interim revision announcement - usp-nf · 2015-03-30 · interim revision announcement to usp 33...

INTERIM REVISIONANNOUNCEMENT

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 Stan-dards� Newly adopted (official) revisions to the USP–NF that become official before the official date of the next Supplement orthat were not ready for adoption by the closing date for the upcoming Supplement. (The official date for these revisions isstated 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 issueof a given PF volume.

Errata—Errata are considered to be text, erroneously published in the USP–NF or its Supplements, that do not accuratelyreflect the intended official requirements of the Council of Experts. At the end of the Interim Revision Announcement sec-tion in this publication is a list of errata and corrections to the USP–NF. The page number indicates where the item isfound in USP–NF. Errata lists are updated as necessary in each Pharmacopeial Forum and also appear on USP’s website(www.usp.org). Errata lists will be cumulative in future Supplements, and the corrected text will appear in the next annualedition of USP–NF.

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INTERIM REVISION ANNOUNCEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127Cephalexin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131Cephalexin Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132Cephalexin for Oral Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133Cephalexin Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1134Cephalexin Tablets for Oral Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135Cephalexin Hydrochloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136Glacial Acetic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137Protamine Sulfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138Protamine Sulfate Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138Protamine Sulfate for Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139

ERRATA LIST FOR USP 32–NF 27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1140

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#2010 The United States Pharmacopeial Convention All Rights Reserved.

Pharmacopeial Forum1128 INTERIM REVISION ANNOUNCEMENT Vol. 36(5) [Sept.–Oct. 2010]

INTERIM REVISIONANNOUNCEMENT

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 Officerand Chairman, USP Council of Experts

Susan de Mars, J.D., Chief Documentary Standards Officer and General CounselWilliam 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, 12601 Twinbrook Parkway,Rockville, MD 20852, USA ([email protected]).

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Pharmacopeial ForumVol. 36(5) [Sept.–Oct. 2010] INTERIM REVISION ANNOUNCEMENT 1129

New USP Reference Standards

The following USP Reference Standards, which werenot available when the associated monograph was madeofficial, have since become available. The respective offi-cial date of each USP–NF standard, test, or assay requir-ing the use of the following USP Reference Standards isindicated in parentheses after the name of the ReferenceStandard. Note that the official date is six months afterthe notice of availability for this Reference Standardwas published in PF.

USP Powdered Echinacea Pallida Extract RS (February 1, 2011)USP Oleyl Oleate RS (September 1, 2010)

Unavailable First-Time Official USPReference Standards

The official dates of any USP–NF standards, tests, or as-says requiring the use of the following new USP Refer-ence Standards are postponed until further noticepending availability of the respective Reference Stan-dards. This listing was updated as of June 15, 2010.Please refer to the current USP Catalog for a more up-to-date availability list. The USP Catalog can be accessedon-line at http://www.uspcatalog.com.

USP Acarbose RSUSP Acarbose System Suitability Mixture RSUSP Albumin Human RSUSP Alteplase RSUSP Amifostine RSUSP Amifostine Thiol RSUSP Antithrombin III Human RSUSP Aprotinin RSUSP Aprotinin System Suitability RSUSP Copolymer Polypropylene RSUSP Diethylstilbestrol Diphosphate RSUSP Eucatropine Hydrochloride RSUSP Gonadorelin Hydrochloride RSUSP Hemoglobin RSUSP Maritime Pine Extract RSUSP Menotropins RSUSP Sargramostim RSUSP Sincalide RSUSP Valrubicin Related Compound A RS

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AnalysisMONOGRAPHS (USP) Samples: Standard solution and Sample solutionAllow the spots to dry, and place the plate in a saturatedchamber containing the solvent system and lined with filterpaper. Develop the chromatogram until the solvent fronthas moved three-fourths of the length of the plate. Removethe plate from the developing chamber, mark the solventfront, allow the plate to air-dry, and examine under short-

. wavelength UV light.Acceptance criteria: The RF value of the principal spot of theCephalexinSample solution corresponds to that of the Standard solution.•5

ASSAY

Change to read:

• PROCEDURE

C16H17N3O4S · H2O 365.40 Mobile phase: 0.985 g/L of sodium-1-pentanesulfonate in amixture of acetonitrile, methanol, triethylamine, and waterC16H17N3O4S 347.40(20:10:3:170), adjusted with phosphoric acid to a pH of5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[(ami-3.0 ± 0.1nophenylacetyl)amino]-3-methyl-8-oxo-, monohydrate, [6R-[6α, ••57β (R*)]]-;

Standard stock solution: 1 mg/mL of USP Cephalexin RS in(6R,7R)-7-[(R)-2-Amino-2-phenylacetamido]-3-methyl-8-oxo-5-waterthia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohy-

Standard solution: •0.4 mg/mL of cephalexin in Mobile phasedrate [23325-78-2].from Standard stock solution•5Anhydrous [15686-71-2].

Sample stock solution: 1 mg/mL of Cephalexin in waterSample solution: •0.4 mg/mL of Cephalexin in Mobile phaseDEFINITIONfrom Sample stock solution•5Cephalexin has a potency of NLT 950 µg and NMT 1030 µg of

Chromatographic systemC16H17N3O4S/mg, calculated on the anhydrous basis.(See Chromatography ⟨621⟩, System Suitability.)

IDENTIFICATION Mode: LC• A. INFRARED ABSORPTION ⟨197K⟩ Detector: UV 254 nm

Column: 4.6-mm × 25-cm; packing L1 of low acidityFlow rate: 1.5 mL/minDelete the following: Injection size: 20 µL

System suitabilitySample: Standard solution•• B. ULTRAVIOLET ABSORPTION ⟨197U⟩ ••5Sample solution: 0.02 mg/mL of Cephalexin in waterSuitability requirementsStandard solution: 0.02 mg/mL of USP Cephalexin RS in ••5water

Relative standard deviation: NMT 2.0%Absorptivity: On the anhydrous basis, at peak maxima aboutAnalysis262 nm: 95.0%–104.0% of Sample solution to Standard solu-Samples: Standard solution and Sample solutiontion corrected for potencyCalculate the quantity, in µg, of C16H17N3O4S per mg of theAcceptance criteria: Peak maxima and minima at the sameCephalexin taken:wavelengths•5

•Result = (rU/rS) × (CS/CU) × PAdd the following:

rU = peak response from the Sample solutionrS = peak response from the Standard solution•5•• B. The retention time of the major peak of the Sample solu- CS = concentration of USP Cephalexin RS in the Stan-

tion corresponds to that of the Standard solution, as obtained dard solution (mg/mL)in the Assay.•5 CU = concentration of Cephalexin in the Sample solu-

tion (mg/mL)P = designated content of cephalexin in USPDelete the following:

Cephalexin RS (µg/mg)Acceptance criteria: 950–1030 µg/mg on the anhydrousbasis•• C. THIN-LAYER CHROMATOGRAPHY

Standard solution: 25 mg/mL of USP Cephalexin RS in waterIMPURITIESwith the aid of 0.1 N hydrochloric acidOrganic ImpuritiesSample solution: 25 mg/mL in water, with 0.1 N hydrochloric• PROCEDURE 1acid

Solution A: Dissolve 1 g of sodium 1-pentanesulfonate in aChromatographic systemmixture of 1000 mL of water and 15 mL of triethylamine.(See Chromatography ⟨621⟩, Thin-Layer Chromatography.)Adjust with phosphoric acid to a pH of 2.5 ± 0.1.Mode: TLC

Solution B: Dissolve 1 g of sodium 1-pentanesulfonate in aAdsorbent: 0.25-mm layer of chromatographic silica gelmixture of 300 mL of water and 15 mL of triethylamine.mixtureAdjust with phosphoric acid to a pH of 2.5 ± 0.1, and addApplication volume: 5 µL350 mL of acetonitrile and 350 mL of methanol.Developing solvent system: Ethyl acetate, acetonitrile, gla-

cial acetic acid, and water (21:7:7:9)

2010 The United States Pharmacopeial Convention All Rights Reserved.

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Mobile phase: See the gradient table below. IDENTIFICATION

Time Solution A Solution B Delete the following:(min) (%) (%)

0 100 0 •• A. THIN-LAYER CHROMATOGRAPHY1 100 0Standard solution: 3 mg/mL of USP Cephalexin RS in water

33.3 0 100 Sample solution: 3 mg/mL of cephalexin from Capsules in34.3 0 100 water and filter

Chromatographic systemDiluent: 18 mg/mL of monobasic potassium phosphate in (See Chromatography ⟨621⟩, Thin-Layer Chromatography.)water Mode: TLCStandard solutions: 0.08 mg/mL and 0.16 mg/mL of Adsorbent: 0.25-mm layer of binder-free silica gelC16H17N3O4S from USP Cephalexin RS in Diluent, taking into Application volume: 10 µLaccount the stated potency of the USP Cephalexin RS Pre-developing solvent system: n-Hexane and tetradecaneSample solution: 5 mg/mL of Cephalexin in Diluent (95:5)Chromatographic system Ninhydrin solution: 66.7 mg/mL of ninhydrin in acetone(See Chromatography ⟨621⟩, System Suitability.) Developing solvent system: 0.1 M citric acid, 0.1 M dibasicMode: LC sodium phosphate, and Ninhydrin solution (60:40:1.5)Detector: UV 254 nm AnalysisColumn: 4.6-mm × 25-cm; packing L1 of low acidity Samples: Standard solution and Sample solutionFlow rate: 1 mL/min Allow the solvent front to move the length of the plate inInjection size: 20 µL the Pre-developing solvent system, remove the plate from theAnalysis chamber, and allow the solvent to evaporate. On this plateSamples: Standard solutions and Sample solution apply 10 µL each of the Sample solution and Standard solu-Plot the responses of the cephalexin peaks from the Stan- tion. Allow the spots to dry, and develop the chromatogramdard solutions versus their concentrations, calculated on the in the Developing solvent system until the solvent front hasanhydrous basis, in mg/mL, and draw a straight line moved three-fourths of the length of the plate. Remove thethrough the two points and zero. From the line so ob- plate from the developing chamber, mark the solvent front,tained and the peak responses of the Sample solution, de- dry the plate for 10 min at 110°, and examine thetermine the concentration, I, in mg/mL, of each chromatogram.cephalexin-related substance of the Sample solution other Acceptance criteria: The RF value of the principal spot of thethan the cephalexin peak. Sample solution corresponds to that of the StandardCalculate the percentage of each cephalexin-related solution.•5substance:

Result = I/C × 100 Add the following:

•I = concentration of each cephalexin-related sub-stance in the Sample solution as determined •• The retention time of the major peak of the Sample solu-from the calibration curve (mg/mL)•5 tion corresponds to that of the Standard solution, as ob-

Acceptance criteria tained in the Assay.•5

Individual impurities: NMT 1.0% of any individualASSAYcephalexin-related substance

Total impurities: NMT 5.0%• PROCEDURE 2: DIMETHYLANILINE ⟨223⟩: Meets the requirement Change to read:SPECIFIC TESTS• OPTICAL ROTATION, Specific Rotation ⟨781S⟩: +149° to +158° • PROCEDURE

Sample solution: 5 mg/mL, in pH 4.4 neutralized phthalate Mobile phase: 0.985 g/L of sodium 1-pentanesulfonate in abuffer (See Reagents, Indicators, and Solutions—Buffer Solutions) mixture of acetonitrile, methanol, triethylamine, and water• CRYSTALLINITY ⟨695⟩: Meets the requirements (20:10:3:170), adjusted with phosphoric acid to a pH of• PH ⟨791⟩: 3.0–5.5, in an aqueous suspension containing 50 3.0 ± 0.1mg/mL ••5• WATER DETERMINATION, Method I ⟨921⟩: 4.0%–8.0% Standard stock solution: 1 mg/mL of USP Cephalexin RS in

waterADDITIONAL REQUIREMENTSStandard solution: •0.4 mg/mL of cephalexin in Mobile phase• PACKAGING AND STORAGE: Preserve in tight containers.from Standard stock solution•5• USP REFERENCE STANDARDS ⟨11⟩

Sample stock solution: Equivalent to 1 mg/mL of cephalexinUSP Cephalexin RSfrom combined contents of NLT 20 Capsules in water. Soni-cate, if necessary, to dissolve the cephalexin. Filter, if neces-sary, to obtain a clear solution.

Sample solution: •0.4 mg/mL of cephalexin in Mobile phase.

from Sample stock solution•5Cephalexin Capsules Chromatographic system(See Chromatography ⟨621⟩, System Suitability.)

DEFINITION Mode: LCCephalexin Capsules contain the equivalent of NLT 90.0% and Detector: UV 254 nm

NMT 120.0% of the labeled amount of cephalexin Column: 4.6-mm × 25-cm; packing L1 of low acidity(C16H17N3O4S). Flow rate: 1.5 mL/min

Injection size: 20 µLSystem suitabilitySample: Standard solution••5


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Suitability requirements Ninhydrin solution: 66.7 mg/mL of ninhydrin in acetone••5 Chromatographic systemRelative standard deviation: NMT 2.0% Mode: TLC

Analysis Adsorbent: 0.25-mm layer of binder-free silica gelSamples: Standard solution and Sample solution Application volume: 10 µLCalculate the percentage of C16H17N3O4S 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/rS) × (CS/CU) × P × F × 100 AnalysisSamples: Standard solution and Sample solution

rU = response from the Sample solution Place the plate in Pre-developing solvent at a depth of 1 cmrS = response from the Standard solution•5 and allow the solvent front to move the length of the plate,CS = 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 SampleCU = 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 solventP = 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, 0.001 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 RF value of the principal spot of thePERFORMANCE TESTS Sample solution corresponds to that of the Standard solution•5• DISSOLUTION ⟨711⟩

Medium: Water; 900 mLApparatus 1: 100 rpm Add the following:Time: 30 minSample solution: Pass a portion of the solution under test •• The retention time of the major peak of the Sample solutionthrough a suitable filter. Dilute with Medium, if necessary, to a

corresponds to that of the Standard solution, as obtained inconcentration of about 20 µg/mL.the Assay.•5Standard solution: 20 µg/mL of USP Cephalexin RS in

Medium ASSAYSpectrometric conditions(See Spectrophotometry and Light-Scattering ⟨851⟩.)Mode: UV Change to read:Analytical wavelength: 262 nm

Analysis• PROCEDURESamples: Standard solution and Sample solution

Mobile phase: 0.985 g/L of sodium 1-pentanesulfonate inTolerances: NLT 80% (Q) of the labeled amount ofacetonitrile, methanol, triethylamine, and water (20:10:3:170),C16H17N3O4S is dissolved.adjusted with phosphoric acid to a pH of 3.0 ± 0.1• UNIFORMITY OF DOSAGE UNITS ⟨905⟩: Meet the requirements

Standard stock solution: 1 mg/mL of USP Cephalexin RS inSPECIFIC TESTS water

Standard solution: Mix 10.0 mL of Standard stock solutionwith 15.0 mL of Mobile phase.Delete the following: ••5

Sample stock solution: Nominally equivalent to 1 mg/mL ofcephalexin from Oral Suspension, constituted as directed in•• WATER DETERMINATION, Method I ⟨921⟩: NMT 10.0%•5the labeling, freshly mixed and free from air bubbles. Soni-

ADDITIONAL REQUIREMENTS cate, if necessary, to assure complete dissolution of the• PACKAGING AND STORAGE: Preserve in tight containers. cephalexin. Filter, if necessary, to obtain a clear solution.• USP REFERENCE STANDARDS ⟨11⟩ Sample solution: Mix 10.0 mL of Sample stock solution and

USP Cephalexin RS 15.0 mL of Mobile phase.Chromatographic system(See Chromatography ⟨621⟩, System Suitability.)Mode: LC

. Detector: UV 254 nmColumn: 4.6-mm × 25-cm; packing L1 of low acidityCephalexin for Oral SuspensionFlow rate: 1.5 mL/minInjection size: 20 µLDEFINITION

System suitabilityCephalexin for Oral Suspension is a dry mixture of CephalexinSample: Standard solutionand one or more suitable buffers, colors, diluents, and flavors. ••5It contains the equivalent of NLT 90.0% and NMT 120.0% ofSuitability requirementsthe labeled amount of C16H17N3O4S per mL when constituted ••5as directed in the labeling.

Relative standard deviation: NMT 2.0%IDENTIFICATION Analysis

Samples: Standard solution and Sample solutionCalculate the percentage of C16H17N3O4S in each mL of OralDelete the following: Suspension taken:

Result = (rU/rS) × (CS/CU) × P × F × 100•• A. THIN-LAYER CHROMATOGRAPHYStandard solution: 3 mg/mL of USP Cephalexin RS in water rU = cephalexin peak response from the Sample solu-Sample solution: 3 mg/mL of Cephalexin, from Oral Suspen- tionsion constituted as directed in the labeling and filtered rS = cephalexin peak response from the Standard so-

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CS = concentration of USP Cephalexin RS in the Stan- Add the following:dard stock solution (mg/mL)

CU = nominal concentration of cephalexin from theSample 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.•5

F = unit conversion factor, 0.001 mg/µgASSAYAcceptance criteria: 90.0%–120.0%

PERFORMANCE TESTS Change to read:• UNIFORMITY OF DOSAGE UNITS ⟨905⟩ For solid packaged in sin-gle-unit containers: meets the requirements

• DELIVERABLE VOLUME ⟨698⟩: Meets the requirements • PROCEDUREMobile phase: 0.985 g/L of sodium 1-pentanesulfonate in aSPECIFIC TESTS mixture of acetonitrile, methanol, triethylamine, and water(20:10:3:170). Adjust with phosphoric acid to a pH of

Delete the following: 3.0 ± 0.1.••5

Standard stock solution: 1 mg/mL of USP Cephalexin RS in•• WATER DETERMINATION, Method I ⟨921⟩: NMT 2.0%•5 water• PH ⟨791⟩: 3.0–6.0, constituted as directed in the labeling Standard solution: •0.4 mg/mL of cephalexin in Mobile phase

from Standard stock solution•5ADDITIONAL REQUIREMENTS Sample stock solution: Equivalent to 1 mg/mL of cephalexin• PACKAGING AND STORAGE: Preserve in tight containers. from combined contents of powdered Tablets (NLT 20) in• USP REFERENCE STANDARDS ⟨11⟩ water. Sonicate, if necessary, to assure complete dissolution ofUSP Cephalexin RS the cephalexin. Filter, if necessary, to obtain a clear solution.Sample solution: •0.4 mg/mL of cephalexin in Mobile phasefrom Sample stock solution•5

Chromatographic system.

(See Chromatography ⟨621⟩, System Suitability.)Cephalexin Tablets Mode: LCDetector: UV 254 nm

DEFINITION Column: 4.6-mm × 25-cm; packing L1 of low acidityCephalexin 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 µLNMT 120.0% of the labeled amount of cephalexin System suitability(C16H17N3O4S). Sample: Standard solution

••5IDENTIFICATION Suitability requirements••5

Relative standard deviation: NMT 2.0%Delete the following:AnalysisSamples: Standard solution and Sample solution•• THIN-LAYER CHROMATOGRAPHY Calculate the percentage of C16H17N3O4S 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 powderedTablets in water and filter •Result = (rU/rS) × (CS/CU) × P × F × 100

Chromatographic systemrU = peak response from the Sample solution(See Chromatography ⟨621⟩, Thin-Layer Chromatography.)rS = peak response from the Standard solution•5Mode: TLCCS = concentration of USP Cephalexin RS in the Stan-Adsorbent: 0.25-mm layer of binder-free silica gel

dard solution (mg/mL)Application volume: 10 µLCU = nominal concentration of cephalexin in the Sam-Pre-developing solvent system: n-Hexane and tetradecane

ple solution (mg/mL)(95:5)P = designated content of cephalexin in USPNinhydrin solution: 66.7 mg/mL of ninhydrin in acetone

Cephalexin RS (µg/mg)Developing solvent system: 0.1 M citric acid, 0.1 M dibasicF = unit conversion factor, 0.001 mg/µgsodium phosphate, and Ninhydrin solution (60:40:1.5)

Acceptance criteria: 90.0%–120.0%AnalysisSamples: Standard solution and Sample solution

PERFORMANCE TESTSAllow the solvent front to move the length of the plate in• DISSOLUTION ⟨711⟩the Pre-developing solvent system, remove the plate from the

For Cephalexinchamber, and allow the solvent to evaporate. On this plate,Medium: Water; 900 mLapply 10 µL each of the Sample solution and Standard solu-Apparatus 1: Use 40-mesh cloth and 100 rpmtion. Allow the spots to dry, and develop the chromatogramTime: 30 minin the Developing solvent system until the solvent front hasSample solution: Pass a portion of the solution under testmoved three-fourths of the length of the plate. Remove thethrough a suitable filter. Dilute, if necessary, with Medium toplate from the developing chamber, mark the solvent front,a concentration that is similar to the Standard solution.dry the plate for 10 min at 110°, and examine the

Standard solution: 20 µg/mL of USP Cephalexin RS inchromatogram.MediumAcceptance criteria: The RF value of the principal spot of the

Spectrometric conditionsSample solution corresponds to that of the Standard solution.•5(See Spectrophotometry and Light-Scattering ⟨851⟩.)


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Mode: UV Add the following:Analytical wavelength: 262 nm

AnalysisSamples: Standard solution and Sample solution •• 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 inC16H17N3O4S is dissolved. the Assay.•5

For Cephalexin hydrochlorideASSAYMedium, Sample solution, Standard solution, Spectromet-

ric conditions, and Analysis: Proceed as directed ForCephalexin. Change to read:

Apparatus 1: Use 10-mesh cloth and 150 rpmTime: 45 minTolerances: NLT 75% (Q) of the labeled amount of • PROCEDUREC16H17N3O4S is dissolved. Mobile phase: 0.985 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

SPECIFIC TESTS 3.0 ± 0.1••5

Standard stock solution: 1 mg/mL of USP Cephalexin RS inDelete the following: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 ofCephalexin Hydrochloride•5 cephalexin from combined contents of NLT 20 powdered Tab-

lets 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•5

Cephalexin or Cephalexin Hydrochloride. Chromatographic system• USP REFERENCE STANDARDS ⟨11⟩ (See Chromatography ⟨621⟩, System Suitability.)

USP Cephalexin RS Mode: LCDetector: UV 254 nmColumn: 4.6-mm × 25-cm; packing L1 of low acidityFlow rate: 1.5 mL/min

. Injection size: 20 µLCephalexin Tablets for Oral Suspension System suitability

Sample: Standard solutionDEFINITION ••5

Cephalexin Tablets for Oral Suspension contain NLT 90.0% and Suitability requirementsNMT 110.0% of the labeled amount of cephalexin ••5

(C16H17N3O4S). Relative standard deviation: NMT 2.0%Analysis

IDENTIFICATION Samples: Standard solution and Sample solutionCalculate the percentage of C16H17N3O4S in each Tablet forOral Suspension:Delete the following:

•Result = (rU/rS) × (CS/CU) × P × F × 100•• A. THIN-LAYER CHROMATOGRAPHY

rU = response from the Sample solutionStandard solution: 3 mg/mL of USP Cephalexin RS in waterrS = response from the Standard solution•5Sample solution: 3 mg/mL of cephalexin from powderedCS = concentration of USP Cephalexin RS in the Sam-Tablets for Oral Suspension in water and filter

ple stock solution (mg/mL)Chromatographic systemCU = nominal concentration of cephalexin in the Sam-(See Chromatography ⟨621⟩, Thin-Layer Chromatography.

ple stock solution (mg/mL)Mode: TLCP = designated content of cephalexin in USPAdsorbent: 0.25-mm layer of binder-free silica gel

Cephalexin RS (µg/mg)Application volume: 10 µLF = unit conversion factor, 0.001 mg/µgPre-developing solvent system: n-Hexane and tetradecane

Acceptance criteria: 90.0%–110.0%(95:5)Ninhydrin solution: 66.7 mg/mL of ninhydrin in acetone PERFORMANCE TESTSDeveloping solvent system: 0.1 M citric acid, 0.1 M dibasic • DISINTEGRATION ⟨701⟩: Tablets for Oral Suspension disintegratesodium phosphate, and Ninhydrin solution (60:40:1.5) in 3 min, using water at 20 ± 5°.Analysis • DISSOLUTION ⟨711⟩Samples: Standard solution and Sample solution Medium: Water; 900 mLAllow the solvent front to move the length of the plate in Apparatus 1: Use 40-mesh cloth and 100 rpmthe Pre-developing solvent system, remove the plate from the Time: 30 minchamber, and allow the solvent to evaporate. On this plate Sample solution: Pass a portion of the solution under testapply 10 µL each of the Standard solution and Sample solu- through a suitable filter. Dilute with Medium, if necessary, to ation. 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 inmoved three-fourths of the length of the plate. Remove the Mediumplate from the developing chamber, mark the solvent front, Spectrometric conditionsdry the plate for 10 min at 110°, and examine the (See Spectrophotometry and Light-Scattering ⟨851⟩.)chromatogram.

Acceptance criteria: The RF value of the principal spot of theSample solution corresponds to that of the Standard solution.•5



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Mode: UV Add the following:Analytical wavelength: 262 nm

AnalysisSamples: Standard solution and Sample solution •• 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 obtainedC16H17N3O4S is dissolved. in the Assay.•5

• DISPERSION FINENESS: Place 2 Tablets for Oral Suspension in 100mL of water, and stir until completely dispersed. A smooth Delete the following:dispersion is obtained that passes through a No. 25 sieve.

• UNIFORMITY OF DOSAGE UNITS ⟨905⟩: Meets the requirements•• B. PROCEDURESPECIFIC TESTS Sample solution: 0.02 mg/mL of cephalexin in water

Analysis: The UV absorption spectrum of the Sample solutionDelete the following: exhibits maxima and minima at the same wavelengths as that

of a similar solution of USP Cephalexin RS, concomitantlymeasured.•5•• WATER DETERMINATION, Method I ⟨921⟩: NMT 9.0%•5

ADDITIONAL REQUIREMENTS Change to read:• PACKAGING AND STORAGE: Preserve in tight containers at con-

trolled room temperature.• •B.•5 IDENTIFICATION TESTS—GENERAL, Chloride ⟨191⟩: 10 mg/• USP REFERENCE STANDARDS ⟨11⟩

mL meets the requirementsUSP Cephalexin RS

ASSAY

. Change to read:Cephalexin Hydrochloride

• PROCEDUREC16H17N3O4S · HCl · H2O 401.87 Mobile phase: 0.985 g/L of sodium 1-pentanesulfonate in a5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[(ami- mixture of acetonitrile, methanol, triethylamine, and waternophenylacetyl)amino]-3-methyl-8-oxo-, monohydrochloride, (20:10:3:170), adjusted with phosphoric acid to a pH ofmonohydrate, [6R-[6α,7β (R*)]]-; 3.0 ± 0.1(6R,7R)-7-[(2R)-2-Amino-2-phenylacetamido]-3-methyl-8-oxo-5- ••5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, monohydro- Standard stock solution: 1 mg/mL of USP Cephalexin RS inchloride, monohydrate; water7-(D-2-Amino-2-phenylacetamido)-3-methyl-3-cephem-4-carbox- Standard solution: •0.4 mg/mL of cephalexin in Mobile phaseylic acid hydrochloride monohydrate [105879-42-3]. from Standard stock solution•5

Sample stock solution: 1.15 mg/mL of Cephalexin Hydro-DEFINITIONchloride in waterCephalexin Hydrochloride contains the equivalent of NLT 800 µg

Sample solution: •0.4 mg/mL of cephalexin in Mobile phaseand NMT 880 µg of cephalexin (C16H17N3O4S) per mg.from Sample stock solution•5

IDENTIFICATION Chromatographic system(See Chromatography ⟨621⟩, System Suitability.)Mode: LCDelete the following: Detector: UV 254 nmColumn: 4.6-mm × 25-cm; packing L1 of low acidityFlow rate: 1.5 mL/min•• A. THIN-LAYER CHROMATOGRAPHYInjection size: 20 µLStandard solution: 25 mg/mL of USP Cephalexin RS in water

System suitabilitywith the aid of 0.1 N hydrochloric acidSample: Standard solutionSample solution: 25 mg/mL in water with the aid of 0.1 N ••5hydrochloric acidSuitability requirementsChromatographic system ••5(See Chromatography ⟨621⟩, Thin-Layer Chromatography.)

Relative standard deviation: NMT 2.0%Mode: TLCAnalysisAdsorbent: 0.25-mm layer of chromatographic silica gelSamples: Standard solution and Sample solutionmixtureCalculate the quantity, in µg, of C16H17N3O4S in each mg ofApplication volume: 5 µLCephalexin Hydrochloride taken:Developing solvent system: Ethyl acetate, acetonitrile, gla-

cial acetic acid, and water (21:7:7:9) •Result = (rU/rS) × (CS/CU) × PAnalysisSamples: Standard solution and Sample solution rU = peak response from the Sample solutionAllow the spots to dry, place the plate in a saturated cham- rS = peak response from the Standard solution•5ber containing the solvent system and lined with filter pa- CS = concentration of USP Cephalexin RS in the Stan-per. Develop the chromatogram until the solvent front has dard stock solution (mg/mL)moved three-fourths of the length of the plate. Remove the CU = concentration of Cephalexin Hydrochloride fromplate 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 USPlength UV light. Cephalexin RS (µg/mg)Acceptance criteria: The RF value of the principal spot of theSample solution corresponds to that of the Standard solution.•5


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Acceptance criteria: 800–880 µg/mg Total impurities: NMT 5.0%• PROCEDURE 2: DIMETHYLANILINE ⟨223⟩: Meets the requirement

IMPURITIESOrganic Impurities SPECIFIC TESTS• PROCEDURE 1 • CRYSTALLINITY ⟨695⟩: Meets the requirements

Solution A: 1 g of sodium 1-pentanesulfonate in a mixture of • PH ⟨791⟩: 1.5–3.0, in a solution containing 10 mg/mL1000 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.

ADDITIONAL REQUIREMENTSSolution B: 1 g of sodium 1-pentanesulfonate in a mixture of• PACKAGING AND STORAGE: Preserve in tight containers.300 mL of water and 15 mL of triethylamine. Adjust with• USP REFERENCE STANDARDS ⟨11⟩phosphoric acid to a pH of 2.5 ± 0.1, and add 350 mL of

USP Cephalexin RSacetonitrile and 350 mL of methanol.Mobile phase: See the gradient table below.

Time Solution A Solution B.

(min) (%) (%) Glacial Acetic Acid0 100 01 100 0

33.3 0 100 34.3 0 100

Diluent: 18 mg/mL of monobasic potassium phosphate in C2H4O2 60.05water Acetic acid [64-19-7].

Standard solutions: 0.08 mg/mL and 0.16 mg/mL ofDEFINITIONC16H17N3O4S from USP Cephalexin RS in Diluent, taking intoGlacial Acetic Acid contains NLT 99.5% and NMT 100.5%, byaccount the stated potency of the USP Cephalexin RS

weight, of C2H4O2.Sample solution: 6 mg/mL of Cephalexin Hydrochloride inDiluent

IDENTIFICATIONChromatographic system(See Chromatography ⟨621⟩, System Suitability.)Mode: LC Change to read:Detector: UV 254 nmColumn: 4.6-mm × 25-cm; packing L1 of low acidityFlow rate: 1 mL/min • IDENTIFICATION TESTS—GENERAL, Acetate ⟨191⟩: Meets theInjection size: 20 µL requirements

Analysis Sample solution •(for lanthanum nitrate test):•5 GlacialSamples: Standard solutions and Sample solution Acetic Acid and water •(1:100)•5

Plot the responses of the cephalexin peaks of the StandardASSAYsolutions versus their concentrations, calculated on the an-• PROCEDUREhydrous basis, in mg/mL, and draw a straight line through

Sample solution: Measure 2 mL of Glacial Acetic Acid into athe two points and zero. From the line so obtained andglass-stoppered flask, previously tared while containing aboutthe peak responses of the Sample solution, determine the20 mL of water, and weigh again to obtain the weight of theconcentration, I, in mg/mL, of each cephalexin-related sub-substance under assay.stance from the Sample solution other than the cephalexin

Analysis: Add 20 mL of water, then add phenolphthalein TS.peak.Titrate with 1 N sodium hydroxide VS. Each mL of 1 N sodiumCalculate the percentage of each cephalexin-related sub-hydroxide is equivalent to 60.05 mg of C2H4O2.stance represented by each peak of the Sample solution,

Acceptance criteria: 99.5%–100.5%other than the cephalexin peak.

IMPURITIESResult = (I/C) × 100Inorganic Impurities• LIMIT OF NONVOLATILE RESIDUE: Evaporate 20 mL in a taredI = concentration of each cephalexin-related sub-

dish, and dry at 105° for 1 h: the weight of the residue doesstance other than cephalexin in the Sample so-not exceed 1.0 mg.lution (mg/mL)

• HEAVY METALS ⟨231⟩: NMT 5 ppmC = concentration mg/mL of cephalexin from theSample solution: To the residue obtained in the test for LimitSample solutionof Nonvolatile Residue add 8 mL of 0.1 N hydrochloric acid,Acceptance criteriawarm gently until solution is complete, dilute with water toIndividual impurities: NMT 1.0% of any individual100 mL, and use 20 mL.cephalexin-related substance is found.

• CHLORIDE AND SULFATE, Chloride ⟨221⟩Sample solution: Dilute 1.0 mL with 20 mL of water.Analysis: 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.Analysis: Add 1 mL of barium chloride TS.Acceptance criteria: No turbidity is produced.

Organic Impurities• PROCEDURE: READILY OXIDIZABLE SUBSTANCES

Sample solution: Dilute 2.0 mL in a glass-stoppered vesselwith 10 mL of water.

Analysis: Add 0.10 mL of 0.10 N potassium permanganate.Acceptance criteria: The pink color is not changed to brownwithin 2 h.



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SPECIFIC TESTS Spectrometric conditions• CONGEALING TEMPERATURE ⟨651⟩: NLT 15.6° (See Spectrophotometry and Light-Scattering ⟨851⟩.)

Mode: UVADDITIONAL 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 between260 and 280 nm of the Sample solution against the Blank isNMT 0.1.

• SULFATE. Sample: 150 mgProtamine Sulfate Analysis: Dissolve the Sample in 75 mL of water, add 5 mL of

3 N hydrochloric acid, heat to boiling, and while maintainingDEFINITION 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 portionswhich has the property of neutralizing heparin. Each mg of of hot water, dry, and ignite to constant weight. The weightProtamine Sulfate, calculated on the dried basis, neutralizes of the barium sulfate, multiplied by 0.4117, represents theNLT 100 USP Heparin Units. weight of sulfate in the portion of Protamine Sulfate taken.

Acceptance criteria: 16%–22% on the dried basisASSAY

ADDITIONAL REQUIREMENTS• PACKAGING AND STORAGE: Preserve in tight containers in aChange to read: refrigerator.

• PROCEDURE Change to read:•Sample solution A: 0.15 mg/mL of Protamine Sulfate inwater

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 withwater to 3.0 mL.

Titrant: USP Heparin Sodium for Assays RS in water (about.80–120 USP Heparin Units/mL)

Analysis: [NOTE—Titrate each Sample solution in duplicate.] Protamine Sulfate InjectionTransfer a volume of the Sample solution to the analytical cellof a suitable colorimeter, and set the apparatus for measure- DEFINITIONment at a suitable wavelength (none is critical) in the visiblerange. Add Titrant in small volumes until there is a sharp in-

Change to read:crease in the absorbance, and note the volume of Titrantadded. Perform the entire Assay in triplicate for a total of 18determinations. Protamine Sulfate Injection is a sterile, isotonic solution of Prota-Calculate the number of USP Heparin Units in the volume of mine Sulfate. •Each mg of Protamine Sulfate, used in the man-Titrant added at the endpoint per mg of Protamine Sulfate. ufacture of the Injection, neutralizes NLT 100 USP HeparinCalculate the USP Heparin Units neutralized per mg of Prota- Units, calculated on the dried basis.•5 It contains NLT 90.0%mine Sulfate taken: and NMT 120.0% of the labeled amount of protamine sulfate.

Result = (VT × CT)/(VS × CS) IDENTIFICATION• IDENTIFICATION TESTS—GENERAL, Sulfate ⟨191⟩VT = volume of Titrant added (mL)

CT = concentration of Titrant (USP Heparin Units/mL) ASSAYVS = volume of the Sample solution (mL)CS = concentration of Protamine Sulfate (mg/mL)

Change to read:Calculate the potency of the Protamine Sulfate as the averageof the 18 values. Calculate the 3 standard deviations for theresults obtained with each of the Sample solutions. Calculate

• PROCEDUREthe 3 standard deviations for the results obtained with eachSample solution: •0.15 mg/mL•5 of protamine sulfate inof the 3 independent assays. The Assay is valid if each of theWater for Injection from a measured volume of Injection6 standard deviations is NMT 5% of the average result. •Analysis: [NOTE—Titrate the Sample solution in duplicate.]Acceptance criteria: Each mg of Protamine Sulfate neutralizesTransfer the same volume of the Sample solution to the analyti-NLT 100 USP Heparin Units, on the dried basis.•5cal cell as used in the Assay for the drug substance. Proceedas directed in the Assay under Protamine Sulfate, using theOTHER COMPONENTSsame concentration of Titrant and the same wavelength as• NITROGEN DETERMINATION, Method II ⟨461⟩used in the Assay for the drug substance. The concentration ofAcceptance criteria: 22.5%–25.5% of N, on the dried basis.the Sample solution of the drug substance should also be 0.15

SPECIFIC TESTS 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:

Result = (v/V) × 100Change to read:v = volume of Titrant added to the Injection Sample

solution (mL)• ULTRAVIOLET ABSORBANCE V = volume of Titrant added to the drug substanceSample solution: 1.0% solution of Protamine Sulfate •in Sample solution (mL)water•5•5


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Acceptance criteria: 90.0%–120.0% cal cell as used in the Assay for the drug substance. Proceedas directed in the Assay under Protamine Sulfate, using the

SPECIFIC TESTS 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 ofthe label claim is given as follows:ADDITIONAL REQUIREMENTS

• PACKAGING AND STORAGE: Preserve in single-dose containers, Result = (v/V) × 100preferably of Type I glass. Store at controlled roomtemperature. 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)•5Change to read:Acceptance criteria: 90.0%–120.0%

PERFORMANCE TESTS• USP REFERENCE STANDARDS ⟨11⟩• UNIFORMITY OF DOSAGE UNITS ⟨905⟩: Meets the requirementsUSP Endotoxin RS

USP Heparin Sodium•for Assays•5 RS SPECIFIC TESTS• INJECTIONS, Constituted Solutions ⟨1⟩: At the time of use, it

meets the requirements.• BACTERIAL ENDOTOXINS TEST ⟨85⟩: It contains NMT 7.0 USP En-

.

dotoxin Units/mg of protamine sulfate.Protamine Sulfate for Injection • STERILITY TESTS ⟨71⟩: Both it and the accompanying solventmeet the requirements

DEFINITION • PH AND CLARITY OF SOLUTION: Dissolve it in the solvent recom-mended in the labeling: the pH of the solution is 6.5–7.5, andthe solution is clear.Change to read:

• OTHER REQUIREMENTS: Both it and the accompanying solventmeet the requirements for Injections ⟨1⟩, Labeling.

Protamine Sulfate for Injection is a sterile mixture of ProtamineADDITIONAL REQUIREMENTSSulfate with one or more suitable, dry diluents. •Each mg of• PACKAGING AND STORAGE: Preserve as described under Injec-Protamine Sulfate, used in the manufacture of the Protamine

tions ⟨1⟩, Containers for Sterile Solids. Preserve the accompany-Sulfate for Injection, neutralizes NLT 100 USP Heparin Units,ing solvent in single-dose or in multiple-dose containers, pref-calculated on the dried basis.•5 It contains NLT 90.0% anderably of Type I glass.NMT 120.0% of the labeled amount of protamine sulfate.

• LABELING: Label it to indicate the approximate neutralizationcapacity in USP Heparin Units.ASSAY

Change to read:Change to read:

• USP REFERENCE STANDARDS ⟨11⟩• PROCEDUREUSP Endotoxin RSSample solution: •0.15 mg/mL•5 of protamine sulfate inUSP Heparin Sodium•for Assays•5 RSWater for Injection. Dissolve from the contents of 1 container

of Protamine Sulfate for Injection.•Analysis: [NOTE—Titrate the Sample solution in duplicate.]Transfer the same volume of the Sample solution to the analyti-



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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 orpending official publication of USP–NF. If necessary, this list will be updated with every issue of PF. This information will also beavailable 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 requirementsas approved by the Council of Experts. USP staff is available to respond to questions regarding the accuracy of a particular require-ment; call 1-800-822-USPC.

USP32–NF27Page

Title Section Description

2409 Sodium Fluoride F18Injection

Radiochemical Purity Line 3 under Chromatographic system: Change ‘‘7.5-mm 6 30-cm column that contains 10-mm packing L17.’’to:10-mm 6 25-cm column that contains 10-mm packing L31.

3411 Propofol Limit of propofol relatedcompound A

Line 6 under Procedure: Change‘‘0.01(rU / rS)in which rU and rS are the peak responses for propofol relatedcompound A obtained from the Test solution and the Standardsolution, respectively’’to:100(CS / CU)(rU / rS)in which CS is the concentration, in mg per mL, of USP PropofolRelated Compound A RS in the Standard solution; CU is the con-centration, in mg per mL, of propofol in the Test solution; and rUand rS are the peak responses for propofol related compound Aobtained from the Test solution and the Standard solution, re-spectively

First Supplement to USP32-NF274063 Haloperidol Decano-

ateAssay Footnote 11 under Table 1: Change ‘‘4-(4’-Chlorobiphenyl-4-

yl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl decano-ate.’’to: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 decano-ate.’’to:4-(4’-Chlorobiphenyl-4-yl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-piperidin-4-yl decanoate.

Second Supplement to USP32-NF274152 h785iOsmolality and

OsmolarityMeasurement of Osmolal-ity

Line 2 under Standard Solutions: Change footnote ‘‘1’’to:2At the bottom of page: Change footnote ‘‘1’’to:2

U S P 3 3 –NF28ReissuePage

Title CATEGORYSection

Description

R-140 Reagent Specifica-tions

3,5-Dimethylphenol Line 4: Change ‘‘from Lancaster Synthesis, Inc., www.lancas-tersynthesis.com’’to:from www.alfa.com

R-142 Reagent Specifica-tions

Ether, Peroxide-Free Line 11: Change ‘‘www.jtbaker.com’’to:www.mallbaker.com

R-203 ChromatographicColumns

L54 Line 4: Change ‘‘from Amersham Pharmacia Biotech (www.amershambiosciences.com)’’to:from www.gelifesciences.com

R-316 Oil- and Water-So-luble Vitamins withMinerals Capsules

STRENGTHVitamin A, Method 1

Line 14 under Analysis: Change ‘‘retinol acetate’’to:retinyl acetate

R-453 Amiodarone Hydro-chloride

SPECIFIC TESTSLimit of Iodides

Line 2 under Standard solution: Change ‘‘1.0 mL of an 88.2 mg/mL solution of potassium iodide’’to:1.0 mL of an 88.2 mg/L solution of potassium iodide

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U S P 3 3 –NF28ReissuePage

Title CATEGORYSection

Description

R-472 Clarithromycin Tab-lets

ASSAYProcedure

Line 1 under Sample stock solution: Change ‘‘Equivalent to 4mg/mL of clarithromycin in methanol.’’to:Equivalent to 4 mg/mL of clarithromycin from finely powderedTablets in methanol.

R-510 Mycophenolate Mo-fetil

SPECIFIC TESTSLoss on Drying h731i

Line 1: Change ‘‘Dry a sample at 608 for 3 h: it loses NMT 0.5%of its weight.’’to:Dry a sample in a vacuum at 608 for 3 h: it loses NMT 0.5% ofits weight.

R-534 Ritonavir IMPURITIESOrganic Impurit ies,Procedure

In each row of Impurity Table 1 under the column head RelativeResponse Factor with a value of ‘‘—’’, changeto:1.0

R-534 Ritonavir IMPURITIESOrganic Impurit ies,Procedure

In each row of Impurity Table 1 under the column head Accep-tance Criteria, NMT (%) with a value of ‘‘—’’, changeto:0.1

First Supplement to the USP33-NF28 ReissueR-645 h1024i Bovine Ser-

umAppendix 1 Line 3 under FDA, first bullet: Change ‘‘http:// www.fda.gov/

Cber/ltr/bse04l900.pdf’’to:Available at: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm105877.htmLine 4 under FDA, second bullet: Change ‘‘Available at http://www.fda.gov/cber/rules/catruminant.pdf’’to:Available at: http://www.reginfo.gov/public/

R-984 Ticlopidine Hydro-chloride

IMPURITIESOrganic Impurit ies,Procedure 2

Footnote a under Impurity Table 2: Change ‘‘N-(2-Chloroben-zyl)-2-(thiophen-2-yl)ethanamine.’’to:2-[N-Methyl-N-(2-chlorobenzyl)aminoethyl] thiophene hydro-chloride.

Second Supplement to the USP33-NF28 ReissueR-1034 h11i USP Reference

StandardsUSP Allopurinol RelatedCompound F RS

Line 1: Change ‘‘[ethyl 3-(2-carbethoxy-’’to:[ethyl (E / Z)-3-2(2-carbethoxy-

R-1041 h11i USP ReferenceStandards

USP Doxepin RelatedCompound A RS

Line 1: Change ‘‘[5-(4-nitrophenyl)-2-furaldehyde-2-carboxy-methyl semicarbazone]’’to:[dibenzo[b,e]oxepin-11(6H)-one]

R-1063 h92i Growth Factorsand Cytokines Usedi n C e l l T h e r a p yManufacturing

SPECIFIC TESTSBioidentity

Line 1 under Resazurin solution: Change ‘‘0.11 mg of resazurinin Phosphate buffered saline.’’to:11 mg of resazurin in 100 mL of Phosphate buffered saline.

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PROPOSEDINTERIM REVISIONANNOUNCEMENTS

This section includes proposals for Interim Revision Announcements (IRAs) that will be published as official USP or NFstandards. There is a 60-day comment period for these proposals, beginning on the 15th of the first month of thisPharmacopeial Forum. The approved official text will be published in a future Pharmacopeial Forum and additionally inthe ‘‘New Official Text’’ section of USP’s web site (www.usp.org). Readers should review material in this section andprovide comments to the Scientific Liaison (use the Staff Directory to find the contact information). Information onhow to comment is found in the Policies and Announcements section. It is important to send comments promptly so thatthe Expert Committee members can consider readers’ input as they are deciding whether to advance standards to officialstatus.

Each proposal is preceded by a Briefing that indicates the proposed revisions.

Proposed

IRA

PROPOSED INTERIM REVISION ANNOUNCEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1143MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1145

Leuprolide Acetate (1-Feb-2011) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145Levetiracetam (1-Feb-2011) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147Norgestimate and Ethinyl Estradiol Tablets (1-Feb-2011) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149Risedronate Sodium (1-Feb-2011) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150

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Pharmacopeial Forum1144 PROPOSED IRA Vol. 36(5) [Sept.–Oct. 2010]

Pharmacopeial ForumVol. 36(5) [Sept.–Oct. 2010] PROPOSED IRA 1145

Degradation standard solution: Dilute 5.0 mL of the Stan-USP MONOGRAPHS dard stock solution with water to 50.0 mL. Transfer 5 mL ofthe solution to a scintillation vial. Add 100 µL of 1 N sodiumhydroxide solution, cap tightly, and shake vigorously. Place inan oven at 100° for 60 min, remove, allow to cool, add 50 µLof 1 M phosphoric acid, recap, and shake vigorously to mix.

Sample solution: 50 µg/mL of Leuprolide Acetate in MobileBRIEFING phase

Chromatographic system(See Chromatography ⟨621⟩, System Suitability.)Mode: LCLeuprolide Acetate, USP 32 page 2761. On the basis ofDetector: UV 220 nmcomments received, it is proposed to remove the retention timeColumn: 4.6-mm × 10-cm; 3-µm packing L1of the acetic acid peak in the test for Content of Acetic Acid. TheFlow rate: 1–1.5 mL/minformula in the Assay is being corrected to reflect the labeling ofInjection size: 20 µLUSP Leuprolide Acetate RS on the anhydrous, acetic acid-free

System suitabilitybasis, which makes the coefficient in the formula unnecessary.Samples: Mobile phase, Standard solution, and Degradationstandard solution[NOTE—Chromatograph the Mobile phase, and verify that no(BB PP: T. Sigambris.) RTS—C83380 extraneous peaks are present.][NOTE—The relative retention times for the degradation prod-uct and leuprolide are about 0.90 and 1.0, respectively.]

Suitability requirements. Retention time: 41–49 min for leuprolide, DegradationLeuprolide Acetate standard solution

Resolution: NLT 1.5 between leuprolide and the degrada-tion product, Degradation standard solution

Tailing factor: 0.8–1.5, Standard solutionRelative standard deviation: NMT 1.5% for leuprolideacetate, Standard solution

AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of C59H84N16O12 in the portion ofLeuprolide Acetate taken:

Result = [(rU/rS)(WS/WU)(P)(0.9527)(100)]/(100 – acetic acidcontent – water content)

C59H84N16O12 · (C2H4O2)n, n = 1 or 2 1209.41 (as free base) •Result = [(rU/rS) × (CS/CU) × P × 100]/(100 – AC – WC)•(1-Luteinizing hormone-releasing factor, 6-D-leucine-9-(N-ethyl-L-Feb-2011)prolinamide)-10-deglycinamide acetate (salt);

5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leu- rU = peak area of the Sample solutioncyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) [74381-53-6]. rS = peak area of the Standard solution

WS = concentration of USP Leuprolide Acetate RS inDEFINITION •CS•(1- the Standard solution (µg/mL)Leuprolide Acetate is a synthetic nonapeptide agonist analog ofFeb-2011)luteinizing hormone-releasing factor. It contains NLT 97.0% WU = concentration of Leuprolide Acetate in the Sam-and NMT 103.0% of leuprolide (C59H84N16O12), calculated on •CU•(1- ple solution (µg/mL)the anhydrous, acetic acid-free basis.Feb-2011)[NOTE—Due to the hygroscopic nature of this material, analyses P = designated purity of USP Leuprolide Acetate RSare performed immediately after opening the container in a (%)glove box under dry nitrogen purge.] AC = acetic acid content (%)[CAUTION—Leuprolide Acetate is a potent hormonal manipulator. WC = water content (%)Avoid skin contact and inhalation of dusts and mists.] Acceptance criteria: 97.0%–103.0%

IDENTIFICATION OTHER COMPONENTS• 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 Change to read:the Assay.

ASSAY • CONTENT OF ACETIC ACIDDiluent: Methanol, adjusted with phosphoric acid to a pH of2.5Change to read: Standard solution: Pipet 2.0 mL of glacial acetic acid into a100-mL volumetric flask, dilute with Diluent to volume, andmix. Transfer 4.0 mL of the solution to a 100-mL volumetric• PROCEDUREflask, dilute with Diluent to volume, and mix. Transfer 10.0 mLSolution A: 15.2 mg/mL of triethylamine in water. Adjust withof this solution to a 100-mL volumetric flask, dilute with Dilu-phosphoric acid to a pH of 3.0.ent to volume, and mix to obtain a solution having a knownSolution B: Acetonitrile and n-propyl alcohol (3:2)concentration of about 0.08 mg/mL.Mobile phase: Solution A and Solution B (17:3)

Sample solution: Transfer about 100 mg of Leuprolide Ace-Standard stock solution: 1 mg/mL of USP Leuprolide Acetatetate, accurately weighed, to a 100-mL volumetric flask, dis-RS in Mobile phasesolve in and dilute with Diluent to volume.Standard solution: 50 µg/mL. Dilute 5.0 mL of the Standard

Chromatographic systemstock solution with Mobile phase to 100.0 mL.(See Chromatography ⟨621⟩, System Suitability.)


Proposed IRA


Mode: GC Resolution: NLT 1.5 between leuprolide and the degrada-Detector: Flame ionization tion product, Degradation standard solutionColumn: 0.53-mm × 30-m fused-silica capillary column that Tailing factor: 0.8–1.5, Standard solutioncontains a 1.2-µm film of phase G35 Relative standard deviation: NMT 1.5% for leuprolide

Temperature acetate, Standard solutionColumn: 100° AnalysisInjection port: 200° Samples: Standard solution and Sample solutionDetector: 250° [NOTE—Record the chromatograms for 90 min.]

Carrier gas: Helium Calculate the percentage of each impurity in the portion ofFlow rate: 10 mL/min C59H84N16O12 · (C2H4O2)n taken:Injection size: 1.0 µL

Result = 0.01 × (rU/rS) × (WS/WU) × PInjection type: Splitless modeSystem suitability

rU = peak response for each impurity from the Sam-Samples: Diluent and Standard solutionple solutionSuitability requirements

rS = leuprolide peak response from the StandardRetention time: 5–7 min, acetic acidstock solution••(1-Feb-2011)

WS = weight of USP Leuprolide Acetate RS in theBlank: Chromatograph the Diluent, and verify that thereStandard stock solution (mg)are no interfering peaks.

WU = weight of Leuprolide Acetate in the Sample solu-Column efficiency: NLT 15,000 theoretical plates, Stan-tion (mg)dard solution

P = designated purity of USP Leuprolide Acetate RSTailing factor: 0.8–1.5, Standard solution(%)Relative standard deviation: NMT 2.0% for glacial acetic

Acceptance criteriaacid, for replicate injections of the Standard solutionIndividual impurities: See Impurity Table 1.AnalysisTotal impurities: NMT 2.5%Samples: Standard solution and Sample solution

Calculate the percentage of acetic acid (C2H4O2) in the por-tion of Leuprolide Acetate taken: Impurity Table 1

Relative AcceptanceResult = (rU/rS) × (839.2/WU)Retention Criteria,

Name Time NMT (%)rU = peak area of the Sample solutionAcetyl-leuprolide 1.5 1.0rS = peak area of the Standard solution

WU = amount of Leuprolide Acetate taken to prepare D-His-leuprolide 0.9 0.5the Sample solution (mg) L-Leu6-leuprolide 1.2 0.5

Acceptance criteria: 4.7%–9.0%D-Ser-leuprolide 0.8 0.5Leuprolide 1.0 —IMPURITIES

Inorganic Impurities Any other impurity — 0.5• RESIDUE ON IGNITION ⟨281⟩: NMT 0.3%Organic Impurities

SPECIFIC TESTS• PROCEDURE • AMINO ACID CONTENTSolution A: 15.2 mg/mL of triethylamine in water. Adjust[NOTE—Use a suitable, validated procedure (see Biotechnology-with phosphoric acid to a pH of 3.0 prior to final dilution.Derived Articles—Amino Acid Analysis ⟨1052⟩).]Solution B: Acetonitrile and n-propyl alcohol (3:2)

Standard solutions: Prepare a solution having known equi-Mobile phase: Solution A and Solution B (17:3)molar amounts of L-alanine, L-arginine, L-aspartic acid, L-Standard stock solution: 1 mg/mL of USP Leuprolide Ace-glutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-ly-tate RS in Mobile phasesine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threo-Standard solution: Dilute 1.0 mL of the Standard stock solu-nine, L-tyrosine, and L-valine with half the equimolar amounttion with Mobile phase to 100.0 mL.of L-cystine. For the validation of the method, an appropriateDegradation standard solution: Dilute 5 mL of Standardinternal standard, such as norleucine, is used. Prepare a sepa-stock solution with water to 50.0 mL. Transfer 5 mL of therate, equimolar solution of L-tryptophan.solution to a scintillation vial. Add 100 µL of 1 N sodium

Sample solution: Transfer 64 mg of Leuprolide Acetate to ahydroxide solution, tightly cap, and shake vigorously. Placesuitable vessel. Dissolve in 1.0 mL of water. Transfer 0.10 mLin an oven at 100° for 60 min, remove, allow to cool, addof this solution to a vacuum hydrolysis tube, add 2.0 mL of50 µL of 1 M phosphoric acid, recap, and shake vigorously to6 N hydrochloric acid, evacuate the tube, and heat for 16 hrmix.at 120°. Transfer 0.10 mL of the hydrolysate so obtained to aSample solution: Transfer about 100 mg of Leuprolide Ace-suitable vessel, add 1 mL of water, and lyophilize. Dissolve intate to a 100-mL volumetric flask, dissolve in and dilute withand dilute to a suitable volume in a buffer solution suitable forMobile phase to volume.amino acid analysis.Chromatographic system

Analysis: Inject equal volumes of the Standard solution and the(See Chromatography ⟨621⟩, System Suitability.)Sample solution into the amino acid analyzer, and record andMode: LCmeasure the responses for each amino acid peak. Express theDetector: UV 220 nmcontent of each amino acid in moles.Column: 4.6-mm × 10-cm; 3-µm packing L1Calculate the relative proportions of the amino acids in theFlow rate: 1–1.5 mL/minSample solution, taking one-seventh of the sum of the num-Injection size: 20 µLber of moles of histidine, glutamic acid, leucine, proline, ty-System suitabilityrosine, and arginine as equal to one.Samples: Mobile phase, Standard solution, Degradation

Acceptance criteria: 0.85–1.1 moles each of glutamic acid,standard solution, and Sample solutionproline, tyrosine, histidine, and arginine per mole of[NOTE—Chromatograph the Mobile phase, and verify thatLeuprolide Acetate; 1.8–2.2 moles of leucine per mole ofno extraneous peaks are present.]Leuprolide Acetate; serine and tryptophan are also present.Suitability requirements • OPTICAL ROTATION, Specific Rotation ⟨781S⟩: −38.0° to −42.0°Retention time: 41–49 min for leuprolide, Degradationexpressed on an anhydrous, acetic acid-free basisstandard solution


Prop

osed

IRA


Sample solution: 10 mg/mL, in 1% acetic acid ASSAY• WATER DETERMINATION, Method Ic ⟨921⟩: NMT 8.0%• BACTERIAL ENDOTOXINS TEST ⟨85⟩: It contains NMT 166.7 USP Change to read:Endotoxin Units per mg of leuprolide acetate.

ADDITIONAL REQUIREMENTS • PROCEDURE• PACKAGING AND STORAGE: Preserve in tight containers. Store at Buffer: 0.26 g/L of monobasic potassium phosphate in water.a temperature not higher than 30°. Adjust with 2% aqueous potassium hydroxide (w/v) to a pH• USP REFERENCE STANDARDS ⟨11⟩ of 5.5.USP Endotoxin RS Solution A: Acetonitrile and Buffer (1:19)USP Leuprolide Acetate RS Solution B: AcetonitrileMobile phase: See the gradient table below.

BRIEFING Time Solution A Solution B(min) (%) (%)

0 100 0Levetiracetam, page R-927 of the First Supplement to the USP 3 100 033–NF 28 Reissue and the Revision Bulletin posted on the USP

20 71 29website on June 26, 2009 with an official date of August 1,2009. On the basis of comments received, it is proposed to System suitability solution: 0.2 mg/mL of USP Levetiracetamrevise the following: RS and 0.08 mg/mL of USP Levetiracetam Related Compound1. 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, diluteEnantiomer 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 inthe use of dehydrated alcohol, which will not cause phase Solution Aseparation. Sample solution: 0.1 mg/mL of Levetiracetam in Solution A

Subject to consideration of comments received, it is proposed to Chromatographic systemimplement this revision via an Interim Revision Announcement (See Chromatography ⟨621⟩, System Suitability.)pertaining to USP 34–NF 29 in PF 37(1) [Jan.–Feb. 2011], with an Mode: LCofficial date of February 1, 2011. Comments regarding this pro- Detector: UV 205 nmposal should be received by November 15, 2010. Column: 4.6-mm × 15-cm; packing L1

Flow rate: 0.9 mL/minInjection size: 10 µL

System suitability(MD-PP: R. Ravichandran.) RTS—C87569; C85247Sample: System suitability solution[NOTE—The relative retention times are listed in Impurity Ta-ble 1.]

Suitability requirementsColumn efficiency: NLT 50,000 theoretical plates for theAdd the following: levetiracetam peak••(1-Feb-2011)

Relative standard deviation: NMT 1.0%.

[NOTE—If system suitability criteria cannot be met, it is rec-•Levetiracetam ommended that the column temperature be maintained at20° to stabilize the system.]

AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of C8H14N2O2 in the portion ofLevetiracetam taken:

Result = [(rU/rS) × (CS/CU) × 100] − FC8H14N2O2 170.21

rU = peak response of levetiracetam from the Sample1-Pyrrolidineacetamide, α-ethyl-2-oxo-, (αS)-;solution(−)-(S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide [102767-28-2].

rS = peak response of levetiracetam from the Stan-DEFINITION dard solutionLevetiracetam contains NLT 98.0% and NMT 102.0% of CS = concentration of USP Levetiracetam RS in the

C8H14N2O2, calculated on the anhydrous and solvent-free basis. Standard solution (mg/mL)CU = 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 andtiracetam S-enantiomer from the System suitability solution, as solvent-free basisobtained in the test for Limit of Levetiracetam R-Enantiomer.


Proposed IRA


IMPURITIES rU = peak response of each impurity from the SampleInorganic Impurities solution• RESIDUE ON IGNITION ⟨281⟩: NMT 0.1% rS = peak response of levetiracetam from the Stan-• HEAVY METALS, Method II ⟨231⟩: 20 ppm dard solutionOrganic Impurities CS = concentration of USP Levetiracetam RS in the• PROCEDURE 1: LIMIT OF LEVETIRACETAM RELATED COMPOUND B Standard solution (mg/mL)

[NOTE—Perform this test only if levetiracetam related com- CU = concentration of Levetiracetam in the Sample so-pound 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 of20% (w/v) potassium hydroxide to a pH of 3.0. 0.19 or less.]

Mobile phase: Acetonitrile and Buffer (3:17) Acceptance criteriaSystem suitability solution: 2 mg/mL of USP Levetiracetam Individual impurities: See Impurity Table 1.Related Compound B RS in Mobile phase Total impurities: NMT 0.4%

Standard solution: 0.002 mg/mL of USP Levetiracetam Re-lated Compound B RS in Mobile phase

Impurity Table 1Sample solution: 2.0 mg/mL of Levetiracetam in Mobilephase Relative Relative Acceptance

Chromatographic system Retention Response Criteria,(See Chromatography ⟨621⟩, System Suitability.) Name Time Factor NMT (%)Mode: LC Pyridin-2-ola 0.37 1.0 0.025Detector: UV 200 nm

Levetiracetam acidb 0.62 1.2 0.3Column: 4.6-mm × 25-cm; packing L1Levetiracetam 1.00 — —Flow rate: 1.0 mL/minLevetiracetam related 1.25 0.35 0.05Injection sizecompound AcSystem suitability: 10 µL

Analysis: 50 µL Any individual — 1.0 0.05System suitability unspecified impurity

Sample: System suitability 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 lim-pound B is 9 min.] it.

Suitability requirements c (S)-N-(1-Amino-1-oxobutan-2-yl)-4-chlorobutanamide. Included in the TotalTailing 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 main-tained at 27° to stabilize the system.]

Relative standard deviation: NMT 2.0% SPECIFIC TESTSAnalysis • WATER DETERMINATION, Method Ia ⟨921⟩: NMT 0.5%

Samples: Standard solution and Sample solution Calculate the percentage of levetiracetam related compound

Change to read:B in the portion of Levetiracetam taken:

Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100 • LIMIT OF LEVETIRACETAM R-ENANTIOMERMobile phase: n-Hexane and •dehydrated•(1-Feb-2011) alcoholrU = peak response of levetiracetam related com-(4:1)pound B from the Sample solution

System suitability solution: 0.1 mg/mL of USP LevetiracetamrS = peak response of levetiracetam related com-Racemic Mixture RS in Mobile phasepound B from the Standard solution

Standard solution: 0.05 mg/mL of USP Levetiracetam RS inCS = concentration of USP Levetiracetam RelatedMobile phaseCompound B RS in the Standard solution

Sample solution: 10 mg/mL of Levetiracetam in Mobile phase(mg/mL)Chromatographic systemCU = concentration of Levetiracetam in the Sample so-(See Chromatography ⟨621⟩, System Suitability.)lution (mg/mL)Mode: LCMr1 = molecular weight of levetiracetam related com-Detector: UV 215 nmpound B free base, 102.1Column: 4.6-mm × 25-cm; 10-µm packing L51Mr2 = molecular weight of levetiracetam related com-Flow rate: 1.0 mL/minpound B, 138.6Injection size: 20 µLAcceptance criteria: NMT 0.10%

System suitability[NOTE—The amount of levetiracetam related compound BSample: System suitability solutionmeasured is to be included in the total impurities in the[NOTE—The relative retention times for levetiracetam R-enan-test for Organic Impurities, Procedure 2.]tiomer and levetiracetam S-enantiomer are 0.55 and 1.0,• PROCEDURE 2respectively.]Buffer, Solution A, Solution B, Mobile phase, System suita-

Suitability requirementsbility solution, and Chromatographic system: Proceed asResolution: NLT 4.0 between R- and S-enantiomersdirected in the Assay.

[NOTE—If a loss of resolution (less than 4.0) is observed, it isStandard solution: 0.005 mg/mL of USP Levetiracetam RS inrecommended that the column temperature be maintainedSolution Aat 25° to stabilize the system.]Sample solution: 5 mg/mL of Levetiracetam in Solution A

AnalysisAnalysisSamples: Standard solution and Sample solutionSamples: Standard solution and Sample solution Calculate the percentage of levetiracetam R-enantiomer in Calculate the percentage of each impurity in the portion ofthe portion of Levetiracetam taken:Levetiracetam taken:

Result = (rU/rS) × (CS/CU) × 100Result = (rU/rS) × (CS/CU) × (1/F) × 100


Prop

osed

IRA


rU = peak response of levetiracetam R-enantiomer tration of about 7 µg/mL of ethinyl estradiol and a knownfrom the Sample solution concentration of norgestimate similar to that expected in the

rS = peak response of levetiracetam from the Stan- Sample solution. Pass through a suitable filter of 0.45-µm poredard solution size.

CS = concentration of USP Levetiracetam RS in the Sample solution: Add a number of Tablets, equivalent to 0.35Standard solution (mg/mL) mg of ethinyl estradiol, to a suitable glass container. Add 10

CU = concentration of Levetiracetam in the Sample so- mL of water, and mix with a vortex mixer until the Tablets arelution (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. Sonicatethe 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, Chromatographic system

and store at room temperature. (See Chromatography ⟨621⟩, System Suitability.)• USP REFERENCE STANDARDS ⟨11⟩ Mode: LC

USP Levetiracetam RS Detector: UV 230 nmUSP 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(C8H14ClNO3 207.65) Injection size: 25 µL

USP Levetiracetam Related Compound B RS System suitability[(S)-2-aminobutanamide hydrochloride] Sample: Standard solution(C4H10N2O · HCl 138.6) [NOTE—The relative retention times for ethinyl estradiol, (Z)-

USP Levetiracetam Racemic Mixture RS norgestimate, (E)-norgestimate, and dibutyl phthalate areA 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)-

norgestimateRelative standard deviation: NMT 2.0% for the peak re-sponse ratio of ethinyl estradiol, (Z)-norgestimate, and (E)-

BRIEFING norgestimate to dibutyl phthalateAnalysisSamples: Standard solution and Sample solution

Norgestimate and Ethinyl Estradiol Tablets, page 4268 of Calculate the percentage of the labeled amount of C20H24O2the Second Supplement to USP 32. Comments were received that in the portion of Tablets taken:the system suitability precision requirement cannot consistentlybe met for the ethinyl estradiol peak of the Standard solution in Result = (RUE/RSE) × (CSE/CUE) × 100the procedure for Organic Impurities due to the low response of

RUE = ratio of the peak responses of ethinyl estradiol tothe analyte at 254 nm. Because the response of this peak is notdibutyl phthalate from the Sample solutionused in the quantitation of impurities, it is proposed to remove

RSE = ratio of the peak responses of ethinyl estradiol tothe precision requirement with respect to the ethinyl estradioldibutyl phthalate from the Standard solutionpeak. The comment period for this revision ends November 15,

CSE = concentration of USP Ethinyl Estradiol RS in the2010. In the absence of significant adverse comments, it is pro-Standard solution (mg/mL)posed to implement this revision via the First Interim Revision

CUE = nominal concentration of ethinyl estradiol in theAnnouncement pertaining to USP 34–NF 29, with an official dateSample solution (mg/mL)of February 1, 2011.

Calculate the percentage of the labeled amount of C23H31NO3

in the portion of Tablets taken:

(SM4: M. Waddell.) RTS—C87596 Result = CSN/CUN × [PA(RUA/RSA) + PS(RUS/RSS)] × 100

CSN = concentration of USP Norgestimate RS in theStandard solution (mg/mL)

. CUN = nominal concentration of norgestimate in theNorgestimate and Ethinyl Estradiol Sample solution (mg/mL)

PA = fraction of (E)-norgestimate in the USP Norgesti-Tabletsmate RS

RUA = ratio of the peak responses of (E)-norgestimateDEFINITIONto dibutyl phthalate from the Sample solutionNorgestimate and Ethinyl Estradiol Tablets contain NLT 90.0%

RSA = ratio of the peak responses of (E)-norgestimateand NMT 110.0% of the labeled amounts of norgestimateto dibutyl phthalate from the Standard solution(C23H31NO3) and ethinyl estradiol (C20H24O2).

PS = fraction of (Z)-norgestimate in the USP Norgesti-IDENTIFICATION mate RS• The retention times of the major peaks of the Sample solution RUS = ratio of the peak responses of (Z)-norgestimate

correspond to those of the Standard solution, as obtained in to dibutyl phthalate from the Sample solutionthe Assay. RSS = ratio of the peak responses of (Z)-norgestimate

to dibutyl phthalate from the Standard solutionASSAY Calculate the ratio of the content of (Z)-norgestimate to• PROCEDURE 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 phthalatein methanol CZ/CE = [(CSN × PS) × (RUS/RSS)]/[CSE(RUE/RSE)]

Standard solution: Dissolve appropriate quantities of USPEthinyl 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 C20H24O2;ume. Add a volume of water equivalent to 20% of the final 90.0%–110.0% of C23H31NO3

volume, and mix to obtain a solution having a known concen-


Proposed IRA


IMPURITIES Subject to consideration of comments received during the com-ment period, it is proposed to implement this revision via anInterim Revision Announcement pertaining to USP 34–NF 29 withChange to read: an official date of February 1, 2011. Comments regarding thisproposal should be received by November 15, 2010.

Organic Impurities• PROCEDURE

Mobile phase, Standard solution, and Sample solution: (MD-GRE: E. Gonikberg.) RTS—C89449Proceed as directed in the Assay.

Chromatographic system(See Chromatography ⟨621⟩, System Suitability.)Mode: LC .

Detector: 254 nm Risedronate SodiumColumn: 4.6-mm × 5-cm; 5-µm packing L1Flow rate: 2 mL/minInjection size: 50 µL

System suitabilitySample: 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 C7H10NNaO7P2 305.09Resolution: NLT 1.5 between (Z)-norgestimate and (E)-

C7H10NNaO7P2 · H2O 323.12norgestimateRelative standard deviation: NMT 2.0% for the ethinyl C7H10NNaO7P2 · 2.5 H2O 350.13estradiol and norgestimate•(Z)-norgestimate and (E)- Phosphonic acid, [1-hydroxy-2-(3-pyridinyl)ethylidene]bis-,norgestimate•(1-Feb-2011) peaks monosodium salt;

Analysis Sodium trihydrogen [1-hydroxy-2-(3-Sample: Sample solution pyridyl)ethylidene]diphosphonate;Calculate the percentage of any impurity having a relative Hemi-pentahydrate [329003-65-8].retention time of about 0.2 or 0.4, relative to the (Z)- Monohydrate [353228-19-0].norgestimate peak, and detected at 254 nm in the portionof Tablets taken: DEFINITION

Risedronate Sodium contains one or two and one-half moleculesResult = (rU/rZ) × (CZ/CE) × F × 100 of hydration. The monohydrate form contains NLT 98.0% and

NMT 102.0% of C7H10NNaO7P2, calculated on the dried basis.rU = peak response for each impurity The hemi-pentahydrate form contains NLT 98.0% and NMTrZ = peak response for (Z)-norgestimate 102.0% of C7H10NNaO7P2, calculated on the anhydrous basis.CZ/CE = ratio of (Z)-norgestimate to ethinyl estradiol as

defined in the Assay IDENTIFICATIONF = 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, separatelytive 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, dis-

solve 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 theUSP Norgestimate RS requirements of the flame test.

ASSAY

BRIEFINGChange to read:

Risedronate Sodium, page 4278 of the Second Supplement to • PROCEDUREUSP 32. It is proposed to widen the tailing requirement in the Mobile phase: 1.8 g/L of edetate disodium in water. AdjustAssay and in Organic Impurities, Procedure 1 from “NMT 1.5” to with 1 N sodium hydroxide to a pH of 9.5 ± 0.1.“NMT 1.6” to address variability observed for Dionex IonPac Standard solution: Dissolve USP Risedronate Sodium RS andAS7 L48 columns. USP Risedronate Related Compound A RS in Mobile phase toIn Organic Impurities, Procedure 1, a note is added to disregard a obtain a solution containing 1.0 mg/mL of anhydrouspeak due to sodium ion, eluting at 1.6 min. In addition, rela- risedronate sodium and 0.1 mg/mL of risedronate relatedtive retention times for two specified impurities in Impurity Ta- compound A.ble 1 are corrected. Sample solution: 1.1 mg/mL of Risedronate Sodium in MobileDifficulties were reported in performing the coulometric Karl phaseFisher titration procedure specified under Water Determination. Chromatographic systemA clarification is added that the coulometric procedure should (See Chromatography ⟨621⟩, System Suitability.)be performed by direct introduction of solid sample into thetitrator. It is also proposed to specify that the volumetric proce-dure may be used as an alternative method.


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Mode: LC Acceptance criteria: NMT 20 ppmDetector: UV 263 nmColumn: 4.0-mm × 25-cm; 10-µm packing L48 Change to read:Flow rate: 0.8 mL/minInjection size: 20 µL

System suitability Organic ImpuritiesSample: Standard solution [NOTE—Perform both Procedure 1 and Procedure 2.]Suitability requirements • PROCEDURE 1

Resolution: NLT 2.3 between risedronate and risedronate Mobile phase, Standard solution, Sample solution, andrelated compound A Chromatographic system: Prepare as directed in the Assay.

Tailing factor: NMT 1.5•1.6•(1-Feb-2011) for the risedronate Diluted standard solution: Dilute a portion of the Standardpeak solution with Mobile phase to obtain a solution containing 5

Relative standard deviation: NMT 1.0% for the µg/mL of anhydrous risedronate sodium and about 0.5 µg/risedronate peak from three replicate injections mL of risedronate related compound A.

Analysis System suitabilitySamples: Standard solution and Sample solution Samples: Standard solution and Diluted standard solutionCalculate the percentage of C7H10NNaO7P2 in the portion of Suitability requirementsRisedronate Sodium taken: Resolution: NLT 2.3 between risedronate related com-

pound A and risedronate, Standard solutionResult = (rU/rS) × (CS/CU) × 100 Tailing factor: NMT 1.5•1.6•(1-Feb-2011) for the risedronatepeak, Standard solutionrU = peak response from the Sample solution Relative standard deviation: NMT 1.0% for therS = peak response from the Standard solution risedronate peak from three replicate injections, StandardCS = concentration of USP Risedronate Sodium RS in solution; NMT 15% for the risedronate related compoundthe Standard solution (mg/mL) A peak from three replicate injections, Diluted standardCU = concentration of Risedronate Sodium in the Sam- solutionple solution (mg/mL) AnalysisAcceptance criteria: 98.0%–102.0% on the dried basis for Samples: Diluted standard solution and Sample solutionthe monohydrate form or on the anhydrous basis for the Calculate the percentage of each impurity in the portion ofhemi-pentahydrate form Risedronate Sodium taken:

IMPURITIES Result= (rU/rS) × (CS/(CU) × (1/F) × 100Inorganic Impurities

• HEAVY METALS rU = peak response of each impurity from the SampleLead nitrate solution: Add 1 mL of nitric acid to 100 mL of solutionwater. Dissolve 100 mg of lead nitrate in it, and then dilute rS = peak response of risedronate from the Dilutedwith water to 1000 mL. standard solutionSodium bicarbonate solution: Transfer 0.840 g of sodium CS = concentration of USP Risedronate Sodium RS inbicarbonate to a 1000-mL volumetric flask containing about the Diluted standard solution (mg/mL)950 mL of water. Dissolve in and dilute with water to vol- CU = concentration of Risedronate Sodium in theume. Adjust with 0.1 N sodium hydroxide or 0.1 N hydro- Sample solution (mg/mL)chloric acid, as necessary, to a pH of 4.40 ± 0.02. F = relative response factor (see Impurity Table 1)Hydrogen sulfide solution: Transfer 200 mL of Sodium bicar-bonate solution to a suitable conical flask, and bubble hydro-

Impurity Table 1gen sulfide gas through the solution until it turns a strip ofLead Acetate Test Paper black (see Reagents, Indicators, and Relative RelativeSolution—Indicators and Test Papers). Response Retention

Standard solutions: Transfer 500 mg of Risedronate Sodium Name Factor Timeto each of three separate beakers. Add 41 mL of water to

3-Pyridyl acetic acid 1.65 0.08•0.22•(1-each beaker, and stir to dissolve. Adjust with 0.1 N sodiumFeb-2011)hydroxide or 0.1 N hydrochloric acid, as necessary, to a pH

2-Pyridinyl isomerof 4.40 ± 0.02. Label the first beaker as Standard solution 1.(USP Risedronate Related 0.81•0.84•(1-Add 200 µL of Lead nitrate solution to the second beakerCompound A RS) 1.0 Feb-2011)(Standard solution 2) and 400 µL to the third beaker (Stan-

Risedronate sodium — 1.0dard solution 3). These solutions contain the equivalent of 0,12.5, and 25 µg of lead (representing 0, 10, and 20 ppm, respectively).

Acceptance criteriaSample solution: Transfer 1.75 g of Risedronate Sodium to aAny individual impurity: NMT 0.10%suitable beaker. Add 41 mL of water, and stir to dissolve.[NOTE—Disregard •the peak due to sodium ion, eluting atAdjust with 0.1 N sodium hydroxide or 0.1 N hydrochloricabout 1.6 min, and•(1-Feb-2011) any peak observed in theacid, as necessary, to a pH of 4.40 ± 0.02.blank. The reporting level for impurities is 0.05%.]Analysis: Add 7 mL of Hydrogen sulfide solution to each of • PROCEDURE 2the beakers containing the Standard solutions and the Sample

Mobile phase: Transfer 16.15 g of dibasic potassium phos-solution. Allow the solutions to stand for at least 5 min. Addphate and 0.46 g of edetate disodium to a 1-L beaker, and60 µL of 1 N hydrochloric acid to each of the beakers con-dissolve in about 400 mL of water. Add 1 vial of commer-taining the Standard solutions, and add 200 µL of 1 N hydro-cially available tetrabutylammonium dihydrogen phosphatechloric acid to the beaker containing the Sample solution, andbuffered solution in methanol1 and 1 mL of hydrochloricstir. Transfer the solutions into 50-mL color-comparisonacid. Adjust with 1 N sodium hydroxide or 1 N hydrochlorictubes, and view downward over a white surface: the color ofacid, as necessary, to a pH of 7.5 ± 0.1, and dilute with waterthe solution obtained from the Sample solution is not darkerto 480 mL. Add 20 mL of methanol, mix well, pass the solu-than that of the solution from Standard solution 3.tion through a nylon filter of 0.45-µm pore size, and degas.

1 Available from Waters Corp. as Part #85101 (PIC A).


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Diluent: Transfer 0.46 g of edetate disodium to a 1-L beaker, Acceptance criteriaand dissolve in 500 mL of water. Adjust with 1 N sodium Risedronate related compound B: NMT 0.10%hydroxide to a pH of 7.5 ± 0.1. Individual impurities: NMT 0.10%

Standard solution: 5 µg/mL of USP Risedronate Related Total impurities: NMT 0.50%, Procedure 1 and Procedure 2Compound B RS in Diluent being combined

Diluted standard solution: 0.5 µg/mL of USP Risedronate [NOTE—Disregard any peak observed in the blank. The re-Related Compound B RS in Diluent from the Standard solution porting level for impurities is 0.05%.]

Sample solution: 2 mg/mL of Risedronate Sodium, in Dilu-SPECIFIC TESTSent, using sonication if necessary

Chromatographic system(See Chromatography ⟨621⟩, System Suitability.) Change to read:Mode: LCDetector: UV 263 nmColumn: 4.6-mm × 15-cm; 5-µm packing L1 • WATER DETERMINATION, Method Ic ⟨921⟩ (where it is labeled as aFlow rate: 1.0 mL/min hemi-pentahydrate): 11.9%–13.9%. •Perform the test by di-Injection size: 10 µL rect introduction of solid sample into the titrator. Alternatively,

System suitability Method 1a may be used.•(1-Feb-2011)Samples: Standard solution and Diluted standard solution • LOSS ON DRYING ⟨731⟩ (where it is labeled as a monohydrate):Suitability requirements (See Thermal Analysis ⟨891⟩.) Determine the percentage of vol-Capacity factor: Greater than 2, Standard solution atile substances by thermogravimetric analysis on an appropri-Tailing factor: Less than 1.5, Standard solution ately calibrated instrument, using 7–15 mg of Risedronate So-Relative standard deviation: NMT 5% from three repli- dium. Heat the specimen under test at a rate of 10°/min in acate injections, Standard solution stream of nitrogen at a flow rate of about 40 mL/min. Record

Relative standard deviation: NMT 10% from three repli- the thermogram from ambient temperature to 250°.cate injections, Diluted standard solution Acceptance criteria: It loses between 5.5% and 7.5% of its

Analysis weight.Samples: Standard solution and Sample solution

ADDITIONAL REQUIREMENTS[NOTE—Disregard any peak eluting before risedronate re-• LABELING: Label to indicate whether it is the monohydrate orlated compound B. The risedronate peak elutes un-

the hemi-pentahydrate form.retained at the void volume.]• PACKAGING AND STORAGE: Preserve in well-closed containers.Calculate the percentage of each impurity in the portion of

Store at room temperature.Risedronate Sodium taken:• USP REFERENCE STANDARDS ⟨11⟩

Result= (rU/rS) × (CS/(CU) × (Mr1/Mr2) × 100 USP Risedronate Sodium RSUSP Risedronate Related Compound A RS

rU = peak response of each impurity from the Sample 2-Pyridinyl isomer [1-hydroxy-2-(2-solution pyridinyl)ethylidene]bis(phosphonic acid) monohydrate.

rS = peak response of risedronate related compound C7H11NO7P2 283.12B from the Standard solution USP Risedronate Related Compound B RS

CS = concentration of USP Risedronate Related Com- Cyclic dimer, disodium tetrahydrate salt, [3,6-bis[(3-pound B RS in the Standard solution (mg/mL) pyridinyl)methyl]-2,5-dihydroxy-2,5-dioxido-1,4,2,5-diox-

CU = concentration of Risedronate Sodium in the Sam- adiphosphorinane-3,6-diyl]bis[phosphonic acid] disodium te-ple solution (mg/mL) trahydrate salt.

Mr1 = molecular weight of risedronate related com- C14H16N2O12P4Na2 · 4H2O 646.22pound B as a free acid, 530.20

Mr2 = molecular weight of risedronate related com-pound B as a tetrahydrate disodium salt,646.22


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interim revision announcement - usp-nf · 2015-03-30 · interim revision announcement to usp 33...

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