الثلاثاء، 8 أبريل، 2008

Phenytoin

Phenytoin is 5,5-diphenyl-2,4-imidazolidinedione
Phenytoin was first synthesized by Biltz in 1908[i]. Phenytoin powder has melting point 295-298 °C. It is practically insoluble in water, sparingly soluble in ethanol and acetone. Phenytoin is soluble in alkali hydroxides[ii],with dissociation const.(pKa) of 8.31[iii] .
Phenytoin exerts antiseizure activity without causing general depression of the CNS, the most significant effect of phenytoin is its ability to modify the pattern of maximal electroshock seizures68. Pharmacokinetic properties of phenytoin show that t1/2 varies between 7-60 hours and tmax is about 2-4 hours[iv] .

Official Preparations are phenytoin tablet (USP & BP) and phenytoin suspension (USP & BP)[v]-[vi]. phenytoin sodium is also official in USP and BP in different dosage forms. phenytoin and phenytoin sodium are bioequivalent and tablets of phenytoin showed better dissolution properties[vii].

Several papers were published on the problems associated with dissolution of the commercial products.
Kotaki [viii]claimed that the commercial phenytoin products show wide variation in dissolution rates. Manson[ix] stated that various phenytoin products show different bioavilabilities in children.
Different techniques were developed by many researchers to overcome phenytoin dissolution problem including:
1. Muhrer[x] enhanced phenytoin dissolution by using dense-gas antisolvent technique.
2. Several research works were done on enhancing phenytoin dissolution by using cyclodextrins derivatives[xi]-[xii].
3. Trapani111 developed quantitative structure property relationship for enhancement of dissolution using b-hydroxy propyl cyclodextrin. He concluded that the dissolution of phenytoin increased more than 100 times.
4. Carbowax was utilized to enhance phenytoin dissolution by using solid dispersion[xiii].
5. Povidone was utilized to enhance the dissolution rate using roll mixing, solid dispersion, spray drying 81-83 80,[xiv],[xv].
6. Chow[xvi]studied the effect of modification of physical properties of phenytoin by recrystallizationusing crystal defect inducing agents.
7. Bioreversible derivatization was introduced as a method for enhancing dissolution profile by many workers 84-86 [xvii],[xviii],[xix].
8. Co-grinding with surfactants and porous silicate was utilized to enhance the dissolution rate[xx]-[xxi].
9. Koeleman[xxii] studied the different dissolution rates of phenytoin and its coprecipitate with montomorillonite.
10. Bastami[xxiii] discussed different factors that affect release of phenytoin from various formulations.
11. Soft gelatin capsule was suggested by Batemann[xxiv] to overcome the dissolution problem.
12. Solvent deposition was used by Johansen to solve the problem[xxv].
Preliminary experiments were performed using different thermoplastic agents and various fillers. It was concluded that gelucire could be utilized as agglomerating agent and lactose as filler to enhance dissolution profile of phenytoin tablet.

[i]. Hardman J. and Limbird L., Goodman and Gillman, the pharmacological basis of therapeutics, Mc Graw Hill, 10th edition, 2001
[ii]. Windholz M., The Merck Index, 11th edition, Merck, 1996
[iii]. Darwish I. A. , El-Massik-MA; Hassan-EE and El-Khordagui-LK, Assessment of a hydroalcoholic surfactant solution as a medium for the dissolution testing of phenytoin , Int. J. Pharm, 140, 1, 16 August 1996, P. 25-32
[iv]. David B. Jack, Handbook of Clinical pharmacokinetic data, Macmillan, 1992, P.25
[v]. United States Pharmacopoeia 28, USP, 2004
[vi]. British Pharmacopoeia 2005, BP
[vii]. Albani-F , Pazzaglia-P; Procaccianti-G; Riva-R and Baruzzi-A l, Bioavailability of phenytoin: comparison of data obtained in vitro, from healthy volunteers and from epileptic patients, Bollettino-Chimico-Farmaceutico; 1981; 120(Dec); P. 715-724
[viii]. Kotaki-H; Shibuya-F and Shibata-M, Dissolution rates of phenytoin and phenobarbital from commercial and hospital pharmacy made tablets, J-Nippon-Hosp-Pharm-Assoc-Sci-Ed; 1976; 2(1); P. 7-11
[ix]. Manson-JI , Beal-SM; Magarey-A; Pollard-AC and O'-Reilly-WJ, Bioavailability of phenytoin from various pharmaceutical preparations in children ,Medical-Journal-of-Australia; 1975; 2(Oct 11); P. 590-592
[x]. Muhrer G. , Ulrich Meier, Francesco Fusaro, Siria Albano and Marco azzotti, Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: Generation of drug microparticles and drug–polymer solid dispersions , Int. J. Pharm, 225,1-2, Aug 2001, P.63-74
[xi]. Masako Oda , Hiroshi Satioh, Michiya Kobayashi and Bruce J. Aungst, β-Cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs, Int. J. Pharm, 280, 1-2, 6 August 2004, P. 95-102
[xii]. Savolainen J. , Jarvinen K, Matilainen L and Jarvinen T, Improved dissolution and bioavailability of phenytoin by sulfobutylether-β-cyclodextrin and hydroxypropyl-β-cyclodextrin complexation, Int. J. Pharm, 165, 1, April 1998, P. 69-78
[xiii]. Franco M. , Trapani G., Latrofa A., Tullio C., Provenzano MR, Serra M, Muggironi M, Biggio G and Liso G, Dissolution properties and anticonvulsant activity of phenytoin-polyethylene glycol 6000 and -polyvinylpyrrolidone K-30 solid dispersions, Int. J. Pharm, 225, 1-2, August 2001, P. 63-73
[xiv]. Nozawa-Y; Mizumoto-T; Higashide-F, Improving dissolution rates of practically insoluble drug phenytoin by roll mixing with polyvinyl pyrrolidone, Pharmaceutica-Acta-Helvetiae; 1985; 60; P.175-177
[xv]. Kala-H; Traue-J, Preparation of dosage forms from drugs with low solubility for enhancement of bioavailability, Acta-Pharm-Technol; 1983; 29(1); P.29-34
[xvi] Albert H. L. Chow , Modification of phenytoin crystals. III. Influence of 3-butanoyloxymethyl-5,5-diphenylhydantoin on solution-phase crystallization and related crystal properties, Int. J. of Pharm., Volume 126, Issues 1-2, 29 December 1995, Pages 11-19

[xvii]. Bundgaard H. and Marianne Johansen, Pro-drugs as drug delivery systems XV. Bioreversible derivatization of phenytoin, acetazolamide, chlorzoxazone and various other NH-acidic compounds by N-aminomethylation to effect enhanced dissolution rates, Int. J. Pharm, 7, 2, December 1980, P. 129-136
[xviii]. Stella-VJ; Martodihardjo-S and Rao-VM, Aqueous solubility and dissolution rate does not adequately predict in vivo performance: probe utilizing some N-acyloxymethyl phenytoin prodrugs, J-Pharm-Sci; 1999; 88(Aug); P.775-779
[xix]. Stella-VJ; Martodihardjo-S and Rao-VM, Some relationships between the physical properties of various 3-acyoxymethyl prodrugs of phenytoin to structure: potential in vivo performance implications , J-Pharm-Sci; 1998; 87(Oct); P.1235-1241.
[xx]. Otsuka-M and Matsuda-Y, Effect of cogrinding with various kinds of surfactants on the dissolution behavior of phenytoin , J-Pharm-Sci; 1995; 84(Dec); P.1434-1437
[xxi]. El-Sayed-AM; Ali-AS and Assi-AA, Enhancing the pharmacological effect of phenytoin using porous silica as carrier , STP-Pharma-Sci; 1993; 3(4); P. 319-324
[xxii]. Koeleman-HA , Van-Zyl-R; Steyn-N; Boneschans-B and Steyn-HS, Influence of montmorillonite on the dissolution and bioavailability of phenytoin, Drug-Dev-Ind-Pharm; 1990; 6(5); P. 791-805
[xxiii]. Bastami-SM and Groves-MJ, Some factors influencing the in vitro release of phenytoin from formulations, Int-J-Pharm; 1978; 1; P.151-164
[xxiv]. Bateman-NE , Lee PY, Finnin BC and Reed BL, Dissolution of phenytoin from soft gelatin capsules, Aust-J-Hosp-Pharm; 1978; 8(4); P.143-145.
[xxv]. Johansen-H; Moller-N, Solvent deposition of drugs on excipients. 2. Interpretation of dissolution, adsorption and absorption characteristics of drugs, Arch-Pharm-Chemi-Sci-Ed; 1977; 5(2); P.33-42.

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