Nicotine Transdermal System
»Nicotine Transdermal System contains not less than 90.0percent and not more than 110.0percent of the labeled amount of nicotine (C10H14N2).
Packaging and storage— Preserve in the hermetic,light-resistant,unit-dose pouch.
Labeling— The labeling indicates theDrug Release Test with which the product complies.
Identification— The retention time of the major peak in the chromatogram of theAssay preparationcorresponds to that in the chromatogram of theStandard preparation,as obtained in theAssay.
Drug release á724ñ—
Test 1: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 1.
Medium: Phosphoric acid solution (1in 1000);250mL,in a tall-form beaker.
Apparatus 7— Proceed as directed in the chapter,using the transdermal system holder—cylinder (see Figure 7b).Center the Transdermal System onto a dry,unused 10-cm ×10-cm piece of Cuprophan dialysis membrane with the adhesive side against the membrane,taking care to eliminate air bubbles between the membrane and the release surface.Attach the membrane to the cylinder using two Parker O-rings,such that one of the borders of the transdermal system is aligned to the groove and it is wrapped around the cylinder.The filled beakers are weighed and pre-equilibrated to 32.0±0.3,prior to immersing the test sample.Reciprocate at a frequency of about 30cycles per minute with an amplitude of 2.0±0.1cm.At the end of each time interval,transfer the test sample to a fresh beaker containing the appropriate volume of Medium,weighed and pre-equilibrated to 32.0±0.3.At the end of each release interval,allow the beakers to cool to room temperature,make up for evaporative losses by adding water to obtain the original weight,and mix.This solution is the final Test solution.
Times: 2,12,and 24hours.
Determine the amount of C10H14N2released by employing the following method.
Mobile phase— Transfer 0.2mLof N,N-dimethyloctylamine to a 1-liter volumetric flask,add 220mLof acetonitrile,and mix.Add 300mLof water,0.2mLof glacial acetic acid,0.20g of anhydrous sodium acetate,and 0.55g of sodium 1-dodecanesulfonate,and dilute with water to volume.Mix for 1hour until clear.Filter and degas.Make adjustments if necessary (seeSystem SuitabilityunderChromatography á621ñ).(Equilibration of the column may take as long as 3hours.)
Standard solution— Dissolve an accurately weighed quantity of USP Nicotine Bitartrate Dihydrate RSinDissolution Medium,and dilute quantitatively,and stepwise if necessary,withDissolution Medium to obtain a solution having a known concentration of about 0.142mg of nicotine bitartrate per mL(or 0.046mg nicotine as free base per mL).[NOTE—About 80mLof this solution is required to prepare theSystem suitability solution.]
System suitability solution— Transfer 8mg (free base)of nicotine to a 100-mLvolumetric flask,and dissolve in 10mLof acetonitrile.Add 5mLof 30percent hydrogen peroxide,and allow 15minutes to react.Dilute withDissolution Medium to volume,and mix.Transfer 20mLof this solution to a 100-mLvolumetric flask,dilute withStandard solutionto volume,and mix.
Chromatographic system(see Chromatography á621ñ)— The liquid chromatograph is equipped with a 254-nm detector and a 4.6-mm ×15-cm column that contains packing L1.The flow rate is about 1mLper minute.Chromatograph theSystem suitability solution,and record the peak responses as directed forProcedure:the resolution,R,between nicotine and any degradation peaks is not less than 1.1;the tailing factor is not more than 2.0;and the relative standard deviation for replicate injections is not more than 1.5%.
Procedure— Separately inject equal volumes (about 50µL)of filtered portions of theStandard solutionand the solution under test into the chromatograph,record the chromatograms,and measure the responses for the major peaks.
Tolerances— The amount of C10H14N2released,as a percentage of the labeled amount of the dose absorbed in vivo,at the times specified below,conforms toAcceptance Table 4.
Time (hours) Amount dissolved
0–2 between 31%and 87%
2–12 between 62%and 191%
12–24 between 85%and 261%
Test 2: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 2.
Phosphate buffer— Dissolve 40.0g of sodium chloride,1.0g of potassium chloride,8.66g of dibasic sodium phosphate,and 1.0g of monobasic potassium phosphate in 5liters of water.
Medium: Phosphate buffer;500mL.
Apparatus 6: 50rpm,double-sided tape being used to attach the Transdermal System to the cylinder.
Times: 6and 24hours.
Determine the amount of C10H14N2released by employing the following method.
Mobile phase— Proceed as directed in theAssay.
System suitability solution— Transfer 1.0mLof theSystem suitability solution,prepared as directed in theAssay,to a 100-mLvolumetric flask,dilute withDissolution Mediumto volume,and mix.
Standard solution— Pipet 6.0mLof theStandard preparation,prepared as directed in theAssay,into a 50-mLvolumetric flask,dilute withDissolution Medium to volume,and mix.Dilute quantitatively and stepwise withDissolution Medium to obtain an appropriate final concentration.
Test solution— At each of the test times,withdraw a 2-mLaliquot of the solution under test.[NOTE—Replace the aliquots withdrawn for analysis with fresh portions ofMedium.]
Chromatographic system(see Chromatography á621ñ)— The liquid chromatograph is equipped with a 260-nm detector and a 4.6-mm ×12.5-cm column that contains packing L1.The flow rate is about 1mLper minute.Chromatograph theStandard solutionused for the 6-hour interval,and record the peak responses as directed forProcedure:the resolution,R,between 4,4¢-dipyridyl dihydrochloride and nicotine is not less than 5.0;the tailing factor is not more than 2.0;and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Separately inject equal volumes (about 100µL)of the filtered portion of theStandard solutionand theTest solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.
Tolerances— The amount of C10H14N2released,as a percentage of the labeled amount of the dose absorbed in vivo,at the times specified,conforms toAcceptance Table 4.
Time (hours) Amount dissolved
6 between 71%and 157%
24 between 156%and 224%
Test 3: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 3.
Medium: water;900mL.
Apparatus 5: 50rpm,the stainless steel disk assembly being replaced with a 5-cm watch glass for an 11-mg Transdermal System and an 8-cm watch glass for a 22-mg Transdermal System.
Times: 1,2,and 4hours.
Standard solution— Prepare a solution of USP Nicotine Bitartrate RSin water having a known concentration of nicotine similar to that of the solution under test.
Procedure— Determine the amount of C10H14N2released by employing UVabsorption at the wavelength of maximum absorbance at about 259nm,in comparison with theStandard solution,using water as the blank.
Tolerances— The amount of C10H14N2released,as a percentage of the labeled amount of the dose absorbed in vivo,at the times specified,conforms to the followingAcceptance Table.
Time (hours) Amount dissolved
1 between 35%and 75%
2 between 55%and 95%
4 not less than 73%
Acceptance Table
Level Tested Criteria
L1 6 No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time.
L2 6 The average value of the 12units (L1+L2)lies within each of the stated ranges and is not less than the stated amount at the final test time;none is more than 5%of the labeled content outside each of the stated ranges;and none is more than 5%of the labeled content below the stated amount at the final test time.
L3 12 The average value of the 24units (L1+L2+L3)lies within each of the stated ranges and is not less than the stated amount at the final test time;not more than 2of the 24units are more than 5%of labeled content outside each of the stated ranges;not more than 2of the 24units are more than 5%of the labeled content below the stated amount at the final test time;and none of the units is more than 10%of the labeled content outside each of the stated ranges or more than 10%of the labeled content below the stated amount at the final test time.
Test 4: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 4.
Medium: 0.025Nhydrochloric acid;600mL.
Apparatus 5: 50rpm,a convex screen being used to hold the Transdermal System in position during testing.
Times: 4and 16hours.
Standard solutionand Procedure— Proceed as directed forProcedureinTest 3.
Tolerances— The amount of C10H14N2released,as a percentage of the labeled amount of the dose absorbed in vivo,at the times specified,conforms toAcceptance Table 4.
Time (hours) Amount dissolved
4 between 36%and 66%
16 between 72%and 112%
Test 5: If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 5.
Phosphate buffer,Medium,and Apparatus— Proceed as directed underTest 2.
Times: 3,6,and 24hours.
Mobile phase— Proceed as directed in theAssay.
System suitability solution,Standard solution,Test solution,and Chromatographic system— Proceed as directed underTest 2.
Procedure— Proceed as directed underTest 2except to inject about 30µL.
Tolerances— The amount of C10H14N2released,as a percentage of the labeled amount of the dose absorbed in vivo,at the times specified,conforms toAcceptance Table 5.
Time (hours) Amount dissolved
3 between 79%and 112%
6 between 108%and 141%
24 between 156%and 202%
Uniformity of dosage units á905ñ: meets the requirements.
Assay—
Mobile phase— Mix 300mLof acetonitrile,700mLof water,and 1mLof triethylamine,filter,and degas.Make adjustments if necessary (seeSystem SuitabilityunderChromatography á621ñ).
Standard preparation— Dissolve an accurately weighed quantity of USP Nicotine Bitartrate Dihydrate RSin water to obtain a stock solution having a known concentration of about 26.87mg per mL.Quantitatively dilute a volume of the stock solution with methanol to obtain a solution having a known concentration of about 5.37mg of USP Nicotine Bitartrate Dihydrate RSper mL.[NOTE—This solution contains 1.75mg of nicotine per mL.]
System suitability solution— Transfer an accurately weighed quantity of about 12.5mg of 4,4¢-dipyridyl dihydrochloride to a 25-mLvolumetric flask,add 5.0mLof theStandard preparation,dilute with methanol to volume,and mix.
Assay preparation— Cut an accurately counted number of Nicotine Transdermal Systems,equivalent to about 175mg of nicotine,into strips 5cm2in area.Remove the protective liners,if any,from the strips,and discard.Transfer the strips to a 250-mLflask,and add 100.0mLof methanol.Insert the stopper into the flask,and shake by mechanical means for about 3hours.Filter,and use the clear filtrate as theAssay preparation.
Chromatographic system(see Chromatography á621ñ)— The liquid chromatograph is equipped with a 260-nm detector and a 4.6-mm ×25-cm column containing packing L1.The flow rate is about 1.5mLper minute.Chromatograph theSystem suitability solution,and record the peak responses as directed forProcedure:the resolution,R,between nicotine and 4,4¢-dipyridyl dihydrochloride is not less than 5.0.Chromatograph theStandard preparation,and record the peak responses as directed forProcedure:the relative standard deviation for replicate injections is not more than 1.0%.
Procedure— Separately inject equal volumes (about 10µL)of theStandard preparationand theAssay preparationinto the chromatograph,record the chromatograms,and measure the areas for the major peaks.Calculate the quantity,in mg,of nicotine (C10H14N2)in each Transdermal System taken by the formula:
(162.23/462.41)(100C/N)(rU/rS),
in which 162.23and 462.41are the molecular weights of nicotine and anhydrous nicotine bitartrate,respectively;Cis the concentration,in mg per mL,of USP Nicotine Bitartrate Dihydrate RSin theStandard preparation;Nis the number of Nicotine Transdermal Systems taken for theAssay preparation;and rUand rSare the nicotine peak responses obtained from theAssay preparationand theStandard preparation,respectively.
Auxiliary Information— Staff Liaison:Ravi Ravichandran,Ph.D.,Senior Scientist
Expert Committee:(PA3)Pharmaceutical Analysis 3
USP28–NF23Page 1371
Pharmacopeial Forum:Volume No.28(4)Page 1166
Phone Number:1-301-816-8330