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Pune: CSIR-NCL and University of Hyderabad discover new hydrated polymorphs of Entresto – Punekar News

Pune, 23 September 2022: CSIR-National Chemical Laboratory (CSIR-NCL), Pune, under a Mission Mode program funded by the Council for Scientific and Industrial Research (CSIR), has initiated research into new forms of crystalline and polymorphic hydrates from Entresto in 2018. Professor Ashwini Kumar Nangia, then Director of CSIR-NCL, and Dr. Rajesh G. Gonnade, Chief Scientist of the Materials Physics and Chemistry Division, led the project.

The in-depth study was published in the Royal Society of Chemistry’s CrystEngComm journal, which discusses crystal engineering and drug polymorphs. The research team successfully characterized and identified six different crystalline forms of Entresto, with varying amounts of water and containing the active pharmaceutical ingredients (APIs) valsartan and sacubitril in their anionic state with bound sodium cations. The various hydrated forms of Entresto contain 2.0-3.2% water and exhibit additional temperature and humidity stability, which is vital for their long-term storage, shelf life and drug bioavailability. This paper is the first of its kind in which researchers have shown that large supramolecular drug complexes pose unique challenges in characterizing polymorphs and hydrated structures by X-ray powder diffraction, thermal measurements, and spectroscopic techniques. The team’s next task will be to understand the molecular packing arrangement and hydrogen bonding with water by determining its crystal structures.

Professor Gautam R. Desiraju, Emeritus Professor, IISc, Bengaluru and former President of the International Union of Crystallography, commented on the significance of this new disclosure, saying that these results are significant as they stand at the intersection of the cutting edge science. , legal issues and commercial viability. He added that careful scrutiny from various quarters is needed to protect the intellectual property of Indian labs and institutions; India is at the forefront of international crystal engineering research.

Entresto is the world’s top-selling drug launched for the treatment of chronic heart failure in advanced critical patients, approved by the US FDA in 2015. It is different from other drugs having a multi-drug supramolecular complex of sacubitril and valsartan as a hemi-trisodium salt cocrystal pentahydrate. Most of the drugs on the market are single drug molecules, while others are fixed-dose combinations (FDCs) or given as a combination of several drugs (cocktail dosage) for treatment. Entresto is a first-class drug designed and developed using crystal engineering principles, supramolecular building blocks and pharmaceutical co-crystals published in academic literature from the early 2000s and filed patents in subsequent years. A drug can exist in the solid state in several crystalline forms, called polymorphs. These are important for the oral tablet formulation and its bioavailability properties, such as solubility, permeability and adsorption in the body. Entresto is also different from other drugs in other ways.

For example, the crystal structure of the cocrystal-salt complex includes six molecules of sacubitril and valsartan, each in their anionic form, along with 18 penta- and hexa-coordinated sodium cations and 15 water molecules, thus providing a molecular formula of C288 H330 N36 O48 Na18 15H2O, with a molecular weight of 5748. On the other hand, most drugs have a molecular weight below 500.

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