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Pharmacopeial Forum Vol. 35(3) [May–June 2009] STAGE 6 HARMONIZATION 683 Attributes EP JP USP MONOGRAPHS (USP) Heavy Metals + + + Loss on Drying + + + Residue on Ignition + + + Assay + + + Legend: + will adopt and implement; - will not stipulate. In EP, Viscosity and Assay will be dealt with in the non-mandatory BRIEFING Functionality-Related Characteristics section. The assay limits will not be included in the Definition (EP). Nonharmonized attributes: Packaging and storage Methylcellulose. The Japanese Pharmacopoeia is the coordi- Specific local attributes: Appearance of solution (EP), Description nating pharmacopeia for the international harmonization of the (JP), Limit of glyoxal (EP). compendial standards for the Methylcellulose monograph, as Cellulose, methyl ether; part of the process of international harmonization of Cellulose methyl ether [9004-67-5]. monographs and general analytical methods of the European, Japanese, and United States pharmacopeias. The following mon- DEFINITION ograph, which represents the ADOPTION STAGE 6 document, Methylcellulose is a methyl ether of cellulose. When dried at 105° is based on the corresponding monograph for Methylcellulose for 1 h, it contains NLT 26.0% and NMT 33.0% of methoxy that was prepared by the Japanese Pharmacopoeia. The Japanese (OCH 3 ) groups. Pharmacopoeia draft was based in part on comments from the European Pharmacopoeia and the United States Pharmacopeia in IDENTIFICATION response to the Provisional Harmonized Text Stage 5A and 5B A. PROCEDURE drafts prepared by the Japanese Pharmacopoeia. Differences be- Analysis: Evenly distribute 1.0 g onto the surface of 100 mL tween the Japanese Pharmacopoeia Adoption Stage 6 document of water in a beaker, tapping the top of the beaker gently if and the current USP monograph for Methylcellulose include the necessary to ensure a uniform layer on the surface, and allow following. to stand for 1–2 min. 1. Definition. Changed from NLT 27.5% and NMT 31.5% of Acceptance criteria: The powdered material aggregates on methoxy to NLT 26.0% and NMT 33.0% of methoxy the surface. groups. Drying time changed from 2 h to 1 h. B. PROCEDURE 2. Identification. Replaced three existing methods with five Analysis: Evenly distribute 1.0 g into 100 mL of boiling water, new methods. and stir the mixture using a magnetic stirrer with a 25-mm 3. Assay. Aligned method with current PDG harmonized mon- long bar: a slurry is formed and the particles do not dissolve. ograph for Hypromellose. Allow the slurry to cool to 5° and stir using a magnetic stirrer. 4. Heavy Metals. Aligned method with current PDG harmo- Acceptance criteria: A clear or slightly turbid solution occurs nized monograph for Hypromellose. with its thickness dependent on the viscosity grade. 5. Loss on Drying. Changed time from 2 h to 1 h to align C. PROCEDURE with PDG proposal. Analysis: To 0.1 mL of the sample solution obtained in Identi- 6. pH. New method proposed by PDG. fication test B add 9 mL of diluted sulfuric acid (9 in 10), 7. Viscosity. Aligned method with current PDG harmonized shake, heat in a water bath for exactly 3 min, immediately monograph for Hypromellose. cool in an ice bath, add carefully 0.6 mL of ninhydrin TS, 8. Packaging and Storage. No change. shake, and allow to stand at 25°. 9. Labeling. Added statement to include units of measurement Acceptance criteria: A red color develops immediately, and it (mPa · s). does not change to purple within 100 min. D. PROCEDURE Analysis: Add 2–3 mL of the solution obtained in Identifica- tion test B onto a glass slide as a thin film and allow the water (EM2: K. Moore.) RTS—C44010 to evaporate. Acceptance criteria: A coherent, clear film forms on the glass slide. E. PROCEDURE Analysis: Add exactly 50 mL of the sample solution obtained Add the following: in Identification test A to exactly 50 mL of water in a beaker. Insert a thermometer into the solution. Stir the solution on a magnetic stirrer/hot plate and begin heating at a rate of Methylcellulose 2°/min to 5°/min. Determine the temperature at which a tur- bidity increase begins to occur and designate the temperature as the flocculation temperature. Attributes EP JP USP Acceptance criteria: The flocculation temperature is higher Definition + + + than 50°. Labeling + + + ASSAY Identification A + + + PROCEDURE Identification B + + + [CAUTIONPerform all steps involving Hydriodic acid carefully, in a well-ventilated hood. Use goggles, acid-resistant gloves, Identification C + + + and other appropriate safety equipment. Be exceedingly Identification D + + + careful when handling the hot vials, because they are under Identification E + + + pressure. In the event of hydriodic exposure, wash with copi- ous amounts of water, and seek medical attention at once.] Apparent Viscosity, Method 1 + + + Apparatus Apparent Viscosity, Method 2 + + + Reaction vial: A 5-mL pressure-tight serum vial, 20 mm in pH + + + outside diameter, 50 mm in height, and 20 mm in outside diameter and 13 mm in inside diameter at the mouth, 2009 The United States Pharmacopeial Convention All Rights Reserved. Stage 6 Harmonization

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Page 1: MONOGRAPHS (USP) Attributes EP JP USP - uspnf.com · Residue on Ignition + + + Assay + + + Legend: + will adopt and implement; − will not stipulate. ... T = ratio of the peak area

Pharmacopeial ForumVol. 35(3) [May–June 2009] STAGE 6 HARMONIZATION 683

Attributes EP JP USPMONOGRAPHS (USP)Heavy Metals + + +

Loss on Drying + + +

Residue on Ignition + + +

Assay + + +

Legend: + will adopt and implement; − will not stipulate.In EP, Viscosity and Assay will be dealt with in the non-mandatory

BRIEFING Functionality-Related Characteristics section. The assay limits willnot be included in the Definition (EP).

Nonharmonized attributes: Packaging and storageMethylcellulose. The Japanese Pharmacopoeia is the coordi- Specific local attributes: Appearance of solution (EP), Descriptionnating pharmacopeia for the international harmonization of the (JP), Limit of glyoxal (EP).compendial standards for the Methylcellulose monograph, as Cellulose, methyl ether;part of the process of international harmonization of Cellulose methyl ether [9004-67-5].monographs and general analytical methods of the European,Japanese, and United States pharmacopeias. The following mon- DEFINITIONograph, which represents the ADOPTION STAGE 6 document, Methylcellulose is a methyl ether of cellulose. When dried at 105°is based on the corresponding monograph for Methylcellulose for 1 h, it contains NLT 26.0% and NMT 33.0% of methoxythat was prepared by the Japanese Pharmacopoeia. The Japanese (OCH3) groups.Pharmacopoeia draft was based in part on comments from theEuropean Pharmacopoeia and the United States Pharmacopeia in IDENTIFICATIONresponse to the Provisional Harmonized Text Stage 5A and 5B • A. PROCEDUREdrafts prepared by the Japanese Pharmacopoeia. Differences be- Analysis: Evenly distribute 1.0 g onto the surface of 100 mLtween the Japanese Pharmacopoeia Adoption Stage 6 document of water in a beaker, tapping the top of the beaker gently ifand the current USP monograph for Methylcellulose include the necessary to ensure a uniform layer on the surface, and allowfollowing. to stand for 1–2 min.1. Definition. Changed from NLT 27.5% and NMT 31.5% of Acceptance criteria: The powdered material aggregates on

methoxy to NLT 26.0% and NMT 33.0% of methoxy the surface.groups. Drying time changed from 2 h to 1 h. • B. PROCEDURE

2. Identification. Replaced three existing methods with five Analysis: Evenly distribute 1.0 g into 100 mL of boiling water,new methods. and stir the mixture using a magnetic stirrer with a 25-mm

3. Assay. Aligned method with current PDG harmonized mon- long bar: a slurry is formed and the particles do not dissolve.ograph for Hypromellose. Allow the slurry to cool to 5° and stir using a magnetic stirrer.

4. Heavy Metals. Aligned method with current PDG harmo- Acceptance criteria: A clear or slightly turbid solution occursnized monograph for Hypromellose. with its thickness dependent on the viscosity grade.

5. Loss on Drying. Changed time from 2 h to 1 h to align • C. PROCEDUREwith PDG proposal. Analysis: To 0.1 mL of the sample solution obtained in Identi-

6. pH. New method proposed by PDG. fication test B add 9 mL of diluted sulfuric acid (9 in 10),7. Viscosity. Aligned method with current PDG harmonized shake, heat in a water bath for exactly 3 min, immediately

monograph for Hypromellose. cool in an ice bath, add carefully 0.6 mL of ninhydrin TS,8. Packaging and Storage. No change. shake, and allow to stand at 25°.9. Labeling. Added statement to include units of measurement Acceptance criteria: A red color develops immediately, and it

(mPa · s). does not change to purple within 100 min.• D. PROCEDURE

Analysis: Add 2–3 mL of the solution obtained in Identifica-tion test B onto a glass slide as a thin film and allow the water(EM2: K. Moore.) RTS—C44010 to evaporate.

Acceptance criteria: A coherent, clear film forms on the glassslide.

• E. PROCEDUREAnalysis: Add exactly 50 mL of the sample solution obtained

Add the following: in Identification test A to exactly 50 mL of water in a beaker.Insert a thermometer into the solution. Stir the solution on amagnetic stirrer/hot plate and begin heating at a rate of▲Methylcellulose2°/min to 5°/min. Determine the temperature at which a tur-bidity increase begins to occur and designate the temperatureas the flocculation temperature.Attributes EP JP USP

Acceptance criteria: The flocculation temperature is higherDefinition + + + than 50°.Labeling + + +

ASSAYIdentification A + + + • PROCEDUREIdentification B + + + [CAUTION—Perform all steps involving Hydriodic acid carefully,

in a well-ventilated hood. Use goggles, acid-resistant gloves,Identification C + + +and other appropriate safety equipment. Be exceedingly

Identification D + + + careful when handling the hot vials, because they are underIdentification E + + + pressure. In the event of hydriodic exposure, wash with copi-

ous amounts of water, and seek medical attention at once.]Apparent Viscosity, Method 1 + + +Apparatus

Apparent Viscosity, Method 2 + + + Reaction vial: A 5-mL pressure-tight serum vial, 20 mm inpH + + + outside diameter, 50 mm in height, and 20 mm in outside

diameter and 13 mm in inside diameter at the mouth,

2009 The United States Pharmacopeial Convention All Rights Reserved.

Stage 6 Harmonization

Page 2: MONOGRAPHS (USP) Attributes EP JP USP - uspnf.com · Residue on Ignition + + + Assay + + + Legend: + will adopt and implement; − will not stipulate. ... T = ratio of the peak area

Pharmacopeial Forum684 STAGE 6 HARMONIZATION Vol. 35(3) [May–June 2009]

equipped with a pressure-tight septum having a polyte- Acceptance criteria: 26.0%–33.0%trafluoroethylene-faced butyl rubber, and air-tight sealing by

IMPURITIESan aluminum crimp or another sealing system providing a suf-Inorganic Impuritiesficient air-tightness.• RESIDUE ON IGNITION ⟨281⟩: NMT 1.5%Heater: A heating module with a square-shaped aluminum• HEAVY METALS, Method III ⟨231⟩: For the Standard Preparation,block having holes 20 mm in diameter and 32 mm in depth,

add the Standard Lead Solution prior to digestion. Omit theso that the reaction vial fits. Capable of mixing the contentsMonitor Preparation. of the vial using a magnetic stirrer equipped in the heating

Acceptance criteria: The color of the test solution is notmodule or using a reciprocal shaker which performs a recip-darker than that of the control solution (NMT 20 ppm).rocating motion approximately 100 times/min.

Hydriodic acid: Use a reagent having a specific gravity of at SPECIFIC TESTSleast 1.69, equivalent to 55%–57% HI. • LOSS ON DRYING ⟨731⟩: Dry a sample at 105° for 1 h: it losesInternal standard solution: 30 mg/mL of n-octane in o- NMT 5.0% of its weight.xylene • PH: Measure the pH of the solution prepared in the test forStandard solution: Into a suitable serum vial, weigh 60–100 Viscosity at 20 ± 2°. Read the indicated pH value after themg of adipic acid, add 2.0 mL of Hydriodic acid, then pipet probe has been immersed for 5 ± 0.5 min.2.0 mL of Internal standard solution into the vial, and close the Acceptance criteria: 5.0–8.0vial securely with a suitable septum stopper. Weigh the vial • VISCOSITY ⟨911⟩and contents, add 45 µL of methyl iodide with a syringe [NOTE—The density is 1.00 g/mL, so there is no necessity forthrough the septum, weigh again, and calculate the weight of determining the density at every measurement in the case ofmethyl iodide added, by difference. Shake, and allow the lay- having the confirmation data.]ers to separate. Use the upper layer as the Standard solution. Method 1: This method is applied to samples with a viscos-Sample solution: Transfer 0.065 g of Methylcellulose to a 5- ity of less than 600 mPa · s. Weigh a quantity of Methylcel-mL thick-walled reaction vial equipped with a pressure-tight lulose, equivalent to 4.000 g, calculated on the dried basis,septum closure, add 60–100 mg of adipic acid, and pipet 2.0 transfer into a wide mouth bottle, and add hot water to ob-mL of Internal standard solution into the vial. Cautiously pipet tain the total weight of the sample and water of 200.0 g.2.0 mL of Hydriodic acid into the mixture, immediately secure Capping the bottle, stir by mechanical means at 400 ± 50 rpmthe closure, and weigh it. Using a magnetic stirrer equipped for 10 or 20 min until particles are thoroughly dispersed andin the heating module, or using a reciprocal shaker, mix the wetted out. Scrape down the walls of the bottle with a spatulacontents of the vial continuously for 60 min while heating the if necessary, to ensure that there is no undissolved material onblock so that the temperature of the contents is maintained at the sides of the bottle, and continue the stirring in a cooling130 ± 2°. If a reciprocal shaker or magnetic stirrer cannot be water bath equilibrated at a temperature below 5° for anotherused, shake the vial well by hand at 5-min intervals during the 20–40 min. Adjust the solution weight if necessary to 200.0 ginitial 30 min of the heating time. Allow the vial to cool, and using cold water. Centrifuge the solution if necessary to expelagain weigh. If the weight loss is less than 0.50% of the con- any entrapped air bubbles. Using a spatula remove any foam,tents and there is no evidence of a leak, use the upper layer of if present. Perform the test with this solution at 20 ± 0.1° tothe mixture as the Sample solution. obtain the kinematic viscosity, ν. Separately, determine theChromatographic system density, ρ, of the solution, and calculate the viscosity, η, as ηMode: GC = ρν.Detector: Thermal conductivity or hydrogen flame Method 2: This method is applied to samples with a viscos-ionization ity of 600 mPa · s or higher. Weigh a quantity of Methylcel-Column: 1.8 to 3 m × 3 to 4-mm column packed with lulose, equivalent to 10.00 g, calculated on the dried basis,10%–20% liquid phase G1, 125–150 µm in diameter on transfer into a wide mouth bottle, and add hot water to ob-100- to 120-mesh support S1A tain the total weight of the sample and water of 500.0 g.Column temperature: 100° Capping the bottle, stir by mechanical means at 400 ± 50 rpmCarrier gas: Helium for the thermal conductivity detector, for 10–20 min until particles are thoroughly dispersed andand helium or nitrogen for the hydrogen flame ionization wetted out. Scrape down the walls of the bottle with a spatuladetector if necessary, to ensure that there is no undissolved material onFlow rate: Adjust so that the retention time of the internal the sides of the bottle, and continue the stirring in a coolingstandard is about 10 min. water bath equilibrated at a temperature below 5° for anotherInjection size: 1 or 2 µL 20–40 min. Adjust the solution weight if necessary to 500.0 gAnalysis using cold water. Centrifuge the solution if necessary to expelSamples: Standard solution and Sample solution any entrapped air bubbles. Using a spatula remove any foam,Calculate the percentage of methoxy in the Methylcellulose if present. Determine the viscosity of this solution at 20 ± 0.1°taken: using a single cylinder type rotational viscometer.Apparatus: Brookfield type LV model or equivalent. RotorResult = 21.864 × (QT/QS) × (WS/W)No., revolution, and calculation multiplier: apply the condi-tions specified in the following table.21.864 = ratio of the formula weights of methoxy to

methyl iodide times 100%QT = ratio of the peak area of methyl iodide to that of Labeled Viscositya Revolution Calculation

internal standard in the Sample solution (mPa·s) Rotor No. (rpm) MultiplierQS = ratio of the peak area of methyl iodide to that of600 or more and 3 60 20internal standard in the Standard solutionless than 1400WS = weight of methyl iodide in the Standard solution

1400 or more and 3 12 100(mg)W = weight of Methylcellulose calculated on the less than 3500

dried basis taken for the Assay (mg) 3500 or more and 4 60 100less than 9500

9500 or more and 4 6 1000less than 99,500

99,500 or more 4 3 2000

aThe labeled viscosity is based on the manufacturer’s specifications.

2009 The United States Pharmacopeial Convention All Rights Reserved.

Stag

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Pharmacopeial ForumVol. 35(3) [May–June 2009] STAGE 6 HARMONIZATION 685

Operation of apparatus: Allow the spindle to rotate for Reagents and Reference materials: Each pharmacopeia will2 min before taking the measurement. Allow a rest period adapt the text to take account of local reference materials andof 2 min between subsequent measurements. Repeat the reagent specifications.operation to rotate the spindle specified above twice andaverage the three readings.

Acceptance criteria: 80.0%–120.0% of that stated on the la- bel for viscosity types less than 600 mPa · s, and75.0%–140.0% of that stated on the label for viscosity types C7H8O 108.1600 mPa · s or higher Phenylmethanol [100-51-6].

ADDITIONAL REQUIREMENTS DEFINITION• ✦PACKAGING AND STORAGE: Preserve in well-closed containers.✦ Benzyl Alcohol contains NLT 98.0% and NMT the equivalent of• LABELING: Label it to indicate its nominal viscosity type [viscos- 100.5% of phenylmethanol (C7H8O).

ity of a solution (1 in 50)] in milli-Pascal second (mPa · s).▲USP33

IDENTIFICATION• INFRARED ABSORPTION ⟨197F⟩: On undried specimen

ASSAY• PROCEDURE

Phenolphthalein solution: Dissolve 0.1 g of phenolphthaleinin 80 mL of ethanol (96%), and dilute with water to 100.0MONOGRAPHS (NF)mL. To test for sensitivity, add 100 mL of carbon dioxide-freewater to 0.1 mL of the Phenolphthalein solution. The solution iscolorless. NMT 0.2 mL of 0.02 M sodium hydroxide is re-quired to change the color to pink.

Sample: 0.900 gAnalysis: To the Sample, add 15 mL of a freshly preparedmixture of pyridine and acetic anhydride (7:1), and boil undera reflux condenser on a water bath for 30 min. Cool, and add

BRIEFING 25 mL of water. Using 0.25 mL of Phenolphthalein solution asthe indicator, titrate with 1 M sodium hydroxide VS. Carry outa blank titration. Calculate the percentage content of C7H8O

Benzyl Alcohol. The European Pharmacopoeia is the coordi- from the formula:nating pharmacopeia for the international harmonization of thecompendial standards for the Benzyl Alcohol monograph, as Result = 10.81 × (n2 − n1)/mpart of the process of international harmonization of

n2 = amount of 1 M sodium hydroxide used for themonographs and general analytical methods of the European,sample (mL)Japanese, and United States pharmacopeias. The following mon-

n1 = amount of 1 M sodium hydroxide used for theograph, which represents the ADOPTION STAGE 6 document,blank (mL)includes a minor change to Procedure: Benzaldehyde and Other

m = amount of sample taken (g)Related Substances (previously labeled Related compounds). TheAcceptance criteria: 98.0%–100.5%procedure has been changed to address the instance in which

the substance contains peaks that overlap with peaks due toIMPURITIESethylbenzene or dicyclohexyl. Instruction has been added to cor-Inorganic Impuritiesrect for this additional peak when calculating the sum, disregard• FATS AND FIXED OILS, Peroxide Value ⟨401⟩: NMT 5any limit that is 0.01 times the area of ethylbenzene.• RESIDUE ON EVAPORATION

Analysis: After ensuring that the Benzyl Alcohol complieswith the test for Fats and Fixed Oils, Peroxide Value, evaporate

(EM1: K. Moore.) RTS—C58790 10.0 g to dryness in a tared quartz or porcelain crucible orplatinum dish on a hot plate at a temperature not exceeding200°. Ensure that the Benzyl Alcohol does not boil duringevaporation. Dry the residue on the hot plate for 1 h, andallow to cool in a desiccator.

Acceptance criteria: The residue weighs NMT 5 mg, corre-Change to read:sponding to NMT 0.05%.

Organic Impurities• PROCEDURE: BENZALDEHYDE AND OTHER RELATED SUBSTANCES▲Benzyl Alcohol

Sample solution: Use the Benzyl Alcohol specimen underexamination.

Standard solution A: Dissolve 0.100 g of ethylbenzene inAttributes EP JP USP10.0 mL of the Sample solution. Dilute 2.0 mL of this solutionDefinition + + + to 20.0 mL with the Sample solution.

Refractive Index + + + Standard solution B: Dissolve 2.000 g of dicyclohexyl in10.0 mL of the Sample solution. Dilute 2.0 mL of this solutionAcidity + + +to 20.0 mL with the Sample solution.Benzaldehyde and Other Related Sub- Reference solution A: (for use in nonparenteral applications)stances + + + Dissolve 0.750 g of benzaldehyde and 0.500 g of cyclohex-

Peroxide Value + + + ylmethanol in the Sample solution, and dilute to 25.0 mLwith the Sample solution. Add 1.0 mL of this solution to aResidue on Evaporation + + +mixture of 2.0 mL of Standard solution A and 3.0 mL ofAssay + + + Standard solution B, and dilute with the Sample solution to20.0 mL.Legend: + will adopt and implement; − will not stipulate. Reference solution B: (for use in parenteral applications)Nonharmonized attributes: Characters, Clarity of Solution, Color Dissolve 0.250 g of benzaldehyde and 0.500 g of cyclohex-of Solution, Labeling, and Packaging and Storage ylmethanol in the Sample solution, and dilute to 25.0 mL

2009 The United States Pharmacopeial Convention All Rights Reserved.

Stage 6 Harmonization