Phenytoin formulations

Alvarez-Nunez FA, Yalkowsky SH. Buffer capacity and precipitation control of pH solubilized phenytoin formulations. Int J Pharm 1999(Aug 5) 185(l) 45-49. 

SM Bastami, MJ Groves. Some factors influencing the in vitro release of phenytoin from formulations. Int J Pharm 1 151-164, 1978. 

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

Alkylation of the hydantoin (89-2) from benzaldehyde with ethyl iodide takes place at the imide nitrogen to afford ethitoin (89-3) [93]. In much the same vein, treatment of the hydantoin (89-5) from propiophenone with methyl iodide (89-5) in the presence of a base affords mephenytoin (89-6) [94]. Replacement of the quite acidic imide proton by an aUcyl group is not required for activity the well-known anticonvulsant phenytoin (89-8) consists of simply the hydantoin obtained from benzophenone (89-7) [95] this is often formulated as its sodium salt. 

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration. 

Specific myoclonic syndromes are usually treated with valproate an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine valproate is the drug of choice followed by lamotrigine and topiramate. 

The USP contains Phenytoin, Phenytoin Sodium and the following formulations ... 

Holcomb et al 5 developed a stability indicating HPLC procedure for the simultaneous determination of phenytoin and pheno-barbital in formulations. They used a Waters Associates, 2 ft x 1/8 in. O.D. stainless steel column packed with u Bondapak Cig on Corasil II. The mobile phase was a mixture... 

Morphine Sulfate Morphine sulfate precipitates in alkaline media and drugs that are incompatible with it, including aminophylline, sodium salts of barbiturates, and phenytoin. Precipitate was found after 2 horns when morphine sulfate was formulated with acyclovir sodium.70 Incompatibilities also are reported with chlorpromazine hydrochloride injections containing chlorocresol. Admixture of morphine sulfate (1 mg/mL), doxorubicin in doxorubicin hydrochloride... 

Several other therapeutic effects of sodium channel blockers have been suggested. Most of these stem from clinical activities of approved anticonvulsants and antiarrhythmics with sodium channel blocking activity. Beneficial effects of sodium channel blockers for the treatment of bipolar disease are suggested by clinical data with lamotrigine [63-67], phenytoin [68], topiramate [69], and carbamazepine [70,71]. In addition, clinical studies with lidocaine suggest efficacy in the treatment of tinnitus [72] and, as an inhaled formulation, in the suppression of cough [73,74]. 

The formulations of phenytoin, carbamazepine and sodium valproate are compared in Table A17.3 overleaf. 

Disposition in the Body. Slowly but almost completely absorbed after oral administration the rate of absorption is variable, being prolonged after large doses, and the bioavailability may vary considerably between different formulations. Aromatic hydroxylation is the major metabolic pathway and about 50 to 70% of a dose may be excreted as free or conjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in 24 hours the excretion of this metabolite is dose-dependent and decreases as the dose is increased. Phenytoin hydroxylation is capacity-limited, and is therefore readily inhibited by agents which compete for its metabolic pathways. Less than 5% of a dose is excreted as unchanged drug. Minor metabolites include 5-(3-hydroxyphenyl)-5-phenylhydantoin, 3,4-dihydro-3,4-dihydroxy-phenytoin, catechol, and 3-D-methylcatechol. Up to about 15% of a dose may be eliminated in the faeces. 

When a child has febrile convulsions the decision to embark on continuous prophylaxis is serious for the child, and depends on an assessment of risk factors, e.g. age, nature and duration of the fits. Most children who have febrile convulsions do not develop epilepsy. Prolonged drug therapy, e.g. with phenytoin or phenobarbitone, has been shown to interfere with cognitive development, the effect persisting for months after the drug is withdrawn. Parents may be supplied with a specially formulated solution of diazepam for rectal administration (absorption from a suppository is too slow) for easy and early administration, and advised on managing fever, e.g. use paracetamol at the first hint of fever, and tepid sponging. 

Alternatively, Rubino and Yalkowsky found that a was a linear function of cosolvent polarity for a given solute. This is illustrated in Fig. 3 for the three lipophilic compounds phenytoin, diazepam, and benzocaine. Thus, knowledge of the solubility of a given drug in water and at least two cosolvents would permit cr to be estimated for other cosolvents by interpolation using an index of the desired cosolvent polarity. These studies permit the use of Eq. (4) as a means to rationally choose or eliminate solvents for formulation studies based on limited experimental solubility data and commonly obtained indexes of solute and solvent polarity. 

The interaction of oral phenytoin with enteral feeding formulations has been reviewed (83). Four prospective, randomized, controlled trials in healthy volunteers showed no interaction. However, numerous anecdotal reports and studies have shown dramatic reductions in serum phenytoin concentrations in patients receiving enteral feeding formulations. The authors therefore concluded that this interaction occurs in patients but not in healthy volunteers. 

Hashim F, El-Din EZ. Effect of some excipients on the dissolution of phenytoin and acetazolamide from capsule formulations. Acta Pharm Penn 1989 98 197-204. 

Monoethanolamine is used primarily in pharmaceutical formulations for buffering purposes and in the preparation of emulsions. Other uses include as a solvent for fats and oils and as a stabilizing agent in an injectable dextrose solution of phenytoin sodium. 

In several cases the special nature of a formulation will preclude dilution by an aqueous infusion fluid. Injectable products containing phenytoin, digoxin and diazepam may come into this category if they are formulated in a nonaqueous but water-miscible solvent (such as an alcohol-water mixture) or as a solubilised (e.g. micellar) preparation. Addition of the formulation to water may result in precipitation of the dmg, depending on the final concentration of the dmg and solvent. It has been suggested that precipitation of the relatively insoluble diazepam may account for the high (3.5%) incidence of thrombophlebitis which occurs when diazepam is given intravenously. 

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