- Identification, synthesis, characterization and quality control strategy of new process-related impurities in fosphenytoin sodium
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Fosphenytoin sodium is a water dissolvable phenytoin prodrug that is directed intravenously to convey phenytoin, conceivably more securely than intravenous phenytoin. It is most ordinarily utilized in the intense treatment of convulsive status epileptics. The examination of the procedure-related contaminants will not help exclusively to advance the process parameters yet additionally to create sensible analytical methods and set the quality standard for a quality control system in pharmaceutical manufacturing. During the production of fosphenytoin sodium, all the process-related impurities are controlled in every stage and three degradation impurities are managed in the final API as per USP monograph. Besides, five unknown and one known contaminants were detected by HPLC method. All these impurities were identified, synthesized, isolated and characterized by IR, 1D-NMR (1H, 13C, DEPT) and HRMS spectral techniques. The mechanism of the formed impurities is examined for the first time. Quality control procedures to manage these impurities were developed to acquire the mass medication of ICH grade quality.
- Singaram, Sathiyanarayanan,Subramanian, Venkatesan Chidambaram,Kabilan, Senthamaraikannan,Raju, Dandu Bhaskara Suresh
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- Hydrolysis of pharmaceutically relevant phosphate monoester monoanions: Correlation to an established structure-reactivity relationship
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The kinetics of dephosphorylation of dilute aqueous solutions of 3- phosphoryloxymethyl-5,5-diphenylhydantoin (1) and estrone phosphate (2) were studied as a function of pH, buffer concentration, and temperature at an ionic strength of 0.5 M. The resulting pH-rate profiles displayed bell- shaped regions with maxima between pH 3 and 5, where the monoanionic phosphate species predominate; mechanistically, these regions involved spontaneous or water-catalyzed dephosphorylation of the monoanionic phosphate species. The profile of 1 was also described with pathways involving a hydronium ion-catalyzed and a spontaneous or water-catalyzed dephosphorylation of the neutral species. The hydrolytic reactivities of the monoanionic species of the phosphomonoester prodrugs of phenytoin (i.e., 1), estrone (i.e., 2), and 2,2,2-trichloroethanol (from the literature) were well predicted by an established structure-reactivity, free-energy relationship. The correlation of these compounds to this relationship supported a common hydrolytic reaction mechanism. The small Bronsted value of -0.27 was consistent with a dephosphorylation mechanism involving a rapid transfer of the lone phosphoryl proton to the bridge-oxygen atom of the ester linkage, followed by the rate-limiting phosphorus-oxygen bond fission proceeding through a largely dissociative transition state.
- Kearney,Stella
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- Design, synthesis and biological evaluation of water-soluble phenytoin prodrugs considering the substrate recognition ability of human carboxylesterase 1
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Human carboxylesterase 1 (hCES1) is a hydrolase that is mainly expressed in the liver and lung and plays the most important role in the metabolic activation of ester–type prodrugs. In this study, design, synthesis and evaluation of water–soluble phenytoin prodrugs were performed with consideration of the substrate recognition ability of hCES1. The phenytoin prodrugs were synthesized in two steps without column chromatography. It was confirmed that all prodrugs are efficiently converted to phenytoin in a human liver microsome (HLM) solution (up to 54.6 nmol/mg protein/min). Although some of the prodrugs were degraded in strongly basic solution, the solubility of all prodrugs was greater than that of phenytoin in buffer solutions at pH 7.4 and 8.3. Among the synthesized phenytoin prodrugs, the 3,3-dimethylglutarate prodrug was superior in terms of solubility and stability, and it showed solubility of 10 mg/mL or more (phenytoin: 0.1 mg/mL) in a solution of pH 8.3. It was also found that the 3,3-dimethylglutarate prodrug was selectively activated by hCES1 but not hCES2 or arylacetamidodeacetylase.
- Haba, Masami,Hosokawa, Masakiyo,Kanayama, Teruhiko,Kondo, Yusuke,Lee, Yeon Joo,Mukai, Kota,Nishio, Kazuki,Takahashi, Masato
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- MANUFACTURING METHOD OF SODIUM FOSPHENYTOIN HYDRATE AND SYNTHETIC INTERMEDIATE THEREOF
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PROBLEM TO BE SOLVED: To provide a manufacturing method of sodium fosphenytoin hydrate capable of shortening time for all manufacturing processes and reducing manufacturing cost and a synthetic intermediate thereof. SOLUTION: There is provided a method for manufacturing 3-hydroxymethyl-5,5-diphenyl-2,4-imidazolidinedione, including a process for heating 5,5-diphenyl-2,4-imidazolidinedione (phenytoin), formaldehyde and alcohol and using no alkaline material. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0029
(2018/05/24)
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- Organic amine salt of fosphenytoin stability and its preparation and use
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The invention relates to a stable organic amine salt of fosphenytoin and the preparation method and use thereof, the related organic amine salt of fosphenytoin having a structure of the general formula as shown in general formula (I), and the use comprisi
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Paragraph 0029; 0035; 0036
(2017/01/19)
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- An oral redox-sensitive self-immolating prodrug strategy
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We report a novel oral prodrug approach where a solubilizing polymer conjugated to the drug is designed to be released by the action of an exogenously administered agent in the intestine. A redox-sensitive self-immolating design was implemented, and the reconversion kinetics were studied for three reducible prodrugs.
- Sun, Tao,Morger, Andrea,Castagner, Bastien,Leroux, Jean-Christophe
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supporting information
p. 5721 - 5724
(2015/03/30)
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- Structure-activity relationships of 3-substituted-5,5-diphenylhydantoins as potential antiproliferative and antimicrobial agents
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A series of twelve 3-substituted-5,5-diphenylhydantoins was synthesized, including some whose anticonvulsant activities have already been reported in the literature. Their antiproliferative activities against HCT-116 human colon carcinoma cells were evalu
- Trisovic, Nemanja,Bozic, Bojan,Obradovic, Ana,Stefanovic, Olgica,Markovic, Snezana,Comic, Ljiljana,Bozic, Biljana,Uscumlic, Gordana
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scheme or table
p. 1597 - 1606
(2012/05/07)
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- Novel synthesis of fosphenytoin: Anti-convulsant prodrug
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A simple, new synthesis of fosphenytoin sodium 1, a prodrug, via imidate ester and employing mild reaction conditions is described. Copyright Taylor & Francis Group, LLC.
- Elati, Chandrashekar R.,Gangula, Srinivas,Naredla, Anitha,Ashok,Bhattacharya, Apurba,Bandichhor, Rakeshwarar
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p. 2950 - 2957
(2008/12/22)
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- Solvent effects on the structure-activity relationship of pharmacological active 3-substituted-5,5-diphenylhydantoins
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Absorption spectra of eight 3-substituted-5,5-diphenylhydantoins have been recorded in fourteen solvents in the range 200-400 nm. The effect of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions are analyzed by means of the
- Banjac, Nebojsa,Uscumlic, Gordana,Valentic, Natasa,Mijin, Dusan
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p. 869 - 878
(2008/02/08)
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- PROCESS FOR PREPARING FOSPHENYTOIN
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Processes for preparing fosphenytoin.
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Page/Page column 13; 14
(2010/11/28)
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- Prodrugs of 5,5-diphenylhydantoin as antiepileptic and antiarrhythmic agents
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The present invention deals with a product with the formula (I) which is a new prodrug of phenytoin, as well as its therapeutically acceptable solvates and addition salts. This product shows a solubility significantly higher than phenytoin itself. In addi
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- Pharmaceutical formulations for parenteral use
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Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with hydroxypropyl-β-cyclodextrin, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration.
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- Pharmaceutical formulations for parenteral use
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Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β- and γ-cyclodextrin, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration.
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- Redox systems for brain-targeted drug delivery
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Inclusion complexes of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of β- and γ-cyclodextrin with the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal forms of dihydropyridine pyridinium salt redox systems for brain-targeted drug delivery provide a means for stabilizing the redox systems, particularly against oxidation. The redox inclusion complexes also provide a means for decreasing initial drug concentrations in the lungs after administration of the systems, leading to decreased toxicity. In selected instances, complexation results in substantially improved water solubility of the redox systems as well.
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- Brain-specific drug delivery
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The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: (a) compounds of the formula wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier, with the proviso that when [DHC] is STR1 wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH2 or OH function group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and (b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entitles [D--QC]+ X- are also disclosed.
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- Phenytoin prodrugs III: Water-soluble prodrugs for oral and/or parenteral use
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Various bioreversible derivatives of phenytoin, a poorly water soluble and erratically absorbed drug after both oral and parenteral dosing, were synthesized. Initial evaluation of these expected prodrugs, i.e., their aqueous solubility, cleavage in the presence of various animal tissues, and anticonvulsant activity in mice, confirmed that a number of the derivatives did indeed behave as prodrugs. The more promising prodrugs were the disodium phosphate ester and various amino groups containing acyl esters of 3-(hydroxymethyl)-5,5-diphenylhydantoin.
- Varia,Schuller,Sloan,Stella
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p. 1068 - 1073
(2007/10/02)
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- Low-melting phenytoin prodrugs as alternative oral delivery modes for phenytoin: A model for other high-melting sparingly water-soluble drugs
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Phenytoin is a high-melting, weakly acidic, and sparingly water-soluble drug. Because of these physicochemical properties, phenytoin is subject to erratic bioavailability in a variety of dosage forms both in its acidic as well as sodium salt forms. A homo
- Yamaoka,Roberts,Stella
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p. 400 - 405
(2007/10/02)
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- Derivatives of 5,5-diphenylhydantoin exhibiting enhanced solubility and the therapeutic use thereof
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Novel derivatives of 5,5-diphenylhydantoin, having the formula: STR1 wherein R is as defined in the specification and claims hereinafter, are disclosed. These compounds exhibit enhanced solubility over diphenylhydantoin per se and find therapeutic usefulness as anticonvulsants, antiepileptics and antiarrhythmics.
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