57-41-0 Usage
Uses
Used in Pharmaceutical Industry:
5,5-Diphenylhydantoin is used as an anticonvulsant for the treatment of epilepsy, particularly for tonic-clonic seizures and status epilepticus. It acts by blocking voltage-sensitive sodium channels in the brain, delaying electrical recovery in neurons and stabilizing the threshold against hyperexcitability.
Used in Cardiology:
5,5-Diphenylhydantoin is used as an oral replacement of lidocaine for paroxysmal tachycardia, especially in cases caused by intoxication of digitalis drugs. It has similar effects on the heart as lidocaine, making it a suitable alternative for managing cardiac conditions.
Used in Neurology:
5,5-Diphenylhydantoin is used to reduce the incidence of grand mal seizures. It appears to stabilize excitable membranes, potentially through effects on Na+, K+, and Ca2+ channels, providing a therapeutic option for patients with seizure disorders.
Used in Research and Development:
5,5-Diphenylhydantoin has been used in research to slow down or prevent mesoendoderm cell migration, contributing to the understanding of cellular processes and potential therapeutic applications in various conditions.
Used as a Sodium Channel Protein Inhibitor:
In the field of neuroscience and pharmacology, 5,5-Diphenylhydantoin is used as a sodium channel protein inhibitor, playing a crucial role in the development of new drugs and therapies for neurological disorders.
Generic formulation
MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (incl. generic products):
Doctors are advised to ensure that their patients are maintained on a specific manufacturer’s product.
Indications
Epilepsy
Monotherapy and adjunctive therapy of focal and generalized tonic- clonic seizures.
Recommendations summarized from NICE (2012)
Seizure types: on referral to tertiary care (focal seizures), contraindicated (generalized tonic- clonic seizures if there are absence or myoclonic seizures or if juvenile myoclonic epilepsy is suspected, absence seizures, myoclonic seizures).
Epilepsy types: on referral to tertiary care (benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy), contraindicated (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy, Dravet syndrome).
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
Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic enzymes (cytochrome P450 CYP2C9 and CYP2C9) and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism.
Several AEDs, including eslicarbazepine, oxcarbazepine, topiramate, and valproate, potentially increase phenytoin serum levels.
Vigabatrin may decrease phenytoin plasma levels.
Carbamazepine, phenobarbital, and valproate may either increase or decrease phenytoin serum levels.
Phenytoin is a potent inducer of hepatic drug- metabolizing enzymes and may reduce the levels of drugs metabolized by these enzymes.
Phenytoin may alter serum levels and/ or effects of carbamazepine, lamotrigine, phenobarbital, and valproate.
With other drugs
Phenytoin serum levels are potentially increased by analgesic/ anti- inflammatory agents (such as azapropazone, phenylbutazone, salicylates), anaesthetics (halothane), antibacterial agents (such as chloramphenicol, erythromycin, isoniazid, sulfadiazine, sulfamethizole, sulfamethoxazoletrimethoprim, sulfaphenazole, sulfisoxazole, sulfonamides), antifungal agents (such as amphotericin b, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole), antineoplastic agents (such as capecitabine, fluorouracil), psychotropic agents (such as chlordiazepoxide, diazepam, disulfiram, fluoxetine, fluvoxamine, methylphenidate, sertraline, trazodone, viloxazine), cardiovascular agents (such as amiodarone, dicoumarol, diltiazem, nifedipine, ticlopidine), H2- antagonists (such as cimetidine), HMG- CoA reductase inhibitors (such as fluvastatin), hormones (such as oestrogens), immunosuppressant drugs (such as tacrolimus), oral hypoglycaemic agents (such as tolbutamide), proton pump inhibitors (such as omeprazole).
Phenytoin plasma levels may be decreased by antibacterial agents (such as ciprofloxacin, rifampicin), antineoplastic agents (such as bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), antiulcer agents (such as sucralfate), antiretrovirals (such as fosamprenavir, nelfinavir, ritonavir), bronchodilators (such as theophylline), cardiovascular agents (such as reserpine), folic acid, hyperglycaemic agents (such as diazoxide), St John抯 wort (Hypericum perforatum).
Phenytoin serum levels may be either increased or decreased by antibacterial agents (such as ciprofloxacin), antineoplastic agents, and psychotropic agents (such as chlordiazepoxide, diazepam, and phenothiazines).
Phenytoin may alter serum levels and/ or effects of the following drugs: antibacterial agents (such as doxycycline, rifampicin, tetracycline), antifungal agents (such as azoles, posaconazole, voriconazole), antihelminthics (such as albendazole, praziquantel), antineoplastic agents (such as teniposide), antiretrovirals (such as delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir/ ritonavir, nelfinavir, ritonavir, saquinavir), bronchodilators (such as theophylline), cardiovascular agents (such as digitoxin, digoxin, mexiletine, nicardipine, nimodipine, nisoldipine, quinidine, verapamil), coumarin anticoagulants (such as warfarin), ciclosporin, diuretics (such as furosemide), HMG- CoA reductase inhibitors (such as atorvastatin, fluvastatin, simvastatin), hormones (such as oestrogens, oral contraceptives), hyperglycaemic agents (such as diazoxide), immunosuppressant drugs, neuromuscular blocking agents (such as alcuronium, cisatracurium, pancuronium, rocuronium, vecuronium), opioid analgesics (such as methadone), oral hypoglycaemic agents (such as chlorpropamide, glyburide, tolbutamide), psychotropic agents (such as clozapine, paroxetine, quetiapine, sertraline), vitamin D.
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
Phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients. Therefore, phenytoin should only be used during pregnancy, especially early pregnancy, if in the judgement of the physician the potential benefits clearly outweigh the risk.
In addition to the reports of increased incidence of congenital malformations, such as cleft lip/ palate and heart malformations in children of women receiving phenytoin, there have been reports of a foetal hydantoin syndrome, consisting of prenatal growth deficiency, micro- encephaly, and mental deficiency in children born to mothers who have received phenytoin. There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
?An increase in seizure frequency during pregnancy occurs in a proportion of patients, possibly due to altered phenytoin absorption or metabolism. Therefore, periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant patient with epilepsy as a guide to an appropriate adjustment of dosage; however, postpartum restoration of the original dosage will probably be indicated.
Breast- feeding is not recommended for women taking phenytoin because phenytoin appears to be secreted in low concentrations in human milk.
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.
Originator
Dilantin ,Parke Davis ,US ,1938
Manufacturing Process
10 g of benzophenone (1 mol), 4 g of potassium cyanide (1.22 mols) and 16 g of ammonium carbonate (3.3 mols) are dissolved in 100 cc of 60% (by volume) ethyl alcohol and the mixture warmed under a reflux condenser without stirring at 58° to 62°C. After warming the mixture for 10 hours apartial vacuum is applied and the temperature is raised enough to permit concentration of the reaction mixture to two-thirds of its initial volume.A slight excess of mineral acid, such as sulfuric or hydrochloric acid is added to acidify the mixture which is then chilled and the solid which separates is filtered off. It is then treated with an aqueous solution of dilute sodium hydroxide to dissolve the hydantoin from the solid unreacted benzophenone. After filtration, the alkaline extract is then acidified to cause the separation of solid pure diphenylhydantoin which is filtered off and dried. It melts at 293° to 296°C.A net yield of about 95% is obtained by the procedure described above. If the time of warming the reaction mixture is increased three-or four-fold, practically 100% net yields are obtained. The same high net yields are also obtained by heating for even longer periods of time. For example, by heating for 90 hours, a 100% net yield, or 67% gross yield, is obtained.
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.
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.
Mechanism of action
Phenytoin is indicated for initial monotherapy or adjunct treatment of complex partial or tonic-clonic seizures, convulsive status
epilepticus, and prophylaxis. It often is selected for initial monotherapy because of its high efficacy and relatively low incidence
of side effects. Phenytoin is not used in the treatment of absence seizures, because it may increase their frequency of
occurrence. Phenytoin binds to and stabilizes the inactivated state of sodium channels, thus producing a
use-dependent blockade of repetitive firing and inhibition of the spread of seizure activity to adjacent cortical areas.
Pharmacokinetics
Phenytoin may be administered either orally or intravenously and is absorbed slowly after oral
administration, with peak plasma levels achieved after 3 to 12 hours. It is extensively plasma protein
bound (~90%), and the elimination half-life is between 15 and 30 hours. These large ranges reflect
the considerable variability observed from patient to patient. Parenteral administration of phenytoin
is usually limited to the intravenous route. Phenytoin for injection is dissolved in a highly alkaline
vehicle (pH 12). This alkaline vehicle is required because phenytoin is weakly acidic and has very
poor solubility in its un-ionized form. Reportedly, however, its phosphate ester fosphenytoin has
water solubility advantages over phenytoin for injection. Intramuscular phenytoin generally is
avoided, because it results in tissue necrosis at the site of injection and erratic absorption because
of high alkalinity. In addition, intermittent intravenous infusion is required to reduce the incidence of
severe phlebitis.
Phenytoin metabolism is relatively slow and predominantly involves aromatic hydroxylation to
p-hydroxylated inactive metabolites. Phenytoin also induces its own metabolism
and is subject to large interindividual variability. The major metabolite, 5-p-hydroxyphenyl-
5-phenylhydantoin, accounts for approximately 75% of a dose. This metabolite is excreted through
the kidney as the β-glucuronide conjugate. Phenytoin clearance is strongly influenced by its
metabolism; therefore, agents that affect phenytoin metabolism may cause intoxication. In addition,
because phenytoin is highly plasma protein bound, agents that displace phenytoin also may cause
toxicity.
Pharmacology
In terms of its effect on the CNS, phenytoin is considered an excellent antiepileptic drug
with insignificant sedative effects. Even in large doses it does not cause hypnosis. It is presumed that phenytoin facilitates secretion of sodium ions from nerve cells, which reduces
the stimulation of neurons. This in turn prevents the activation of neurons upon receiving
impulses from the epileptogenic center. In addition, phenytoin reduces the incoming flow
of potassium ions during repolarization. It is possible that phenytoin significantly slows the
distribution of excitation in the brain as a direct result of the redistribution of the ion flow.
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
Synthesis
Phenytoin, 5,5-diphenylimidazolidinedione (9.1.1) is synthesized in two different
ways. The first involves a rearrangement on the reaction of benzil with urea to form the desired
product (9.1.1) .The second method involves the reaction of benzophenone with sodium cyanide in the
presence of ammonium carbonate, followed by the simultaneous cyclization of the resulting product (carboxyaminonitrile) and its rearrangement under the reaction conditions to
form phenytoin .
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.
Carcinogenicity
Phenytoin and its sodium salt are reasonably anticipated to be human carcinogens based on sufficient evidence from studies in experimental animals.
Environmental Fate
Routes and Pathways
Exposure is usually oral, but the intravenous route may be used
to treat status epilepticus.
Relevant Physicochemical Properties
Appearance: clear, colorless, or slightly yellow in solution
Solubility: ethyl alcohol
Metabolism
Phenytoin is hydroxylated in the liver to inactive
metabolites chiefly 5-(4-hydroxyphenyl)-5-
phenylhydantoin by an enzyme system which is
saturable. Phenytoin undergoes enterohepatic recycling
and is excreted in the urine, mainly as its hydroxylated
metabolite, in either free or conjugated form.
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.]
Toxicity evaluation
Since metabolism of the drug is a saturable process, much of
the toxicity of phenytoin is thought to be due to increased
concentrations of the drug, especially of nonprotein-bound
drug. The free drug may cross the blood–brain barrier, and if
present in excess, could produce some of the adverse neurological
manifestations. Other toxicities may be related to folic
acid deficiency induced by phenytoin. Reactive intermediates
formed during metabolism of phenytoin may also be responsible
for some of the drug’s toxicity.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 57-41-0 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 7 respectively; the second part has 2 digits, 4 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 57-41:
(4*5)+(3*7)+(2*4)+(1*1)=50
50 % 10 = 0
So 57-41-0 is a valid CAS Registry Number.
InChI:InChI=1/C15H12N2O2.Na/c18-13-15(17-14(19)16-13,11-7-3-1-4-8-11)12-9-5-2-6-10-12;/h1-10H,(H2,16,17,18,19);/q;+1/p-1
57-41-0Relevant articles and documents
Increased shelf-life of fosphenytoin: Solubilization of a degradant, phenytoin, through complexation with (SBE)(7m)-β-CD
Narisawa, Shinji,Stella, Valentino J.
, p. 926 - 930 (1998)
Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values -1 at pH 7.4 and pH 8.0, respectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)(7m)-β-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41-45 M-1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 °C in the presence of 0.03 or 0.06 M (SBE)(7m)-β-CD. It was projected from the solubility of phenytoin and the kinetic information that fosphenytoin shelf lives as high as nine years at 25 °C and pH 7.4 in the presence of 60 mM of (SBE)(7m)-β-CD might be possible while longer shelf lives might be possible at pH 8.
Phenytoin prodrugs IV: Hydrolysis of various 3-(hydroxymethyl)phenytoin esters
Varia,Schuller,Stella
, p. 1074 - 1079 (1984)
The aqueous chemical stability of various bioreversible derivatives or prodrugs of phenytoin, a poorly water-soluble and erratically absorbed drug after both oral and intramuscular parenteral dosing, were evaluated. This study, together with assessments of other physicochemical properties including cleavage in the presence of various animal tissues and anticonvulsant activity in mice, helped identify a number of promising candidate prodrugs. Various amino groups containing acyl esters of 3-(hydroxymethyl)phenytoin [3-(hydroxymethyl)-5,5-diphenylhydantoin] were identified as potential orally and perhaps parenterally useful prodrugs, while the disodium phosphate ester of 3-(hydroxymethyl)phenytoin appears to be ideally suited as a parenteral form of phenytoin.
Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin
Scriba, Gerhard K. E.,Lambert, Didier M.
, p. 549 - 553 (1999)
Glycine, which has weak anticonvulsant properties, has been shown to potentiate the activity of several antiepileptic drugs but not phenytoin. Recently, studies have shown that N-(benzyloxycarbonyl)glycine (Z-glycine) antagonized seizures more than glycine in addition to possessing activity in the maximal electroshock test, a convulsive model in which glycine is inactive. In the present study esters of 3-hydroxymethylphenytoin, a phenytoin prodrug, and Z-glycine as well as the homologous N-(benzyloxycarbonyl)-ω-amino acids, z-β-alanine and Z-γ-aminobutyric acid (Z-GABA), were prepared and tested for their anticonvulsant and acute neurotoxic activities. The phenytoin prodrugs were obtained by esterification of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride-mediated esterification of 3-hydroxymethylphenytoin with the respective N-benzyloxycarbonyl-protected amino acid. The Z-glycine-phenytoin ester was the most active anticonvulsant derivative. Compared with phenytoin the compound exhibited a decreased median effective dose (ED50) in the MES test and an increased median toxic dose (TD50), resulting in an significantly improved protective index expressed as the ratio between TD50 and ED50. The present data suggest that covalent binding of phenytoin to Z-glycine results in an improved pharmacological profile of the drug.
Synthesis of a novel phenytoin derivative: Crystal structure, Hirshfeld surface analysis and DFT calculations
Guerrab, Walid,Lgaz, Hassane,Kansiz, Sevgi,Mague, Joel T.,Dege, Necmi,Ansar,Marzouki, Riadh,Taoufik, Jamal,Ali, Ismat H.,Chung, Ill-Min,Ramli, Youssef
, (2020)
Hydantoin compounds are important heterocyclic scaffolds and a class of well-known bioactive molecules with a broad spectrum of pharmacological properties. Consequently, considerable efforts have been devoted to the design and synthesis of a broad range of hydantoin derivatives. In this context, the compound 3-allyl-5,5-diphenylimidazolidine-2,4-dione, C18H16N2O2 (3ADID) was synthesized and its structure was determined by X-ray structure analysis. Further, the molecular structure was examined using Hirshfeld topology analysis and Density Functional Theory (DFT)-B3LYP calculations with the basis set 6–311++G (d,p). In the title molecule, C18H16N2O2, the imidazolidine ring is planar with the allyl substituent oriented nearly perpendicular to it. In the crystal, hydrogen bonded chains of molecules are arranged in sets of three about the 32 axes by C–H···π (ring) interactions. Hirshfeld surface map and 2D fingerprint plots were used to explore intermolecular interactions. The optimized geometry, global reactivity descriptors, and HOMO-LUMO orbitals of the molecule were computed by DFT and discussed. To evaluate the chemical reactivity and charge distribution on the molecule, molecular electrostatic potential (MEP) and atomic charges, computed by Mulliken population analysis and NBO theory were determined. The local reactivity was examined by determining the Fukui functions and dual descriptor indices. DFT calculations at the same level of theory, with the POP[dbnd]NBO keyword, were used to evaluate charge delocalization and hyperconjugative interactions through Natural Bond orbital analysis.
Method for preparing phenytoin sodium in mixed crystal form
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Paragraph 0046-0049, (2020/07/15)
The invention provides a method for preparing phenytoin sodium in a mixed crystal form. The method comprises the following steps of 1) preparing phenytoin: taking a reaction kettle, adding water and diphenyl ethanedione, adjusting to be alkaline, adding urea, heating to reflux, filtering after the reaction is finished, dropwise adding concentrated hydrochloric acid, crystallizing, stirring, carrying out centrifugal filtration, washing a filter cake with water, discharging to obtain a phenytoin crude wet product, pulping, carrying out centrifugal filtration, and discharging to obtain a phenytoin wet product, and 2) preparing phenytoin sodium: taking another reaction kettle, put the phenytoin wet product in the reaction kettle, adding water, heating, dropwise adding a sodium hydroxide solution, adjusting the pH value, decolorizing, finely filtering, cooling to room temperature, stirring, crystallizing, carrying out centrifugal filtration, washing a filter cake, drying the washed solid, and discharging to obtain the mixed crystal form phenytoin sodium. According to the phenytoin sodium prepared by the preparation method, the mixed crystal proportion of the anhydrous substance and themonohydrate is consistent with the mixed crystal proportion of a reference preparation, and tablets prepared from the mixed crystal phenytoin sodium produced by the method can be consistent with the reference preparation in in-vitro dissolution and in-vivo bioequivalence.
Experimental and theoretical study of bidirectional photoswitching behavior of 5,5′-diphenylhydantoin Schiff bases: Synthesis, crystal structure and kinetic approaches
Georgiev, Anton,Georgieva, Stela,Peneva, Petia,Rusew, Rusi,Shivachev, Boris,Todorov, Petar
, p. 15081 - 15099 (2020/10/02)
Herein, the synthesis and characterization of four novel 5,5′-diphenylhydantoin Schiff bases containing different aromatic species are presented. Their structure-property relationship was studied by X-ray, optical and electrochemical methods as well as DFT calculations in terms of their E/Z photoisomerization and enol/keto phototaumerization. The big challenge in photoinduced motion is achieving control and stability over the two isomers. Solvent-driven bidirectional photoswitching behavior was studied in nonpolar 1,4-dioxane and polar aprotic DMF. T-type photochromism in 1,4-DOX and opposite behavior in DMF as P-type switches (bistable system) were observed. The obtained results lead to a conclusion that by variation of the solvent environment a direct control over the bidirectional switching behaviour from T-type to P-type can be achieved.
Method for preparing phenytoin sodium
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Paragraph 0079; 0083; 0085; 0088; 0090; 0093; 0095-0119, (2020/12/08)
The invention relates to the field of biological medicines, and discloses a method for preparing phenytoin sodium. The method is characterized by comprising the following steps: (1) carrying out an oxidation reaction on benzoin in a first solvent to obtain diphenyl ethanedione, wherein the first solvent is a mixed solution of an alcohol and water, and the alcohol is at least one selected from C1-C3 monohydric alcohols; (2) carrying out a rearrangement reaction on diphenyl ethanedione to obtain phenytoin; and (3) carrying out salt forming reaction on the phenytoin in water, and performing purifying to obtain the phenytoin sodium. According to the method provided by the invention, few solvent systems are introduced, acetic acid is prevented from being used, subsequent treatment is relativelysimple, and the prepared phenytoin sodium is relatively high in yield and purity and is convenient to large-scale production.
Oxidation of Thioamides to Amides with Tetrachloro- and Tetrabromoglycolurils
Arrous, S.,Boudebouz, I.,Parunov, I. V.
, p. 1874 - 1877 (2020/02/03)
Tetrabromo- and tetrachloroglycolurils have been shown to act as good oxidants capable of converting thioamides to the corresponding amides. This approach offers such advantages as good yields (81–99%), short reaction times (10–25 min), simple workup procedure, and environmental safety.
Synthetic method of phenytoin sodium
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Paragraph 0025; 0033; 0037; 0039; 0041; 0045; 0049, (2019/03/28)
The invention relates to a synthetic method of phenytoin sodium, belonging to the technical field of biomedicine. The synthetic method of the phenytoin sodium comprises the following steps of oxidation reaction, condensation reaction and salt formation reaction, wherein a amidation reaction process is promoted through adding a phase transfer catalyst 4-dimethylamiopryidine in the condensation reaction; a two-phase system of n-butanol and water is adopted, so that the generation of diphenylacetylene diurea is greatly inhibited, and reaction time is obviously shortened; ethanol serves as a solvent in the salt formation reaction, after a sodium hydroxide ethanol solution reacts with phenytoin, cyclohexane with defective solvent ice is added to promote the phenytoin sodium to precipitate as white crystal, and compared with the salt formation reaction with water as a solvent, the phenytoin sodium is faster in precipitation rate and high in precipitation degree and purity.
Hydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains
Fetzer, Christian,Korotkov, Vadim S.,Sieber, Stephan A.
supporting information, p. 7124 - 7127 (2019/08/07)
Proteolysis mediated by ClpXP is a crucial cellular process linked to bacterial pathogenesis. The development of specific inhibitors has largely focused on ClpP. However, this focus was challenged by a recent finding showing that conformational control by ClpX leads to a rejection of ClpP binders. Thus, we here follow up on a hit molecule from a high throughput screen performed against the whole ClpXP complex and demonstrate that stable inhibition with high potency is possible. Further investigations revealed that the small molecule binds to ClpP without affecting its activity. Likewise, the molecule does not inhibit ClpX and retains the overall oligomeric state of ClpXP upon binding. Structure activity relationship studies confirmed structural constraints in all three parts of the molecule suggesting binding into a defined stereospecific pocket. Overall, the inhibition of ClpXP without affecting the individual components represents a novel mechanism with perspectives for further optimization for in situ applications.
