Background: A simple and sensitive quantitation analytical technique by liquid chromatography–tandem mass spectrometry (LC-MS/MS) is essential for fedratinib in biological media with kinetic study in healthy rabbits. Objective: The main objectives of the present research work are to LC-MS/MS method development and validate procedure for the quantitation of fedratinib and its application to kinetic study in rabbits. Methods: Separation of processed samples were employed on zorbax SB C18 column (50mm×4.6 mm) 3.5µm with a movable phase of methanol, acetonitrile and 0.1% formic acid in the ratio of 30:60:10. The movable phase was monitored through column at 0.8 ml/min flow rate. The drug and ibrutinib internal standard (IS) were evaluated by monitoring the transitions of m/z -525.260/57.07 and 441.2/55.01 for fedratinib and IS respectively in multiple reaction monitoring mode. Results: The linear equation and coefficient of correlation (R2) results were y =0.00348x+0.00245 and 0.9984 respectively. Intra and inter-day precision %RSD findings of the developed technique were found in the range of 2.4 – 5.3% for the quality control (QC)-samples (252.56, 1804.0 and 2706 ng/ml). The proposed method was subjected for pharmacokinetic study in healthy rabbits and from the kinetic study, fedratinib was shown mean AUClast was 13190±18.1 hr*ng/ml and Cmax was found to be 3550±4.31 ng/ml in healthy rabbits. Conclusion: The validated method can be applicable for the pharmacokinetic and toxicokinetic studies in the clinical and forensic analysis of fedratinib in different kinds of biological matrices successfully.

An oral dosage form containing gastro-retentive floating tablets forms a stomach-specific drug delivery system for the treatment of hypertension. Valsartan belongs to the BCS class II (poo Classification System). It is desirable to improve the extent of bioavailability (23%).  The objective of the present study was to apply design of experiment to optimize floating drug delivery of valsartan by employing 22 factorial design.  Improvement of the aqueous solubility of valsartan was done by solid dispersions using hot melt extrusion technique.  Plasdone S630 copovidone is a variable carrier and drug to carrier ratio of 1:2 was optimized.  Valsartan floating tablets were prepared by employing factorial design (22), where HPMC K15M (X1) and pregelatinized starch (X2) were independent variables and drug dissolution was the dependent parameter (Y1) to prepare matrix tablets.  The factorial analysis, steepest ascent method was utilized for obtaining optimized formulation. In vitro evaluation, In vivo radiographic study and biopharmaceutical analysis in rabbits for valsartan optimized formulation (FT-5). Floating lag time (FLT) for valsartan optimized formulation (FT-5) was 15 s and total floating time (TFT) of the tablets was about 33 h, which was satisfactory.  A four-point (1 h, 4 h, 8 h and 16 h) dissolution analysis gave satisfactory dissolution profile up to 24 h.  The release kinetics of valsartan optimized formulation (FT-5) followed zero order and the release mechanism was found to be Korsemeyer Peppas model, i.e. swelling type.  The dissolution efficiency for valsartan floating tablets was 1190.89% against the marketed formulation of 39.77%. The accelerated stability profile of valsartan optimized formulation (FT-5) was evaluated in terms of drug content and percent cumulative dissolution of valsartan in 24 h, in a 6 months study.  In vivo X-ray image study for valsartan optimized formulation (FT-5) indicated the presence of intact tablet up to 12 h in gastric region of rabbit.  The biopharmaceutical analysis in rabbits was conducted for valsartan optimized formulation (FT-5). The HPLC method was established and validated for the in vivo analysis.  The Cmax was 453.2 ng/mL compared to that of the marketed tablets (522.4 ng/mL).  The mean residence time (MRT) for the valsartan optimized formulation (FT-5) was 14.82 h as against 4 h for marketed tablet.  The relative bioavailability of valsartan optimized formulation (FT-5) was 650% higher than the marketed tablet.  To overcome the poor bioavailability of valsartan, it was suitably modified using hot-melt extrusion for improving therapeutic outcome. In conclusion, gastro-retentive drug delivery system is an excellent approach for improving the bioavailability of valsartan.