»Naltrexone Hydrochloride contains not less than 98.0percent and not more than 102.0percent of C20H23NO4·HCl,calculated on the anhydrous,solvent-free basis.
Packaging and storage Preserve in tight containers.
Completeness of solution á641ñ A650-mg portion dissolves in 10mLof water to yield a clear solution.
Identification,Infrared Absorption á197Kñ
Test specimen Dissolve about 150mg in 25mLof water in a small separator,add a few drops of 6Nammonium hydroxide slowly until no more white precipitate is formed.Extract with three 5-mLportions of chloroform,filter the extracts through a dry filter,collecting the filtrate in a small flask.Evaporate the filtrate on a steam bath to dryness,and dry the residue at 105for one hour.
Specific rotation á781Sñ: between -187and -197,calculated on the anhydrous,solvent-free basis.
Test solution: 25mg per mL,in water.
Water,Method Iá921ñ Determine the water content as directed.[NOTEThe result of this test is used in the calculation ofLimit of total solvents.]
Residue on ignition á281ñ: not more than 0.1%.
Heavy metals,Method IIá231ñ: not more than 0.002%.
Limit of total solvents
Internal standard stock solution Prepare a solution of isopropyl alcohol,which has been tested and found to be free of methanol and alcohol,having a concentration of about 0.12mg per mL.
Internal standard solution Transfer 5.0mLof theInternal standard stock solution to a 100-mLvolumetric flask,dilute with water to volume,and mix.
Standard solution Transfer 2.0mLof anhydrous methanol and 2.0mLof alcohol to a 100-mLvolumetric flask,dilute with water to volume,and mix.Transfer 3.0mLof this solution and 5.0mLofInternal standard stock solution to a 100-mLvolumetric flask,dilute with water to volume,and mix.
Test solution Transfer about 75mg of Naltrexone Hydrochloride,accurately weighed,to a suitable container,add 5.0mLofInternal standard solution,and shake to dissolve.
Chromatographic system(see Chromatography á621ñ) The gas chromatograph is equipped with a flame-ionization detector and a 4-mm ×1.8-m glass column packed with 80-to 100-mesh support S3.The column temperature is maintained at 150,and the injection port and detector temperature are maintained at 170.Chromatograph theStandard solution,and record the peak responses as directed forProcedure:the relative retention times are about 0.24for methanol,0.53for alcohol,and 1.0for isopropyl alcohol.
Procedure Separately inject equal volumes (about 5µL)of theStandard solution and theTest solution into the gas chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the percentages of methanol and alcohol in the portion of Naltrexone Hydrochloride taken by the formula:
(240/W)(RU/RS),in whichWis the weight,in mg,of Naltrexone Hydrochloride in theTest solution;andRUandRSare the peak response ratios of methanol or alcohol to isopropyl alcohol obtained from theTest solution and theStandard solution,respectively.To these added percentages,add the percentage of water determined in the test forWater:the sum of water and alcoholic solvents is not more than 5.0%for the anhydrous form and not more than 11.0%for the dihydrate form.
Related compounds Proceed as directed in theAssay.From the chromatogram of theAssay preparation,calculate the percentage of each related compound in Naltrexone Hydrochloride taken by the formula:
10F(C/W)(rU/rS),in whichFis the relative response factor for each impurity,Cis the concentration,in mg per mL,of USP Naltrexone RSin theStandard preparation,Wis the weight,in mg,of Naltrexone Hydrochloride taken for theAssay preparation,rUis the peak response of the relevant related compound obtained from theAssay preparation,andrSis peak response of naltrexone obtained from theStandard preparation.[NOTEThe relative response factor is 0.3for 2,2¢-bisnaltrexone and 10-ketonaltrexone,and 1.0for all other related compound peaks.]Not more than 0.5%of any individual related compound is found,and the total of all related compounds is not more than 1.5%.
Content of chloride Transfer about 300mg,accurately weighed,to a 250-mLconical flask,add 50mLof methanol,50mLof water,and 3mLof nitric acid,and mix to dissolve.Titrate with 0.1Nsilver nitrate VS,determining the endpoint potentiometrically.Each mLof 0.1Nsilver nitrate is equivalent to 3.545mg of chloride:between 9.20%and 9.58%,calculated on the anhydrous,solvent-free basis is found.
Solution A Dissolve about 1.08g of sodium 1-octanesulfonate and about 23.8g of sodium acetate in 800mLof water.Add 1.0mLof triethylamine and 200mLof methanol,and mix.Adjust with glacial acetic acid to a pHof 6.5±0.1.Filter and degas prior to use.
Solution B Dissolve about 1.08g sodium 1-octanesulfonate and about 23.8g sodium acetate in 400mLof water.Add 1.0mLtriethylamine and 600mLof methanol,and mix.Adjust with glacial acetic acid to a pHof 6.5±0.1.Filter and degas prior to use.
Mobile phase Use variable mixtures ofSolution AandSolution Bas directed forChromatographic system.
Standard preparation Transfer an accurately weighed quantity of about 22.5mg of USP Naltrexone RSto a 10-mLvolumetric flask.Add 1.5mLof methanol and 0.6mLof 0.1Nhydrochloric acid.Dissolve by swirling the flask,and dilute with 0.1Mphosphoric acid to volume.
Resolution solution Transfer about 3.0mg,accurately weighed,of USP Naltrexone Related Compound A RSto a 10-mLvolumetric flask.Add 3.0mLof methanol,and dissolve by swirling.Dilute with 0.1Mphosphoric acid to volume,and mix.Transfer 0.5mLof this solution to a 10-mLvolumetric flask,add 5.0mLofStandard preparation,dilute with 0.1Mphosphoric acid to volume,and mix.
Assay preparation Transfer an accurately weighed quantity of about 25mg of Naltrexone Hydrochloride to a 10-mLvolumetric flask.Dissolve in and dilute with 0.1Mphosphoric acid to volume,and mix.
Chromatographic system(see Chromatography á621ñ) The liquid chromatograph is equipped with a 280-nm detector and a 3.9-mm ×15-cm column that contains packing L1and is programmed to provide,at a flow rate of about 1mLper minute,a variable mixture ofSolution AandSolution B.At the time the specimen is injected into the chromatograph,the percentage ofSolution Ais 100%;over the next 35minutes,the proportion ofSolution Bis increased linearly to 100%,and then over the next minute,decreased linearly to 100%ofSolution A.Allow the system to equilibrate until the late eluting peak has been observed,approximately 17minutes later.Chromatograph about 20µLof theResolution solution,and record the peak responses as directed underProcedure:the relative retention times are about 0.55for noroxymorphone,0.70for 10-hydroxynaltrexone,1.0for naltrexone,1.26for naltrexone related compound A,1.80for 2,2¢-bisnaltrexone,and 1.99for 10-ketonaltrexone;the resolution,R,between naltrexone and naltrexone related compound Ais not less than 2.0;the tailing factor for the naltrexone peak is not greater than 1.4;and the relative standard deviation for replicate injections is not more than 2.0%.
Procedure Separately inject equal volumes (about 20µL)of theStandard preparation andAssay preparation into the chromatograph,record the chromatograms,and measure the responses for all the peaks.Calculate the quantity,in mg,of C20H23NO4·HCl in the portion of Naltrexone Hydrochloride taken by the formula:
(377.86/341.41)10C(rU/rS),in which 377.86and 341.41are the molecular weights of naltrexone hydrochloride and naltrexone,respectively;Cis the concentration,in mg per mL,of USP Naltrexone RSin theStandard preparation,andrUandrSare the peak responses of naltrexone obtained from theAssay preparation and theStandard preparation,respectively.
Auxiliary Information Staff Liaison:Daniel K.Bempong,Ph.D.,Scientist
Expert Committee:(PA2)Pharmaceutical Analysis 2
USP28NF23Page 1329Pharmacopeial Forum:Volume No.28(2)Page 329