Extended Phenytoin Sodium Capsules
DEFINITION
Extended Phenytoin Sodium Capsules contain NLT 95.0% and NMT 105.0% of the labeled amount of phenytoin sodium (C15H11N2NaO2).
IDENTIFICATION
• A. Procedure
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 a 1-in-2 mixture of ether and chloroform. Evaporate the combined extracts, and dry the residue of phenytoin at 105
for 4 h.
for 4 h.
Acceptance criteria:
The IR absorption spectrum of a potassium bromide dispersion of the residue exhibits maxima only at the same wavelengths as that of a similar preparation of USP Phenytoin RS.
• B. Identification Tests—General, Sodium 
191
:
The contents of Capsules meet the requirements of the flame test.
191:
The contents of Capsules meet the requirements of the flame test.
ASSAY
• Procedure
Buffer:
0.05 M monobasic potassium phosphate. Adjust with phosphoric acid to a pH of 3.5.
Mobile phase:
Methanol and Buffer (11:9)
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 from the Sample stock solution in Mobile phase
Chromatographic system
Mode:
LC
Detector:
UV 229 nm
Column:
4.6-mm × 25-cm; packing L1
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 3000 theoretical plates
Tailing factor:
NMT 2.0
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage label claim of C15H11N2NaO2 in the portion of Capsules taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response from the Standard solution |
| CS | = | = concentration of USP Phenytoin RS in the Standard solution (mg/mL) |
| CU | = | = nominal concentration of phenytoin 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%
PERFORMANCE TESTS
• Dissolution 711
711
Test 1
Medium:
Water; 900 mL
Apparatus 1:
50 rpm
Times:
30, 60, and 120 min
Mobile phase:
Methanol and water (7:3)
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.
Chromatographic system
Mode:
LC
Detector:
UV 229 nm
Column:
4.6-mm × 25-cm; packing L1
Flow rate:
1 mL/min
Injection size:
10 µL
System suitability
Sample:
Standard solution
Suitability requirements
Column efficiency:
NLT 3200 theoretical plates
Tailing factor:
NMT 2.0
Relative standard deviation:
NMT 2.0%
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of C15H11N2NaO2 dissolved:
Result = (rU/rS) × CS × (Mr1/Mr2) × V × (100/L)
| rU | = | = peak response from the Sample solution |
| rS | = | = peak response 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 |
| V | = | = volume of Medium, 900 mL |
| L | = | = Capsule label claim (mg) |
Tolerances (for products labeled as 30-mg Capsules)
The percentage of the labeled amount of 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 the acceptance table below.
| 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 (S1 + S2) 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 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 the acceptance table below.
| 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. |
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 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 the acceptance table below.
| 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. |
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 C15H11N2NaO2 dissolved by using the method described under Test 1.
Tolerances (for products labeled as 200- and 300-mg Capsules)
The percentage of the labeled amount of 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 the acceptance table below.
| 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. |
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 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 the accompanying Acceptance Table.
Acceptance Table
| 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. |
• Uniformity of Dosage Units 905:
Meet the requirements
905:
Meet the requirements
Procedure for content uniformity
Buffer, Mobile phase, Chromatographic system, System suitability, and Analysis:
Proceed as directed in the Assay.
Standard solution:
Dissolve USP Phenytoin RS in methanol, and dilute with Mobile phase to obtain a concentration of 0.5 mg/mL.
Sample solution:
Place one intact Capsule or one opened Capsule with its contents in a suitable container, add approximately 15 mL of methanol, and place in a shaking water bath at 37 for 30 min. Sonicate for 60 min with occasional shaking. Dilute with methanol to volume. Dilute with Mobile phase, if necessary, to obtain a final concentration of 0.5 mg/mL.
for 30 min. Sonicate for 60 min with occasional shaking. Dilute with methanol to volume. Dilute with Mobile phase, if necessary, to obtain a final concentration of 0.5 mg/mL.
IMPURITIES
Organic Impurities
• Procedure
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% from phenytoin; NMT 5.0% from 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 for the corresponding phenytoin related compound from the Sample solution |
| rS | = | = peak response for the corresponding phenytoin related compound from the Standard solution |
| CS | = | = concentration of the appropriate USP reference standard in the Standard solution (µg/mL) |
| CU | = | = concentration of the Sample solution (µg/mL) |
Acceptance criteria:
NMT 0.5% of phenytoin related compound A; NMT 1.0% of phenytoin related compound B
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
11
USP Phenytoin RS 
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USP Phenytoin Related Compound A RS
Diphenylglycine.
C14H15NO2 227.26
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Diphenylglycine.
C14H15NO2 227.26
USP Phenytoin Related Compound B RS
Diphenylhydantoic acid.
C15H14N2O3 270.29
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Diphenylhydantoic acid.
C15H14N2O3 270.29
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Ravi Ravichandran, Ph.D.
Principal Scientific Liaison 1-301-816-8330 |
(SM42010) Monographs - Small Molecules 4 |
| 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 4311
Pharmacopeial Forum: Volume No. 29(1) Page 108