U.S. Pharmacopeia National Formulary Aine 3 Table of Contents * General Chapters TOC * USP General Notices 4 USP Monographs M-Z * Complete Index A: S. - PHARMACOPEIA The Si dof QUSP 37 Phenytoin Sodium GigHiiNiNaOs, 274.25 Z.4-Imidazolidinedione, 5,5-diphenyl, monosodium sat. 5's-Diphenylhydantoin sodium salt [630-93-3] » Phenytoin Sodium contains not less than ‘98.0 percent and not more than 102.0 percent of CisHiN2NaO;, calculated on the dried basis. Packaging and storage—Preserve in tight containess USP Reference standards (11) Use Phenytoin RS UsP Peron Raed Compound ARS Biphenpaicin. CutsNOr 227.26 Usp Phenyton Related Compound 8 RS Bichenyiyeantor aid CeitnnOn 270.23 Clarity and color of solution —DisoWve 1.0 9 in 20 ml of Biba dioxide tte water, and 3d 0.10 N sodium hysox son paced eheryton is dsseved no re é MOmL of the O10 N sosum hydroxide i requed to eo ence Tenticaton “rhe 30 9 of Renin So adh Oeghe ee fa et iaa Ben ee a eee te Ie ry oS See aC ca ela pole cnet yee Ske tin ee ces ee SRE, wae oo he cv rs cla eeile 3 Pyt B: It responds to the flame test for Sodium (191). Loss on drying (731)—Dry it at 105° for 4 hours: it loses rot more than 2.396 ofS weight teary metals, Hai a Reine Sompouds Wi gle eno apo soll de rer sacs er en Str lh Ditech cue ot ae te te es Ores ‘ARS, ard USP Phenytoin Related Compound B apo: 0.00296. 1, System suitably repare as die” ‘in Mobile phase, and dilute quantitatively, and stepwise if Dray, wh ible phase to btain# soliton having Khown concentrations of 0.5 1g per ml, Tug per ml, 9g per ml, and 9g per mL, respectively. Test solution—Use the Assay stock preparation. Chromatographic system—Proceed as directed in the As say, except to infect the Standard solution instead of the Standard preparation: the relative standard deviation for rep- lcate injections is not more than 5.086 for each compound Procedure Separately iject equal volumes (about 201.) of the Standard Solution and the Test solution into the chro- matograph, record the chromatograms, and measure the peak Fespotses, Calculate the prentage of phenytoin 1c Gted compound A, phenytoin related compound B, und Benzophenone in the portion of Phenytcin Sodium taken by TOOCCIOKA/ #3) in which C ig the concentration, in ug per mL, of the re spective anelyte in the Standard solution; D is the concentra tion, in 4g per mL, of Phenytoin Sodium in the Test solution; and’, and f, are the peak responses for phenytoin related mpound A, phenytoin related compound &, or benzophe- Aone obtained from the Test solution and the Standard solu Official Monographs / Phenytoin 4289 tion, respectively: not more than 0.9% each of phenytoin tonted Eompound & and phenytoin related compound B is ibund an Pot more that 0196 of Benzaphenae Found, veutete the percentage of every other imputy in the por- {ian of Phenytoin Sodium taken by the formula 100(274.25/252.27KC/OXt/ 1) in which Cis the concentration, in wg per mb, of USP Phenytoin RS in the “tandord solution; 274.25 and 252.27 fre te molecular weights of phenytoin sodium and dhtenyiom, respecivey rand rare the peak responses of ach impurity obtained from the Test solution and the Stan. dard solution, respectively, and the other term is as defined above, Not more than 0.9% of total impurities is found, excluding benzophenone. Assay— ‘Mobile phase—Prenare a fitered and degassed mixture of 0.05 M monobasic ammonium phosphate buffer, adjusted toa pt of 2.5 with phosphoric acid, acetonitaie’ and meth, nol (45:35:20). Make adjustments it necessary (ce System Suitably under Chromatography (621). ‘Standard stock preparation-—Transter about 100 mg of USF Phenytoin RS, accurately weighed, to a 100-ml. volu- metric fase, dissolve in Mobile phase, and sonicate, if neces- sary. to dissolve. System suitebilty stock soltion—Transfer 5.0 mi of the standard stock preparation to a 50-mL. volumetric flask, and dllute with Mobile phase to volume to obtain a solution hav- {ng a krown concentration of about 100 ug per ml. System suitability solution—Transfer about 75.0 rng of benzoin to a 50-ml. volumetric flask, dissolve in 10 mL of ethanol, end alfute with a mixture of 0.05 M monobasic iinmonivin phosphate buffer, previously adjusted with Phosphoric acid te a pH of 2:5 and acetonitrile (45:35), to Nolume. Transfer 1.0 mL of the solution so obtained to a TosmL volumetzc flask, and dilute with the System suitability sock scltan to volume. Standard preporation-—Transfer mi of the Standard stock preparation to a 100-mL volumetric flask, and dilute with ‘Mobile phase to volume. ‘Asscy stock preparation—Transfer about 100mg of Phenytain Sodium, accurately weighed, to.2,100-m_ volu- mete ask, gssolve n and dist with Moble phase t0 vol ‘Assay preparation—Transfer 5.0 mL-of the Assay stock preparation to a 100-mL volumetric flask, dlute with Mobile phase to volume, and mix. ‘Chromatographic system—The liquid chromatogra equipped with a 220-nm detector and a 4:6.mm x 25-cm, celurnn that contains Sum packing LI. The flo rte about 1.5 mL per minute. Chromatograph the Standard preparation, a record the responses as directed for Proce- ure: the relative standard deviation for replicate injections fot more than 1.0%. Chromatograph the System siti Solution, and record the peak responses as directed for Pro- Cecure: the relative retention times are 1.0 for phenytoin {ind about 1.3 for berzoiny the column efficiency is not less than 9400 theoretical plates for the phenytoin peak; the tail ing factor is not more than 1.5; and the resolution, R, be- twieen phenytoin and benzoin fs not less than 1.5. Procedure—Separately inject equal volumes (about 20 iL) of the Standard preparation and the Assay preparation iato the chromatograph, record the chromatograms, and meas- tre the peak cexporses forthe major peat. Calculate the Quantity, in. mg, of CutlNsNaOs in the portion of Phenytoin Soditim taken by the formula 2000€(274,25/252.27\(u/ 1) in which Cis the concentration, in mg perm, of USP Phenytoin 85 in the Standard preparation; 274.25 and 252.87 are the molecular weights of phenytoin sodium and, is a $ = 5 3 s a4290 Phenytoin / Official Monographs Bhenyoin, respectively and ry and rs ae the peak responses Ebtained trom the Asay preparation and the Standard rons ‘ation respectively ee eee er eS Extended Phenytoin Sodium Capsuies DEFINTION Pe AEH Bit Sodium Capsules contain NLT 95.0% and NMT 108.0% of the labeled amount of phenytor sodium (CisHyNpNa03), DEicaTion +A ProceDune Sample: 300 mg of phenytoin sodium from the cone tes f Capsule, SO ml of water in separate YOmL of 3N hydrochloric aid and extac wat Tes successive portions, measuring 100, 66, ond 30 nt pectvely Of a Tar-2 mature of ether and eo: Eaporate the combined extracts and dy Ue ean of phenytoin a 103" for 8 Acceptance criteria The Wa Potssium bromige dipersion ofthe wesiue extn ‘maxima only a the same wavelengths os that of os lar preparation of USP Mrtytars Re tion spectrum of a ++ B. loemTincaTion Te Sodium (191): The Eontents of Capsules meet the requirements of the fisme test ASSAY ‘> Proceoure Buffer: 0.05 M monobasic potassium phosphate, Adjust with phosphoric aed toa peeat Se Mobile phase:”"Methanol dod Bue (11:9) Standard solution: O.6mg/mt of US? Phenytoin RS in Mobile phase. (NoreDisschve te required Coon st Phenytoin ina small amount of metifanol beter She tng 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 roomn ter, seems ang alte wih methanolic” sample solution: Nominaly 0.6 mayin of phenytoin cen the Sample stock voUrton in ene ae vomatographic system (See Chromatography (621), System Sutabity.) Mode: "te Detector: UV 229 nm elumns 4 6-mom x 25-cm; packing L1 ml Standard solution bility requirements Column efficiency: NLT 3000 theoretical plates Talling factor: Nia 2.0 _apislative standard deviation: NMT 2.0% \nalys | Samples: Standard solution and Sample solution ‘Calculate the percentage label claim of CysthNaNaOs in the portion of Capsules taken: Result = (Cults) x (Cs/Cu) x (Ma/Ma) x 100 te = Peak response from the Sample solutian Deak response froin the Standard solution Cs = concentration of USP Phenytoin RS in the Standard solution (mg/ml Ce = nominal concentration of phenytoin in the Sample solution (mg/ml) Mu = molecular weight of phenytoin sodium, 274.25 Ma = molecular weight of phenytoin, 252.27 UsP 37 Acceptance ciiteria: 95.0%-105,095 PERFORMANCE TESTS = Bussouurion 7711) Test 1 Water; 900 mt Medi Apparatus 1: ates 30, 60, 478 120 min Mobile phases” Methanol and water (7:3) Standard solution" Dusolve USP Phcajicn RE in methanel, and dilute with water to obtain caewn- {ration sina to that of the Sample selon, Sample solution: Pass a portion of the solution under fest through a suitable iter, Chromatographic system (See Chromatography (621), System Sutobity,) Mode: tc Detector: UV 229 nm Column: 4.6-mm x 25-cm; packing Lt Flow rate: 1 mL/min Injection size: VO nL system: suitability ample: Standard soltion Sultablity requirerment Column effcleney: NLT 3200 theoretical plates Tallin factor: NIT 2 0 Relative standard deviation: NMT 2.0% Analysis Samples: Standard soliton and. Sample solution Calculate the percentage of CssHiNiNaOs ditolved: (ful) X Cs x (Ma/Mia) x V x (LO0/L) fe = peak esonse from the Sample slain Ba response rom he Sri ain Result ©. 5 Gohcettation of Ue Pherae Stoned soulon (mgr Ma = nclcuar weight f perm sodium, waas Ma molecular weight of phenytoin, 252.27 volume of Medum, $00 mC L_ = Capsule label claim 1) Tolerances (for products labeled as 30-mg Capsites) ‘The percentage of the labeled amount of SasBuNiNaO, dissolved is NMT 409% (Q) in 30 min, 50% (@) in 60 min, and NLT 6596 (O°) in 120 my, The requirements are met if the quantities dissolved {from the Capsules tested conform to the acceptance table below. ‘amber —stage_| "Tested Acceptance Criteria Pos 6 | Fach ut s within the range beoncon 1546 and Q~ 5%, i wathn the ange Q” £1035, and is NUT Q” + Sta the Sted Times = © | Average of 12 units Gx + 5 bwin the range between Q-~ 10% snd Qt wan the range 896, and nt Gro Uniti oti the range between) = 20% and Q + 1036, no unt ouside the fange Q' 18%, and no units ies than O° 10n atth gute Tene E 12 | Average of 26 units (5, + 5; + 5) wn the range between © — 10% and Qi within she range Q! 4 896 and is NET’; NMT 2 units are outside the range between @ = 2096 and + 10% and no units outside the range @ 30% ano + 20%; NMT 2 units are outice te | ange Q' 18%, and no uit ouside the range 0 + 259%; NM 2 units are les than Q” ~ 10%, and no unites than = 2086 at Ue stated Ties