Synthesis and in vitro/in vivo evaluation of novel oral N-alkyl- and N,N-dialkyl-carbamate esters of entacapone (original) (raw)
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Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs
Journal of Pharmacy and Pharmacology, 2001
Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that is used as an adjunct to l-dopa therapy in the treatment of Parkinson's disease. The bioavailability of orally administered entacapone is, however, relatively low (29–46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in-vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 w...
Synthesis of a water-soluble prodrug of entacapone
Bioorganic & Medicinal Chemistry Letters, 2000
AbstractÐEntacapone was reacted with phosphorous oxychloride in dry pyridine to yield a phosphate ester. The phosphate promoiety increased aqueous solubility of the parent drug by more than 1700-and 20-fold at pH 1.2 and 7.4, respectively. The phosphate ester provides adequate stability (t 1/2 =2227 h; pH 7.4) towards chemical hydrolysis, and allowed for release of the parent drug via enzymatic hydrolysis in liver homogenate. #
Advanced pharmaceutical bulletin, 2013
Analysis of drug utilized the organic solvent which are costlier, toxic and causing environment pollution. Hydrotropic solution may be a proper choice to preclude the use of organic solvents so that a simple, accurate, novel, safe and precise method has been developed for estimation of poorly water soluble drug Entacapone (Water Solubility-7.97e-(02) g/l). Solubility of entacapone is increased by using 8M Urea as hydrotropic agent. There was more than 67 fold solubility enhanced in hydrotropic solution as compare with distilled water. The entacapone (ENT) shows the maximum absorbance at 378 nm. At this wavelength hydrotropic agent and other tablet excipients do not shows any significant interference in the spectrophotometric assay. The developed method was found to be linear in the range of 4-20 μg/ml with correlation coefficient (r(2)) of 0.9998. The mean percent label claims of tablets of ENT in tablet dosage form estimated by the proposed method were found to be 99.17±0.63. The d...
Stability-indication LC determination of entacapone in tablets
Chromatographia, 2007
A rapid and sensitive RP-HPLC method with UV detection at 305 nm for routine quality control of entacapone in tablets was developed. The procedure was validated by specificity, robustness, linearity, accuracy, repeatability and intermediate precision. Experimental design was used during validation to calculate method robustness. The method employs an Ace RP-18 (250 · 4.6 mm i.d., particle size 5 lm), with a mobile phase consisting of water pH 3.0: acetonitrile (65:35, v/v). Entacapone solutions were exposed to direct UV radiation (254 nm), alkaline hydrolysis, acid hydrolysis and effect of oxidation by hydrogen peroxide to evaluate method stability-indication and peak purity tool was utilized to verify the peak purity. The results confirm that the method is highly suitable for its intended purpose.
Stability-Indicating Method of Entacapone-Related Substances Using UPLC in Finished Dosage Form
Current Science
A rapid, specific, sensitive and robust method for entacapone-related substances in carbidopa, entacapone and levodopa film-coated tablet was developed using ACQUITY UPLC with BEH C18 column. Mobile phase (A), i.e. 0.1% orthophosphoric acid and mobile phase (B), i.e. acetonitrile with water in the ratio 75 : 25 (v/v) with gradient method were employed. The method was evaluated for identification of process impurities and unknown impurities. It has been validated according to ICH (Q2) R1 guidelines. The values of LOD and LOQ for impurity and entacapone were found to be 0.01% and 0.03% respectively. Degradation studies were carried out in peroxide, acid, alkali conditions and contribution to mass balance was established. It was stable under heat, light-exposed and humid conditions.
Purpose: Entacapone, a catechol-O-methyltransferase inhibitor, is poorly water soluble (BCS class IV). The dissolution profile of pure Entacapone is improved in the presence of an alkaline buffer and after addition of a surfactant by facilitating the drug release process at the solid/liquid interface. Rationale: According to USP the best dissolution medium for Entacapone is phosphate buffer 5.8 in type II paddle-type apparatus with a paddle speed of 50 rpm. Materials and Methods: In this article an effect of various parameters (buffer, surfactant, and RPM) on the dissolution profile of Entacapone is studied by applying factorial design 33 (phosphate buffer-5.3, 5.8, and 6.8; sodium lauryl sulfate-0.5%, 1.0%, and 1.5%; rotation speed of paddle-50, 75, and 100). Pure Entacapone pellets were formed using a hydraulic press. Conclusion: The release profile data revealed that the dissolution profile of Entacapone is remarkably improved in the alkaline medium (6.8), addition of surfactant does not affect the release profile, whereas increasing RPM of the paddle reduces the dissolution profile; hence it can be stated that Entacapone dissolution is pH dependent, showing maximum dissolution and pH 6.8 which is contradictory to the conditions specified in USP 2010.
Development of characterization methods for entacapone in a pharmaceutical bulk
Journal of Pharmaceutical and Biomedical Analysis, 2011
A comprehensive approach was taken to develop analytical procedures for the characterization of entacapone in a pharmaceutical bulk. A novel reversed-phase HPLC method was developed and validated for the assay of entacapone and the determination of impurities. The method employed a C18 column, a mobile phase of potassium phosphate buffer (pH 2.75, 30 mM)-methanol (50:50, v/v) at a flow rate of 1.0 mL/min, and ultraviolet (UV) detection at 310 nm. The method was linear over the range from 50% to 150% of the assay concentration (0.2 mg/mL). The limit of quantitation was 0.13 g/mL, and the limit of detection was 0.05 g/mL. Average recovery was 100.10% with a relative standard deviation (N = 9) of 0.45%. Degradation studies showed that entacapone eluted as a spectrally pure peak and was well resolved from its degradation products. The method was specific, sensitive, precise, linear, and accurate.
Pharmaceutical Methods, 2012
The aim of this work is to establish two simple, economical, and rapid spectrophotometric methods for the quantification of entacapone in bulk material and in tablets. Further, this study is designed to validate the developed methods as per ICH guidelines. Materials and Methods: In Methods I and II, a stock standard solution was prepared by dissolving 10 mg of entacapone in 100 mL of 10% v/v acetonitrile to obtain a concentration of 100 µg/mL. After suitable dilution, 10 µg/mL of entacapone was prepared and scanned in the UV-visible range 500-200 nm; entacapone showed a maximum absorbance at 384.40 nm. In Method I, area under curve (AUC) of the zero-order spectrum was recorded between 348.00 and 410.20 nm. While, in Method II, zero-order spectra were derivatized into first-order, and the AUC was recorded between 386.40 and 460.20 nm. For a linearity study, series of dilutions were prepared from stock solutions. Results: In Method I, and II, entacapone followed linearity in the concentration range of 2-12 µg/mL and 5-30 µg/mL with (r 2 >0.999). The amounts of entacapone estimated by both these methods were found to be 99.24 ± 0.054 and 98.68 ± 1.04, respectively. Conclusion: The developed methods are simple, precise, rugged, robust, and economical. Both these methods can be used for routine analysis of entacapone from its tablet formulation.
Journal of Pharmacology and Experimental Therapeutics, 2003
Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t 1/2 ) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after ABBREVIATIONS. COMT, catechol-O-methyltransferase; t 1/2 , elimination half-life (-phase); S-COMT; soluble catechol-O-methyltransferase; MB-COMT, membrane-bound catechol-O-methyltransferase; AUE, area under the effect-time curve; AUC, area under the plasma drug concentration-time curve; C 0 , initial plasma concentration; E 0 , baseline effect; E max , maximum attainable effect.