Zileuton
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C11H12N2O2S 236.29
Urea,N-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-,(±)-.
(±)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea [111406-87-2].
»Zileuton contains not less than 98.5percent and not more than 101.5percent of C11H12N2O2S,calculated on the anhydrous basis.
Packaging and storage— Preserve in tight,light-resistant containers,and store at room temperature.
Identification—
A:Infrared Absorption á197Kñ.
B: The retention time of the major peak in the chromatogram of the Assay preparationcorresponds to that in the chromatogram of the Standard preparation,as obtained in the Assay.
Specific rotation á781Sñ: between –0.5and +0.5.
Test solution: 10mg per mL,in methanol.
Water,Method Iá921ñ: not more than 1.5%.
Residue on ignition á281ñ: not more than 0.2%.
Chromatographic purity—
NOTE—For Test 1and Test 2the System suitability solution,the Standard solution,and the Test solution are to be refrigerated at or below 5immediately after preparation and during analysis using a refrigerated autosampler.The solutions are stable at or below 5for about 36hours.
TEST1—
Buffer solution— Prepare as directed in the Assay.
Mobile phase— Prepare a filtered and degassed mixture of Buffer solutionand acetonitrile (82:18).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
System suitability solution— Dissolve accurately weighed quantities of USP Zileuton RSand USP Zileuton Related Compound A RSin acetonitrile,and dilute quantitatively,and stepwise if necessary,to obtain a solution having a known concentration of about 5µg of each USP Reference Standard per mL.
Standard solution— Dissolve an accurately weighed quantity of USP Zileuton RSin acetonitrile to obtain a solution having a known concentration of about 10µg per mL.
Test solution— Transfer about 125mg of Zileuton,accurately weighed,to a 50-mLvolumetric flask,dissolve in and dilute with acetonitrile to volume,and mix.
Chromatographic system— Prepare as directed in the Assay,except to use a flow rate of 2.2mLper minute.Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between zileuton and zileuton related compound Ais not less than 1.5;and the relative standard deviation for replicate injections is not more than 5.0%.
Procedure— Separately inject equal volumes (about 20µL)of the Standard solution and the Test solutioninto the chromatograph,and measure the areas for the major peaks.Calculate the percentage of each impurity in the portion of Zileuton taken by the formula:
100F(CS/CU)(ri/rS),
in which Fis the relative response factor for each impurity,which is 1.0for any peak with a relative retention time of 0.5,0.7,1.2,1.6,3.2,or 3.4,and is 1.2,1.4,and 1.7for peaks with relative retention times of 0.8,2.1,and 2.8,respectively;CSis the concentration,in mg per mL,of USP Zileuton RSin the Standard solution;CUis the concentration,in mg per mL,of zileuton in the Test solution;riis the peak response for each impurity obtained from the Test solution;and rSis the peak response for zileuton obtained from the Standard solution:not more than 0.1%of any individual impurity with a relative retention time of 0.7,0.8,1.6,2.1,3.2,or 3.4is found;not more than 0.2%of any individual impurity with a relative retention time of 0.5or 1.2is found;and not more than 0.3%of any individual impurity with a relative retention time of 2.8is found.
TEST2—
Perchloric acid solution— Dissolve 5.0mLof perchloric acid in 1000mLof water.
Mobile phase— Prepare a filtered and degassed mixture of Perchloric acid solutionand acetonitrile (1:1).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard stock solution— Dissolve an accurately weighed quantity of USP Zileuton Related Compound B RSin acetonitrile to obtain a solution having a known concentration of about 0.25mg per mL.Transfer 5.0mLof this solution to a 50-mLvolumetric flask,dilute with acetonitrile to volume,and mix.
System suitability solution— Dissolve an accurately weighed quantity of USP Zileuton Related Compound C RSin acetonitrile to obtain a solution having a known concentration of about 10µg per mL.Transfer 5.0mLof this solution and 5.0mLof the Standard stock solutionto a 50-mLvolumetric flask,dilute with acetonitrile to volume,and mix.
Standard solution— Transfer 5.0mLof the Standard stock solutionto a 50-mLvolumetric flask,dilute with acetonitrile to volume,and mix.
Test solution— Proceed as directed for Test solutionunder Test 1.
Chromatographic system— Prepare as directed in the Assay.Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between zileuton related compound Band zileuton related compound Cis not less than 20.Chromatograph the Standard solution,and record the peak responses as directed for Procedure:the relative standard deviation for replicate injections is not more than 5.0%.
Procedure— Separately inject equal volumes (about 50µL)of the Standard solutionand the Test solution into the chromatograph,record the chromatograms,and measure the areas for the major peaks.Calculate the percentage of each impurity in the portion of Zileuton taken by the formula:
100(CS/CU)(ri/rS),
in which CSis the concentration,in mg per mL,of USP Zileuton Related Compound B RSin the Standard solution;CUis the concentration,in mg per mL,of zileuton in the Test solution;riis the peak response for each impurity obtained from the Test solution;and rSis the peak response for zileuton related compound Bobtained from the Standard solution:not more than 0.1%of any individual impurity is found;and not more than 0.7%of total impurities is found,the results forTest 1and Test 2being added.
Assay—
NOTE—The Standard preparation and the Assay preparation are to be refrigerated at or below 5immediately after preparation and during analysis using a refrigerated autosampler.The solutions are stable at or below 5for about 36hours.
Buffer solution— Dissolve 7.7g of ammonium acetate and 0.25g of acetohydroxamic acid in about 900mLof water in a 1000-mLvolumetric flask,adjust with perchloric acid to a pHof 2.0,dilute with water to volume,and mix.
Mobile phase— Prepare a filtered and degassed mixture of Buffer solutionand acetonitrile (72:28).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Internal standard preparation— Transfer about 30mg of methylparaben,accurately weighed,to a 100-mLvolumetric flask,dissolve in and dilute with acetonitrile to volume,and mix.
Standard stock preparation— Dissolve an accurately weighed quantity of USP Zileuton RSin acetonitrile to obtain a solution having a known concentration of about 1mg per mL.
Standard preparation— Transfer 5.0mLof the Standard stock preparationand 4.0mLof the Internal standard preparationto a 50-mLvolumetric flask,dilute with acetonitrile to volume,and mix.
Assay preparation— Transfer about 100mg of Zileuton,accurately weighed,to a 100-mLvolumetric flask,dissolve in and dilute with acetonitrile to volume,and mix.Transfer 5.0mLof this solution and 4.0mLof the Internal standard preparationto a 50-mLvolumetric flask,dilute with acetonitrile to volume,and mix.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 260-nm detector and a 4.6-mm ×30-cm column that contains 10-µm packing L1.The flow rate is about 1.5mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the resolution,R,between zileuton and methylparaben is not less than 5.0;the tailing factor is not more than 1.3;and the relative standard deviation for replicate injections is not more than 0.6%.
Procedure— Separately inject equal volumes (about 20µL)of the Assay preparationand the Standard preparationinto the chromatograph,record the chromatograms,and measure the peak areas.Calculate the quantity,in mg,of C11H12N2O2Sin the portion of Zileuton taken by the formula:
1000C(RU/RS),
in which Cis the concentration,in mg per mL,of USP Zileuton RSin the Standard preparation;and RUand RSare the peak area ratios obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Karen A Russo,Ph.D.,Scientist
Expert Committee:(PA1)Pharmaceutical Analysis 1
USP28–NF23Page 2050
Pharmacopeial Forum:Volume No.30(3)Page 948
Phone Number:1-301-816-8379
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