Nitrofurantoin Capsules
DEFINITION
Nitrofurantoin Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of nitrofurantoin (C8H6N4O5).
IDENTIFICATION
• A. Infrared Absorption
Sample:
Add 10 mL of 6 N acetic acid to a quantity of the contents of Capsules equivalent to 100 mg of nitrofurantoin. Boil the solution for a few min, and filter while hot. Cool to room temperature, collect the precipitate of nitrofurantoin, and dry at 105
for 1 h.
for 1 h.
Acceptance criteria:
The IR absorption spectrum of a mineral oil dispersion of the precipitate so obtained exhibits maxima only at the same wavelength as that of a similar solution of USP Nitrofurantoin RS.
• B.
The retention time of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
• Procedure
Solution A:
Dissolve 6.8 g of monobasic potassium phosphate in 500 mL of water. Add a volume of 1.0 N sodium hydroxide (about 30 mL) sufficient to adjust to a pH of 7.0, and dilute with water to 1 L.
Mobile phase:
Acetonitrile and Solution A (3:22)
Internal standard solution:
1 mg/mL of acetanilide in water
Standard solution:
Dissolve 50 mg of USP Nitrofurantoin RS in 40.0 mL of dimethylformamide, and add 50.0 mL of Internal standard solution.
Sample solution:
Transfer, as completely as possible, the contents of 20 Capsules to a 500-mL flask. Place the emptied Capsules in a beaker, add 25 mL of dimethylformamide, and agitate for 1 min. Decant into the flask containing the Capsule contents. Rinse the emptied Capsules with another two 25-mL portions of dimethylformamide, and decant into the flask. Add sufficient dimethylformamide to bring the volume to about 250 mL. Insert the stopper in the flask, and shake by mechanical means for 15 min. Dilute with dimethylformamide to volume, and mix. If necessary, the sample may be homogenized using a disperser. Pass through a medium-porosity, sintered-glass filter into a suitable flask. Transfer an aliquot, equivalent to 50 mg of nitrofurantoin, to a flask. Add an accurately measured volume of dimethylformamide to bring the volume in the flask to 40.0 mL. To the flask add 50.0 mL of Internal standard solution, mix, and cool to room temperature. Pass a portion of the solution through a nylon filter of 0.45-µm pore size, discarding the first few mL of the filtrate.
Chromatographic system
Mode:
LC
Detector:
UV 254 nm
Column:
3.9-mm × 30-cm; packing L1
Injection size:
5–10 µL
System suitability
Sample:
Standard solution
[Note—Adjust the operating parameters so that the retention time of the nitrofurantoin peak is about 8 min, and the peak heights are about half full-scale. ]
Suitability requirements
Resolution:
NLT 3.0 between acetanilide and nitrofurantoin
Relative standard deviation:
NMT 2.0%, determined from peak response ratios of replicate injections
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C8H6N4O5 in the portion of the powder included in the sample aliquot:
Result = (RU/RS) × (CS/CU) × 100
| RU | = | = peak response ratio from the Sample solution |
| RS | = | = peak response ratio from the Standard solution |
| CS | = | = concentration of USP Nitrofurantoin RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of the Sample solution (mg/mL) |
Acceptance criteria:
90.0%–110.0%
PERFORMANCE TESTS
• Dissolution 
711
711
Test 1 (where it is labeled as containing nitrofurantoin macrocrystals)
Medium:
pH 7.2 (± 0.05) phosphate buffer; 900 mL
Apparatus 1:
100 rpm
Times:
1, 3, and 8 h
Standard solution:
USP Nitrofurantoin RS in Medium
Spectrometric conditions
Mode:
UV
Analytical wavelength:
375 nm
Sample solution:
Pass a portion of the solution under test through a suitable filter. Dilute with Medium if necessary.
Blank:
Medium
Tolerances:
The percentage of the labeled amount of C8H6N4O5 dissolved at the 1-h point conforms to Acceptance Table 2, and the percentages dissolved at the 3- and 8-h points conform to the criteria for the final test time in Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | 20%–60% |
| 3 | NLT 45% |
| 8 | NLT 60% |
Test 2 (where it is labeled as containing both nitrofurantoin macrocrystalline and monohydrate forms):
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.
Acid medium:
0.01 N hydrochloric acid for 1 h; 900 mL
pH 7.5 buffer medium:
Prepare a pH 7.5 buffer concentrate by dissolving 62.2 g of potassium hydroxide and 129.3 g of monobasic potassium phosphate in water, dilute with water to 1 L, and mix. After 1 h, change the Acid medium to pH 7.5 buffer medium by adding 50 mL of pH 7.5 buffer concentrate, and run for an additional 6 h.
Apparatus 2:
100 rpm, with sinkers made of Teflon-coated steel wire prepared by forming a coil approximately 22 mm long from a 13-cm length of 20-gauge wire (see Figure 1)
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Figure 1. Sinker.
Times:
1, 3, and 7 h
Acid-stage standard solution:
0.025 mg/mL of USP Nitrofurantoin RS in Acid medium
Buffer-stage standard solution:
0.075 mg/mL of USP Nitrofurantoin RS in pH 7.5 buffer medium
Spectrometric conditions
Mode:
UV
Analytical wavelength:
375 nm
Analysis:
Determine the amount of C8H6N4O5 dissolved from UV absorbances at the isosbestic wavelength at about 375 nm on filtered portions of each solution under test, suitably diluted, if necessary, with Acid medium or pH 7.5 buffer medium when appropriate, in comparison with the appropriate Standard solution.
Tolerances:
The percentages of the labeled amount of C8H6N4O5 dissolved at the specified times conform to the accompanying Acceptance Table.
| Time (h) |
Amount Dissolved (Individual) |
Amount Dissolved (Mean) |
|---|---|---|
| 1 | 2%–16% | 5%–13% |
| 3 | 27%–69% | 39%–56% |
| 7 | NLT 68% | NLT 81% |
Acceptance Table
| Level | Number Tested | Criteria |
|---|---|---|
| L1 | 12 | The mean percentage of dissolved label claim lies within the range for the means at each interval and is NLT the stated amount at the final test time. All individual values lie within the ranges for the individuals at each interval and are NLT the stated amount at the final test time. |
| L2 | 12 | The mean percentage of dissolved label claim lies within the range for the means at each interval and is NLT the stated amount at the final test time. NMT 2 of the 24 individual values lie outside the stated ranges for individuals at each interval, and NMT 2 of 24 are less than the stated amount at the final test time. |
Test 3 (where it is labeled as containing both nitrofurantoin macrocrystalline and monohydrate forms):
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.
Acid medium, pH 7.5 buffer medium, Apparatus 2, Times, Acid-stage standard solution, Buffer-stage standard solution, and Analysis:
Proceed as directed in Test 2.
Tolerances:
The percentages of the labeled amount of C8H6N4O5 dissolved at the specified times conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved (Individual) |
Amount Dissolved (Mean) |
|---|---|---|
| 1 | 2%–16% | 5%–13% |
| 3 | 50%–80% | 55%–75% |
| 7 | NLT 85% | NLT 90% |
Test 4 (where it is labeled as containing both nitrofurantoin macrocrystalline and monohydrate forms):
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
Acid medium:
0.01 N hydrochloric acid for 1 h; 900 mL, deaerated
pH 7.5 buffer medium:
Prepare a pH 7.5 buffer concentrate by dissolving 62.2 g of potassium hydroxide and 129.3 g of monobasic potassium phosphate in water, dilute with water to 1 L, and mix. After 1 h change the Acid medium to pH 7.5 buffer medium by adding 50 mL of pH 7.5 buffer concentrate, and run for an additional 9 h.
Apparatus 2:
100 rpm, with helix sinkers
Times:
1, 3, and 10 h
Standard stock solution:
Transfer 25 mg of USP Nitrofurantoin RS to a 10-mL volumetric flask. Add 7.5 mL of dimethylformamide, and sonicate until dissolved. Allow to cool to room temperature, and dilute with dimethylformamide to volume.
Acid-stage standard solution:
Dilute 2.0 mL of the Standard stock solution with Acid medium to 200 mL.
Buffer-stage standard solution:
Transfer 3.0 mL of the Standard stock solution to a 100-mL volumetric flask, and dilute with pH 7.5 buffer medium to volume.
Stock capsule shell blank:
Place 10 empty, clean Capsules into a 900-mL volumetric flask, and add 800 mL of Acid medium. Gently heat to 37 ± 0.5, and stir until all the Capsules are dissolved. Allow to cool to room temperature, and dilute with Acid medium to volume.
, and stir until all the Capsules are dissolved. Allow to cool to room temperature, and dilute with Acid medium to volume.
Buffer-stage capsule shell blank:
Transfer 100.0 mL of the Stock capsule shell blank to a 1000-mL volumetric flask. Add 56 mL of pH 7.5 buffer medium, dilute with Acid medium to volume, and mix. Filter, using the same filter as for the Sample solution.
Sample solution:
Pass portions of the solution under test through a 1.2-µm glass/0.45-µm polyethersulfone combination filter, discarding the first few mL.
Spectrometric conditions
Mode:
UV-Vis
Analytical wavelength:
375 nm
Analysis:
Determine the amount of C8H6N4O5 dissolved from portions of the Sample solution in comparison with the appropriate Acid-stage standard solution or Buffer-stage standard solution. Correct for the appropriate capsule shell blank absorbance, using a 0.1-cm cell, and the appropriate medium as the blank.
Tolerances:
The percentages of the labeled amount of C8H6N4O5 dissolved at the specified times conform to Acceptance Table 2.
| Time (h) |
Amount Dissolved |
|---|---|
| 1 | NMT 25% |
| 3 | 25%–50% |
| 10 | NLT 80% |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
Procedure for content uniformity
Solution A, Mobile phase, Internal standard solution, Standard solution, Chromatographic system, and Analysis:
Proceed as directed in the Assay.
Sample solution:
Transfer the contents of 1 Capsule to a suitable flask, and add a volume of dimethylformamide to obtain a solution having a concentration of about 1.2 mg/mL of nitrofurantoin. Shake the flask for 15 min. [Note—If necessary, the sample may be homogenized, using a disperser. ] In the case of a 50- or 100-mg Capsule, transfer 40.0 mL of this solution to a suitable flask, add 50.0 mL of Internal standard solution, mix, and cool to room temperature. Pass a portion of the solution through a nylon filter of 0.45-µm pore size, discarding the first few mL of the filtrate. In the case of a 25-mg Capsule, transfer 20.0 mL of the solution to a suitable flask, and add 25.0 mL of Internal standard solution instead of 50.0 mL.
IMPURITIES
Organic Impurities
• Procedure: Limit of Nitrofurazone
Solution A:
Prepare as directed in the Assay.
Mobile phase:
Tetrahydrofuran and Solution A (1:9)
Standard stock solution:
5.0 µg/mL of USP Nitrofurazone RS in dimethylformamide
Standard solution:
Transfer 2.0 mL of the Standard stock solution into a glass-stoppered flask, add 20.0 mL of water, and mix.
System suitability stock solution:
5.0 µg/mL each of nitrofurazone and nitrofurantoin in dimethylformamide
System suitability solution:
System suitability stock solution and Mobile phase (1:10)
Sample solution:
Transfer a portion of Capsule contents equivalent to 100 mg of nitrofurantoin into a 25-mL glass-stoppered flask. Add 2.0 mL of dimethylformamide, and shake for 5 min. Add 20.0 mL of water, mix, and allow to stand for 15 min. Pass a portion of the mixture through a nylon filter of 0.45-µm pore size.
Chromatographic system
Mode:
LC
Detector:
UV 375 nm
Column:
3.9-mm × 30-cm; packing L1
Flow rate:
1.6 mL/min
Injection size:
60–100 µL
System suitability
Samples:
Standard solution and System suitability solution
[Note—Adjust the operating parameters so that the nitrofurazone peak in the chromatogram of the Standard solution has a retention time of about 10.5 min and a height of about 0.1 full scale. ]
Suitability requirements
Resolution:
NLT 4.0 between the nitrofurazone and nitrofurantoin peaks, System suitability solution
Relative standard deviation:
NMT 2.0%, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Acceptance criteria:
The height of any peak from the Sample solution at a retention time corresponding to that of the main peak from the Standard solution is NMT the height of the main peak from the Standard solution. NMT 0.01% of nitrofurazone is found.
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers, and store at controlled room temperature.
• Labeling:
Capsules that contain the macrocrystalline form of nitrofurantoin are so labeled. When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Leonel M. Santos, Ph.D.
Senior Scientific Liaison 1-301-816-8168 |
(SM12010) Monographs - Small Molecules 1 |
| 711 |
Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison 1-301-816-8106 |
(GCDF2010) General Chapters - Dosage Forms |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4059
Pharmacopeial Forum: Volume No. 35(1) Page 92