determinations. The percentage of NMT 5% of its weight. the label claim is given as follows: v ULTRAVIOLET ABSORBANCE Sample solution: 1.0% solution of Protamine Sulfate in V water 5 5 Result = (v/v) 100 = volume of Titrant added to the Injection Sample solution (ml) = volume of Titrant added to the drug substance Sample solution (ml)

13 . Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1139 Acceptance criteria: 90.0% 120.0% cal cell as used in the Assay for the drug substance. Proceed as directed in the Assay under Protamine Sulfate, using the same concentration of Titrant and the same wavelength as BACTERIAL ENDOTOXINS TEST 85 : It contains NMT 7.0 USP En- used in the Assay for the drug substance. The concentration of dotoxin Units/mg of protamine sulfate. the Sample solution of the drug substance should also be 0.15 OTHER REQUIREMENTS: It meets the requirements under Injec- mg/ml. Perform the entire Assay in triplicate, and calculate tions 1. the average of the triplicate determinations. The percentage of the label claim is given as follows: ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in single-dose containers, Result = (v/v) 100 preferably of Type I glass. Store at controlled room temperature. v = volume of Titrant added to the Protamine Sulfate LABELING: Label it to indicate the approximate neutralization for Injection Sample solution (ml) capacity in USP Heparin Units. V = volume of Titrant added to the drug substance Sample solution (ml) Acceptance 5 criteria: 90.0% 120.0% USP REFERENCE STANDARDS 11 USP Endotoxin RS USP Heparin Sodium for Assays 5 RS Protamine Sulfate for Injection DEFINITION Protamine Sulfate for Injection is a sterile mixture of Protamine Sulfate with one or more suitable, dry diluents. Each mg of Protamine Sulfate, used in the manufacture of the Protamine Sulfate for Injection, neutralizes NLT 100 USP Heparin Units, calculated on the dried basis. 5 It contains NLT 90.0% and NMT 120.0% of the labeled amount of protamine sulfate. erably Sample solution: 0.15 mg/ml 5 of protamine sulfate in Water for Injection. Dissolve from the contents of 1 container of Protamine Sulfate for Injection. : [NOTE Titrate the Sample solution in duplicate.] Transfer the same volume of the Sample solution to the analyti- PERFORMANCE TESTS UNIFORMITY OF DOSAGE UNITS 905 : Meets the requirements INJECTIONS, Constituted Solutions 1 : At the time of use, it meets the requirements. BACTERIAL ENDOTOXINS TEST 85 : It contains NMT 7.0 USP Endotoxin Units/mg of protamine sulfate. STERILITY TESTS 71 : Both it and the accompanying solvent meet the requirements PH AND CLARITY OF SOLUTION: Dissolve it in the solvent recommended in the labeling: the ph of the solution is , and the solution is clear. OTHER REQUIREMENTS: Both it and the accompanying solvent meet the requirements for Injections 1, Labeling. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve as described under Injections 1, Containers for Sterile Solids. Preserve the accompanying solvent in single-dose or in multiple-dose containers, pref- of Type I glass. LABELING: Label it to indicate the approximate neutralization capacity in USP Heparin Units. USP REFERENCE STANDARDS 11 USP Endotoxin RS USP Heparin Sodium for Assays 5 RS

14 1140 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept. Oct. 2010] ERRATA Following is a list of errata and corrections to USP NF. The page number indicates where the item is found and in which official or pending official publication of USP NF. If necessary, this list will be updated with every issue of PF. This information will also be available as a cumulative table in future Supplements and will appear in its corrected form in a future annual edition of USP NF. An erratum consists of content erroneously published that does not accurately reflect the intended official or effective requirements as approved by the Council of Experts. USP staff is available to respond to questions regarding the accuracy of a particular requirement; call USPC. USP32 NF27 Title Section Description Page 2409 Sodium Fluoride F18 Injection Radiochemical Purity Line 3 under : Change 7.5-mm cm column that contains 10-mm packing L mm 6 25-cm column that contains 10-mm packing L Propofol Limit of propofol related Line 6 under Procedure: Change compound A 0.01(r U / r S ) in which r U and r S are the peak responses for propofol related compound A obtained from the Test solution and the Standard solution, respectively 100(C S / C U )(r U / r S ) in which C S is the concentration, in mg per ml, of USP Propofol Related Compound A RS in the Standard solution; C U is the concentration, in mg per ml, of propofol in the Test solution; and r U and r S are the peak responses for propofol related compound A obtained from the Test solution and the Standard solution, respectively First Supplement to USP32-NF Haloperidol Decanoate Assay Footnote 11 under Table 1: Change 4-(4 -Chlorobiphenyl-4- yl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl decanoate. 4-(3 -Chlorobiphenyl-4-yl)-1-[4-(4-fluorophenyl)-4-oxobutyl]- piperidin-4-yl decanoate. Footnote 12 under Table 1: Change 4-(3 -Chlorobiphenyl-4- yl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl decanoate. 4-(4 -Chlorobiphenyl-4-yl)-1-[4-(4-fluorophenyl)-4-oxobutyl]- piperidin-4-yl decanoate. Second Supplement to USP32-NF h785i Osmolality and Osmolarity Measurement of Osmolality Line 2 under Standard Solutions: Change footnote 1 2 At the bottom of page: Change footnote 1 2 USP33 Title NF28 Reissue Page R-140 Reagent Specifications R-142 Reagent Specifications R-203 Chromatographic Columns R-316 Oil- and Water-Soluble Vitamins with Minerals Capsules R-453 Amiodarone Hydrochloride CATEGORY Section 3,5-Dimethylphenol Ether, Peroxide-Free L54 STRENGTH Vitamin A, Method 1 Limit of Iodides Description Line 4: Change from Lancaster Synthesis, Inc., from Line 11: Change Line 4: Change from Amersham Pharmacia Biotech (www. amershambiosciences.com) from Line 14 under : Change retinol acetate retinyl acetate Line 2 under Standard solution: Change 1.0 ml of an 88.2 mg/ ml solution of potassium iodide 1.0 ml of an 88.2 mg/l solution of potassium iodide # 2010 The United States Pharmacopeial Convention All Rights Reserved.

15 Vol. 36(5) [Sept. Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1141 USP33 Title NF28 Reissue Page R-472 Clarithromycin Tablets R-510 Mycophenolate Mofetil CATEGORY Section Procedure Loss on Drying h731i R-534 Ritonavir IMPURITIES Organic Impurities, Procedure R-534 Ritonavir IMPURITIES Organic Impurities, Procedure First Supplement to the USP33-NF28 Reissue R-645 h1024i Bovine Serum Appendix 1 R-984 Ticlopidine Hydrochloride IMPURITIES Organic Impurities, Procedure 2 Second Supplement to the USP33-NF28 Reissue R-1034 h11i USP Reference Standards USP Allopurinol Related Compound F RS R-1041 h11i USP Reference Standards R-1063 h92i Growth Factors and Cytokines Used in Cell Therapy Manufacturing USP Doxepin Related Compound A RS Bioidentity Description Line 1 under Sample stock solution: Change Equivalent to 4 mg/ml of clarithromycin in methanol. Equivalent to 4 mg/ml of clarithromycin from finely powdered Tablets in methanol. Line 1: Change Dry a sample at 608 for 3 h: it loses NMT 0.5% of its weight. Dry a sample in a vacuum at 608 for 3 h: it loses NMT 0.5% of its weight. In each row of Impurity Table 1 under the column head Relative Response Factor with a value of, change 1.0 In each row of Impurity Table 1 under the column head Acceptance Criteria, NMT (%) with a value of, change 0.1 Line 3 under FDA, first bullet: Change Cber/ltr/bse04l900.pdf Available at: SafetyAvailability/ucm htm Line 4 under FDA, second bullet: Change Available at Available at: Footnote a under Impurity Table 2: Change N-(2-Chlorobenzyl)-2-(thiophen-2-yl)ethanamine. 2-[N-Methyl-N-(2-chlorobenzyl)aminoethyl] thiophene hydrochloride. Line 1: Change [ethyl 3-(2-carbethoxy- [ethyl (E/Z)-3-2(2-carbethoxy- Line 1: Change [5-(4-nitrophenyl)-2-furaldehyde-2-carboxymethyl semicarbazone] [dibenzo[b,e]oxepin-11(6h)-one] Line 1 under Resazurin solution: Change 0.11 mg of resazurin in Phosphate buffered saline. 11 mg of resazurin in 100 ml of Phosphate buffered saline. # 2010 The United States Pharmacopeial Convention All Rights Reserved.

16

17 PROPOSED INTERIM REVISION ANNOUNCEMENTS This section includes proposals for s (IRAs) that will be published as official USP or NF standards. There is a 60-day comment period for these proposals, beginning on the 15 th of the first month of this. The approved official text will be published in a future and additionally in the New Official Text section of USP s web site ( Readers should review material in this section and provide comments to the Scientific Liaison (use the Staff Directory to find the contact information). Information on how to comment is found in the Policies and Announcements section. It is important to send comments promptly so that the Expert Committee members can consider readers input as they are deciding whether to advance standards to official status. Each proposal is preceded by a Briefing that indicates the proposed revisions. Proposed IRA

18 1144 PROPOSED IRA Vol. 36(5) [Sept. Oct. 2010] PROPOSED INTERIM REVISION ANNOUNCEMENTS MONOGRAPHS (USP) Leuprolide Acetate (1-Feb-2011) Levetiracetam (1-Feb-2011) Norgestimate and Ethinyl Estradiol Tablets (1-Feb-2011) Risedronate Sodium (1-Feb-2011) Proposed IRA # 2010 The United States Pharmacopeial Convention All Rights Reserved.

19 . Vol. 36(5) [Sept. Oct. 2010] PROPOSED IRA 1145 USP MONOGRAPHS BRIEFING Leuprolide Acetate, USP 32 page On the basis of comments received, it is proposed to remove the retention time of the acetic acid peak in the test for Content of Acetic Acid. The formula in the Assay is being corrected to reflect the labeling of USP Leuprolide Acetate RS on the anhydrous, acetic acid-free basis, which makes the coefficient in the formula unnecessary. (BB PP: T. Sigambris.) RTS C83380 Leuprolide Acetate Degradation standard solution: Dilute 5.0 ml of the Standard stock solution with water to 50.0 ml. Transfer 5 ml of the solution to a scintillation vial. Add 100 µl of 1 N sodium hydroxide solution, cap tightly, and shake vigorously. Place in an oven at 100 for 60 min, remove, allow to cool, add 50 µl of 1 M phosphoric acid, recap, and shake vigorously to mix. Sample solution: 50 µg/ml of Leuprolide Acetate in Mobile phase Detector: UV 220 nm Column: 4.6-mm 10-cm; 3-µm packing L1 Flow rate: ml/min Injection size: 20 µl Samples: Mobile phase, Standard solution, and Degradation standard solution [NOTE Chromatograph the Mobile phase, and verify that no extraneous peaks are present.] [NOTE The relative retention times for the degradation product and leuprolide are about 0.90 and 1.0, respectively.] Suitability requirements Retention time: min for leuprolide, Degradation standard solution Resolution: NLT 1.5 between leuprolide and the degradation product, Degradation standard solution Tailing factor: , Standard solution Relative standard deviation: NMT 1.5% for leuprolide acetate, Standard solution Calculate the percentage of C 59H 84N 16O 12 in the portion of Leuprolide Acetate taken: Result = [(r U/r S)(W S/W U)(P)(0.9527)(100)]/(100 acetic acid content water content) C 59H 84N 16O 12 (C 2H 4O 2)n, n = 1 or (as free base) Result = [(ru/r S) (C S/C U) P 100]/(100 AC Luteinizing hormone-releasing factor, 6-D-leucine-9-(N-ethyl-L- WC) (1- Feb-2011) prolinamide)-10-deglycinamide acetate (salt); 5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leu- r U = peak area of the Sample solution cyl-l-arginyl-n-ethyl-l-prolinamide acetate (salt) [ ]. r S = peak area of the Standard solution = concentration of USP Leuprolide Acetate RS in DEFINITION CS (1- the Standard solution (µg/ml) Leuprolide Acetate is a synthetic nonapeptide agonist analog of luteinizing hormone-releasing factor. It contains NLT 97.0% W S Feb-2011) W U = concentration of Leuprolide Acetate in the Samand NMT 103.0% of leuprolide (C 59H 84N 16O 12), calculated on CU (1- ple solution (µg/ml) the anhydrous, acetic acid-free basis. [NOTE Due to the hygroscopic nature of this material, analyses are performed immediately after opening the container in a glove box under dry nitrogen purge.] [CAUTION Leuprolide Acetate is a potent hormonal manipulator. Avoid skin contact and inhalation of dusts and mists.] 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. CONTENT OF ACETIC ACID Diluent: Methanol, adjusted with phosphoric acid to a ph of 2.5 Standard solution: Pipet 2.0 ml of glacial acetic acid into a 100-mL volumetric flask, dilute with Diluent to volume, and mix. Transfer 4.0 ml of the solution to a 100-mL volumetric flask, dilute with Diluent to volume, and mix. Transfer 10.0 ml of this solution to a 100-mL volumetric flask, dilute with Dilu- ent to volume, and mix to obtain a solution having a known concentration of about 0.08 mg/ml. Sample solution: Transfer about 100 mg of Leuprolide Acetate, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with Diluent to volume. Solution A: 15.2 mg/ml of triethylamine in water. Adjust with phosphoric acid to a ph of 3.0. Solution B: Acetonitrile and n-propyl alcohol (3:2) Mobile phase: Solution A and Solution B (17:3) Standard stock solution: 1 mg/ml of USP Leuprolide Acetate RS in Mobile phase Standard solution: 50 µg/ml. Dilute 5.0 ml of the Standard stock solution with Mobile phase to ml. Feb-2011) P = designated purity of USP Leuprolide Acetate RS (%) AC = acetic acid content (%) WC = water content (%) Acceptance criteria: 97.0% 103.0% OTHER COMPONENTS Proposed IRA

20 1146 PROPOSED IRA Vol. 36(5) [Sept. Oct. 2010] Proposed IRA Mode: GC Resolution: NLT 1.5 between leuprolide and the degrada- Detector: Flame ionization tion product, Degradation standard solution Column: 0.53-mm 30-m fused-silica capillary column that Tailing factor: , Standard solution contains a 1.2-µm film of phase G35 Relative standard deviation: NMT 1.5% for leuprolide Temperature acetate, Standard solution Column: 100 Injection port: 200 Detector: 250 [NOTE Record the chromatograms for 90 min.] Carrier gas: Helium Calculate the percentage of each impurity in the portion of Flow rate: 10 ml/min C 59H 84N 16O 12 (C 2H 4O 2)n taken: Injection size: 1.0 µl Injection type: Splitless mode Result = 0.01 (r U/r S) (W S/W U) P Samples: Diluent and Standard solution r U = peak response for each impurity from the Sam- Suitability requirements ple solution Retention time: 5 7 min, acetic acid r S = leuprolide peak response from the Standard stock solution (1-Feb-2011) Blank: Chromatograph the Diluent, and verify that there W S = weight of USP Leuprolide Acetate RS in the are no interfering peaks. Standard stock solution (mg) Column efficiency: NLT 15,000 theoretical plates, Stantion (mg) W U = weight of Leuprolide Acetate in the Sample soludard solution Tailing factor: , Standard solution P = designated purity of USP Leuprolide Acetate RS Relative standard deviation: NMT 2.0% for glacial acetic (%) acid, for replicate injections of the Standard solution Acceptance criteria Individual impurities: See Impurity Table 1. Total impurities: NMT 2.5% Calculate the percentage of acetic acid (C 2H 4O 2) in the portion of Leuprolide Acetate taken: Impurity Table 1 Result = (r U/r S) (839.2/W U) Relative Acceptance Retention Criteria, r U = peak area of the Sample Name Time NMT (%) r S = peak area of the Standard solution Acetyl-leuprolide W U = amount of Leuprolide Acetate taken to prepare D-His-leuprolide the Sample solution (mg) L-Leu 6 -leuprolide Acceptance criteria: 4.7% 9.0% D-Ser-leuprolide IMPURITIES Leuprolide 1.0 Inorganic Impurities Any other impurity 0.5 RESIDUE ON IGNITION 281 : NMT 0.3% Organic Impurities Solution A: 15.2 mg/ml of triethylamine in water. Adjust AMINO ACID CONTENT with phosphoric acid to a ph of 3.0 prior to final dilution. [NOTE Use a suitable, validated procedure (see Biotechnology- Solution B: Acetonitrile and n-propyl alcohol (3:2) Derived Articles Amino Acid 1052 ).] Mobile phase: Solution A and Solution B (17:3) Standard solutions: Prepare a solution having known equi- Standard stock solution: 1 mg/ml of USP Leuprolide Aceglutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-ly- molar amounts of L-alanine, L-arginine, L-aspartic acid, L- tate RS in Mobile phase Standard solution: Dilute 1.0 ml of the Standard stock solunine, L-tyrosine, and L-valine with half the equimolar amount sine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threotion with Mobile phase to ml. Degradation standard solution: Dilute 5 ml of Standard of L-cystine. For the validation of the method, an appropriate stock solution with water to 50.0 ml. Transfer 5 ml of the internal standard, such as norleucine, is used. Prepare a sepa- solution to a scintillation vial. Add 100 µl of 1 N sodium rate, equimolar solution of L-tryptophan. hydroxide solution, tightly cap, and shake vigorously. Place Sample solution: Transfer 64 mg of Leuprolide Acetate to a in an oven at 100 for 60 min, remove, allow to cool, add suitable vessel. Dissolve in 1.0 ml of water. Transfer 0.10 ml 50 µl of 1 M phosphoric acid, recap, and shake vigorously to of this solution to a vacuum hydrolysis tube, add 2.0 ml of mix. 6 N hydrochloric acid, evacuate the tube, and heat for 16 hr Sample solution: Transfer about 100 mg of Leuprolide Acesuitable vessel, add 1 ml of water, and lyophilize. Dissolve in at 120. Transfer 0.10 ml of the hydrolysate so obtained to a tate to a 100-mL volumetric flask, dissolve in and dilute with Mobile phase to volume. and dilute to a suitable volume in a buffer solution suitable for amino acid analysis. : Inject equal volumes of the Standard solution and the Sample solution into the amino acid analyzer, and record and Detector: UV 220 nm measure the responses for each amino acid peak. Express the Column: 4.6-mm 10-cm; 3-µm packing L1 content of each amino acid in moles. Flow rate: ml/min Calculate the relative proportions of the amino acids in the Injection size: 20 µl Sample solution, taking one-seventh of the sum of the num- ber of moles of histidine, glutamic acid, leucine, proline, ty- Samples: Mobile phase, Standard solution, Degradation rosine, and arginine as equal to one. standard solution, and Sample solution Acceptance criteria: moles each of glutamic acid, [NOTE Chromatograph the Mobile phase, and verify that proline, tyrosine, histidine, and arginine per mole of no extraneous peaks are present.] Leuprolide Acetate; moles of leucine per mole of Suitability requirements Leuprolide Acetate; serine and tryptophan are also present. Retention time: min for leuprolide, Degradation OPTICAL ROTATION, Specific Rotation 781S : 38.0 to 42.0 standard solution expressed on an anhydrous, acetic acid-free basis

21 . Vol. 36(5) [Sept. Oct. 2010] PROPOSED IRA 1147 Sample solution: 10 mg/ml, in 1% acetic acid WATER DETERMINATION, Method Ic 921 : NMT 8.0% BACTERIAL ENDOTOXINS TEST 85 : It contains NMT USP Endotoxin Units per mg of leuprolide acetate. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers. Store at a temperature not higher than 30. USP REFERENCE STANDARDS 11 USP Endotoxin RS USP Leuprolide Acetate RS Buffer: 0.26 g/l of monobasic potassium phosphate in water. Adjust with 2% aqueous potassium hydroxide (w/v) to a ph of 5.5. Solution A: Acetonitrile and Buffer (1:19) Solution B: Acetonitrile Mobile phase: See the gradient table below. BRIEFING Time Solution A Solution B (min) (%) (%) Levetiracetam, page R-927 of the First Supplement to the USP NF 28 Reissue and the Revision Bulletin posted on the USP website on June 26, 2009 with an official date of August 1, On the basis of comments received, it is proposed to solution: 0.2 mg/ml of USP Levetiracetam revise the following: RS and 0.08 mg/ml of USP Levetiracetam Related Compound 1. Difficulties were reported in meeting the requirements for A RS in Solution A. Prepare by first dissolving the required column efficiency in the Assay. According to Chromatogra- amount of USP Levetiracetam RS in a suitable volumetric flask. phy 621, column efficiency is valid only for separations Add 10% of the flask volume of 0.1 N potassium hydroxide. made at constant temperature, mobile phase composition, Let the mixture react at room temperature for about 15 min, and flow rate. Because the Assay is a gradient elution pro- and then neutralize by adding 0.1 N hydrochloric acid at 10% cedure, the column efficiency requirement is being deleted. of the flask volume. Add the required amount of USP Leve- 2. The Mobile phase in the test for Limit of Levetiracetam R- tiracetam Related Compound A RS, sonicate to dissolve, dilute Enantiomer in the current monograph uses alcohol, which with Solution A to volume, and mix. can cause phase separation. It is being revised to specify Standard solution: 0.1 mg/ml of USP Levetiracetam RS in the use of dehydrated alcohol, which will not cause phase Solution A separation. Sample solution: 0.1 mg/ml of Levetiracetam in Solution A Subject to consideration of comments received, it is proposed to implement this revision via an pertaining to USP 34 NF 29 in PF 37(1) [Jan. Feb. 2011], with an official date of February 1, Comments regarding this pro- Detector: UV 205 nm posal should be received by November 15, Column: 4.6-mm 15-cm; packing L1 Flow rate: 0.9 ml/min Injection size: 10 µl (MD-PP: R. Ravichandran.) RTS C87569; C85247 Sample: solution [NOTE The relative retention times are listed in Impurity Table 1.] Suitability requirements Column efficiency: NLT 50,000 theoretical plates for the Add the following: Levetiracetam levetiracetam peak (1-Feb-2011) Relative standard deviation: NMT 1.0% [NOTE If system suitability criteria cannot be met, it is recommended that the column temperature be maintained at 20 to stabilize the system.] Calculate the percentage of C 8H 14N 2O 2 in the portion of Levetiracetam taken: Result = [(r U/r S) (C S/C U) 100] F C 8H 14N 2O Pyrrolidineacetamide, α-ethyl-2-oxo-, (αs)-; r U = peak response of levetiracetam from the Sample ( )-(S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide [ ]. solution r S = peak response of levetiracetam from the Stan- DEFINITION dard solution Levetiracetam contains NLT 98.0% and NMT 102.0% of C S = concentration of USP Levetiracetam RS in the C 8H 14N 2O 2, calculated on the anhydrous and solvent-free basis. Standard solution (mg/ml) C U = concentration of Levetiracetam in the Sample so- IDENTIFICATION lution (mg/ml) A. INFRARED ABSORPTION 197K F = percentage of levetiracetam R-enantiomer from B. The retention time of the major peak for levetiracetam the test for Limit of Levetiracetam R-Enantiomer from the Sample solution corresponds to that of the leve- Acceptance criteria: 98.0% 102.0% on the anhydrous and tiracetam S-enantiomer from the solution, as solvent-free basis obtained in the test for Limit of Levetiracetam R-Enantiomer. Proposed IRA

22 1148 PROPOSED IRA Vol. 36(5) [Sept. Oct. 2010] IMPURITIES r U = peak response of each impurity from the Sample Inorganic Impurities solution RESIDUE ON IGNITION 281 : NMT 0.1% r S = peak response of levetiracetam from the Stan- HEAVY METALS, Method II 231 : 20 ppm dard solution Organic Impurities C S = concentration of USP Levetiracetam RS in the 1: LIMIT OF LEVETIRACETAM RELATED COMPOUND B Standard solution (mg/ml) [NOTE Perform this test only if levetiracetam related com- C U = concentration of Levetiracetam in the Sample sopound B is a known process impurity.] lution (mg/ml) Buffer: 1.22 g of sodium 1-decanesulfonate in 1 L of water F = relative response factor (see Impurity Table 1) containing about 1.3 ml of phosphoric acid. Adjust with [NOTE Disregard any peak with a relative retention time of 20% (w/v) potassium hydroxide to a ph of or less.] Mobile phase: Acetonitrile and Buffer (3:17) Acceptance criteria solution: 2 mg/ml of USP Levetiracetam Individual impurities: See Impurity Table 1. Related Compound B RS in Mobile phase Standard solution: mg/ml of USP Levetiracetam Related Total impurities: NMT 0.4% Compound B RS in Mobile phase Sample solution: 2.0 mg/ml of Levetiracetam in Mobile Impurity Table 1 phase Relative Relative Acceptance Retention Response Criteria, Name Time Factor NMT (%) Pyridin-2-ol a Detector: UV 200 nm Levetiracetam acid b Column: 4.6-mm 25-cm; packing L1 Flow rate: 1.0 ml/min Levetiracetam 1.00 Injection size Levetiracetam related : 10 µl compound A c : 50 µl Any individual unspecified impurity Sample: solution a Not included in the Total impurities limit. [NOTE The retention time for levetiracetam related com- b (S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid. Included in the Total impurities limpound B is 9 min.] it. Suitability requirements c (S)-N-(1-Amino-1-oxobutan-2-yl)-4-chlorobutanamide. Included in the Total Tailing factor: NMT 3.0 impurities limit only if levetiracetam related compound B is a known process [NOTE If a significant tailing of the levetiracetam related impurity. compound B peak is observed (greater than 3.0), it is recommended that the column temperature be maintained at 27 to stabilize the system.] Relative standard deviation: NMT 2.0% WATER DETERMINATION, Method Ia 921 : NMT 0.5% Calculate the percentage of levetiracetam related compound B in the portion of Levetiracetam taken: Proposed IRA Result = (r U/r S) (C S/C U) (M r1/m r2) 100 r U = peak response of levetiracetam related compound B from the Sample solution r S = peak response of levetiracetam related compound B from the Standard solution C S = concentration of USP Levetiracetam Related Compound B RS in the Standard solution (mg/ml) C U = concentration of Levetiracetam in the Sample solution (mg/ml) M r1 = molecular weight of levetiracetam related compound B free base, M r2 = molecular weight of levetiracetam related compound B, Acceptance criteria: NMT 0.10% [NOTE The amount of levetiracetam related compound B measured is to be included in the total impurities in the test for Organic Impurities, Procedure 2.] 2 Buffer, Solution A, Solution B, Mobile phase, solution, and : Proceed as directed in the Assay. Standard solution: mg/ml of USP Levetiracetam RS in Solution A Sample solution: 5 mg/ml of Levetiracetam in Solution A Calculate the percentage of each impurity in the portion of Levetiracetam taken: Result = (r U/r S) (C S/C U) (1/F) 100 LIMIT OF LEVETIRACETAM R-ENANTIOMER Mobile phase: n-hexane and dehydrated (1-Feb-2011) alcohol (4:1) solution: 0.1 mg/ml of USP Levetiracetam Racemic Mixture RS in Mobile phase Standard solution: 0.05 mg/ml of USP Levetiracetam RS in Mobile phase Sample solution: 10 mg/ml of Levetiracetam in Mobile phase Detector: UV 215 nm Column: 4.6-mm 25-cm; 10-µm packing L51 Flow rate: 1.0 ml/min Injection size: 20 µl Sample: solution [NOTE The relative retention times for levetiracetam R-enan- tiomer and levetiracetam S-enantiomer are 0.55 and 1.0, respectively.] Suitability requirements Resolution: NLT 4.0 between R- and S-enantiomers [NOTE If a loss of resolution (less than 4.0) is observed, it is recommended that the column temperature be maintained at 25 to stabilize the system.] Calculate the percentage of levetiracetam R-enantiomer in the portion of Levetiracetam taken: Result = (r U/r S) (C S/C U) 100

23 . C Vol. 36(5) [Sept. Oct. 2010] PROPOSED IRA 1149 r U = peak response of levetiracetam R-enantiomer tration of about 7 µg/ml of ethinyl estradiol and a known from the Sample solution concentration of norgestimate similar to that expected in the r S = peak response of levetiracetam from the Stan- Sample solution. Pass through a suitable filter of 0.45-µm pore dard solution size. C S = concentration of USP Levetiracetam RS in the Sample solution: Add a number of Tablets, equivalent to 0.35 Standard solution (mg/ml) mg of ethinyl estradiol, to a suitable glass container. Add 10 C U = concentration of Levetiracetam in the Sample so- ml of water, and mix with a vortex mixer until the Tablets are lution (mg/ml) completely disintegrated. Add 40 ml of Internal standard solu- Acceptance criteria: NMT 0.8% tion, and mix with a vortex mixer for at least 23 min. Sonicate the sample for at least 5 min, filter an aliquot through a suita- ADDITIONAL REQUIREMENTS ble filter of 0.45-µm pore size, and use the filtrate. PACKAGING AND STORAGE: Preserve in well-closed containers, and store at room temperature. USP REFERENCE STANDARDS 11 USP Levetiracetam RS Detector: UV 230 nm USP Levetiracetam Related Compound A RS Column: 4.6-mm 5-cm; 5-µm packing L1 [(S)-N-(1-amino-1-oxobutan-2-yl)-4-chlorobutanamide] Flow rate: 2.1 ml/min (C 8H 14ClNO ) Injection size: 25 µl USP Levetiracetam Related Compound B RS [(S)-2-aminobutanamide hydrochloride] Sample: Standard solution (C 4H 10N 2O HCl 138.6) [NOTE The relative retention times for ethinyl estradiol, (Z)- USP Levetiracetam Racemic Mixture RS norgestimate, (E)-norgestimate, and dibutyl phthalate are A 1:1 mixture of levetiracetam S-enantiomer and a mixture about 0.5, 1.0, 1.2, and 1.5, respectively.] containing (2S)-2-(2-oxopyrrolidin-1-yl)butanamide and Suitability requirements (2R)-2-(2-oxopyrrolidin-1-yl)butanamide (RB 1-Aug-2009) Resolution: NLT 1.5 between (Z)-norgestimate and (E)- norgestimate Relative standard deviation: NMT 2.0% for the peak response BRIEFING ratio of ethinyl estradiol, (Z)-norgestimate, and (E)- norgestimate to dibutyl phthalate Norgestimate and Ethinyl Estradiol Tablets, page 4268 of Calculate the percentage of the labeled amount of C 20H 24O 2 the Second Supplement to USP 32. Comments were received that the system suitability precision requirement cannot consistently in the portion of Tablets taken: be met for the ethinyl estradiol peak of the Standard solution in Result = (R UE/R SE) (C SE/C UE) 100 the procedure for Organic Impurities due to the low response of the analyte at 254 nm. Because the response of this peak is not R UE = ratio of the peak responses of ethinyl estradiol to used in the quantitation of impurities, it is proposed to remove dibutyl phthalate from the Sample solution the precision requirement with respect to the ethinyl estradiol R SE = ratio of the peak responses of ethinyl estradiol to peak. The comment period for this revision ends November 15, dibutyl phthalate from the Standard solution In the absence of significant adverse comments, it is pro- C SE = concentration of USP Ethinyl Estradiol RS in the posed to implement this revision via the First Interim Revision Standard solution (mg/ml) Announcement pertaining to USP 34 NF 29, with an official date C UE = nominal concentration of ethinyl estradiol in the of February 1, Sample solution (mg/ml) Calculate the percentage of the labeled amount of C 23H 31NO 3 in the portion of Tablets taken: (SM4: M. Waddell.) RTS C87596 Result = C SN/C UN [P A(R UA/R SA) + P S(R US/R SS)] 100 C SN = concentration of USP Norgestimate RS in the Standard solution (mg/ml) UN = nominal concentration of norgestimate in the Norgestimate and Ethinyl Estradiol Sample solution (mg/ml) Tablets P A = fraction of (E)-norgestimate in the USP Norgestimate RS DEFINITION R UA = ratio of the peak responses of (E)-norgestimate Norgestimate and Ethinyl Estradiol Tablets contain NLT 90.0% to dibutyl phthalate from the Sample solution and NMT 110.0% of the labeled amounts of norgestimate R SA = ratio of the peak responses of (E)-norgestimate (C 23H 31NO 3) and ethinyl estradiol (C 20H 24O 2). to dibutyl phthalate from the Standard solution P S = fraction of (Z)-norgestimate in the USP Norgesti- IDENTIFICATION mate RS The retention times of the major peaks of the Sample solution R US = ratio of the peak responses of (Z)-norgestimate correspond to those of the Standard solution, as obtained in to dibutyl phthalate from the Sample solution the Assay. R SS = ratio of the peak responses of (Z)-norgestimate to dibutyl phthalate from the Standard solution Calculate the ratio of the content of (Z)-norgestimate to ethinyl estradiol in the portion of Tablets taken, for use in Mobile phase: Tetrahydrofuran, methanol, and water (5:2:13) the Organic Impurities procedure: Internal standard solution: 0.05 mg/ml of dibutyl phthalate in methanol C Z/C E = [(C SN P S) (R US/R SS)]/[C SE(R UE/R SE)] Standard solution: Dissolve appropriate quantities of USP Ethinyl Estradiol RS and USP Norgestimate RS in a volume of The terms are as defined above. Internal standard solution equivalent to 80% of the final vol- Acceptance criteria: 90.0% 110.0% of C 20H 24O 2; ume. Add a volume of water equivalent to 20% of the final 90.0% 110.0% of C 23H 31NO 3 volume, and mix to obtain a solution having a known concen- Proposed IRA

24 1150 PROPOSED IRA Vol. 36(5) [Sept. Oct. 2010]. IMPURITIES Subject to consideration of comments received during the comment period, it is proposed to implement this revision via an pertaining to USP 34 NF 29 with an official date of February 1, Comments regarding this proposal should be received by November 15, Organic Impurities Mobile phase, Standard solution, and Sample solution: Proceed as directed in the Assay. (MD-GRE: E. Gonikberg.) RTS C89449 Detector: 254 nm Column: 4.6-mm 5-cm; 5-µm packing L1 Risedronate Sodium Flow rate: 2 ml/min Injection size: 50 µl Sample: Standard solution [NOTE The relative retention times for ethinyl estradiol, (Z)-norgestimate, and (E)-norgestimate are about 0.5, 1.0, and 1.2, respectively.] Suitability requirements C 7H 10NNaO 7P Resolution: NLT 1.5 between (Z)-norgestimate and (E)- norgestimate C 7H 10NNaO 7P 2 H 2O Relative standard deviation: NMT 2.0% for the ethinyl C 7H 10NNaO 7P H 2O estradiol and norgestimate (Z)-norgestimate and (E)- Phosphonic acid, [1-hydroxy-2-(3-pyridinyl)ethylidene]bis-, norgestimate (1-Feb-2011) peaks monosodium salt; Sodium trihydrogen [1-hydroxy-2-(3- Sample: Sample solution pyridyl)ethylidene]diphosphonate; Calculate the percentage of any impurity having a relative Hemi-pentahydrate [ ]. retention time of about 0.2 or 0.4, relative to the (Z)- Monohydrate [ ]. norgestimate peak, and detected at 254 nm in the portion of Tablets taken: DEFINITION Risedronate Sodium contains one or two and one-half molecules Result = (r U/r Z) (C Z/C E) F 100 of hydration. The monohydrate form contains NLT 98.0% and NMT 102.0% of C 7H 10NNaO 7P 2, calculated on the dried basis. r U = peak response for each impurity The hemi-pentahydrate form contains NLT 98.0% and NMT r Z = peak response for (Z)-norgestimate 102.0% of C 7H 10NNaO 7P 2, calculated on the anhydrous basis. C Z/C E = ratio of (Z)-norgestimate to ethinyl estradiol as defined in the Assay IDENTIFICATION F = relative response factor of these impurities, 1.54 A. INFRARED ABSORPTION 197 : The spectra of trifluorovinyl Acceptance criteria: The sum of the impurities having rela- chloride polymer and mineral oil dispersions of it, separately tive retention times of about 0.2 and 0.4 is NMT 4.0%. prepared from a test specimen, exhibit maxima in the regions of 4000 to 1350 cm 1 and 1350 to 450 cm 1, respectively, PERFORMANCE TESTS only at the same wavelengths as those of similar preparations DISINTEGRATION 701 : 15 min of USP Risedronate Sodium RS. [NOTE If a difference appears UNIFORMITY OF DOSAGE UNITS 905 : Meet the requirements in the infrared spectra of the analyte and the standard, dissolve equal portions of the test specimen and the USP Refer- ADDITIONAL REQUIREMENTS ence Standard in equal volumes of water containing about 50 PACKAGING AND STORAGE: Preserve in well-closed containers. mg/ml of potassium bromide. Evaporate the solutions to dry- USP REFERENCE STANDARDS 11 ness at 105 for 120 min. Repeat the test on the residues.] USP Ethinyl Estradiol RS B. IDENTIFICATION TESTS GENERAL Sodium 191 : It meets the USP Norgestimate RS requirements of the flame test. Proposed IRA BRIEFING Risedronate Sodium, page 4278 of the Second Supplement to USP 32. It is proposed to widen the tailing requirement in the Assay and in Organic Impurities, Procedure 1 from NMT 1.5 to NMT 1.6 to address variability observed for Dionex IonPac AS7 L48 columns. In Organic Impurities, Procedure 1, a note is added to disregard a peak due to sodium ion, eluting at 1.6 min. In addition, rela- tive retention times for two specified impurities in Impurity Ta- ble 1 are corrected. Difficulties were reported in performing the coulometric Karl Fisher titration procedure specified under Water Determination. A clarification is added that the coulometric procedure should be performed by direct introduction of solid sample into the titrator. It is also proposed to specify that the volumetric procedure may be used as an alternative method. Mobile phase: 1.8 g/l of edetate disodium in water. Adjust with 1 N sodium hydroxide to a ph of 9.5 ± 0.1. Standard solution: Dissolve USP Risedronate Sodium RS and USP Risedronate Related Compound A RS in Mobile phase to obtain a solution containing 1.0 mg/ml of anhydrous risedronate sodium and 0.1 mg/ml of risedronate related compound A. Sample solution: 1.1 mg/ml of Risedronate Sodium in Mobile phase