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5,5-Diphenylhydantoin

Description Generic formulation Indications Dose titration Plasma levels monitoring Cautions Interactions Special populations Behavioural and cognitive effects in patients with epilepsy Psychiatric use
5,5-Diphenylhydantoin
5,5-Diphenylhydantoin structure
CAS No.
57-41-0
Chemical Name:
5,5-Diphenylhydantoin
Synonyms
Ekko;LATH;base;Eptal;Hidan;Denyl;Convul;Danten;Epamin;Epised
CBNumber:
CB3139264
Molecular Formula:
C15H12N2O2
Formula Weight:
252.27
MOL File:
57-41-0.mol

5,5-Diphenylhydantoin Properties

Melting point:
293-295 °C(lit.)
Boiling point:
395.45°C (rough estimate)
Density 
1.1562 (rough estimate)
refractive index 
1.5906 (estimate)
Flash point:
11 °C
storage temp. 
2-8°C
solubility 
DMSO: soluble
pka
pKa 8.43(H2O,t =25,I=0.025) (Uncertain)
form 
Powder
color 
White to almost white
Water Solubility 
<0.01 g/100 mL at 19 ºC
Merck 
14,7322
BRN 
384532
Stability:
Stable. Combustible. Incompatible with strong oxidizing agents, strong bases.
InChIKey
CXOFVDLJLONNDW-UHFFFAOYSA-N
CAS DataBase Reference
57-41-0(CAS DataBase Reference)
NIST Chemistry Reference
5,5-Diphenylhydantoin(57-41-0)
EPA Substance Registry System
2,4-Imidazolidinedione, 5,5-diphenyl-(57-41-0)
SAFETY
  • Risk and Safety Statements
  • Hazard and Precautionary Statements (GHS)
Hazard Codes  T,Xn,F
Risk Statements  45-61-22-63-40-39/23/24/25-23/24/25-11-20/21/22
Safety Statements  53-45-36/37-16-7
RIDADR  2811
WGK Germany  3
RTECS  MU1050000
Autoignition Temperature 550 °C
HazardClass  6.1(b)
PackingGroup  II
HS Code  29332100
Hazardous Substances Data 57-41-0(Hazardous Substances Data)
Toxicity LD50 in mice (mg/kg): 92 i.v.; 110 s.c. (Stille, Brunckow)
Symbol(GHS):
Signal word: Danger
Hazard statements:
Code Hazard statements Hazard class Category Signal word Pictogram P-Codes
H225 Highly Flammable liquid and vapour Flammable liquids Category 2 Danger P210,P233, P240, P241, P242, P243,P280, P303+ P361+P353, P370+P378,P403+P235, P501
H302 Harmful if swallowed Acute toxicity,oral Category 4 Warning P264, P270, P301+P312, P330, P501
H303 May be harmfulif swallowed Acute toxicity,oral Category 5 P312
H317 May cause an allergic skin reaction Sensitisation, Skin Category 1 Warning P261, P272, P280, P302+P352,P333+P313, P321, P363, P501
H340 May cause genetic defects Germ cell mutagenicity Category 1A, 1B Danger
H350 May cause cancer Carcinogenicity Category 1A, 1B Danger
H351 Suspected of causing cancer Carcinogenicity Category 2 Warning P201, P202, P281, P308+P313, P405,P501
H360 May damage fertility or the unborn child Reproductive toxicity Category 1A, 1B Danger
H370 Causes damage to organs Specific target organ toxicity, single exposure Category 1 Danger P260, P264, P270, P307+P311, P321,P405, P501
H372 Causes damage to organs through prolonged or repeated exposure Specific target organ toxicity, repeated exposure Category 1 Danger P260, P264, P270, P314, P501
Precautionary statements:
P201 Obtain special instructions before use.
P202 Do not handle until all safety precautions have been read and understood.
P210 Keep away from heat/sparks/open flames/hot surfaces. — No smoking.
P260 Do not breathe dust/fume/gas/mist/vapours/spray.
P261 Avoid breathing dust/fume/gas/mist/vapours/spray.
P264 Wash hands thoroughly after handling.
P264 Wash skin thouroughly after handling.
P270 Do not eat, drink or smoke when using this product.
P280 Wear protective gloves/protective clothing/eye protection/face protection.
P311 Call a POISON CENTER or doctor/physician.
P301+P310 IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P307+P311 IF exposed: call a POISON CENTER or doctor/physician.
P308+P313 IF exposed or concerned: Get medical advice/attention.
P405 Store locked up.
P501 Dispose of contents/container to..…

5,5-Diphenylhydantoin price More Price(17)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich D4007 5,5-Diphenylhydantoin ≥99% 57-41-0 5g $35.3 2018-11-13 Buy
Sigma-Aldrich 1535008 Phenytoin United States Pharmacopeia (USP) Reference Standard 57-41-0 200mg $348 2018-11-13 Buy
TCI Chemical D0894 5,5-Diphenylhydantoin >99.0%(T) 57-41-0 25g $34 2018-11-22 Buy
TCI Chemical D0894 5,5-Diphenylhydantoin >99.0%(T) 57-41-0 500g $289 2018-11-22 Buy
Alfa Aesar A17013 5,5-Diphenylhydantoin, 99% 57-41-0 100g $34 2018-11-13 Buy

5,5-Diphenylhydantoin Chemical Properties,Uses,Production

Description

Phenytoin is a first- generation antiepileptic drug (AED) known with the proprietary brand name of Epanutin® (Pfizer, Tadworth) in the UK and Dilantin® (Pfizer, New York, NY) in the USA.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (incl. generic products):

Indications

Epilepsy
Monotherapy and adjunctive therapy of focal and generalized tonic- clonic seizures.

Recommendations summarized from NICE (2012)

Dose titration

Epilepsy
150–300 mg od or divided into two doses, then increased to 200– 500 mg daily (dose to be increased gradually as necessary, with plasma phenytoin concentration monitoring).

Plasma levels monitoring

Phenytoin has a narrow therapeutic index and the relationship between dose and plasma. Phenytoin concentration is non- linear: small dosage increases in some patients may produce large increases in plasma concentration with acute toxic adverse effects. Similarly, a few missed doses or a small change in phenytoin absorption may result in a marked change in plasma phenytoin concentration. Monitoring of plasma phenytoin concentration improves dosage adjustments. The usual total plasma phenytoin concentration for optimum response is 0– 20 mg/ L (careful interpretation of total plasma phenytoin concentration is necessary in pregnancy, the elderly, and certain disease states where protein binding may be reduced and it may be more appropriate to measure free plasma phenytoin concentration).

Cautions

Patients with acute porphyrias (contraindication).

Interactions

With AEDs
With other drugs
With alcohol/food
Acute alcohol intake may increase phenytoin serum levels while chronic alcoholism may decrease serum levels. There are no specific foods that must be excluded from diet when taking phenytoin (phenytoin doses should be taken preferably with or after food).

Special populations

Hepatic impairment
Reduce dose to avoid toxicity.

Renal impairment
Nil.

Pregnancy

Behavioural and cognitive effects in patients with epilepsy

Phenytoin has an overall favourable behavioural profile, although it has been occasionally associated with negative effects on mood and psychotic symptoms (especially at higher doses). The cognitive profile is more problematic, especially in the attention and memory domains. Cognitive adverse effects associated with phenytoin are often dose- dependent and may be particularly obvious in visually guided motor functions.

Psychiatric use

Phenytoin has no approved indications in psychiatry, although the results of small randomized studies have shown that it may be useful in the maintenance treatment of bipolar disorder, major depressive disorder, and impulsive aggression.

Chemical Properties

white crystals or powder

Chemical Properties

Phenytoin is a crystalline compound

Uses

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

Uses

A sodium channel protein inhibitor

Definition

ChEBI: A imidazolidine-2,4-dione that consists of hydantoin bearing two phenyl substituents at position 5.

brand name

Anticonvulsant. Dilantin (Pfizer) [Name previously used: Diphenylhydantoin.].

Biological Functions

Phenytoin is a valuable agent for the treatment of generalized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms. The establishment of phenytoin (at that time known as diphenylhydantoin) in 1938 as an effective treatment for epilepsy was more than simply the introduction of another drug for treatment of seizure disorders. Until that time the only drugs that had any beneficial effects in epilepsy were the bromides and barbiturates, both classes of compounds having marked CNS depressant properties. The prevailing view among neurologists of that era was that epilepsy was the result of excessive electrical activity in the brain and it therefore seemed perfectly reasonable that CNS depressants would be effective in antagonizing the seizures. Consequently,many patients received high doses of barbiturates and spent much of their time sedated. Also, since CNS depression was considered to be the mechanism of action of AEDs, the pharmaceutical firms were evaluating only compounds with profound CNS depressant properties as potential antiepileptic agents. It was, therefore, revolutionary when phenytoin was shown to be as effective as phenobarbital in the treatment of epilepsy without any significant CNS depressant activity. This revolutionized the search for new anticonvulsant drugs as well as immediately improving the day-to-day functioning of epileptic patients.
An understanding of absorption, binding, metabolism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, triiodothyronine, valproic acid, sulfafurazole, and salicylic acid.

General Description

Fine white or almost white crystalline powder. Odorless or almost odorless. Tasteless.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

5,5-Diphenylhydantoin is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). 5,5-Diphenylhydantoin is incompatible with strong oxidizers and strong bases.

Fire Hazard

Flash point data for 5,5-Diphenylhydantoin are not available; however, 5,5-Diphenylhydantoin is probably combustible.

Clinical Use

Phenytoin (Dilantin) was originally introduced for the control of convulsive disorders but has now also been shown to be effective in the treatment of cardiac arrhythmias. Phenytoin appears to be particularly effective in treating ventricular arrhythmias in children.
Phenytoin, like lidocaine, is more effective in the treatment of ventricular than supraventricular arrhythmias. It is particularly effective in treating ventricular arrhythmias associated with digitalis toxicity, acute myocardial infarction, open-heart surgery, anesthesia, cardiac catheterization, cardioversion, and angiographic studies.
Phenytoin finds its most effective use in the treatment of supraventricular and ventricular arrhythmias associated with digitalis intoxication. The ability of phenytoin to improve digitalis-induced depression of A-V conduction is a special feature that contrasts with the actions of other antiarrhythmic agents.

Clinical Use

Phenytoin is one of very few drugs that displays zero-order (or saturation) kinetics in its metabolism.At low blood levels the rate of phenytoin metabolism is proportional to the drug’s blood 1evels (i.e., first-order kinetics). However, at the higher blood levels usually required to control seizures, the maximum capacity of drug-metabolizing enzymes is often exceeded (i.e., the enzyme is saturated), and further increases in the dose of phenytoin may lead to a disproportionate increase in the drug’s blood concentration. Since the plasma levels continue to increase in such a situation, steady-state levels are not attained, and toxicity may ensue. Calculation of half-life (t1/2) values for phenytoin often is meaningless, since the apparent half-life varies with the drug blood level.
Acute adverse effects seen after phenytoin administration usually result from overdosage. They are generally characterized by nystagmus, ataxia, vertigo, and diplopia (cerebellovestibular dysfunction). Higher doses lead to altered levels of consciousness and cognitive changes.
A variety of idiosyncratic reactions may be seen shortly after therapy has begun. Skin rashes, usually morbilliform in character, are most common. Exfoliative dermatitis or toxic epidermal necrolysis (Lyellís syndrome) has been observed but is infrequent. Other rashes occasionally have been reported, as have a variety of blood dyscrasias and hepatic necrosis.

Side effects

The most common side effect in children receiving long-term therapy is gingival hyperplasia, or overgrowth of the gums (occurs in up to 50% of patients). Although the condition is not serious, it is a cosmetic problem and can be very embarrassing to the patient. Hirsutism also is an annoying side effect of phenytoin, particularly in young females. Thickening of subcutaneous tissue, coarsening of facial features, and enlargement of lips and nose (hydantoin facies) are often seen in patients receiving long-term phenytoin therapy. Peripheral neuropathy and chronic cerebellar degeneration have been reported, but they are rare.
There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis. Only a few well-documented drug combinations with phenytoin may necessitate dosage adjustment. Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients: cimetidine, chloramphenicol, disulfiram, sulthiame, and isoniazid (in slow acetylators). Phenytoin often causes a decline in plasma carbamazepine levels if these two drugs are given concomitantly.
Ethotoin and mephenytoin are congeners of phenytoin that are marketed as AEDs in the United States. They are not widely used.

Side effects

The rapid IV administration of phenytoin can present a hazard. Respiratory arrest, arrhythmias, and hypotension have been reported.

Safety Profile

Confirmed carcinogen producing lymphoma, Hodgkin's disease, tumors of the skin and appendages. Experimental carcinogenic and tumorigenic data. A human poison by ingestion. Poison experimentally by ingestion, subcutaneous, intravenous, and intraperitoneal routes. Moderately toxic by an unspecified route. Experimental teratogenic and reproductive effects. Human systemic effects by ingestion: dermatitis, change in motor activity (specific assay), ataxia (loss of muscle coordmation), degenerative brain changes, encephalitis, hallucinations, dtstorted perceptions, irritabihty, and jaundice. Human teratogenic effects by ingestion: developmental abnormalities of the central nervous system, carlovascular (circulatory) system, musculoskeletal system, craniofacial area, skin and skin appendages, eye, ear, other developmental abnormalities. Effects on newborn include abnormal growth statistics (e.g., reduced weight gain), physical abnormakties, other postnatal measures or effects, and delayed effects. Human mutation data reported. A drug for the treatment of grand mal and psychomotor seizures. When heated to decomposition it emits toxic fumes of NOx

Potential Exposure

Phenytoin is an amide pharmaceutical used in the treatment of grand mal epilepsy, Parkinson’s syndrome; and in veterinary medicine. Human exposure to phenytoin occurs principally during its use as a drug. Figures on the number of patients using phenytoin are not available, but phenytoin is given to a major segment of those individuals with epilepsy. The oral dose rate is initially 100 mg given 3 times per day and can gradually increase by 100 mg every 24 weeks until the desired therapeutic response is obtained. The intravenous dose is 200350 mg/day.

Drug interactions

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug–drug interactions.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required. UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Purification Methods

Crystallise the hydantoin from EtOH. [Beilstein 24 III/IV 1748.]

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Similar organic amides react with azo and diazo compounds, releasing toxic gases. Contact with reducing agents can release flammable gases. Amides are very weak bases but they can react as acids, forming salts. Mixing amides with dehydrating agents such as phosphorus pentoxide or thionyl chloride generates the corresponding nitrile.

Precautions

Phenytoin either should not be used or should be used cautiously in patients with hypotension, severe bradycardia, high-grade A-V block, severe heart failure, or hypersensitivity to the drug.
Because of the increase in A-V transmission observed with phenytoin administration, it should not be given to patients with atrial flutter or atrial fibrillation. Phenytoin will probably not restore normal sinus rhythm and may dangerously accelerate the ventricular rate.

5,5-Diphenylhydantoin Preparation Products And Raw materials

Raw materials

Preparation Products


5,5-Diphenylhydantoin Suppliers

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5,5-Diphenylhydantoin Spectrum


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