Phenytoin sodium

Chemical Properties

White or almost white, crystalline powder, slightly hygroscopic.

Uses

antibacterial

Uses

Antiepileptic

Uses

5,5-Diphenylhydantoin sodium salt has been used:

• in the cream preparation for treating burn wounds
• in seizure behavior testing as an anticonvulsant in Drosophila
• in in vivo embryo toxicity test in mouse embryonic stem cells

brand name

Diphenylan (Lannett); Phenytek (Mylan); Phenytex (Watson) [Name previously used: Diphenylhydantoin Sodium.].

General Description

Phenytoin sodium, 5,5-diphenyl-2,4-imidazolidinedione, 5,5-diphenylhydantoin,diphenyl-hydantoin sodium (Dilantin), has been used fordecades in the control of grand mal types of epilepticseizure. It is structurally analogous to the barbiturates butdoes not possess their extensive sedative properties. Thecompound is available as the sodium salt. Solutions for parenteraladministration contain 40% propylene glycol and10% alcohol to dissolve the sodium salt.

Biological Activity

Reduces incidence of grand mal seizures; appears to stabilize excitable membranes perhaps through effects on Na+, K+, and Ca2+ channels.

Clinical Use

Phenytoin sodium’s cardiovascular effects were uncoveredduring observation of toxic manifestations of the drugin patients being treated for seizure disorders. Phenytoinsodium was found to cause bradycardia, prolong the PRinterval, and produce T-wave abnormalities on electrocardiograms.It is a class IB antiarrhythmic agent. Today,phenytoin sodium’s greatest clinical use as an antiarrhythmicdrug is in the treatment of digitalis-induced arrhythmias.34 Its action is similar to that of lidocaine. It depressesventricular automaticity produced by digitalis, without adverseintraventricular conduction. Because it also reversesthe prolongation of AV conduction by digitalis, phenytoinsodium is useful in supraventricular tachycardias caused bydigitalis intoxication.

Safety Profile

Confirmed carcinogen. Experimental teratogen. Other experimental reproductive effects. Poison by ingestion, subcutaneous, intravenous, and intraperitoneal routes. Human systemic effects by ingestion: anorexia, respiratory depression, nausea or vomiting, hemorrhage, dermatitis, and endocrine effects. Mutation data reported. An anticonvulsant and cardiac depressant used for the treatment of grand mal and psychomotor seizures. When heated to decomposition it emits very toxic fumes of NOx and Na2O.

Synthesis

57-41-0

630-93-3

Example 2: General procedure for the synthesis of 2,4-dioxo-5,5-diphenylimidazoline-1-sodium salt from 5,5-diphenylglycolide urea: 5,5-diphenylglycolide urea (20 g) was dissolved in 120 mL of deionized water and sodium hydroxide solution (3.56 g in 22.5 mL of water), and stirred in a 250 mL four-necked round-bottomed flask at 25-30 °C until complete dissolution. The reaction mixture was filtered. The reaction mixture was filtered, the clarified filtrate was collected and sodium chloride solution (4 g in 10 mL of water) was added to it. The reaction mixture was cooled to 5-10 °C under nitrogen protection and stirred for 60 min. The solid product was filtered under vacuum and washed with 20 mL of cold water. The solid was dried under nitrogen atmosphere at 50-60°C to give 18.5 g of dry 2,4-dioxo-5,5-diphenylimidazoline-1- sodium salt in about 85% yield. Example 3: 5,5-Diphenylglycolide (25 g) was dissolved in 150 mL of deionized water and sodium hydroxide solution (4.45 g in 25 mL of water) in a 250 mL four-necked round-bottomed flask with stirring at 25-30 °C until completely dissolved. The reaction mixture was filtered, the clarified filtrate was collected and sodium chloride solution (7.5 g in 22 mL of water) was added to it. The reaction mixture was cooled to 5-10°C under nitrogen protection and stirred for 60 minutes. The solid product was filtered under vacuum and washed with 20 mL of cold water. The solid was dried under nitrogen atmosphere at 50-60°C to give 25.3 g of dry 2,4-dioxo-5,5-diphenylimidazoline-1- sodium salt in about 93% yield. Example 4: 5,5-Diphenylglycolide (25 g) was dissolved in 150 mL of deionized water and sodium hydroxide solution (4.45 g in 25 mL of water) in a 250 mL four-necked round-bottomed flask with stirring at 25-30 °C until completely dissolved. The reaction mixture was filtered, the clarified filtrate was collected and sodium chloride solution (10 g in 28 mL of water) was added to it. The reaction mixture was cooled to 5-10°C under nitrogen protection and stirred for 60 minutes. The solid product was filtered under vacuum and washed with 20 mL of cold water. The solid was dried under nitrogen atmosphere at 50-60°C to give 25.9 g of dry 2,4-dioxo-5,5-diphenylimidazoline-1- sodium salt in about 95.3% yield. Example 5: Potassium hydroxide (152 g) was dissolved in 96 mL of deionized water in a 3L round-bottomed flask, methanol (480 mL) was added at 25-30°C and cooled to 0-5°C. The mixture was then purified by addition of urea. Urea (49.5 g) and diphenylethylenedione (100 g) were added at 0-5 °C. The reaction mixture was refluxed for 60 min. The reaction mixture was refluxed for 60 min, 144.0 mL of water was added and cooled to 0 °C. The reaction mixture was then cooled to 0 °C. 10 g of diatomaceous earth and 10 g of activated carbon were added and stirred at 0-5 °C for 30-60 min. The reaction mixture was filtered through a bed of diatomaceous earth, washed with cooled 100 mL of water, and the filtrate was collected in a 3L round bottom flask. The pH was adjusted to 6.0-7.0 with concentrated hydrochloric acid at 30-45 °C. The slurry was stirred for 30 min, filtered and washed with 1000 mL of hot water to give 178.1 g of wet 5,5-diphenylglycolide with a moisture content of 38.7% and an anhydrous weight of 109.2 g. Wet 5,5-diphenylglycolide (178 g) was dissolved in 600 mL of deionized water and a solution of sodium hydroxide ( 16.7 g was dissolved in 105 mL of water) in a 2L round-bottomed flask and stirred at 30-40 °C until complete dissolution. The reaction mixture was filtered, the clarified filtrate was collected and sodium chloride solution (2 g in 32 mL of water) was added to it. The filtrate was cooled to 5-10°C under nitrogen protection and stirred for 60 minutes. The solid product was filtered under vacuum and washed with 100 mL of cold water. The solid was dried under nitrogen atmosphere at 50-60°C to give 102.6 g of dry 2,4-dioxo-5,5-diphenylimidazoline-1- sodium salt.

Carcinogenicity

Phenytoin and its sodium salt are reasonably anticipated to be human carcinogens based on sufficient evidence from studies in experimental animals.

Solubility in water

1 g dissolves in ca. 66 ml of water. The aqueous solution is turbid unless the pH is adjusted above 11.7, which is the pH of the saturated solution. 1 g dissolves in 10.5 mL of alcohol. Practically insoluble in ether and chloroform.

Toxics Screening Level

The IRSL for Dilantin is 0.07 μg/m3.

References

[1] Patent: WO2007/129184, 2007, A2. Location in patent: Page/Page column 3-6
[2] Patent: WO2007/129184, 2007, A2. Location in patent: Page/Page column 4