Carbomer Copolymer
»Carbomer Copolymer is a high molecular weight copolymer of acrylic acid and a long chain alkyl methacrylate cross-linked with polyalkenyl ethers of polyalcohols.
NOTE—Different types of Carbomer Copolymers may not have identical properties with respect to their use for specific pharmaceutical purposes,e.g.,as controlled-release agents,bioadhesives,topical gels,thickening agents,and emulsifying agents.Therefore,different types of Carbomer Copolymers should not be interchanged unless performance equivalency has been ascertained.
Packaging and storage— Preserve in tight containers,at a temperature not exceeding 45.
Labeling— Label it to indicate the nominal viscosity range and the measured viscosity,the solvent or solvents used in the polymerization process,and the nominal and residual solvent levels for each solvent.
Identification—
A: Infrared Absorption á197Kñ—The IRspectrum exhibits main bands at or near (±5)wave numbers (cm-1)1710,1454,1414,1245,1172,1115,and 801,with the strongest band at 1710.
B: Add about 5g of Carbomer Copolymer to 500mLof water,and stir:a dispersion is formed,with a foam layer that persists after allowing to stand at room temperature for 1hour.
Viscosity á911ñ— Carefully add 5.00g of Carbomer Copolymer,previously dried in vacuum at 80for 1hour,to 500mLof water in a 1000-mLbeaker,while stirring continuously at 1000±50rpm,with the stirrer shaft set to one side of the beaker at an angle of 60and the propeller positioned near the bottom of the beaker.The stirrer used is a three-blade,2-inch diameter marine impeller.Add the Carbomer Copolymer at a uniform rate over a period of 45to 90seconds,being sure that loose aggregates of powder are broken up,and continue stirring at 1000±50rpm for 15minutes.Remove the stirrer,and place the beaker containing the dispersion in a 25±2water bath for 30minutes.Insert a paddle stirrer to a depth necessary to ensure that air is not drawn into the dispersion,and while stirring at 300±25rpm,titrate potentiometrically (seeTitrimetry á541ñ)with a calomel-glass electrode system to a pHbetween 7.3and 7.8by adding sodium hydroxide solution (18in 100)below the surface.The total volume of sodium hydroxide solution used is about 11mL.Allow 2to 3minutes before the final pHdetermination.[NOTE—If the final pHexceeds 7.8,discard the mucilage,and prepare another using less sodium hydroxide for neutralization.]Return the beaker containing the neutralized mucilage to the 25±2water bath for 1hour.Using a rotational viscosimeter equipped with a suitable spindle at a spindle immersion depth as defined in the accompanying table (where Ais the cylinder diameter,in cm;Bis the cylinder height,in cm;Cis the shaft diameter,in cm;Dis the distance,in cm,from the top of the cylinder to the lower tip of the shaft;and Eis the spindle immersion depth,in cm),perform the viscosity determination without delay to avoid slight viscosity changes that occur 75minutes after neutralization.
Visc.Ranges,in cPa Spindle No. A B C D E Multiplier
100–400 1 5.626 2.248 0.32 2.697 6.112 5
400–1600 2 4.693 0.165 0.32 2.697 4.921 20
1000–4000 3 3.469 0.165 0.32 2.697 4.921 50
2000–8000 4 2.730 0.165 0.32 2.697 4.921 100
4000–16,000 5 2.114 0.165 0.32 2.697 4.921 200
10,000–40,000 6 1.462 0.157 0.32 3.017 4.921 500
40,000–160,000 7 — — 0.32 — 5.037 2,000
With the spindle rotating at 20rpm,observe and record the scale reading.Calculate the viscosity,in millipascal seconds,by multiplying the scale reading by the constant for the spindle used at 20rpm.The viscosity value so obtained is within the limits specified in the accompanying table.
Carbomer Copolymer 1%Viscosity Specification
A 4500–13,500
B 10,000–29,000
C 25,000–45,000
Loss on drying á731ñ— Dry it in vacuum at 80for 1hour:it loses not more than 2.0%of its weight.
Limit of ethyl acetate and cyclohexane— [NOTE—This test is required only for those Carbomer Copolymers where the labeling indicates that ethyl acetate or a mixture of ethyl acetate and cyclohexane was used in the polymerization process.]
Standard stock solution— Transfer 5.0mLof methanol to a 10-mLserum vial,insert a rubber septum,and seal with a metal cap.Add 25.0µLof ethyl acetate and 20.0µLof cyclohexane through the septum into the vial,and mix.
Standard solution— Transfer 20.0mLof methanol to a 30-mLserum vial,insert a rubber septum,and seal with a metal cap.Through the rubber septum,add 10µLof methyl ethyl ketone (internal standard)and 50.0µLof theStandard stock solution,and mix to obtain a solution containing 0.225mg of ethyl acetate and 0.156mg of cyclohexane.
Test solution— Transfer about 50mg of Carbomer Copolymer,accurately weighed,to a 30-mLserum vial,add 20.0mLof methanol,insert a rubber septum,and seal with a metal cap.Through the rubber septum,add 10µLof methyl ethyl ketone,and mix.
Chromatographic system(see Chromatography á621ñ)— The gas chromatograph is equipped with a flame-ionization detector and a 2-mm ×3-m column packed with 1%liquid phase G25on 60-to 80-mesh support S12.The carrier gas is helium,flowing at a linear velocity of about 33cm per minute.The column temperature is maintained at 115for 4minutes after injection,then the temperature is increased at a rate of 6per minute to 175,and maintained at 175for 5minutes.The injection port and detector temperatures are maintained at 250.Chromatograph theStandard solution,and record the peak responses as directed forProcedure:the relative retention times are about 0.7for methyl ethyl ketone,0.9for ethyl acetate,and 1.0for cyclohexane;the resolution,R,between ethyl acetate and cyclohexane is not less than 1.0;and the relative standard deviation for replicate injections is not more that 2.5%.
Procedure— Separately inject equal volumes (about 2µL)of theStandard solutionand theTest solutioninto the chromatograph,record the chromatograms,and measure the areas for the major peaks.Calculate the percentages of ethyl acetate and cyclohexane in the portion of Carbomer Copolymer taken by the formula:
100(WS/WT)(RU/RS),
in whichWSis the weight,in mg,of ethyl acetate or cyclohexane in theStandard solution;WTis the weight,in mg,of Carbomer Copolymer taken to prepare theTest solution;andRUandRSare the peak area ratios of the relevant analyte peak to methyl ethyl ketone obtained from theTest solution and theStandard solution,respectively:not more than 0.5%of ethyl acetate and not more than 0.3%of cyclohexane is found.
Limit of acrylic acid—
pH3.0Phosphate buffer— Dissolve 6.80g of monobasic potassium phosphate in about 300mLof water,dilute with water to 500mL,and mix.Dilute 100mLof this solution with water to 1L,adjust with phosphoric acid to a pHof 3.0±0.1,and mix.
Mobile phase— Use filtered and degassedpH3.0Phosphate buffer.
Standard solution— Dissolve an accurately weighed quantity of acrylic acid in water,and dilute quantitatively,and stepwise if necessary,to obtain a solution having a known concentration of about 0.1mg per mL.Dilute this solution quantitatively,and stepwise if necessary,with water to obtain a solution having a known concentration of about 25µg per mL.
Test solution— Transfer about 100mg of Carbomer Copolymer,accurately weighed,to a tared serum vial.Add water to obtain about 10.0g of solution.Cap the vial,and shake by mechanical means for 2hours.Add 2drops of sodium hydroxide solution (5in 10),and shake by hand for 15seconds.Add 1.0mLof calcium chloride solution (1in 10),and shake until the gel collapses.Centrifuge for 15minutes,and use the clear supernatant.
Chromatographic system(see Chromatography á621ñ)— The liquid chromatograph is equipped with a 200-nm detector and an 8-mm ×10-cm column that contains packing L1.The flow rate is about 1mLper minute.Chromatograph theStandard solution,and record the peak responses as directed forProcedure:the relative standard deviation for replicate injections is not more than 5%.
Procedure— Separately inject equal volumes (about 10µL)of theStandard solutionand theTest solutioninto the chromatograph,record the chromatograms,and measure the responses for the acrylic acid peaks.Calculate the percentage of free acrylic acid in the portion of Carbomer Copolymer taken by the formula:
(C/W)(rU/rS),
in whichCis the concentration,in µg per mL,of acrylic acid in theStandard solution;Wis the weight,in mg,of Carbomer Copolymer taken to prepare theTest solution;andrUandrSare the acrylic acid peak responses obtained from theTest solution and theStandard solution,respectively:not more than 0.25%is found.
Content of carboxylic acid— Slowly add about 400mg of Carbomer Copolymer,previously dried in vacuum at 80for 1hour and accurately weighed,to 400mLof water in a 1000-mLbeaker,while stirring continually at about 1000rpm,with the stirrer shaft set at an angle of about 60and to one side of the beaker,with the propeller positioned near the bottom of the beaker.Continue stirring for 15minutes.Reduce the stirring speed,and using a calomel-glass electrode system,titrate potentiometrically with 0.25Nsodium hydroxide VSto a pHof 10.0(seeTitrimetry á541ñ).After each addition of 0.25Nsodium hydroxide VS,allow 1minute for mixing before recording the pH.Calculate the percentage of carboxylic acid in the portion of Carbomer Copolymer taken by the formula:
100(45.02VN/W),
in which 45.02is the molecular weight of the carboxylic acid (-COOH)group;Vis the volume,in mL,of sodium hydroxide consumed;Nis the normality of the sodium hydroxide solution;andWis the weight,in mg,of Carbomer Copolymer taken.The carboxylic acid content is not less than 52.0%and not more than 62.0%.
Auxiliary Information— Staff Liaison:Catherine Sheehan,B.Sc.,Scientist
Expert Committee:(EMC)Excipients:Monograph Content
USP28–NF23Page 2974
Pharmacopeial Forum:Volume No.29(3)Page 691
Phone Number:1-301-816-8262