Extended Phenytoin Sodium Capsules
»Extended Phenytoin Sodium Capsules contain not less than 95.0percent and not more than 105.0percent of the labeled amount of phenytoin sodium (C15H11N2NaO2).
Packaging and storage— Preserve in tight,light-resistant containers.Protect from moisture.Store at controlled room temperature.
Labeling— When more than oneDissolution test is given,the labeling states theDissolution test used only ifTest 1is not used.
Identification—
A: The contents of Capsules meet the requirements of Identificationtest Aunder Phenytoin Sodium.
B: The contents of Capsules meet the requirements of the flame test for Sodium á191ñ.
Dissolution á711ñ—
Test 1:
Medium: water;900mL.
Apparatus 1: 50rpm.
Times: 30,60,and 120minutes.
Determine the amount of C15H11N2NaO2dissolved by employing the following method.
Mobile phase— Prepare a filtered and degassed mixture of methanol and water (7:3).Make adjustments if necessary (seeSystem Suitability underChromatography á621ñ).
Standard solution— Prepare a solution of USP Phenytoin RSin methanol,and dilute with water to obtain a solution having a concentration similar to that of the solution under test.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 229-nm detector and a 4.6-mm ×25-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 column efficiency is not less than 3200theoretical plates;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 10µL)of the Standard solutionand the solution under test into the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of phenytoin sodium (C15H11N2NaO2)dissolved by the formula:
(274.25/252.27)900C(rU/rS),
in which 274.25and 252.27are the molecular weights of phenytoin sodium and phenytoin,respectively;Cis the concentration,in mg per mL,of USP Phenytoin RSin theStandard solution;andrUand rSare the peak responses obtained from the solution under test and theStandard solution,respectively.
Tolerances (for products labeled as 30-mg capsules)— The percentage of the labeled amount of C15H11N2NaO2dissolved is not more than 40%(Q)in 30minutes,is 56%(Q¢)in 60minutes,and is not less than 65%(Q¢¢)in 120minutes.The requirements are met if the quantities dissolved from the Capsules tested conform to the accompanying Acceptance Table.
Acceptance Table
Stage Number Tested Acceptance Criteria
S1 6 Each unit is within the range between Q-15%and Q-5%,is within the range Q¢±10%,and is not less than Q¢¢+5%at the stated Times.
S2 6 Average of 12units (S1+S2)is within the range between Q-10%and Q,is within the range Q¢±8%,and is not less than Q¢¢;no unit is outside the range between Q-20%and Q+10%,no unit is outside the range Q¢±18%,and no unit is less than Q¢¢-10%at the stated Times.
S3 12 Average of 24units (S1+S2+S3)is within the range between Q-10%and Q,is within the range Q¢±8%and is not less than Q¢¢;not more than 2units are outside the range between Q-20%and Q+10%,and no unit is outside the range Q-30%and Q+20%;not more than 2units are outside the range Q¢±18%,and no unit is outside the range Q¢±25%;not more than 2units are less than Q¢¢-10%,and no unit is less than Q¢¢-20%at the statedTimes.
Tolerances (for products labeled as 100-mg capsules)— The percentage of the labeled amount of C15H11N2NaO2dissolved is not more than 45%(Q)in 30minutes,is 60%(Q¢)in 60minutes,and is not less than 70%(Q¢¢)in 120minutes.The requirements are met if the quantities dissolved from the Capsules tested conform to the accompanying Acceptance Table.
Acceptance Table
Stage Number Tested Acceptance Criteria
S1 6 Each unit is within the range between Q-25%and Q-5%,is equal to Q¢±20%,and is not less than Q¢¢+5%at the stated Times.
S2 6 Average of 12units (S1+S2)is within the range between Q-20%and Q,is within the range Q¢±15%,and is not less than Q¢¢;no unit is outside the range between Q-30%and Q+10%,no unit is outside the range Q¢±25%,and no unit is less than Q¢¢-10%at the stated Times.
S3 12 Average of 24units (S1+S2+S3)is within the range between Q-20%and Q,is within the range Q¢±15%and is not less than Q¢¢;not more than 2units are outside the range between Q-30%and Q+10%,and no unit is outside the range between Q-40%and Q+20%;not more than 2units are outside the range Q¢±25%,and no unit is outside the range Q¢±35%;not more than 2units are less than Q¢¢-10%,and no unit is less than Q¢¢-20%at the stated Times.
Test 2: If the product complies with this test,the labeling indicates that it meets USPDissolution Test 2.Proceed as directed in Test 1,except for using Apparatus 1at 75rpm and the following Tolerances.
Tolerances (for products labeled as 100-mg capsules)— The percentage of the labeled amount of C15H11N2NaO2dissolved is not more than 45%(Q)in 30minutes,is 65%(Q¢)in 60minutes,and is not less than 70%(Q¢¢)in 120minutes.The requirements are met if the quantities dissolved from the Capsules tested conform to the accompanying Acceptance Table.
Acceptance Table
Stage Number Tested Acceptance Criteria
S1 6 Each unit is within the range between Q-25%and Q-5%,is equal to Q¢±20%,and is not less than Q¢¢+5%at the stated Times.
S2 6 Average of 12units (S1+S2)is within the range between Q-25%and Q-5%,is within the range of Q¢-20%and Q¢+10%,and is not less than Q¢¢;no unit is outside the range between Q-30%and Q+5%,no unit is outside the range Q¢-25%and Q¢+20%,and no unit is less than Q¢¢-10%at the stated Times.
S3 12 Average of 24units (S1+S2+S3)is within the range between Q-25%and Q-5%,is within the range of Q¢-20%and Q¢+10%,and is not less than Q¢¢;not more than 2units are outside the range between Q-30%and Q+5%;and no unit is outside the range of Q-40%and Q+15%;not more than 2units are outside the rangeQ¢-25%and Q¢+20%,and no unit is outside the range Q¢-35%and Q¢+25%;not more than 2units are less than Q¢¢-10%;and no unit is less than Q¢¢-20%at the stated Times.
Test 3: If the product complies with this test,the labeling indicates that it meets USPDissolution Test 3.
Medium: water;900mL.
Apparatus 1: 75rpm.
Times: 30,60,and 120minutes.
Determine the amount of C15H11N2NaO2dissolved by employing the method described underTest 1.
Tolerances(for products labeled as 200-mg and 300-mg capsules)— The percentage of the labeled amount of C15H11N2NaO2dissolved is not more than 30%(Q)in 30minutes,is 50%(Q¢)in 60minutes,and is not less than 60%(Q¢¢)in 120minutes.The requirements are met if the quantities dissolved from the Capsules tested conform to the accompanyingAcceptance Table.
Acceptance Table
Stage Number Tested Acceptance Criteria
S1 6 Each unit is within the range between Q-20%and Q+5%,is equal to Q¢-20%and Q¢+25%,and is not less than Q¢¢+5%at the stated Times.
S2 6 Average of 12units (S1+S2)is within the range between Q-20%and Q,is within the range of Q¢±20%,and is not less than Q¢¢;no unit is outside the range between Q-25%and Q+10%,no unit is outside the range Q¢±25%,and no unit is less than Q¢¢-10%at the stated Times.
S3 12 Average of 24units (S1+S2+S3)is within the range between Q-20%and Q,is within the range of Q¢±20%,and is not less than Q¢¢;not more than 2units are outside the range between Q-25%and Q+10%,and no unit is outside the range Q-25%and Q+15%;not more than 2units are outside the rangeQ¢±25%;and no unit is outside the range Q¢±30%;not more than 2units are less than Q¢¢-10%;and no unit is less than Q¢¢-20%at the stated Times.
Uniformity of dosage units á905ñ: meet the requirements.
PROCEDUREFOR CONTENT UNIFORMITY—
Phosphate buffer and Mobile phase— Proceed as directed in the Assay.
Standard solution— Dissolve an accurately weighed quantity of USP Phenytoin RSin methanol,and dilute quantitatively,and stepwise if necessary,with Mobile phaseto obtain a solution having a known concentration of about 0.5mg per mL.
Test solution— Place one intact Capsule or one opened capsule with its contents in a suitable container,add approximately 15mLof methanol,and place in a shaking water bath at 37for 30minutes.Sonicate for 60minutes with occasional shaking.Dilute with methanol to volume,and mix.Dilute with Mobile phase,if necessary,to obtain a final concentration of about 0.5mg per mL.
Chromatographic system (see Chromatograpy á621ñ)— Proceed as directed in the Assay,except to chromatograph the Standard solutioninstead of the Standard preparation.
Procedure— Proceed as directed in the Assay,except to inject the Standard solutionand the Test solutioninstead of the Standard preparationand the Assay preparation.
Related compounds—
Phosphate buffer and Mobile phase— Proceed as directed in the Assay.
Standard solution— Dissolve accurately weighed quantities of USP Phenytoin RS,USP Phenytoin Related Compound A RS,and USP Phenytoin Related Compound B RSin methanol,and dilute quantitatively,and stepwise if necessary,with methanol to obtain a solution having known concentrations of about 600,3,and 3µg per mL,respectively.
Test solution— Use the Assay preparation.
Chromatographic system (see Chromatography á621ñ)— Prepare as directed in the Assay.Chromatograph the Standard solution,and record the peak responses as directed for Procedure:the relative retention times are about 0.38for phenytoin related compound A,0.45for phenytoin related compound B,and 1.0for phenytoin;the resolution,R,between phenytoin related compound Band phenytoin is not less than 8,and the resolution,R,between phenytoin related compound Aand phenytoin related compound Bis not less than 1.5;the tailing factor for the phenytoin peak is not more than 2.0;and the relative standard deviation for replicate injections is not more than 2.0%determined from phenytoin,and not more than 5.0%determined from phenytoin related compound Aor phenytoin related compound B.
Procedure— Separately inject equal volumes (about 10µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in µg,of each phenytoin related compound in the portion of Capsules taken by the formula:
100C(rU/rS),
in which Cis the concentration,in µg per mL,of the appropriate USP Reference Standard in the Standard solution;and rUand rSare the peak responses for the corresponding phenytoin related compound obtained from the Test solutionand the Standard solution,respectively:not more than 0.5%of phenytoin related compound Ais found;and not more than 1.0%of phenytoin related compound Bis found.
Assay—
Phosphate buffer— Prepare a solution of 0.05Mmonobasic potassium phosphate in water,adjust with phosphoric acid to a pHof 3.5,and mix.
Mobile phase— Prepare a filtered and degassed mixture of methanol and Phosphate buffer(11:9).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Standard preparation— Dissolve an accurately weighed quantity of USP Phenytoin RSin methanol,and dilute quantitatively,and stepwise if necessary,with Mobile phaseto obtain a solution having a known concentration of about 0.6mg per mL.
Assay preparation— Transfer the contents of 10Capsules to a 250-mLvolumetric flask.Add about 150mLof methanol,and sonicate for 20minutes.Cool to room temperature,dilute with methanol to volume,mix,and filter.Transfer an accurately measured portion of the filtered solution,equivalent to about 60mg of phenytoin,to a 100-mLvolumetric flask,dilute with Mobile phaseto volume,and mix.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 229-nm detector and a 4.6-mm ×25-cm column that contains packing L1.The flow rate is about 1mLper minute.Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the column efficiency is not less than 3000theoretical plates;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 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of phenytoin sodium (C15H11N2NaO2)in the portion of Capsules taken by the formula:
(274.25/252.27)100C(rU/rS),
in which 274.25and 252.27are the molecular weights of phenytoin sodium and phenytoin,respectively;Cis the concentration,in mg per mL,of USP Phenytoin RSin the Standard preparation;and rUand rSare the peak responses obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Salvador C.Salado,M.S.,Scientist and Latin American Liaison
Expert Committee:(PA3)Pharmaceutical Analysis 3
USP28–NF23Page 1551
Pharmacopeial Forum:Volume No.29(1)Page 108
Phone Number:1-301-816-8165