Pentoxifylline Extended-Release Tablets
»Pentoxifylline Extended-Release Tablets contain not less than 95.0percent and not more than 105.0percent of the labeled amount of pentoxifylline (C13H18N4O3).
Packaging and storage— Preserve in well-closed containers.Protect from light,and store between 15and 30.
Labeling— The labeling indicates the Drug Release Testwith which the product complies.
Identification—
A:Infrared Absorption á197Kñ—
Test specimen— Finely powder not fewer than 5Tablets.(Acoarse screen may be used to separate the powder from the tablet film-coating if necessary.)Transfer an accurately weighed portion of the powder,equivalent to about 200mg of pentoxifylline,to a 15-mLcentrifuge tube,add about 10mLof methanol,cap the tube,and shake vigorously for about 5minutes.Centrifuge for about 5minutes to allow undissolved material to settle.Decant the supernatant into a suitable beaker,and evaporate the solution with the aid of a current of air to dryness at about 35.Dissolve the residue in about 15mLof methylene chloride,transfer to a separatory funnel,add about 10mLof water,and shake.Allow the layers to separate,transfer the methylene chloride layer,and pass through a funnel partially filled with anhydrous sodium sulfate,collecting the filtrate in a small beaker.Evaporate the solution with the aid of a current of air to dryness at about 35.Dissolve the residue so obtained in 8to 10mLof ether,and then chill in an ice bath,if necessary,to induce crystallization.Collect the crystals on filter paper,wash with about 2mLof cold ether,and allow to air-dry.Prepare a mixture of about 1.5%(w/w)of the crystals in potassium bromide.
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.
Drug release á724ñ—
TEST1— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 1.
Medium: water;900mLor 1000mL.
Apparatus 2: 100rpm.
Times: 1,4,8,and 12hours.
Procedure— Determine the amount of C13H18N4O3dissolved by employing UVabsorption at the wavelength of maximum absorbance at about 274nm on filtered portions of the solution under test,suitably diluted with Dissolution Medium,if necessary,in comparison with a Standard solution having a known concentration of USP Pentoxifylline RSin the same Medium.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to Acceptance Table 1.
Time (hours) Amount dissolved
1 not more than 30%
4 between 30%and 55%
8 not less than 60%
12 not less than 80%
TEST2— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 2.
Medium: water;900mL.
Apparatus 2: 75rpm.
Times: 1,6,10,and 20hours.
Procedure— Proceed as directed under Test 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 between 8%and 30%
6 between 35%and 60%
10 between 53%and 78%
20 not less than 80%
TEST3— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 3.
Medium: water;900mL.
Apparatus 1: 100rpm.
Times: 2,8,12,and 20hours.
Procedure— Proceed as directed under Test 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
2 between 15%and 35%
8 between 55%and 75%
12 between 75%and 95%
20 not less than 85%
TEST4— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 4.
Medium: water;900mL.
Apparatus 2: 50rpm.
Times: 1,8,and 24hours.
Procedure— Proceed as directed forTest 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 between 0%and 20%
8 between 35%and 60%
24 not less than 80%
TEST5— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 5.
Medium: water;900mL.
Apparatus 2: 75rpm.
Times: 1,2,4,6,and 20hours.
Procedure— Proceed as directed forTest 1,except to use the wavelength of maximum absorbance at about 264nm instead of 274nm.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 between 5%and 25%
2 between 10%and 35%
4 between 20%and 50%
6 between 30%and 60%
20 not less than 80%
TEST6— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 6.
Medium: simulated gastric fluid (without enzymes);900mL.
Apparatus 2: 50rpm.
Times: 2,8,12,and 24hours.
Procedure— Proceed as directed forTest 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
2 between 10%and 30%
8 between 40%and 60%
12 between 55%and 75%
24 not less than 85%
TEST7— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 7.
Medium: water;900mL.
Apparatus 2: 50rpm.
Times: 1,3,8,and 18hours.
Procedure— Proceed as directed forTest 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 not more than 25%
3 between 25%and 45%
8 between 55%and 75%
18 not less than 80%
TEST8— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 8.
Medium: water;900mL.
Apparatus 2: 75rpm.
Times: 1,2,4,10,and 16hours.
Procedure— Proceed as directed forTest 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 between 10%and 20%
2 between 15%and 35%
4 between 25%and 45%
10 between 55%and 75%
16 not less than 80%
TEST9— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 9.
Medium: water;900mL.
Apparatus 2: 50rpm.
Times: 1,3,6,12,and 18hours.
Procedure— Proceed as directed forTest 1,except to use the wavelength of maximum absorbance at about 230nm instead of 274nm.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 between 0%and 20%
3 between 20%and 40%
6 between 30%and 60%
12 between 50%and 80%
18 not less than 80%
TEST10— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 10.
Medium: water;900mL.
Apparatus 2: 75rpm.
Times: 1,6,12,and 20hours.
Procedure— Proceed as directed forTest 1.
Tolerances— The percentages of the labeled amount of C13H18N4O3dissolved at the times specified conform to the following table.
Time (hours) Amount dissolved
1 not more than 20%
6 between 35%and 65%
12 between 60%and 90%
20 not less than 80%
Uniformity of dosage units á905ñ: meet the requirements.
Chromatographic purity—
Perchloric acid solution,Mobile phase,Extracting solution,and System suitability solution— Prepare as directed in the Assay.
Standard solution— Dissolve an accurately weighed quantity of USP Pentoxifylline RSin Extracting solutioncontaining an amount of methanol equal to 0.8%of the total volume to be used,and dilute quantitatively,and stepwise if necessary,with Extracting solutionto obtain a solution having a known concentration of about 0.96µg per mL.
Test solution— Transfer 10.0mLof the first dilution filtrate from the Assay preparationto a 25-mLvolumetric flask,dilute with Extracting solutionto volume,and mix.The final concentration of pentoxifylline in this solution is about 0.32mg per mL.
Chromatographic system (see Chromatography á621ñ)— Proceed as directed in the Assay.Chromatograph the Standard solution,and record the peak responses for pentoxifylline as directed for Procedure:the relative standard deviation for replicate injections is not more than 5.0%.
Procedure— Separately inject equal volumes (about 10µL)of the Standard solutionand the Test solutioninto the chromatograph,and allow the chromatogram to run five times longer than the retention time of the pentoxifylline peak.Record the chromatograms,and measure all the peak responses from the Test solution,except that for pentoxifylline.Calculate the percentage of each impurity in the portion of Tablets taken by the formula:
312C(ri/rS),
in which Cis the concentration,in mg per mL,of USP Pentoxifylline RSin the Standard solution;riis the peak response for each impurity obtained from the Test solution;and rSis the peak response for pentoxifylline obtained from the Standard solution:not more than 0.3%of any individual impurity is found;and not more than 1.0%of total impurities is found.
Assay—
Perchloric acid solution— Dissolve 1.0g of perchloric acid in 1000mLof water,and mix.
Mobile phase— Prepare a filtered and degassed mixture of Perchloric acid solution,acetonitrile,tetrahydrofuran,and methanol (80:15:2.5:2).Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).
Extracting solution— Prepare a mixture of water and alcohol (7:3).
System suitability solution— Transfer about 20mg of USP Pentoxifylline RSand about 10mg of caffeine,each accurately weighed,to a 25-mLvolumetric flask.Add 0.2mLof methanol,and swirl the flask to distribute the methanol.Dilute with Extracting solutionto volume,and mix.Pipet 3.0mLof the resulting solution into a 50-mLvolumetric flask,dilute with Extracting solutionto volume,and mix.
Standard preparation— Dissolve an accurately weighed quantity of USP Pentoxifylline RSin Extracting solutioncontaining an amount of methanol equal to 0.8%of the total volume to be used,and dilute quantitatively,and stepwise if necessary,with Extracting solutionto obtain a solution having a known concentration of about 0.048mg per mL.
Assay preparation— Weigh and finely powder not fewer than 20Tablets.Transfer an accurately weighed portion of the powder,equivalent to about 40mg of pentoxifylline,to a 50-mLvolumetric flask.Pipet 0.4mLof methanol into the flask,and swirl for at least 1minute.Add about 30mLof Extracting solution,and sonicate for 60minutes with occasional swirling of the flask.Add an additional 15mLof Extracting solution,allow to cool to room temperature,dilute with Extracting solutionto volume,and mix.Centrifuge or pass through a suitable filter.Reserve a portion of this first dilution for preparation of the Test solutionin the Chromatographic puritytest.Pipet 3.0mLof the clear solution into a 50-mLvolumetric flask,dilute with Extracting solutionto volume,and mix.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 273-nm detector and a 4.6-mm ×25-cm column that contains packing L1.The flow rate is about 0.7mLper minute.Chromatograph the System suitability solution,and record the peak responses as directed for Procedure:the resolution,R,between caffeine and pentoxifylline is not less than 10.0.Chromatograph the Standard preparation,and record the peak responses for pentoxifylline as directed for Procedure: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 pentoxifylline (C13H18N4O3)in the portion of Tablets taken by the formula:
833C(rU/rS),
in which Cis the concentration,in mg per mL,of USP Pentoxifylline RSin the Standard preparation;and rUand rSare the peak responses obtained from the Assay preparationand the Standard preparation,respectively.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(PA5)Pharmaceutical Analysis 5
USP28–NF23Page 1512
Pharmacopeial Forum:Volume No.29(6)Page 1961
Phone Number:1-301-816-8305