Synthesis of a water-soluble prodrug of entacapone

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...

Life Sciences, 2000

Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N -alkyl and N,Ndialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N -alkyl and N,N -dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t 1/2 ϭ 14.9Ð 20.7 h), but hydrolyzed rapidly (t 1/2 ϭ 0.8Ð2.7 h) in human serum. However, in contrast to N -alkyl carbamates, N,N -dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N -Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N -alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.

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...

Chromatographia, 2014

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.

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.

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.

The Pharma Innovation Journal, 2014

The objective of the present investigation was to formulate Entacapone sustained release matrix tablets using various grades of HydroxyPropyl Methyl Cellulose such as K4M, K15M and K100M by the direct compression method. The effect of concentration and viscosity of polymer on in vitro drug release and release kinetics was studied extensively including swelling and erosion index. The results of precompression properties of the powder blend were found to be in theoretical range for processing into tablet dosage form. The post compression properties results were found to be uniform within the pharmacopoeial limits. In vitro release study exhibited that drug release extended up to 7 h to 18 h. It concludes that an increase in the viscosity of polymer decreased the drug release. The drug release mechanism was observed to follow zero order kinetics and non Fickian diffusion mechanism. Drugexcipient compatibility was characterized by FTIR and DSC study and confirmed that no incompatibility...

Research Square (Research Square), 2024

Entacapone is utilized as an adjunct to levodopa therapy for the treatment of Parkinson's syndrome. According to the Biopharmaceutics Classi cation System, it is classi ed as a class IV drug. The solubility of a substance can be enhanced by utilizing nanoemulsion, which can also effectively traverse the bloodbrain barrier owing to its nanoscale dimensions. The formulation utilized various proportions of Capmul Medium Chain Mono and Diglycerides as the oil phase, Pluronic F127, and Phospholipin 90 as hydrophilic and lipophilic surfactants. Optimization was performed using 3 2 factorial designs in Design Expert ® 8.0.5.2 software, incorporating mixing speed, time, and sonication parameters. The nanoemulsion exhibited an average particle size of 120.8±1.9nm, with a low polydispersity index of 0.144, indicating a uniform globule size. The zeta potential suggested good stability, while the XRD pattern indicated decreased drug crystallinity. The TEM images con rm that the size of the particles falls within the range of 120-150 nm and there is no evidence of aggregation. The drug was released at a rate of 80.33±0.92% for 8 hours. The current study demonstrates enhancements in the solubility and stability of formulated nanoemulsions designed for oral delivery.