Metformin Hydrochloride Extended-Release Tablets
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This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition
Issued and maintained by the United States Pharmacopeial Convention (USP)
1 DEFINITION
Metformin Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of metformin hydrochloride (C4H11N5 · HCl).
2 IDENTIFICATION
A. The retention time of the major peak from the Sample solution corresponds to that from the Standard solution, as obtained in the Assay.
3 ASSAY
3.1 PROCEDURE
Buffer solution: 0.5 g/L of sodium 1-heptanesulfonate and 0.5 g/L of sodium chloride in water. Before final dilution, adjust with 0.06 M phosphoric acid to a pH of 3.85.
Mobile phase: Acetonitrile and Buffer solution (1:9). [NOTE—To improve the separation, the composition of acetonitrile and Buffer solution may be changed to 1:19, if necessary.]
Diluent: 1.25% solution of acetonitrile in water
Standard solution: (L/4000) mg/mL of USP Metformin Hydrochloride RS in Diluent, where L is the labeled quantity, in mg, of metformin hydrochloride in each Tablet
System suitability stock solution: 12.5 µg/mL each of USP Metformin Related Compound B RS and USP Metformin Related Compound C RS in Diluent
System suitability solution: Dilute 0.5 mL of the System suitability stock solution with the Standard solution to 50 mL.
Sample stock solution: Finely powder NLT 10 Tablets. Transfer powder, equivalent to the average Tablet weight, to a homogenization vessel, and add 500 mL of a 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 five pulses, each of 5 s, at about 20,000 rpm, and allow to soak for 2 min. Repeat these steps two additional times.]
Sample solution: Pass a portion of the Sample stock solution through a suitable filter of 0.45-µm pore size, 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〉, System Suitability.)
Mode: LC
Detector: UV 218 nm
Column: 3.9-mm × 30-cm; 10-µm packing L1
Column temperature: 30°
Flow rate: 1 mL/min Injection volume: 10 µL
Run time: Until after the elution locus of metformin related compound C
System suitability
Sample: System suitability solution
[NOTE—The relative retention times for metformin related compound B, metformin, and metformin related compound C are 0.86, 1.0, and 2.1–2.3, respectively. Metformin related compound C can have a variable retention time. The composition of the Mobile phase may be changed to 1:19, if it elutes at a relative retention time of less than 2.1.]
Suitability requirements
Resolution: NLT 1.5 between the peaks due to metformin related compound B and metformin Tailing factor: NLT 0.8 and NMT 2.0 for the metformin peak
Relative standard deviation: NMT 1.5% for the metformin peak and NMT 10% for each of the peaks due to metformin related compound
B and metformin related compound C Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × 100
rU = peak response from the Sample solution
rS = peak response from the Standard solution
CS = concentration of USP Metformin Hydrochloride RS in the Standard solution (mg/mL)
CU = nominal concentration of metformin hydrochloride in the Sample solution
Acceptance criteria: 90.0%–110.0%
4 PERFORMANCE TESTS
Change to read:
4.1 DISSOLUTION 〈711〉
4.1.1 Test 1
Medium: pH 6.8 phosphate buffer solution; 1000 mL
Apparatus 1: 100 rpm for Tablets labeled to contain 750 mg
Apparatus 2: 100 rpm for Tablets labeled to contain 500 mg Times: 1, 3, and 10 h
Detector: UV 232 nm
Standard solution: USP Metformin Hydrochloride RS in Medium
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 concentration similar to that of the Standard solution.
Analysis: Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) released at each time point:
Result = [(AU/AS) × CS × (V − VS) + (C60 × VS) + (C180 × VS)] × (100/L)
AU = absorbance of the Sample solution
AS = absorbance of the Standard solution
CS = concentration of the Standard solution (mg/mL)
V = initial volume of Medium in the vessel (mL)
VS = volume withdrawn from the vessel for previous samplings (mL)
C60 = concentration of metformin hydrochloride in Medium determined at 1 h (mg/mL)
C180 = concentration of metformin hydrochloride in Medium determined at 3 h (mg/mL)
L = label claim (mg/Tablet) Tolerances: See Table 1.
Table 1
| Time (h) | Amount Dissolved, 500-mg Tablet (%) | Amount Dissolved, 750-mg Tablet (%) |
| 1 | 20–40 | 22–42 |
| 3 | 45–65 | 49–69 |
| 10 | NLT 85 | NLT 85 |
The percentages of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.
4.1.2 Test 2
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Medium: Prepare as directed for Test 1; 1000 mL.
Apparatus 2: 100 rpm
Times: 1, 2, 6, and 10 h
Detector: UV 232 nm
Standard solution: USP Metformin Hy drochloride RS in Medium
Sample solution: Pass a portion of the solution under test through a suitable polyethylene filter of 0.45-µm pore size. Dilute, if necessary, with Medium to a concentration that is similar to that of the Standard solution.
Analysis: Calculate, in mg/mL, the content of metformin hydrochloride (C4H11N5 · HCl) (Ct), in Medium at each time point (t):
Result = (AU × CS × DU)/AS
AU = absorbance of the Sample solution
CS = concentration of metformin hydrochloride in the Standard solution (mg/mL)
DU = dilution factor of the solution under test
AS = absorbance of the Standard solution
Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at each time point by the following formulas.
Percentage dissolved at the first time point (1 h):
Result = (C1 × V × 100)/L
C1 = content of metformin hydrochloride in Medium at the first time interval (mg/mL)
V = volume of Medium, 1000 mL
L = label claim (mg/Tablet)
Percentage dissolved at the second time point (2 h):
Result = [C2 × (V − SV1) + C1 × SV1] × (100/L)
C2 = content of metformin hydrochloride in Medium at the second time interval (mg/mL)
V = volume of Medium, 1000 mL
SV1 = volume of the sample withdrawn at 1 h (mL)
C1 = content of metformin hydrochloride in Medium at 1 h (mg/mL)
L = label claim (mg/Tablet)
Percentage dissolved at the nth time point:
Result = {Cn × [V − (n − 1)VS] + (C1 + C2 + … + Cn-1) × VS} × (100/L)
Cn = content of metformin hydrochloride in Medium at the nth time interval (mg/mL)
V= volume of Medium, 1000 mL
n = time interval of interest
VS = volume of sample withdrawn at each time interval (mL)
C = as C1, C2, C3, … Cn-1, the content of metformin hydrochloride in Medium at each time interval (mg/mL)
L = label claim (mg/Tablet)
Tolerances: See Table 2.
Table 2
| Time (h) | Amount Dissolved (%) |
| 1 | 20–40 |
| 2 | 35–55 |
| 6 | 65–85 |
| 10 | NLT 85 |
The percentages of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.
4.1.3 Test 3
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.
Medium, Apparatus 1, and Apparatus 2: Proceed as directed in Test 1.
Times: 1, 2, 5, and 12 h for Tablets labeled to contain 500 mg; and 1, 3, and 10 h for Tablets labeled to contain 750 mg Detector: UV 232 nm
Standard solution: USP Metformin Hy drochloride RS in Medium
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 concentration similar to that of the Standard solution.
Analysis: Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) released at each time point:
Result = {[(AU/AS) × CS × (V-VS) + (C60 × VS) + (C120 × VS) + (C300 × VS) + (C720 × VS)] × 100}/L
AU = absorbance of the Sample solution
AS = absorbance of the Standard solution
CS = concentration of the Standard solution (mg/mL)
V = initial volume of Medium in the vessel (mL)
VS = volume withdrawn from the vessel for previous samplings (mL) S
C60 = concentration of metformin hydrochloride in Medium determined at 1 h (mg/mL)
C120 = concentration of metformin hydrochloride in Medium determined at 2 h (mg/mL)
C300 = concentration of metformin hydrochloride in Medium determined at 5 h (mg/mL)
C720 = concentration of metformin hydrochloride in Medium determined at 12 h (mg/mL)
L = label claim (mg/Tablet)
Table 3. For Tablets Labeled to Contain 500 mg
| Time (h) | Amount Dissolved (%) |
| 1 | 20–40 |
| 2 | 35–55 |
| 5 | 60–80 |
| 12 | NLT 85 |
Table 4. For Tablets Labeled to Contain 750 mg
| Time (h) | Amount Dissolved (%) |
| 1 | 22–42 |
| 3 | 49-69 |
| 10 | NLT 85 |
The percentages of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.
4.1.4 Test 4
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
Medium: Prepare as directed for Test 1; 1000 mL.
Apparatus 2: 100 rpm
Times: 1, 3, 6, and 10 h Detector: UV 250 nm (shoulder)
Standard solution: USP Metformin Hy drochloride RS in Medium
Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute, if necessary, with Medium to a concentration similar to that of the Standard solution.
Analysis: Calculate, in mg/mL, the content of metformin hydrochloride (C4H11N5 · HCl) (Ct), in Medium at each time point (t), by the formulas specified in Test 2.
Tolerances: See Table 5.
Table 5
| Time (h) | Amount Dissolved (%) |
| 1 | 20–40 |
| 3 | 45–65 |
| 6 | 65–85 |
| 10 | NLT 85 |
The percentages of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.
4.1.5 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 solution; 900 mL, deaerated
Apparatus 1: 100 rpm, with the vertical holder described in Figure 1 and Figure 2
Times: 2, 8, and 16 h
Detector: UV 250 nm
Standard solution: USP Metformin Hydrochloride RS in Medium
Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute, if necessary, with Medium to a concentration similar to that of the Standard solution.
Analysis: Place a vertical sample holder into each basket (see Figures 1 and 2). Place 1 Tablet inside the sample holder, making sure that the Tablets are vertical at the bottom of the baskets.
Calculate, in mg/mL, the content of metformin hydrochloride (C4H11N5 · HCl) (Ct), in Medium at each time point (t), by the formulas specified in Test 2.
Tolerances: See Table 6 .
Table 6
| Time (h) | Amount Dissolved, 500-mg Tablet (%) | Amount Dissolved, 1000-mg Tablet (%) |
| 2 | NMT 30 | NMT 30 |
| 8 | 60–85 | 65–90 |
| 16 | NLT 90 | NLT 90 |
The percentages of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.
4.1.6 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 solution; 1000 mL, deaerated
Apparatus 2: 100 rpm, with USP sinker, if necessary
Detector: UV 233 nm
Standard solution: USP Metformin Hy drochloride RS in Medium
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 concentration similar to that of the Standard solution.
Analysis: Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) released at each time point:
Result = {[(AU/AS) × CS × (V-VS) + (C60 × VS) + (C180 × VS) + (C600 × VS)] × 100}/L
AU = absorbance of the Sample solution
AS = absorbance of the Standard solution
CS = concentration of the Standard solution (mg/mL)
V = initial volume of Medium in the vessel (mL)
VS = volume withdrawn from the vessel for previous samplings (mL) S
C60 = concentration of metformin hydrochloride in Medium determined at 1 h (mg/mL)
C180 = concentration of metformin hydrochloride in Medium determined at 3 h (mg/mL)
C600 = concentration of metformin hydrochloride in Medium determined at 10 h (mg/mL)
L = label claim (mg/Tablet)
Tolerances: See Table 7.
Table 7
| Time (h) | Amount Dissolved, 500-mg Tablet (%) | Amount Dissolved, 750-mg Tablet (%) |
| 1 | 20–40 | 20–40 |
| 3 | 45–65 | 45–65 |
| 10 | NLT 85 | NLT 85 |
The percentages of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.
4.1.7 Test 7
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 7.
Medium: Prepare as directed in Test 1; 1000 mL.
Apparatus 1: 100 rpm for Tablets labeled to contain 750 mg
Apparatus 2: 50 rpm, with USP sinker, for Tablets labeled to contain 500 mg
Times: 1, 3, and 10 h
Detector: UV 232 nm
Standard solution: USP Metformin Hydrochloride RS in Medium
Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Dilute, if necessary, with Medium to a concentration similar to that of the Standard solution.
Analysis: Calculate the percentage of the labeled amount of metformin hydrochloride (C4H11N5 · HCl) released at each time point:
Result = {[(AU/AS) × CS × (V-VS) + (C60 × VS) + (C180 × VS) + (C600 × VS)] × 100}/L
AU = absorbance of the Sample solution
AS = absorbance of the Standard solution
CS = concentration of the Standard solution (mg/mL)
V = initial volume of Medium in the vessel (mL)
VS = volume withdrawn from the vessel for previous samplings (mL) S
C60 = concentration of metformin hydrochloride in Medium determined at 1 h (mg/mL)
C180 = concentration of metformin hydrochloride in Medium determined at 3 h (mg/mL)
C600 = concentration of metformin hydrochloride in Medium determined at 10 h (mg/mL)
L = label claim (mg/Tablet)
