Darifenacin Research Articles

Self-Nanoemulsifying/ Self-Assembled Cubic Nanoparticles Lyophilized Tablet: A Novel Biphasic Release Approach to Enhance the Bioavailability of a Lipophilic Drug.

This study aimed to prepare a combined self-nanoemulsifying and self-assembled cubic nanoparticles (SNE/SAC) lyophilized tablet eliciting biphasic release pattern escorted with enhanced bioavailability for drugs hampered with slow dissolution and poor absorption. The antimuscarinic Darifenacin hydrobromide (DRF) was selected as a model drug used to treat overactive bladder-associated nocturia. The DRF-SNE/SAC lyophilized tablet was prepared so that upon reconstitution a mixture of DRF-loaded cubic nanoparticles and nanoemulsion dispersion is obtained. The nanoemulsion portion is responsible for the fast release followed by controlled release of the remaining dose loaded in cubic nanoparticles. A comparative pharmacokinetic study adopting randomized crossover design in male albino rabbits versus marketed product Frequefenacine® tablet was performed. Half of the dose (52.05% ± 4.21%) was rapidly released in the first 4h followed by sustained release of the remaining drug where (90.16% ± 8.85%) was released in 24h. The tested system showed 2.45 folds higher % relative bioavailability and 1.57 folds higher Cmax with 1.62 longer residence time relative to reference product. The results endow the ability of the developed DRF-SNE/SAC lyophilized tablet to be considered as a propitious approach for the treatment of overactive bladder-associated nocturia without midnight dose administration.

Application of D-Optimal Mixture Design in the Development of Nanocarrier-Based Darifenacin Hydrobromide Gel.

Darifenacin hydrobromide, a BCS Class II drug, is poorly bioavailable due to extensive first-pass metabolism. The present study is an attempt to investigate an alternative route of drug delivery by developing a nanometric microemulsion-based transdermal gel for the management of an overactive bladder. Oil, surfactant, and cosurfactant were selected based on the solubility of the drug, and surfactant: cosurfactant in surfactant mixture (Smix) was selected at a 1:1 ratio as inferred from the pseudo ternary phase diagram. The D-optimal mixture design was used to optimize the o/w microemulsion wherein the globule size and zeta potential were selected as dependable variables. The prepared microemulsions were also characterized for various physico-chemical properties like transmittance, conductivity, and TEM. The optimized microemulsion was gelled using Carbopol 934 P and assessed for drug release in vitro and ex vivo, viscosity, spreadability, pH, etc. Drug excipient compatibility studies showed that the drug was compatible with formulation components. The optimized microemulsion showed a globule size of less than 50 nm and a high zeta potential of -20.56 mV. The ME gel could sustain the drug release for 8 hours as reflected in in vitro and ex vivo skin permeation and retention studies. The accelerated stability study showed no significant change in applied storage conditions. An effective, stable, non-invasive microemulsion gel containing darifenacin hydrobromide was developed. The achieved merits could translate into increased bioavailability and dose reduction. Further confirmatory in vivo studies on this novel formulation, which is a cost-effective & industrially scalable option, can improve the pharmacoeconomics of overactive bladder management.

Electro-polymerized poly-methyldopa as a novel synthetic mussel-inspired molecularly imprinted polymeric sensor for darifenacin: Computational and experimental study

The massive progress in molecularly imprinted polymers has encouraged the inclusion of new molecules as functional monomers to attain more selective recognition. Herein and for the first time, methyldopa which is a promising dopamine synthetic analogue with multiple phenolic, carboxylic and aminic functional groups, was adopted for fabricating a highly selective molecularly imprinted polymer via a facile electro-polymerization approach. Firstly, a validated computational simulation was conducted based on density functional theory and Mulliken charges for screening binding affinity between the template drug, Darifenacin (DAR), and different monomers, namely; o-phenylenediamine, dopamine and methyldopa. Theoretically, the most stable complex with a binding energy of -170.29 kJ/mol was formed with methyldopa. Simulation analysis was also exploited to predict the optimum stoichiometric ratio between DAR and methyldopa where 1:4 was suggested as the appropriate one for polymer preparation. Such observations were then experimentally verified through UV-spectrophotometry and Job's method in addition to 1H-NMR spectroscopy for identifying possible molecular interactions and binding sites. Poly-methyldopa (PMD) polymer was generated in presence of DAR, followed by electro-deposition of gold nanoparticles on a pencil graphite electrode substrate (AuNP@PMD/PGE). The fabricated electrode was thoroughly characterized by means of atomic force microscope, field-emission scanning electron microscope, X-ray photoelectron spectroscopy and cyclic voltammetry. Using differential pulse voltammetry, the sensor yielded a reproducible voltammetric response over a dynamic linearity range of 3.0 × 10−6 M - 5.0 × 10−5 M of DAR with a detection limit of 9.4 × 10−7 M. The high selectivity and sensitivity of the sensor towards the target analyte over various interfering components promoted its straightforward applicability in dosage form and spiked human plasma.

Zinc Oxide Nanostructured-Based Sensors for Anodic Stripping Voltammetric Determination of Darifenacin

Herein for the first time, the construction and the electroanalytical applications of novel darifenacin (DFC) voltammetric sensors were described. Zinc oxide nanostructures act as a proper redox mediator and exhibit efficient catalytic activity towards the electrooxidation of the DFC molecule. At the optimum measuring conditions, DFC exhibited an irreversible anodic oxidation peak at 0.880 V with an assumed adsorption-reaction mechanism at the electrode surface. Based on the effect of the pH and the scan rate studies, electrooxidation of DFC takes place through the oxidation of the nitrogen atom (N12) in the five-membered ring of the darifenacin molecule with the participation of one electron and one proton in agreement with the molecular orbital calculations. Calibration curves were linear within the DFC concentration ranging from 0.33 to 6.54 × 10−6 mol l−1 with a limit of detection (LOD) and limit of quantification (LOQ) values of 0.08 and 0.23 × 10−6 mol l−1. The proposed sensors exhibited enhanced performance with high measurement reproducibility and prolonged lifetime. The presented voltammetric approach was utilized for precise determination of darifenacin in biological samples and pharmaceutical formulations with acceptable recoveries compared with the traditional spectrophotometric methods.

FORMULATION AND EVALUATION OF DARIFENACIN HYDROBROMIDE TRANSDERMAL PATCH

The aim of present study is to formulate and characterize darifenacin hydrobromide transdermal patch and the effects of non-ionic surfactants span 20 and tween 20 on drug permeation were studied. Transdermal patches were prepared by solvent casting method using PVA, PVP, HPMC E5, HPMC E15 polymers. Propylene glycol and Glycerol were used as plasticizers and Span 20 and Tween 20 were used as permeation enhancers. The prepared patches were evaluated for physicochemical properties like drug content, thickness, weight variation, folding endurance, moisture uptake, watervapour transmission studies. Physicochemical properties have shown better. Drug release studies by in-vitro diffusion, ex-vivo permeation as well as skin irritation. Formulations DPAT2, DPLT3 showed better drug release rate, ux and Q when compared to DPAS2, DPLS2. From the results it was concluded that darifenacin hydrobromide transdermal patch 24 (DPAT2) formulation would reduce the administration frequency, side effects and may avoid uctuations of drug level in the blood in comparison to immediate release formulations which might enhance the patient compliance.

Formulation and In-Vitro Evaluation of Darifenacin Hydrobromide as Buccal Films

Darifenacin hydrobromide (DH) is the more recent uroselective M3 receptor antagonist for treating uncomplicated overactive bladder (OAB). This study was aimed to formulate DH as fast dissolving buccal films (FDBFs) using a solvent casting method to enhance patient’s compliance.
 Films were prepared by using polyvinyl alcohol (PVA) as a film forming polymer. Different types and concentrations of superdisintegrants (croscarmellose sodium, sodium starch glycolate, indion 414) were used to select the best formula by studying the physicochemical properties of the films, disintegration time (DT) and percent drug release.
 The results revealed that formula (F9) that containing 7.5mg DH, 2%w/v PVA, 30%w/w glycerol, 0.5%w/v tween 80, 4%w/w indion 414 was the preferred formula. F9 showed the shortest in-vitro disintegration time (31.28sec). In-vitro dissolution profile showed the lowest T80% of the drug in 3.05 min and the highest release of the drug (94%) within 5 min (D5min %).
 It was concluded that the FDBFs of DH could be considered as a promising drug delivery system with an enhanced disintegration and dissolution rate and better patient compliance.

Development and Evaluation of a (SEDDS) Self - Emulsifying Drug Delivery System for Darifenacin Hydrobromide

Development and Evaluation of a (SEDDS) Self - Emulsifying Drug Delivery System for Darifenacin Hydrobromide

A comprehensive review on analytical methods for darifenacin hydrobromide in various Pharmaceutical dosage form

A comprehensive review on analytical methods for darifenacin hydrobromide in various Pharmaceutical dosage form

Development and Validation of UV-Visible Spectrophotometric Method for Estimation of Darifenacin Hydrobromide in Bulk and Formulation

Development and Validation of UV-Visible Spectrophotometric Method for Estimation of Darifenacin Hydrobromide in Bulk and Formulation

Development and validation of RP-HPLC method for the determination of Darifenacin Hydrobromide in bulk drug and pharmaceutical dosage form

The main objective of present study is to develop and validate a new, simple, precise and accurate RP-HPLC method for the determination of Darifenacin Hydrobromide (DFH) in bulk and pharmaceutical dosage forms. The separation and quantification of the drug was achieved on a RP C18 column (250×4.6mm, 5μm) using a mobile phase of acetonitrile: buffer (50:50), pH 3.0 ± 0.2 at a flow rate of 1 mL/min with detection of analyte at 287 nm. The separation was achieved with in 4.0 ± 0.3 min. The method showed good linearity in the range of 10-100 μg/mL. The intra and inter day RSD ranged from 0.20-0.58%. The recovery (mean ± SD) of low, medium and high concentrations were 98.50 ± 0.20, 100.27 ± 0.15 and 100.90 ± 0.09 respectively. The limit of detection and limit of quantification were 0.31 and 0.61 μg/mL, respectively. It can be concluded that the present method could be superior over the methods which were reported earlier. Kathmandu University Journal of Science, Engineering and TechnologyVol. 13, No. 1, 2017, Page: 36-44

Darifenacin Hydrobromide loaded nanostructured lipid carrier for oral administration

Darifenacin hydrobromide is a selective ?3 receptor antimuscarinic drug and it is used in the management of urinary frequency, urgency, and incontinence in detrusor instability. It slightly soluble in water, undergoes extensive hepatic first-pass metabolism and has short elimination half-life (3–4 hours). Therefore, It has low bioavailability (15.4 % - 18.6 %). Darifenacin hydrobromide loaded NLCs were formulated by emulsification sonication using different ratios of solid lipid to liquid lipid, different types of surfactants, and different concentration of surfactants. Formula sixteen was considered as an optimized formula based on its particle size, PDI, zeta potential and entrapment efficiency. Formula sixteen subjected to further characterization such as DSC, FT – IR, XRD, AFM, and release study. FT-IR and DSC studies showed no interaction between drug and excipients. XRD study showed that drug in amorphous form. AFM study showed discrete lipid nanoparticles with no aggregation. Release study showed burst release in the first hour followed by sustained and controlled release up to 12 hours. The over all study showed the potential of NLC as a carrier for enhancing the bioavailability of darifenacin hydrobromide as compared to the conventional dosage form.
 Key words: Darifenacin hydrobromide, nanostructured lipid carrier, bioavailability.

Development of Sensitive Spectrophotometric Method for Analysis of Darifenacin Hydrobromide Liposomes in Rat Plasma

Development of Sensitive Spectrophotometric Method for Analysis of Darifenacin Hydrobromide Liposomes in Rat Plasma

Enantiospecific HPLC and CE Methods for Separation and Determination of S-Darifenacin in Pharmaceutical Formulations

Two separation techniques were developed for the determination of S-(−)darifenacin (DAR) in the presence of its R-(+) isomer: The first method is high performance liquid chromatography (HPLC) and the second is capillary electrophoresis (CE). Chiral separation for chromatographic HPLC method development was carried out for S-DAR on Daicel CROWNPAK CR (+) (5 μm, 4.0 × 150 mm) column which contains (3,3-diphenyl-1,1-binaphthyl)-crown-6 coated onto a 5.5 μm silica support. The mobile phase system was aqueous acidic 70 % HClO4 (pH 2.5): methanol in the proportion of 90:10 v/v. This current mobile phase was delivered at flow rate 0.8 mL min−1 using UV detector adjusted at 286 nm. In CE method, the enantiomers were separated using 50 μm inner diameter fused-silica capillary cut to total lengths of 31.2 cm using 50 mM phosphate buffer as background electrolyte adjusted to pH 2.5 by triethanolamine. A wide range of cyclodextrins (CDs) were used such as highly sulfated α, γ CDs, hydroxyl propyl-β-CD and sulfobutyl ether-β-CD as chiral selectors. The effects of chiral additives regarding its concentration and content of organic modifier on the enantioseparation were investigated. Linear concentration ranges were from 2.5 to 50 and 40 to 300 μg mL−1 with detection limits 0.67 and 12.28 μg mL−1 for chromatographic HPLC and electrophoretic CE methods, respectively. The two methods were validated according to ICH guidelines with respect to linearity, accuracy, precision, LOQ, LOD and robustness. The suggested methods are suitable for separation and quantitation of S-DAR in tablets.

Development and Validation of a Stability-Indicating RP-HPLC Method for Determination of Darifenacin Hydrobromide in Bulk Drugs

An isocratic stability-indicating reversed phase high performance liquid chromatographic method (RP-HPLC) was developed for determination of process related impurities and assay of darifenacin hydrobromide (DRF) in bulk drugs. DRF was subjected to various stress conditions such as hydrolysis (acid, base, and neutral), oxidation, photolysis and thermal degradation as per International Conference on Harmonization (ICH Q1A(R2) and Q1B) prescribed conditions to investigate the stability-indicating ability of the method. Significant degradation was observed during acidic hydrolysis and oxidative stress conditions. The chromatographic separation was accomplished on a Prodigy C8 column (250 × 4.6 mm, 5 μm) with mobile phase consisting of 0.05 M ammonium acetate (pH adjusted to 7.2 by using ammonia solution) and methanol (36% acetonitrile) in 35:65 v/v ratio in an isocratic elution mode at a flow rate of 1.0 mL/min at 25°C. Detection of analytes was carried out using photo diode array detector at a wavelength of 215 nm. The developed LC method was validated with respect to accuracy, linearity, precision, limits of detection and quantitation and robustness as per ICH guidelines.

Development and validation of a derivative ultraviolet spectrophotometric method for the determination of darifenacin in tablets using experimental designs and its comparison with chromatographic method

A set of experimental designs was applied to develop and validate a spectrophotometric method using derivative transformation coupled with zero-crossing methodology for the quantification of darifenacin hydrobromide in extended-release tablet form. In the presence of the matricial interference, a central composite (face-centered) design was necessary to reach the best condition without interference in the quantification. The optimal system was confirmed using the function named Derringer’s desirability to assess high precision and low quantification limit. The best condition pointed was the first order to derivative transformation, Δλ = 4, scale factor 150, scanning speed 280 nm/s and anulation point in 239.4 nm as wavelength. From these parameters it was possible to perform the method validation resulting in R2 = 0.999, concentration ranging from 0.10 to 2.50 μg/mL, recovery 98.65% and mean precision 97.67% (RSD = 0.0136). Additionally, robustness was assessed by a Plackett-Burman design, and no significant variability was obtained. The spectrophotometric method was compared with high-performance liquid chromatography method, resulting in no significant difference between the methods.

Darifenacin in a real-world practice: results of a 6-month phase IV. trial

Introduction: Patients often stop treatment and report adverse events when treated with drugs for overactive bladder (OAB). Which predictors influence compliance and treatment success was studied for M3 selective anticholinergic darifenacin in a real-world situation. Methods: Prospective observational multicentre 24-week phase IV trial. Patients with OAB were prescribed darifenacin. Adverse effects and compliance with treatment were evaluated. Treatment success was evaluated as change in the bother score on the 6-point scale for condition assessment. Results: 710 patients: 218 males, 492 females, mean age 61 years. 19.2 % were either lost or reported no improvement, 48.2 % reported improvement by 1 or 2 grades and 32.7 % improved by 3 or more grades. Better treatment success was found among those with more problems (higher bother) and younger. Gender, previous exposure to anticholinergics or presence of adverse effects were not related to treatment success. 581 (81.8 %) of included patients were on treatment for the duration of the study and 542 (76.3 %) continued after 6 months. The most significant predictor for discontinuation of treatment was the presence of adverse events (reactions), others were age (younger tend to stop treatment) and duration of problems (those with shorter duration tend to stop). Grade of problems, previous anticholinergic or gender were not related to discontinuation of treatment. Adverse events were reported by 192 patients (27 %). Females reported adverse events more often than males. Duration or grade of symptoms and age were not related to adverse events. Conclusions: Darifenacin is equally effective in both genders. It is the first-choice anticholinergic and is also useful in cases where other anticholinergics fail.

Development and validation of RP-UPLC method for the determination of darifenacin hydrobromide, its related compounds and its degradation products using design of experiments

A selective stability-indicating ultra-performance liquid chromatographic (UPLC) method was developed for the quantitative determination of darifenacin hydrobromide (DFN) and its related compounds in API and pharmaceutical dosages. The chromatographic separation was achieved on an Acquity UPLC BEH C18 column (100, 2.1mm and 1.7μm) at a flow rate of 0.3mL/min, and detection was performed at 210nm. The typical retention behaviors of impurities at various pH values were depicted graphically. The LC conditions were optimized by design of experiments (DOE) to obtain optimal separation in the shortest possible run time. A central composite design (CCD) was employed to study the main effects and interactions of the independent variables. The drug and its thirteen impurities were eluted within 13min. The method exhibited consistent, high-quality recoveries (93.8±2.1 to 99.8±1.5 (mean±RSD)) with a high precision for the drug and impurities. Linear regression analysis revealed an excellent correlation between peak responses and concentrations (R2 values of 0.9991–0.9999) for the drug and impurities. The stability-indicating capability of the method was verified by forced degradation experiments and mass balance study. LC–MS revealed protonated molecular ion peaks [M+H]+ at m/z 428.20, m/z 425.20 and m/z 281.30 for the acid (Imp-4), oxidized (Imp-6) and N-dealkylated (Imp-1) forms of DFN, respectively. Possible degradation pathways were established based on the known reactivity of the drug through hydrolysis, oxidation, N-dealkylation, phenyl hydroxylation, dihydrobenzofuran ring hydroxylation and ring opening. The m/z values of unknown degradation products were matched with the proposed structures and reported DFN metabolites.

A New Solvent System (Cyclopentyl Methyl Ether–Water) in Process Development of Darifenacin HBr

Darifenacin is a potent and competitive M3 selective receptor antagonist (M3SRA), and its hydrobromide salt (1) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromide (1).

DENSITOMETRIC EVALUATION OF STABILITY – INDICATING HPTLC METHOD FOR THE ANALYSIS OF DARIFENACIN HYDROBROMIDE IN BULK AND IN TABLET DOSAGE FORM

A simple and sensitive thin-layer chromatographic method has been established for analysis of darifenacin hydrobromide in pharmaceutical dosage form. Chromatography on silica gel 60 F254 plates using toluene:acetone:methanol (6:3:3 v/v/v) as the mobile phase furnished compact spots at Rf 0.34 ± 0.02. Densitometric analysis was performed at 286 nm. To show the specificity of the method, darifenacin hydrobromide was subjected to acid, base, neutral hydrolysis, oxidation, photolysis, and thermal decomposition. The drug underwent degradation only under oxidative condition; also the degraded product was well separated from pure drug with significantly different Rf value. Linear regression analysis revealed a good linear relationship between peak area and amount of darifenacin hydrobromide in the range of 50–450 ng/spot. The minimum amount of darifenacin hydrobromide that could be authentically detected and quantified was 30.36 and 90.79 ng/spot, respectively. The method was validated, in accordance with ICH guidelines for precision, accuracy, and robustness. As the method could effectively separate the drug from its degradation products, it can be regarded as stability indicating.

Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC-ESI/MSn

The present study describes the identification and characterization of two process impurities and major stress degradants in darifenacin hydrobromide using high performance liquid chromatography (HPLC) analysis. Forced degradation studies confirmed that the drug substance was stable under acidic, alkaline, aqueous hydrolysis, thermal and photolytic conditions and susceptible only to oxidative degradation. Impurities were identified using liquid chromatography coupled with ion trap mass spectrometry (LC-MS/MS(n)). Proposed structures were unambiguously confirmed by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and elemental analysis (EA). Based on the spectroscopic, spectrometric and elemental analysis data, the unknown impurities were characterized as 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-2-oxo-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-A), 2-[1-(2-benzofuran-5-yl-ethyl)-pyrrolidin-3-yl]-2,2-diphenylacetamide (Imp-B), 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)-ethyl]-1-oxy-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-C) and 2-{1-[2-(7-bromo-2,3-dihydrobenzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-D). Plausible mechanisms for the formation and control of these impurities have also been proposed. The method was validated as per regulatory guidelines to demonstrate specificity, sensitivity, linearity, precision, accuracy and the stability-indicating nature. Regression analysis showed a correlation coefficient value greater than 0.99 for darifenacin hydrobromide and its impurities. The accuracy of the method was established based on the recovery obtained between 86.6 and 106.7% for all impurities.