metforminhydrochlorideertablets usp

Revision BulletinOfficial September 1, 2010 Metformin 1

. Relative standard deviation: NMT 1.5% for themetformin peak and NMT 10% for each of the peaksMetformin Hydrochloride Extended-due to metformin related compound B and metforminRelease Tabletsrelated compound C

AnalysisDEFINITION Samples: Standard solution and Sample solutionMetformin Hydrochloride Extended-Release Tablets contain NLT Calculate the percentage of C4H11N5 · HCl in the portion of90.0% and NMT 110.0% of the labeled amount of Tablets taken:metformin hydrochloride (C4H11N5 · HCl).

Result = (rU/rS) × (CS/CU) × 100IDENTIFICATION• The retention time of the major peak from the Sample solu- rU = peak response from the Sample solutiontion corresponds to that from the Standard solution, as ob- rS = peak response from the Standard solutiontained in the Assay. CS = concentration of USP Metformin Hydrochloride

RS in the Standard solution (mg/mL)ASSAYCU = nominal concentration of metformin hydrochlo-• PROCEDURE

ride in the Sample solutionBuffer solution: 0.5 g/L of sodium heptanesulfonate and 0.5Acceptance criteria: 90.0%–110.0%g/L of sodium chloride in water. Prior to final dilution, adjust

with 0.06 M phosphoric acid to a pH of 3.85. PERFORMANCE TESTSMobile phase: Acetonitrile and Buffer solution (1:9). [NOTE—To improve the separation, the composition of acetonitrileand Buffer solution may be changed to 1:19, if necessary.] Change to read:

Diluent: 1.25% solution of acetonitrile in waterStandard solution: (L/4000) mg/mL of USP Metformin Hy- • DISSOLUTION ⟨711⟩drochloride RS in Diluent, where L is the labeled quantity, in Test 1mg, of metformin hydrochloride in each Tablet Medium: pH 6.8 phosphate buffer (6.8 g of monobasic po-

System suitability stock solution: 12.5 µg/mL of each of tassium phosphate in 1000 mL of water; adjust with 0.2 NUSP Metformin Related Compound B RS and USP Metformin sodium hydroxide to a pH of 6.8 ± 0.1); 1000 mLRelated Compound C RS in Diluent Apparatus 1: 100 rpm for Tablets labeled to contain 750

System suitability solution: Dilute 0.5 mL of the System mgsuitability stock solution with the Standard solution to 50 mL. Apparatus 2: 100 rpm for Tablets labeled to contain 500

Sample stock solution: Finely powder NLT 10 Tablets. mgTransfer powder, equivalent to the average Tablet weight, to Times: 1, 3, and 10 ha homogenization vessel, and accurately add 500 mL of Detector: UV 232 nm10% acetonitrile solution. Alternately, homogenize and allow Standard solution: USP Metformin Hydrochloride RS into soak until the sample is fully homogenized. [NOTE—A sug- Mediumgested homogenization sequence is as follows. Homogenize Sample solution: Pass a portion of the solution under testthe sample using five pulses, each of 5 s, at about 20,000 through a suitable hydrophilic polyethylene filter of 0.45-rpm, and allow to soak for 2 min. Repeat these steps two µm pore size. Dilute, if necessary, with Medium to a con-additional times.] centration similar to the Standard solution.

Sample solution: Pass a portion of the Sample stock solution Analysis: Calculate the percentage of C4H11N5 · HCl re-through a suitable filter of 0.45-µm pore size, discarding the leased at each time point:first 3 mL of filtrate. Transfer 25 mL of the filtrate to a 200-mL volumetric flask, and dilute with water to volume. Result = [(AU/AS) × CS × (V − VS) + (C60 × VS) + (C180 × VS) ×

Chromatographic system 100]/L(See Chromatography ⟨621⟩, System Suitability.)Mode: LC AU = absorbance of the Sample solutionDetector: UV 218 nm AS = absorbance of the Standard solutionColumn: 3.9-mm × 30-cm; 10-µm packing L1 CS = concentration of the Standard solution (mg/mL)Column temperature: 30° V = initial volume of Medium in the vessel (mL)Flow rate: 1 mL/min VS = volume withdrawn from the vessel for previousInjection size: 10 µL samplings (mL)Run time: Until after the elution locus of metformin related C60 = concentration of metformin hydrochloride in Me-compound C dium determined at 1 h (mg/mL)

System suitability C180 = concentration of metformin hydrochloride in Me-Sample: System suitability solution dium determined at 3 h (mg/mL)[NOTE—The relative retention times for metformin related L = label claim (mg/Tablet)compound B, metformin, and metformin related com- Tolerances: The percentages of the labeled amount ofpound C are 0.86, 1.0, and 2.1–2.3, respectively. C4H11N5 · HCl dissolved at the times specified conform toMetformin related compound C can have a variable reten- Acceptance Table 2.tion time. The composition of the Mobile phase may bechanged to 1:19, if it elutes at a relative retention time of Time Amount Dissolved, Amount Dissolved,less than 2.1.] (h) 500-mg Tablet 750-mg Tablet

Suitability requirements1 20%–40% 22%–42%Resolution: NLT 1.5 between peaks due to metformin3 45%–65% 49%–69%related compound B and metformin10 NLT 85% NLT 85%Tailing factor: NLT 0.8 and NMT 2.0 for the metformin

peak

2010 The United States Pharmacopeial Convention All Rights Reserved.

Revision Bulletin2 Metformin Official September 1, 2010

Test 2: If the product complies with this test, the labeling Test 3: If the product complies with this test, the labelingindicates that it meets USP Dissolution Test 2. indicates that it meets USP Dissolution Test 3.Medium: Prepare as directed for Test 1; 1000 mL Medium, Apparatus 1, Apparatus 2, and Analysis: Pro-Apparatus 2: 100 rpm ceed as directed in Test 1.Times: 1, 2, 6, and 10 h Times: 1, 2, 5, and 12 h for Tablets labeled to contain 500Detector: UV 232 nm mg; and 1, 3, and 10 h for Tablets labeled to contain 750Standard solution: USP Metformin Hydrochloride RS in mgMedium Detector: UV 232 nm

Sample solution: Pass a portion of the solution under test Standard solution: USP Metformin Hydrochloride RS inthrough a suitable polyethylene filter of 0.45-µm pore size. MediumDilute, if necessary, with Medium to a concentration that is Sample solution: Pass a portion of the solution under testsimilar to the Standard solution. through a suitable hydrophilic polyethylene filter of 0.45-

Analysis: Calculate, in mg/mL, the content of C4H11N5 · µm pore size. Dilute, if necessary, with Medium to a con-HCl, Ct, in Medium at each time point, t: centration similar to the Standard solution.

Analysis: Calculate the percentage of C4H11N5 · HCl re-Result = (AU × CS × DU)/AS leased at each time point:

AU = absorbance of the Sample solution •Result = {[(AU/AS) × CS × (V − VS) + (C60 × VS) + (C120 × VS)CS = concentration of metformin hydrochloride in the + (C300 × VS) + (C720 × VS)] × 100}/L•(RB 2-Nov-2009)

Standard solution (mg/mL)DU = dilution factor of the solution under test AU = absorbance of the Sample solutionAS = absorbance of the Standard solution AS = absorbance of the Standard solutionCalculate the percentage of C4H11N5 · HCl dissolved at each CS = concentration of the Standard solution (mg/mL)time point by the following formulas. V = initial volume of Medium in the vessel (mL)

Percentage dissolved at the first time point (1 h): VS = volume withdrawn from the vessel for previoussamplings (mL)

Result = (C1 × V × 100)/L C60 = concentration of metformin hydrochloride in Me-dium determined at 1 h (mg/mL)

C1 = content of metformin hydrochloride in Medium C120 = concentration of metformin hydrochloride in Me-at the first time interval (mg/mL) dium determined at 2 h (mg/mL)

V = volume of Medium, 1000 mL C300 = concentration of metformin hydrochloride in Me-L = label claim (mg/Tablet) dium determined at 5 h (mg/mL)Percentage dissolved at the second time point (2 h): •C720 = concentration of metformin hydrochloride in Me-

dium determined at 12 h (mg/mL)•(RB 2-Nov-2009)Result = [C2 × (V − SV1) + C1 × SV1 × 100]/L L = label claim (mg/Tablet)

Tolerances: The percentages of the labeled amount ofC2 = content of metformin hydrochloride in Medium C4H11N5 · HCl dissolved at the times specified conform toat the second time interval (mg/mL) Acceptance Table 2.V = volume of Medium, 1000 mLSV1 = volume of the sample withdrawn at 1 h (mL)

For Tablets Labeled to Contain 500 mgC1 = content of metformin hydrochloride in Mediumat 1 h (mg/mL) Time

L = label claim (mg/Tablet) (h) Amount DissolvedPercentage dissolved at the nth time point: 1 20%–40%

2 35%–55%Result = {Cn × [V − (n − 1)VS] + (C1 + C2 + … + Cn−1) × VS ×5 60%–80%100}/L

12 NLT 85%Cn = content of metformin hydrochloride in Medium

at the nth time interval (mg/mL)V = volume of Medium, 1000 mL For Tablets Labeled to Contain 750 mgn = time interval of interest

TimeVS = volume of sample withdrawn at each time inter- (h) Amount Dissolvedval (mL)

1 22%–42%C = as C1, C2, C3, … Cn–1, the content of metforminhydrochloride in Medium at each time interval 3 49%–69%(mg/mL) 10 NLT 85%

L = label claim (mg/Tablet)Tolerances: The percentages of the labeled amount of Test 4: If the product complies with this test, the labelingC4H11N5 · HCl dissolved at the times specified conform to indicates that it meets USP Dissolution Test 4.Acceptance Table 2. Medium: Prepare as directed for Test 1; 1000 mL

Apparatus 2: 100 rpmTimes: 1, 3, 6, and 10 hTimeDetector: UV 250 nm (shoulder) (h) Amount DissolvedStandard solution: USP Metformin Hydrochloride RS in1 20%–40% Medium

2 35%–55% Sample solution: Pass a portion of the solution under test6 65%–85% through a ▲suitable filter of 0.45-µm pore size.▲USP33 Dilute,

10 NLT 85% if necessary, with Medium to a concentration similar to theStandard solution.



Analysis: Calculate, in mg/mL, the content of C4H11N5 · CS = concentration of the Standard solution (mg/mL)HCl, Ct, in Medium at each time point, t, by the formulas V = initial volume of Medium in the vessel (mL)specified in Test 2. VS = volume withdrawn from the vessel for previous

Tolerances: The percentages of the labeled amount of samplings (mL)C4H11N5 · HCl dissolved at the times specified conform to C60 = concentration of metformin hydrochloride in Me-Acceptance Table 2. dium determined at 1 h (mg/mL)

C180 = concentration of metformin hydrochloride in Me-dium determined at 3 h (mg/mL)Time

C600 = concentration of metformin hydrochloride in Me- (h) Amount Dissolveddium determined at 10 h (mg/mL)

1 20%–40% L = label claim (mg/Tablet)3 45%–65% Tolerances: The percentages of the labeled amount of6 65%–85% C4H11N5 · HCl dissolved at the times specified conform to

10 NLT 85% Acceptance Table 2.

Test 5: If the product complies with this test, the labelingTime Amount Dissolved, Amount Dissolved,indicates that it meets USP Dissolution Test 5. (h) 500-mg Tablet 750-mg TabletMedium: pH 6.8 phosphate buffer (6.8 g of monobasic po-

1 20%–40% 20%–40%tassium phosphate in 1000 mL of water; adjust with 0.2 N3 45%–65% 45%–65%sodium hydroxide to a pH of 6.8 ± 0.1); 900 mL, deaerated

Apparatus 1: 100 rpm, with the vertical holder described 10 NLT 85% NLT 85%in Figure 1 and Figure 2

Test 7: If the product complies with this test, the labelingTimes: 2, 8, and 16 hindicates that it meets USP Dissolution Test 7.Detector: UV 250 nmMedium: Prepare as directed in Test 1; 1000 mLStandard solution: USP Metformin Hydrochloride RS inApparatus 1: 100 rpm for Tablets labeled to contain 750MediummgSample solution: Pass a portion of the solution under test

Apparatus 2: 50 rpm, with USP sinker, for Tablets labeledthrough a ▲suitable filter of 0.45-µm pore size.▲USP33 Dilute,to contain 500 mgif necessary, with Medium to a concentration similar to the

Times: 1, 3, and 10 hStandard solution.Detector: UV 232 nmAnalysis: Place a vertical sample holder into each basketStandard solution: USP Metformin Hydrochloride RS in(see Figures 1 and 2). Place 1 Tablet inside the sampleMediumholder, making sure that the Tablets are vertical at the bot-

Sample solution: Pass a portion of the solution under testtom of the baskets.through a suitable filter of 0.45-µm pore size. Dilute, if nec-Calculate, in mg/mL, the content of C4H11N5 · HCl, Ct, inessary, with Medium to a concentration similar to the Stan-Medium at each time point, t, by the formulas specified indard solution.Test 2.

Analysis: Calculate the percentage of C4H11N5 · HCl re-Tolerances: The percentages of the labeled amount ofleased at each time point:C4H11N5 · HCl dissolved at the times specified conform to

Acceptance Table 2.Result = {[(AU/AS) × CS × (V − VS) + (C60 × VS) + (C180 × VS) +

(C600 × VS)] × 100}/LTime Amount Dissolved, Amount Dissolved, (h) 500-mg Tablet 1000-mg Tablet AU = absorbance of the Sample solution

2 NMT 30% NMT 30% AS = absorbance of the Standard solutionCS = concentration of the Standard solution (mg/mL)8 60%–85% 65%–90%V = initial volume of Medium in the vessel (mL)16 NLT 90% NLT 90%VS = volume withdrawn from the vessel for previous

samplings (mL)Test 6: If the product complies with this test, the labelingC60 = concentration of metformin hydrochloride in Me-indicates that it meets USP Dissolution Test 6.

dium determined at 1 h (mg/mL)Medium: pH 6.8 phosphate buffer (6.8 g of monobasic po-C180 = concentration of metformin hydrochloride in Me-tassium phosphate in 1000 mL of water; adjust with 0.2 N

dium determined at 3 h (mg/mL)sodium hydroxide to a pH of 6.8 ± 0.05); 1000 mL,C600 = concentration of metformin hydrochloride in Me-deaerated

dium determined at 10 h (mg/mL)Apparatus 2: 100 rpm, with USP sinker, if necessaryL = label claim (mg/Tablet)Detector: UV 233 nmTolerances: The percentages of the labeled amount ofStandard solution: USP Metformin Hydrochloride RS inC4H11N5 · HCl dissolved at the times specified conform toMediumAcceptance Table 2.Sample solution: Pass a portion of the solution under test

through a suitable hydrophilic polyethylene filter of 0.45-µm pore size. Dilute, if necessary, with Medium to a con- Time Amount Dissolved, Amount Dissolved,centration similar to the Standard solution. (h) 500-mg Tablet 750-mg Tablet

Analysis: Calculate the percentage of C4H11N5 · HCl re- 1 20%–40% 20%–40%leased at each time point:3 45%–65% 40%–60%10 NLT 85% NLT 80%Result = {[(AU/AS) × CS × (V − VS) + (C60 × VS) + (C180 × VS) +

(C600 × VS)] × 100}/LTest 8: If the product complies with this test, the labelingindicates that it meets USP Dissolution Test 8.AU = absorbance of the Sample solution

AS = absorbance of the Standard solution



Medium: Prepare as directed in Test 1; 1000 mL AU = absorbance of the Sample solutionApparatus 1: 100 rpm for Tablets labeled to contain 750 AS = absorbance of the Standard solutionmg CS = concentration of the Standard solution (mg/mL)

Apparatus 2: 100 rpm, with sinker, for Tablets labeled to V = initial volume of Medium in the vessel (mL)contain 500 mg VS = volume withdrawn from the vessel for previous

Times: 1, 2, 6, and 10 h samplings (mL)Detector: UV 232 nm C1 = concentration of metformin hydrochloride in Me-Standard solution: USP Metformin Hydrochloride RS in dium determined at the first time pointMedium (mg/mL)

Sample solution: Pass a portion of the solution under test C2 = concentration of metformin hydrochloride in Me-through a suitable filter of 0.45-µm pore size. Dilute, if nec- dium determined at the second time pointessary, with Medium to a concentration similar to the Stan- (mg/mL)dard solution. C3 = concentration of metformin hydrochloride in Me-

Analysis: Calculate the percentage of C4H11N5 · HCl re- dium determined at the third time pointleased at each time point: (mg/mL)

C4 = concentration of metformin hydrochloride in Me-Result = {[(AU/AS) × CS × (V − VS) + (C60 × VS) + (C120 × VS) + dium determined at the fourth time point

(C360 × VS) + (C600 × VS)] × 100}/L (mg/mL)L = label claim (mg/Tablet)

AU = absorbance of the Sample solution Tolerances: The percentages of the labeled amount ofAS = absorbance of the Standard solution C4H11N5 · HCl dissolved at the times specified conform toCS = concentration of the Standard solution (mg/mL) Acceptance Table 2.V = initial volume of Medium in the vessel (mL)VS = volume withdrawn from the vessel for previous

For Tablets Labeled to Contain 500 mgsamplings (mL)C60 = concentration of metformin hydrochloride in Me- Time

dium determined at 1 h (mg/mL) (h) Amount DissolvedC120 = concentration of metformin hydrochloride in Me- 1 20%–40%

dium determined at 2 h (mg/mL) 5 45%–65%C360 = concentration of metformin hydrochloride in Me-

12 70%–90%dium determined at 6 h (mg/mL)20 NLT 85%C600 = concentration of metformin hydrochloride in Me-

dium determined at 10 h (mg/mL)L = label claim (mg/Tablet)

For Tablets Labeled to Contain 750 mgTolerances: The percentages of the labeled amount ofC4H11N5 · HCl dissolved at the times specified conform to TimeAcceptance Table 2. (h) Amount Dissolved

1 20%–45%Time Amount Dissolved, Amount Dissolved, 4 45%–70% (h) 500-mg Tablet 750-mg Tablet 10 70%–95%

1 20%–40% 20%–40% 24 NLT 85%2 30%–50% 35%–55%

•Test 10: If the product complies with this test, the labeling6 65%–85% 75%–95%indicates that it meets USP Dissolution Test 10.10 NLT 85% NLT 85%Medium: 0.05 M phosphate buffer (prepared by dissolving6.8 g of potassium dihydrogen phosphate in 250 mL ofTest 9: If the product complies with this test, the labelingwater, adding 77 mL of 0.2 N sodium hydroxide and 500indicates that it meets USP Dissolution Test 9.mL of water, adjusting with 2 N sodium hydroxide or 2 NMedium: 0.05 M phosphate buffer, pH 6.8; 1000 mLhydrochloric acid to a pH 6.8, and diluting with water to•Apparatus 1: 100 rpm, for Tablets labeled to contain1000 mL), pH 6.8; 1000 mL750 mg• (RB 1-Mar-2010)

Apparatus 1: 100 rpm for Tablets labeled to contain 750Apparatus 2: 100 rpm, •for Tablets labeled to contain 500mgmg•(RB 1-Mar-2010)

Apparatus 2: 100 rpm for Tablets labeled to contain 500Times: 1, 5, 12, and 20 h for Tablets labeled to containmg500 mg; and 1, 4, 10, and 24 h for Tablets labeled to

Times: 1, 3, and 10 hcontain 750 mgStandard solution: L/100,000 mg/mL of USP MetforminStandard solution: 0.5 mg/mL of USP Metformin Hydro-Hydrochloride RS in Medium, where L is the Tablet labelchloride RS in Mediumclaim in mg. This solution is stable for 72 h at roomSample solution: Pass a portion of the solution under testtemperature.through a suitable filter of 0.45-µm pore size.

Sample solution: At the times specified, withdraw 10 mLDetector: UV 232 nmof the solution under test and replace with 10 mL of Me-Path length: 0.01 cm, flow celldium previously equilibrated at 37.0 ± 0.5°. Centrifuge atBlank: Medium2500 rpm for 10 min. Dilute a portion of the supernatantAnalysis: Calculate the percentage of C4H11N5 · HCl re-with Medium to obtain a theoretical concentration of L/leased at each time point:100,000 mg/mL, where L is the Tablet label claim in mg.

Result = [(AU/AS) × CS × (V − VS) + (C1 × VS) + (C2 × VS) + (C3

× VS) + (C4 × VS)] × 100/L



Detector: UV 233 nm At 1 h:Path length: 1 cm

Result = Q1Blank: MediumAnalysis: Calculate the concentration (mg/mL) of

At 3 h:metformin hydrochloride (Ci) at each time point:

Result = Q3 + [(Q1 × 10)/V]Ci = (AU/AS) × CS

At 10 h:AU = absorbance of the Sample solutionAS = absorbance of the Standard solution

Result = Q10 + {[(Q1 × 10)/V] + [(Q3 × 10)/V]}CS = concentration of the Standard solution (mg/mL)Calculate the cumulative percentage of metformin hydro- AU = absorbance of the Sample solutionchloride dissolved (Qi) at each time point (i): AS = absorbance of the Standard solutionAt i = 1: CS = concentration of the Standard solution (mg/mL)

L = label claim (mg/Tablet)Q1 = (C1 × V/L) × 100V = volume of Medium, 1000 mLD = dilution factor of the Sample solutionAt i = 3:Tolerances: The percentages of the labeled amount ofC4H11N5 · HCl dissolved at the times specified conform toQ3 = [C3(V − VS) + (C1 × VS)] × 100/LAcceptance Table 2.

At i = 10:TimeQ10 = [C10(V − 2VS) + (C1 + C3)VS] × 100/L (h) Amount Dissolved

1 25%–45%V = initial volume of Medium, 1000 mL3 50%–70%VS = sampling volume, 10 mL

L = label claim (mg/Tablet) 10 NLT 80%Tolerances: The percentages of the labeled amount of

• (RB 1-Sep-2010)C4H11N5 · HCl dissolved at the times specified conform to• UNIFORMITY OF DOSAGE UNITS ⟨905⟩: Meet the requirementsAcceptance Table 2.

IMPURITIESTime Organic Impurities(h) Amount Dissolved • PROCEDURE1 25%–45% Mobile phase, Sample solution, and Chromatographic3 50%–70% system: Prepare as directed in the Assay.

Analysis: From the chromatogram of the Sample solution10 NLT 85%obtained in the Assay, calculate the percentage of each im-

• (RB 2-Nov-2009) purity in the portion of Tablets taken:•Test 11: If the product complies with this test, the labeling

Result = (rU/rT) × 100indicates that it meets USP Dissolution Test 11.Medium: pH 6.8 phosphate buffer; 1000 mL

rU = peak response for each impurityApparatus 1: 100 rpm for Tablets labeled to contain 750rT = sum of all the peak responsesmgAcceptance criteriaApparatus 2: 100 rpm for Tablets labeled to contain 500

Individual impurities: NMT 0.1%mgTotal impurities: NMT 0.6%Times: 1, 3, and 10 h[NOTE—Disregard any peak less than 0.05%, and disre-Standard solution: 7.5 µg/mL of USP Metformin Hydro-gard any peak observed in the blank.]chloride RS in Medium

Sample solution: At the times specified, withdraw 10 mL ADDITIONAL REQUIREMENTSof the solution under test, and pass it through a suitable • PACKAGING AND STORAGE: Preserve in well-closed, light-resis-filter of 0.45-µm pore size, discarding the first 3 mL. Dilute tant containers, and store at controlled room temperature.3.0 mL of the filtrate with Medium to 200 mL. For Tablets • LABELING: When more than one dissolution test is given, thelabeled to contain 750 mg, dilute 2.0 mL of the filtrate labeling states the Dissolution Test used only if Test 1 is notwith Medium to 200 mL. Replace the volume of Medium used.taken with the same volume of Medium preheated at 37.0 • USP REFERENCE STANDARDS ⟨11⟩± 0.5°. USP Metformin Hydrochloride RSDetector: UV 232 nm USP Metformin Related Compound B RSPath length: 1 cm USP Metformin Related Compound C RSBlank: Medium Calculate the percentage of metformin hydrochloride dis-solved at each time point:

Qi = (AU/AS) × (CS/L) × V × D × 100



Figure 1



Figure 2


metforminhydrochlorideertablets usp

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