Extended Phenytoin Sodium Capsules
If you find any inaccurate information, please let us know by providing your feedback here
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
Extended Phenytoin Sodium Capsules contain NLT 95.0% and NMT 105.0% of the labeled amount of phenytoin sodium (C15H11N2NaO2).
2 IDENTIFICATION
A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy
Sample: 300 mg of phenytoin sodium from the contents of Capsules in 50 mL of water in a separator. Add 10 mL of 3 N hydrochloric acid, and extract with three successive portions, measuring 100, 60, and 30 mL, respectively, of ether and chloroform (1:2). Evaporate the combined extracts, and dry the residue of phenytoin at 105° for 4 h.
Acceptance criteria: The spectrum of the Sample corresponds to that of a similarly prepared USP Phenytoin RS.
B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
3 ASSAY
Change to read:
3.1 Procedure
Buffer: 0.05 M monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 3.5.
Mobile phase: Methanol and Buffer (55:45)
Standard solution: 0.6 mg/mL of USP Phenytoin RS in Mobile phase. [Note-Dissolve the required quantity of phenytoin in a small amount of methanol before diluting with Mobile phase.]
Sample stock solution: Transfer the contents of 10 Capsules to a 250-mL volumetric flask. Add 150 mL of methanol, and sonicate for 20 min.
Cool to room temperature, and dilute with methanol to volume.
Sample solution: Nominally 0.6 mg/mL of phenytoin sodium (ERR 1-Jan-2022) from the Sample stock solution in Mobile phase
3.2 Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 229 nm
Column: 4.6-mm × 25-cm; packing L1
Flow rate: 1 mL/min
Injection volume: 10 μL
3.3 System suitability
Sample: Standard solution
3.4 Suitability requirements
Column efficiency: NLT 3000 theoretical plates
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
3.5 Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) in the portion of Capsules taken:
Result = (rU/rS) × (CS/CU) × (Mr1 /Mr2 ) × 100
rU = peak response of phenytoin from the Sample solution
rS = peak response of phenytoin from the Standard solution
CS = concentration of USP Phenytoin RS in the Standard solution (mg/mL)
CU = nominal concentration of phenytoin sodium (ERR 1-Jan-2022) in the Sample solution (mg/mL)
Mr1 = molecular weight of phenytoin sodium, 274.25
Mr2 = molecular weight of phenytoin, 252.27
Acceptance criteria: 95.0%–105.0%
4 PERFORMANCE TESTS
Dissolution 〈711〉
4.1 Test 1
Medium: Water; 900 mL
Apparatus 1: 50 rpm
Times: 30, 60, and 120 min
Mobile phase: Methanol and water (70:30)
Standard solution: Dissolve USP Phenytoin RS in methanol, and dilute with water to obtain a concentration similar to that of the Sample solution.
Sample solution: Pass a portion of the solution under test through a suitable filter.
4.1.1 Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 229 nm
Column: 4.6-mm × 25-cm; packing L1
Flow rate: 1 mL/min
Injection volume: 10 μL
4.1.2 System suitability
Sample: Standard solution
4.1.3 Suitability requirements
Column efficiency: NLT 3200 theoretical plates
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
4.1.4 Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved:
Result = (rU/rS) × C × (Mr1 /Mr2 ) × V × (100/L)
rU = peak response from the Sample solution
rS = peak response from the Standard solution
C = concentration of USP Phenytoin RS in the Standard solution (mg/mL)
Mr1 = molecular weight of phenytoin sodium, 274.25
Mr2 = molecular weight of phenytoin, 252.27
V = volume of Medium, 900 mL
L = label claim (mg/Capsule)
Tolerances (for products labeled as 30-mg Capsules): The percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved is NMT 40% (Q) in 30 min, 56% (Q′) in 60 min, and NLT 65% (Q′′) in 120 min. The requirements are met if the quantities dissolved from the Capsules tested conform to Table 1.
Table 1
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Each unit is within the range between Q − 15% and Q − 5%, is within the range Q′ ± 10%, and is NLT Q′′ + 5% at the stated Times. |
| S2 | 6 | Average of 12 units (S + S ) is within the range between Q − 10% and Q, is within the range Q′ ± 8%, and is NLT Q′′; no unit is outside the range between Q − 20% and Q + 10%, no unit is outside the range Q′ ± 18%, and no unit is less than Q′′ − 10% at the stated Times. |
| S3 | 12 | Average of 24 units (S1 + S2 + S3 ) is within the range between Q − 10% and Q, is within the range Q′ ± 8%, and is NLT Q′′; NMT 2 units are outside the range between Q − 20% and Q + 10%, and no unit is outside the range Q − 30% and Q + 20%; NMT 2 units are outside the range Q′ ± 18%, and no unit is outside the range Q′ ± 25%; NMT 2 units are less than Q′′ − 10%, and no unit is less than Q′′ − 20% at the stated Times. |
Tolerances (for products labeled as 100-mg Capsules): The percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved is NMT 45% (Q) in 30 min, 60% (Q′) in 60 min, and NLT 70% (Q′′) in 120 min. The requirements are met if the quantities dissolved from the Capsules tested conform to Table 2.
Table 2
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Each unit is within the range between Q − 25% and Q − 5%, is equal to Q′ ± 20%, and is NLT Q′′ + 5% at the stated Times. |
| S2 | 6 | Average of 12 units (S1 + S2 ) is within the range between Q − 20% and Q, is within the range Q′ ± 15%, and is NLT Q′′; no unit is outside the range between Q − 30% and Q + 10%, no unit is outside the range Q′ ± 25%, and no unit is less than Q′′ − 10% at the stated Times. |
| S3 | 12 | Average of 24 units (S1 + S2 + S3 ) is within the range between Q − 20% and Q, is within the range Q′ ± 15%, and is NLT Q′′; NMT 2 units are outside the range between Q − 30% and Q + 10%, and no unit is outside the range between Q − 40% and Q + 20%; NMT 2 units are outside the range Q′ ± 25%, and no unit is outside the range Q′ ± 35%; NMT 2 units are less than Q′′ − 10%, and no unit is less than Q′′ − 20% at the stated Times. |
4.2 Test 2
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2. Proceed as directed in Test 1, except use Apparatus 1 at 75 rpm and the following Tolerances.
Tolerances (for products labeled as 100-mg Capsules): The percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved is NMT 45% (Q) in 30 min, 65% (Q′) in 60 min, and NLT 70% (Q′′) in 120 min. The requirements are met if the quantities dissolved from the Capsules tested conform to Table 3.
Table 3
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Each unit is within the range between Q − 25% and Q − 5%, is equal to Q′ ± 20%, and is NLT Q′′ + 5% at the stated Times. |
| S2 | 6 | Average of 12 units (S1 + S2 ) is within the range between Q − 25% and Q − 5%, is within the range of Q′ − 20% and Q′ + 10%, and is NLT Q′′; no unit is outside the range between Q − 30% and Q + 5%, no unit is outside the range Q′ − 25% and Q′ + 20%, and no unit is less than Q′′ −10% at the stated Times. |
| S3 | 12 | Average of 24 units (S1 + S2 + S3 ) is within the range between Q − 25% and Q − 5%, is within the range of Q′ − 20% and Q′ + 10%, and is NLT Q′′; NMT 2 units are outside the range between Q − 30% and Q + 5%; and no unit is outside the range of Q − 40% and Q + 15%; NMT 2 units are outside the range Q′ − 25% and Q′ + 20%, and no unit is outside the range Q′ − 35% and Q′ + 25%; NMT 2 units are less than Q′′ − 10%; and no unit is less than Q′′ − 20% at the stated Times. |
4.3 Test 3
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.
Medium: Water; 900 mL
Apparatus 1: 75 rpm
Times: 30, 60, and 120 min
Determine the amount of phenytoin sodium (C15H11N2NaO2) dissolved by using the method described in Test 1.
Tolerances (for products labeled as 200- and 300-mg Capsules): The percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved is NMT 30% (Q) in 30 min, 50% (Q′) in 60 min, and NLT 60% (Q′′) in 120 min. The requirements are met if the quantities dissolved from the Capsules tested conform to Table 4.
Table 4
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Each unit is within the range between Q − 20% and Q + 5%, is equal to Q′ – 20% and Q′ + 25%, and is NLT Q′′ + 5% at the stated Times. |
| S2 | 6 | Average of 12 units (S1 + S2 ) is within the range between Q − 20% and Q, is within the range of Q′ ± 20%, and is NLT Q′′; no unit is outside the range between Q − 25% and Q + 10%, no unit is outside the range Q′ ± 25%, and no unit is less than Q′′ − 10% at the stated Times. |
| S3 | 12 | Average of 24 units (S1 + S2 + S3 ) is within the range between Q − 20% and Q, is within the range of Q′ ± 20%, and is NLT Q′′; NMT 2 units are outside the range between Q − 25% and Q + 10%, and no unit is outside the range Q − 25% and Q + 15%; NMT 2 units are outside the range Q′ ± 25%; and no unit is outside the range Q′ ± 30%; NMT 2 units are less than Q′′ − 10%; and no unit is less than Q′′ − 20% at the stated Times. |
4.4 Test 4
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.
Medium, Apparatus 1, Times, and Analysis: Proceed as directed for Test 1.
Tolerances (for products labeled as 30-mg Capsules): The percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved is NMT 40% (Q) in 30 min, 56% (Q′) in 60 min, and NLT 65% (Q′′) in 120 min. The requirements are met if the quantities dissolved from the Capsules tested conform to Table 5.
Table 5
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Each unit is within the range between Q − 10% and Q, is within the range Q′ − 9% and Q′ + 7%, and is NLT Q′′ + 5% at the stated Times. |
| S2 | 6 | Average of 12 units (S1 + S2 ) is within the range between Q − 8% and Q + 2%, is within the range Q′ − 9% and Q′ + 7%, and is NLT Q′′; no unit is outside the range between Q − 20% and Q + 10%, no unit is outside the range Q′ − 19% and Q′ + 17%, and no unit is less than Q′′ − 10% at the stated Times. |
| S3 | 12 | Average of 24 units (S1 + S2 + S3 ) is within the range between Q − 8% and Q + 2%, is within the range Q′ − 9% and Q′ + 7%, and is NLT Q′′; NMT 2 units are outside the range between Q − 20% and Q + 10%, and no unit is outside the range Q − 30% and Q + 20%; NMT 2 units are outside the range Q′ − 19% and Q′ + 17%, and no unit is outside the range Q′ − 26% and Q′ + 24%; NMT 2 units are less than Q′′ − 10%, and no unit is less than Q′′ − 20% at the stated Times. |
4.5 Test 5
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.
Medium, Apparatus 1, Times, and Analysis: Proceed as directed for Test 1.
Tolerances (for products labeled as 100-mg Capsules): The percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved is NMT 45% (Q) in 30 min, 65% (Q′) in 60 min, and NLT 80% (Q′′) in 120 min. The requirements are met if the quantities dissolved from the Capsules tested conform to Table 6.
Table 6
| Stage | Number Tested | Acceptance Criteria |
| S1 | 6 | Each unit is within the range between Q − 25% and Q − 5%, is between Q′ + 20% and Q′− 15%, and is NLT Q′′ + 5% at the stated Times. |
| S2 | 6 | Average of 12 units (S1 + S2 ) is within the range between Q − 25% and Q − 5%, is within the range Q′ ± 15%, and is NLT Q′′; no unit is outside the range between Q − 30% and Q + 10%, no unit is outside the range Q′ + 25% and Q′− 20%, and no unit is less than Q′′ − 10% at the stated Times. |
| S3 | 12 | Average of 24 units (S1 + S2 + S3 ) is within the range between Q − 25% and Q − 5%, is within the range Q′ ± 15%, and is NLT Q′′; NMT 2 units are outside the range between Q − 30% and Q + 10%, and no unit is outside the range Q − 35% and Q + 20%; NMT 2 units are outside the range between Q′ + 25% and Q′− 20%, and no unit is outside the range Q′ + 30% and Q′− 25%; NMT 2 units are less than Q′′ − 10%, and no unit is less than Q′′ − 20% at the stated Times. |
4.6 Test 6
If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.
Medium: Water; 900 mL, deaerated
Apparatus 1: 50 rpm
Times: 30, 60, and 180 min
Buffer: 2.72 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.5.
Mobile phase: Acetonitrile and Buffer (50:50)
Standard stock solution: 2.0 mg/mL of USP Phenytoin RS in methanol. Sonicate if necessary.
Standard solution: 0.1 mg/mL of USP Phenytoin RS from Standard stock solution, in Medium
Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, and discard the first 2 mL of filtrate.
Replace the portion of solution removed from the vessel with an equivalent volume of Medium equilibrated to 37 ± 0.5°.
4.6.1 Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: UV 229 nm
Column: 4.6-mm × 15-cm; 5 μm packing L1
Column temperature: 35°
Flow rate: 1.5 mL/min
Injection volume: 10 μL
Run time: NLT 1.7 times the retention time of phenytoin
4.6.2 System suitability
Sample: Standard solution
4.6.3 Suitability requirements
Tailing factor: NMT 2.0
Relative standard deviation: NMT 2.0%
4.6.4 Analysis
Samples: Standard solution and Sample solution
Determine the concentration (Ci ) of phenytoin sodium (C15H11N2NaO2) in the sample withdrawn from the vessel at each time point (i):
Result = (rU /rS ) × CS × (Mr1 /Mr2 )
rU = peak response of phenytoin from the Sample solution
rS = peak response of phenytoin from the Standard solution
CS = concentration of USP Phenytoin RS in the Standard solution (mg/mL)
Mr1 = molecular weight of phenytoin sodium, 274.25
Mr2 = molecular weight of phenytoin, 252.27
Calculate the percentage of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved at each time point (i):
Result1 = C1 × V × (1/L) × 100
Result2 = [(C2 × V) + (C1 × VS )] × (1/L) × 100
Result3 = {(C3 × V) + [(C2 + C1 ) × VS ]} × (1/L) × 100
Ci = concentration of phenytoin sodium in the portion of sample withdrawn at each time point (mg/mL)
V = volume of Medium, 900 mL
L = label claim (mg/Capsule)
VS = volume of the Sample solution withdrawn from the vessel and replaced with Medium at each time point (mL)
Tolerances (for products labeled as 100-mg Capsules): See Table 7.
Table 7
| Time Point (j) | Time (min) | Amount Dissolved (%) |
|---|---|---|
| 1 | 30 | NMT 52 (Q) |
| 2 | 60 | 65 (Q’) |
| 3 | 180 | NLT 80 (Q’’) |
The requirements are met if the percentages of the labeled amount of phenytoin sodium (C15H11N2NaO2) dissolved from the Capsules at the times specified conform to Table 8.
Table 8
| Stage | Number Tested | Acceptance Criteria |
| L2 | 12 | Average of 12 units is within the range between Q − 20% and Q, is within the range Q′ ± 10%, and is NLT Q′′; no unit is outside the range between Q − 30% and Q + 10%, no unit is outside the range Q′ ± 20%, and no unit is less than Q′′ − 10% at the stated Times. |
| L3 | 12 | Average of 24 units (L2 + L3) is within the range between Q − 20% and Q, is within the range Q′ ± 10%, and is NLT Q′′; NMT 2 units are outside the range between Q − 30% and Q + 10%, and no unit is outside the range Q − 40% and Q + 20%; NMT 2 units are outside the range Q′ ± 20%, and no unit is outside the range Q′ ± 30%; NMT 2 units are less than Q′′ − 10%, and no unit is less than Q′′ − 20% at the stated Times. |
Uniformity of Dosage Units 〈905〉: Meet the requirements
5 IMPURITIES
Change to read:
Organic Impurities
Buffer, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay.
Standard solution: 600 μg/mL of USP Phenytoin RS, 3 μg/mL of USP Phenytoin Related Compound A RS, and 3 μg/mL of USP Phenytoin Related Compound B RS in methanol
System suitability
Sample: Standard solution
[Note-The relative retention times for phenytoin related compound A, phenytoin related compound B, and phenytoin are 0.38, 0.45, and 1.0,respectively.]
Suitability requirements
Resolution: NLT 8 between phenytoin related compound B and phenytoin; NLT 1.5 between phenytoin related compound A and phenytoin related compound B
Tailing factor: NMT 2.0 for the phenytoin peak
Relative standard deviation: NMT 2.0% for phenytoin; NMT 5.0% for phenytoin related compound A or phenytoin related compound B
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each phenytoin related compound in the portion of Capsules taken:
Result = (rU /rS ) × (CS /CU) × 100
rU = peak response of phenytoin related compound A or phenytoin related compound B from the Sample solution
rS = peak response of phenytoin related compound A or phenytoin related compound B from the Standard solution
CS = concentration of the corresponding analyte in the Standard solution (μg/mL)
CU = nominal concentration of phenytoin sodium (ERR 1-Jan-2022) in the Sample solution (μg/mL)
Calculate the percentage of any individual unspecified degradation product in the portion of Capsules taken:
Result = (rU /rS ) × (CS /CU ) × 100
rU = peak response of each unspecified degradation product from the Sample solution
rS = peak response of phenytoin from the Standard solution
CS = concentration of USP Phenytoin RS in the Standard solution (μg/mL)
CU = nominal concentration of phenytoin sodium (ERR 1-Jan-2022) in the Sample solution (μg/mL)
Acceptance criteria: See Table 9.
Table 9
| Name | Relative Retention Time | Acceptance Criteria, NMT (%) |
|---|---|---|
| Phenytoin related compound A | 0.38 | 0.5 |
| Phenytoin related compound B | 0.45 | 1.0 |
| Phenytoin | 1.0 | – |
| Any individual, unspecified degradation product | – | 0.2 |
6 ADDITIONAL REQUIREMENTS
Packaging and Storage: Preserve in tight, light-resistant containers. Protect from moisture. 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 〈11〉
USP Phenytoin RS
USP Phenytoin Related Compound A RS
Diphenylglycine.
C14H13 NO2 227.26
USP Phenytoin Related Compound B RS
Diphenylhydantoic acid.
C15H14N2O3 270.29
