Diphenoxylate Hydrochloride and Atropine Sulfate Oral Solution
»Diphenoxylate Hydrochloride and Atropine Sulfate Oral Solution contains not less than 93.0percent and not more than 107.0percent of the labeled amount of diphenoxylate hydrochloride (C30H32N2O2·HCl),and not less than 80.0percent and not more than 120.0percent of the labeled amount of atropine sulfate [(C17H23NO3)2·H2SO4·H2O].
Packaging and storage— Preserve in tight,light-resistant containers.
Identification— Transfer a volume of Oral Solution,equivalent to about 100mg of diphenoxylate hydrochloride,to a separator,add 1mLof 3Nhydrochloric acid and sufficient water to make about 100mL,and extract with five 25-mLportions of a mixture of chloroform and isopropyl alcohol (9:1).After each extraction transfer the bottom chloroform layer to a second separator,filtering each portion through a sintered-glass filter.Wash the combined chloroform solutions with two 25-mLportions of water,discard the washings,and evaporate the chloroform on a steam bath to dryness.To the residue add 10mLof ether previously saturated with hydrochloric acid,carefully evaporate to dryness,then add a second portion of the acid-saturated ether,and again evaporate to dryness.Make a slurry of the residue with n-hexane,allow the solids to settle,and carefully decant the supernatant.Dry the solids at 105for 1hour:the diphenoxylate hydrochloride so obtained meets the requirements for Identificationtests Aand Bunder Diphenoxylate Hydrochloride.
Uniformity of dosage units á905ñ—
FOR ORAL SOLUTION PACKAGED IN SINGLE-UNIT CONTAINERS: meets the requirements.
Deliverable volume á698ñ—
FOR ORAL SOLUTION PACKAGED IN MULTIPLE-UNIT CONTAINERS: meets the requirements.
pHá791ñ: between 3.0and 4.3,determined in a dilution of the Oral Solution with an equal volume of water.
Alcohol content á611ñ: between 13.5%and 16.5%of C2H5OH.
Assay for diphenoxylate hydrochloride— Transfer an accurately measured volume of Oral Solution,equivalent to about 100mg of diphenoxylate hydrochloride,to a separator,add 4mLof 3Nhydrochloric acid,and extract with six 30-mLportions of chloroform.Wash the combined chloroform extracts with 25mLof water,and discard the washing.Transfer the chloroform to a beaker,and evaporate nearly to dryness.Add 100mLof glacial acetic acid and 4mLof mercuric acetate TSto the beaker,and titrate with 0.05Nperchloric acid in dioxane VS,determining the endpoint potentiometrically.Each mLof 0.05Nperchloric acid is equivalent to 24.45mg of diphenoxylate hydrochloride (C30H32N2O2·HCl).
Assay for atropine sulfate—
pH2.8Buffer— Dissolve 1.9g of aminoacetic acid and 1.5g of sodium chloride in 250mLof water.Adjust by the gradual addition of about 85mLof 0.1Nhydrochloric acid to a pHof 2.8.
Internal standard solution— Transfer about 20mg of homatropine hydrobromide to a 200-mLvolumetric flask,dissolve in and dilute with water to volume,and mix.
Standard preparation— Transfer about 25mg of USP Atropine Sulfate RS,accurately weighed,to a 200-mLvolumetric flask.Dissolve in and dilute with water to volume,and mix.Pipet 2mLof the resulting solution into a 125-mLseparator containing about 50mLof water.Add 2.0mLof Internal standard solution,10.0mLof pH2.8Buffer,and 25mLof water-saturated methylene chloride.Insert the stopper,shake for 2minutes,and allow the layers to separate.Discard the lower,organic layer.Repeat the extraction four times,using 25-mLportions of water-saturated methylene chloride each time,allowing the layers to separate and discarding the organic layer each time.To the remaining aqueous layer add 3mLof 0.1Nsodium hydroxide,and shake briefly.Using a pHmeter,adjust the solution to a pHof 9.0±0.3.Immediately add 10mLof water-saturated methylene chloride,insert the stopper,and shake.Transfer the lower,organic layer to a 50-mLcontainer.Repeat the extraction twice more with 10-mLportions of water-saturated methylene chloride,combining the organic extracts.Under a stream of nitrogen,evaporate the organic extracts to dryness.Dissolve the residue in 0.1mLof methylene chloride.
Assay preparation— Transfer an accurately measured volume of Oral Solution,equivalent to about 250µg of atropine sulfate,to a 125-mLseparator.Proceed as directed for Standard preparation,beginning with “Add 2.0mLof Internal standard solution.”
Chromatographic system(see Chromatography á621ñ)— The gas chromatograph is equipped with a flame-ionization detector and a 4-mm ×1.2-m glass column that contains 3%phase G3on support S1.The column is maintained at a temperature of 230,and the injection port and detector at 250.Helium is used as the carrier gas at a flow rate of 40mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the resolution,R,between atropine and the internal standard is not less than 2.0;and the relative standard deviation for replicate injections is not more than 2.5%.
Procedure— Separately inject equal volumes (about 2µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in µg,of atropine sulfate [(C17H23NO3)2·H2SO4·H2O]in each mLof the Oral Solution taken by the formula:
2(694.85/676.83)(C/V)(RU/RS),
in which 694.85and 676.83are the molecular weights of atropine sulfate monohydrate and anhydrous atropine sulfate,respectively;Cis the concentration,in µg per mL,of USP Atropine Sulfate RS(corrected to the monohydrate)in the Standard preparation;Vis the volume,in mL,of Oral Solution taken;and RUand RSare the peak response ratios of atropine to the internal standard obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Elena Gonikberg,Ph.D.,Scientist
Expert Committee:(PA4)Pharmaceutical Analysis 4
USP28–NF23Page 670
Pharmacopeial Forum:Volume No.29(6)Page 1874
Phone Number:1-301-816-8251