Very recently, Food and Drug Administration (FDA) has approved a few new drug applications (NDA) with regulatory flexibility for quality by design (QbD) based analytical approach. The concept of QbD applied to analytical method development is known now as AQbD (analytical quality by design). It allows the analytical method for movement within method operable design region (MODR). Unlike current methods, analytical method developed using analytical quality by design (AQbD) approach reduces the number of out-of-trend (OOT) results and out-of-specification (OOS) results due to the robustness of the method within the region. It is a current trend among pharmaceutical industry to implement analytical quality by design (AQbD) in method development process as a part of risk management, pharmaceutical development, and pharmaceutical quality system (ICH Q10). Owing to the lack explanatory reviews, this paper has been communicated to discuss different views of analytical scientists about implementation of AQbD in pharmaceutical quality system and also to correlate with product quality by design and pharmaceutical analytical technology (PAT).

The epithelial-to-mesenchymal transition (EMT) has received significant interest as a novel target in cancer prevention, metastasis, and resistance. The conversion of cells from an epithelial, adhesive state to a mesenchymal, motile state is one of the key events in the development of cancer metastasis. Polyphenols have been reported to be efficacious in the prevention of cancer and reversing cancer progression. Recently, the antimetastatic efficacy of polyphenols has been reported, thereby expanding the potential use of these compounds beyond chemoprevention. Polyphenols may affect EMT pathways, which are involved in cancer metastasis; for example, polyphenols increase the levels of epithelial markers, but downregulate the mesenchymal markers. Polyphenols also alter the level of expression and functionality of important proteins in other signaling pathways that control cellular mesenchymal characteristics. However, the specific proteins that are directly affected by polyphenols in these signaling pathways remain to be elucidated. The aim of this review is to analyze current evidence regarding the role of polyphenols in attenuating EMT-mediated cancer progression and metastasis. We also discuss the role of the most important polyphenol subclasses and members of the polyphenols in reversing metastasis and targeting EMT. Finally, limitations and future directions to improve our understanding in this field are discussed.

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The present study aims at developing a simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma using sildenafil-d8, N-desmethyl sildenafil-d8 as internal standards (IS). Chromatographic separation was performed on Zorbax SB C18, 4.6 Â 75 mm, 3.5 mm column with an isocratic mobile phase composed of 10 mM ammonium acetate and acetonitrile (5/95 v/v), at a flow-rate of 0.6 ml min À1 . Sildenafil, sildenafil-d8, N-desmethyl sildenafil and N-desmethyl sildenafil-d8 were detected with proton adducts at m/z 475.2 / 283.4, 483.4 / 283.4, 461.3 / 283.4 and 469.4 / 283.4 in multiple reaction monitoring (MRM) positive mode respectively. Both drug, metabolite and internal standards were extracted by liquid-liquid extraction. The method was validated over a linear concentration range of 1.0-1000.0 ng ml À1 for sildenafil and 0.5-500.0 ng ml À1 for N-desmethyl sildenafil with correlation coefficient (r 2 ) $ 0.9998 for sildenafil and (r 2 ) $ 0.9987 for N-desmethyl sildenafil. This method demonstrated intra and inter-day precision within 1.5 to 5.1 and 2.2 to 3.4% for sildenafil and within 1.3 to 3.1 and 2.8 to 4.3% for N-desmethyl sildenafil. This method demonstrated intra and inter-day accuracy for sildenafil within 97.3 to 98.3 and 96.7 to 97.2% and for N-desmethyl sildenafil within 95.3 to 96.3 and 95.0 to 97.2%. Both analytes were found to be stable throughout three freeze/thaw cycles, bench top and postoperative stability studies. This method was used successfully for the analysis of plasma samples following oral administration of 100 mg in 43 healthy Indian male human volunteers under fasting conditions.