Febuxostat

Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 5 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insufficiency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout flares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the first major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and efficacy is required.

Compatibility study (based on microenvironmental pH and isothermal stress testing) of Febuxostat was carried out with selected excipients (Microcrystalline cellulose (MCC), Mannitol, Lactose, Hydroxypropyl-β-cyclodextrin (HP-β-CD), Polyethylene glycol(PEG) 6000, Polyvinyl pyrollidoneK30, Eudragit EPO, Sodium starch glycollate, Croscarmellose sodium (CCMC), Sodium lauryl sulphate, Magnesium stearate (MgS), Sodium steryl fumarate, Aerosil 200 and Purified talc) using FTIR and HPLC. Among them, Aerosil 200, MgS, Purified talc, Lactose and MCC were selected for the formulation of Febuxostat tablet. Three different polymers viz. PEG 6000, HP-b-CD and CCMC were selected as independent variables to enhance the dissolution rate by their complexation. Fifteen formulations obtained from Box Behnken design (BBD) (Minitab 16) were prepared through kneading method. Contour plot suggested CCMC (13.01mg) and HP-b-CD (65.45mg) excluding PEG 6000 for optimized formulation. Drug release profile of optimized formulation compared separately with formulation without filler, without polymer, physical mixture and a marketed product using similarity (fs) and dissimilarity (fd) factors showed similarity with marketed product. Similarly, similarity and dissimilarity factors for formulation without filler and optimized formulation was obtained within the range (fs= 82.34 and fd=5.42) indicating that the filler does not have any effect on the drug release. fs and fd for formulation without polymer and physical mixture lied outside the range suggesting the importance of the polymer complexation in the formulation. An accurate, simple, precise and robust reversed-phase liquid chromatographic method was developed for the estimation of Febuxostat. Furthermore, solid state characterization evaluated by FTIR showed that complexation between the polymers has occurred in the optimized formulation.

A rapid, accurate, linear, and sensitive RP-HPLC method has been developed and validated for estimation of febuxostat in the bulk drug and marketed tablet formulation. The chromatographic separation was achieved on Kromasil C18 Column (250 mm × 4.6 mm, 5 μm particle size) using solvent methanol:water(65 : 35 v/v, pH 3.0 adjusted with OPA)as a mobile phase at flow rate of 1.0 ml/min and25°C column temperature was maintained and analysis were carried out at detection wavelength316 nm. The linearity study was studied in the concentration range 10-50 μg/ml for febuxostat and correlation coefficient was found to be 0.999. The percentage purity of febuxostat was found in the range of 98-101%. The limit of detection and limit of quantification were found to be1.22μg/ml and3.58μg/ml. The method was validated for linearity, precision, accuracy, specificity and selectivity. The obtained results indicates that the proposed method allows selective analysis of febuxostat, in the presence of their degradation products formed under a variety of stress conditions. The developed procedure is also applicable for the determination of instability of the drugs in commercial products.

Drug delivery via nanoparticle-based carriers has shown promising results for different types of diseases. Delivery of anti-gout agents into body is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform for febuxostat. The work presented here describes the development of nanoparticles based on compritol. The method employed for the preparation of SLN is micro emulsification technique followed by high pressure homogenization. Phase diagram was developed to know the region of stable micro emulsion formation. Eight different formulas were developed with different concentrations of lipid, surfactant and aqueous concentrations. The developed formulations were evaluated for particle size distribution, zeta potential, entrapment efficiency, DSC thermal analysis and in vitro drug release studies. Among all the formulations developed, F3 formulation is showing better drug entrapment efficiency and controlled release of drug up to 24h. There was 12 fold increase in the solubility of drug in the developed formulation. The solid lipid nanoparticles of febuxostat can be prepared by using simple micro emulsification technique. The formulations had shown better release profile and solubility characteristics.

This study is aimed at Developing and validating an UPLC method for febuxostat and its related substances that might coexist in bulk drugs and its tablet formulations as impurities that may originate from synthesis process or degradation. A chromatographic system consisting Waters Acquity UPLC HSS C18 (1.8 µm) column, mobile phase of  ammonium acetate with pH 4.5 as Buffer phase and Acetonitrile: Methanol in 1:1 ratio as organic phase, with gradient elution at flow of 0.4 mL/min and UV detector set at 315 nm has shown a good chromatographic separation for Febuxostat and its related substances. The developed method was validated as per ICH Guidelines and shown equivalency with API Vendor method. The developed UPLC method has run time of only 10 minutes making the method productive and may be applied for Quality control Testing.