Metformin Hydrochloride Extended-Release Tablets

» Metformin Hydrochloride Extended-Release Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of metformin hydrochloride (C4H11N5·HCl).

Packaging and storage— Preserve in well-closed, light-resistant containers, and store at controlled room temperature.

Labeling— When more than one Dissolution Test is given, the labeling states the Dissolution Test used only if Test 1 is not used.

USP Reference standards

—
USP Metformin Hydrochloride RS

.
USP Metformin Related Compound B RS

.
USP Metformin Related Compound C RS

Identification— The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation, as obtained in the Assay.

Dissolution

711

—

test 1—

Medium: pH 6.8 phosphate buffer prepared by dissolving 6.8 g of monobasic potassium phosphate in 1000 mL of water and adjusting with 0.2 N sodium hydroxide to a pH of 6.8 ± 0.1; 1000 mL.

Apparatus 2: 100 rpm, for Tablets labeled to contain 500 mg.

Apparatus 1: 100 rpm, for Tablets labeled to contain 750 mg.

Times: 1, 3, and 10 hours.

Procedure— Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 232 nm on portions of the solution under test passed through a 0.45-µm hydrophilic polyethylene filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the amount of metformin hydrochloride (C4H11N5·HCl), in percentage, released at each time point by the formula:

in which C is the concentration, in mg per mL, of the Standard solution; AU and AS are the absorbances of the solution under test and the Standard solution, respectively; V is the initial volume, in mL, of Medium in the vessel; VS is the volume, in mL, withdrawn from the vessel for previous samplings; C60 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 1 hour; C180 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 3 hours; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	500-mg Tablet, Amount dissolved	750-mg Tablet, Amount dissolved
1	between 20% and 40%	between 22% and 42%
3	between 45% and 65%	between 49% and 69%
10	not less than 85%	not less than 85%

test 2— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Prepare as directed for Medium in Test 1; 1000 mL.

Apparatus 2: 100 rpm.

Times: 1, 2, 6, and 10 hours.

Procedure— Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 232 nm on portions of the solution under test passed through a 0.45-µm polyethylene filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the content of metformin hydrochloride (C4H11N5·HCl), Ct, in mg per mL, in the Medium at each time point, t, by the formula:

in which AU and AS are the absorbances of the solution under test and the Standard solution, respectively; CS is the concentration of metformin hydrochloride, in mg per mL, in the Standard solution; and DU is the dilution factor of the solution under test. Calculate the percentage of metformin hydrochloride (C4H11N5·HCl) dissolved at each time point by the following formulas:

Percentage dissolved at the first time point (1 hour):

in which C1 is the content of metformin hydrochloride, in mg per mL, in the Medium at the first time interval; 1000 is the volume, in mL, of Medium; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Percentage dissolved at the second time point (2 hours):

in which C2 is the content of metformin hydrochloride, in mg per mL, in the Medium at the second time interval; 1000 is the volume, in mL, of Medium; SV1 is the volume, in mL, of the sample withdrawn at 1 hour; C1 is the content of metformin hydrochloride, in mg per mL, in the Medium at 1 hour; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Percentage dissolved at the nth time point:

in which Cn is the content of metformin hydrochloride, in mg per mL, in the Medium at the nth time interval; n is the time interval of interest; SV is the volume, in mL, of sample withdrawn at each time interval; C1, C2, C3, ... Cn–1 is the content of metformin hydrochloride, in mg per mL, in the Medium at each time interval; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	Amount dissolved
1	between 20% and 40%
2	between 35% and 55%
6	between 65% and 85%
10	not less than 85%

test 3— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium, Apparatus, and Procedure— Proceed as directed for Test 1.

Times: 1, 2, 5, and 12 hours for Tablets labeled to contain 500 mg; and 1, 3, and 10 hours for Tablets labeled to contain 750 mg.

in which C is the concentration, in mg per mL, of the Standard solution; AU and AS are the absorbances of the solution under test and the Standard solution, respectively; V is the initial volume, in mL, of Medium in the vessel; VS is the volume, in mL, withdrawn from the vessel for previous samplings; C60 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 1 hour; C120 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 2 hours; C300 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 5 hours; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

for tablets labeled to contain 500 mg:

Time (hours)	Amount dissolved
1	between 20% and 40%
2	between 35% and 55%
5	between 60% and 80%
12	not less than 85%

for tablets labeled to contain 750 mg:

Time (hours)	Amount dissolved
1	between 22% and 42%
3	between 49% and 69%
10	not less than 85%

test 4— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: Prepare as directed for Medium in Test 1; 1000 mL.

Apparatus 2: 100 rpm.

Times: 1, 3, 6, and 10 hours.

Procedure— Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 250 nm (shoulder) on portions of the solution under test passed through a 0.45-µm polyethylene filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the content of metformin hydrochloride (C4H11N5·HCl), Ct, in mg per mL, in the Medium at each time point, t, by the formulas specified in Test 2.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	Amount dissolved
1	between 20% and 40%
3	between 45% and 65%
6	between 65% and 85%
10	not less than 85%

test 5— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

Medium: pH 6.8 phosphate buffer prepared by dissolving 6.8 g of monobasic potassium phosphate in 1000 mL of water and adjusting with 0.2 N sodium hydroxide to a pH of 6.8 ± 0.1; 900 mL, deaerated.

Apparatus 1: 100 rpm, with the vertical holder described below.

Times: 2, 8, and 16 hours.

Procedure— Place a vertical sample holder into each basket (see Figures 1 and 2). Place one Tablet inside the sample holder, making sure that the Tablets are vertical at the bottom of the baskets. Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 250 nm on portions of the solution under test passed through a 0.45-µm polyethylene filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the content of metformin hydrochloride (C4H11N5·HCl), Ct, in mg per mL, in the Medium at each time point, t, by the formulas specified in Test 2.

Figure 1

Figure 2

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	500-mg Tablet, Amount dissolved	1000-mg Tablet, Amount dissolved
2	not more than 30%	not more than 30%
8	between 60% and 85%	between 65% and 90%
16	not less than 90%	not less than 90%

test 6— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.

Medium: pH 6.8 phosphate buffer prepared by dissolving 6.8 g of monobasic potassium phosphate in 1000 mL of water and adjusting with 0.2 N sodium hydroxide to a pH of 6.8 ± 0.05; 1000 mL, deaerated.

Apparatus 2: 100 rpm, with USP sinker, if necessary.

Procedure— Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 233 nm on portions of the solution under test passed through a 0.45-µm hydrophilic polyethylene filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the amount of metformin hydrochloride (C4H11N5·HCl), in percentage, released at each time point by the formula:

in which C is the concentration, in mg per mL, of the Standard solution; AU and AS are the absorbances of the solution under test and the Standard solution, respectively; V is the initial volume, in mL, of Medium in the vessel; VS is the volume, in mL, withdrawn from the vessel for previous samplings; C60 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 1 hour; C180 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 3 hours; C600 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 10 hours; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	500-mg Tablet, Amount dissolved	750-mg Tablet, Amount dissolved
1	between 20% and 40%	between 20% and 40%
3	between 45% and 65%	between 45% and 65%
10	not less than 85%	not less than 85%

test 7— If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.

Medium —Prepare as directed for Medium in Test 1; 1000 mL.

Apparatus 2: 50 rpm, with USP sinker, for Tablets labeled to contain 500 mg.

Apparatus 1: 100 rpm, for Tablets labeled to contain 750 mg.

Times: 1, 3, and 10 hours.

Procedure— Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 232 nm on portions of the solution under test passed through a suitable 0.45-µm filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the amount of metformin hydrochloride (C4H11N5·HCl), in percentage, released at each time point by the formula:

in which C is the concentration, in mg per mL, of the Standard solution; AU and AS are the absorbances of the solution under test and the Standard solution, respectively; V is the initial volume, in mL, of Medium in the vessel; VS is the volume, in mL, withdrawn from the vessel for previous samplings; C60 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 1 hour; C180 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 3 hours; C600 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 10 hours; 100 is the conversion factor to percentage; and L is the Tablet label claim, in mg.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	500-mg Tablet, Amount dissolved	750-mg Tablet, Amount dissolved
1	between 20% and 40%	between 20% and 40%
3	between 45% and 65%	between 40% and 60%
10	not less than 85%	not less than 80%

test 8 —If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 8.

Medium —Prepare as directed for Medium in Test 1; 1000 mL.

Apparatus 2: 100 rpm, with sinker, for Tablets labeled to contain 500 mg.

Apparatus 1: 100 rpm, for Tablets labeled to contain 750 mg.

Times: 1, 2, 6, and 10 hours

Procedure— Determine the amount of C4H11N5·HCl dissolved by UV absorption at the wavelength of maximum absorbance at about 232 nm on portions of the solution under test passed through a suitable 0.45-µm filter, suitably diluted with Medium, if necessary, in comparison with a Standard solution having a known concentration of USP Metformin Hydrochloride RS in the same Medium. Calculate the amount of metformin hydrochloride (C4H11N5·HCl), in percentage, released at each time point by the formula (1):

in which C is the concentration, in mg per mL, of the Standard solution; AU and AS are the absorbances of the solution under test and the Standard solution, respectively; V is the initial volume, in mL, of Medium in the vessel; VS is the volume, in mL, withdrawn from the vessel for previous samplings; C60 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 1 hour; C120 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 2 hours; C360 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 6 hours; C600 is the concentration, in mg per mL, of metformin hydrochloride in the Medium determined at 10 hours; 100 is the conversion factor to percentage; and L is the tablet label claim, in mg.

Tolerances— The percentages of the labeled amount of C4H11N5·HCl dissolved at the times specified conform to Acceptance Table 2.

Time (hours)	500-mg Tablet, Amount dissolved	750-mg Tablet, Amount dissolved
1	between 20% and 40%	between 20% and 40%
2	between 30% and 50%	between 35% and 55%
6	between 65% and 85%	between 75% and 95%
10	not less than 85%	not less than 85%

Uniformity of dosage units

905

: meet the requirements.

Chromatographic purity—

Mobile phase and Chromatographic system— Prepare as directed in the Assay.

Test solution— Use the Assay preparation, prepared as directed in the Assay.

Procedure— Inject a volume (about 10 µL) of the Test solution into the chromatograph, record the chromatogram, and measure all of the peak responses. Calculate the percentage of each impurity in the portion of Tablets taken by the formula:

100(ri / rs)

in which ri is the peak response for each impurity, and rs is the sum of the responses of all the peaks: not more than 0.1% of any individual impurity is found, and not more than 0.6% of total impurities is found. Disregard any peak less than 0.05%, and disregard any peak observed in the blank.

Assay—

Buffer solution— Transfer 1.0 g each of sodium heptanesulfonate and sodium chloride to a 2000-mL volumetric flask, add 1800 mL of water, and mix. Adjust with 0.06 M phosphoric acid to a pH of 3.85, and dilute with water to volume.

Mobile phase— Prepare a filtered and degassed mixture of Buffer solution and acetonitrile (90:10). Make adjustments if necessary (see System Suitability under Chromatography

621

). [note—To improve the separation, the composition may be changed to 95:5, if necessary.]

Diluent— Use a 1.25% solution of acetonitrile in water.

Standard preparation— Dissolve an accurately weighed quantity of USP Metformin Hydrochloride RS in Diluent, and dilute quantitatively, and stepwise if necessary, with Diluent to obtain a solution having a known concentration of about (L/4000) mg per mL, where L is the labeled quantity, in mg, of metformin hydrochloride in each Tablet.

System suitability preparation— Dissolve suitable quantities of USP Metformin Related Compound B RS and USP Metformin Related Compound C RS in Diluent to obtain a solution containing about 12.5 µg of each per mL. Pipet 0.5 mL of this solution into a 50-mL volumetric flask, and dilute with the Standard preparation to volume.

Assay stock preparation— Weigh and finely powder not fewer than 10 Tablets. Transfer an accurately weighed portion of the powder, equivalent to the average Tablet weight, to a homogenization vessel, and accurately add 500 mL of 10% acetonitrile solution. Alternately, homogenize and allow to soak until the sample is fully homogenized. [note—A suggested homogenization sequence is as follows: Homogenize the sample using 5 pulses, each of 5 second, at about 20,000 rpm; allow to soak for 2 minutes. Repeat these steps a further two times.]

Assay preparation— Pass a portion of the Assay stock preparation through a filter having a 0.45-µm porosity, discarding the first 3 mL of filtrate. Transfer 25 mL of the filtrate to a 200-mL volumetric flask, and dilute with water to volume.

Chromatographic system (see Chromatography

621

)— The liquid chromatograph is equipped with a 218-nm detector and a 3.9-mm × 30-cm column that contains 10-µm packing L1. The flow rate is about 1.0 mL per minute. The column temperature is maintained at 30

. Chromatograph the System suitability preparation, and record the peak responses as directed for Procedure: the relative retention times are about 0.86 for metformin related compound B, 1.0 for metformin, and about 2.1 to 2.3 for metformin related compound C [note—This impurity can have a variable retention time; the composition of the Mobile phase may be changed to 95:5, if metformin related compound C elutes at a relative retention time of less than 2.1.]; the resolution, R, between peaks due to metformin related compound B and metformin is not less than 1.5; the tailing factor for the metformin peak is not less than 0.8 and not more than 2.0; and the relative standard deviation for replicate injections is not more than 1.5% for the metformin peak and not more than 10% for each of the peaks due to metformin related compound B and metformin related compound C.

Procedure— Separately inject equal volumes (about 10 µL) of the Standard preparation and the Assay preparation into the chromatograph, carrying out the run until after the elution locus of metformin related compound C; record the chromatograms; and measure the responses for the major peaks. Calculate the quantity, in mg per Tablet, of metformin hydrochloride (C4H11N5·HCl) by the formula:

C(V/W)TD(rU / rS)

in which C is the concentration, in mg per mL, of USP Metformin Hydrochloride RS in the Standard preparation; V is the volume, in mL, of the Assay stock preparation; W is the weight, in mg, of sample used to prepare the Assay stock preparation; T is the average Tablet weight, in mg; D is the dilution factor of the Assay preparation; and rU and rS are the peak responses obtained from the Assay preparation and the Standard preparation, respectively.

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
Monograph	Elena Gonikberg, Ph.D. Senior Scientist 1-301-816-8251	(MDGRE05) Monograph Development-Gastrointestinal Renal and Endocrine
Reference Standards	Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org
711	Margareth R.C. Marques, Ph.D. Senior Scientist 1-301-816-8106	(BPC05) Biopharmaceutics05

USP32–NF27 Page 2907

Pharmacopeial Forum: Volume No. 32(6) Page 1726

Chromatographic Column—

METFORMIN HYDROCHLORIDE EXTENDED-RELEASE TABLETS

Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.