CSIR-NCL Pune research team discovers novel hydrate polymorphs of Entresto
A research team from the CSIR-NCL, Pune, has successfully characterised and identified six different crystalline forms of Entresto
A research team from the Council of Scientific and Industrial Research – National Chemical Laboratory (CSIR-NCL), Pune, has successfully characterised and identified six different crystalline forms of Entresto, with varying water content and containing the active pharmaceutical ingredients (APIs) Valsartan and Sacubitril in their anionic state with bonded sodium cations. Entresto is the world’s top-selling drug launched for the treatment of chronic heart failure in advanced critical patients, approved by the US food and drug administration (FDA) in 2015.
The research on novel crystalline hydrate forms and polymorphs of Entresto was initiated by the CSIR-NCL in 2018 as part of a ‘mission mode’ programme funded by the CSIR. Professor Ashwini Kumar Nangia, the then director of CSIR-NCL, and Rajesh G Gonnade, chief scientist from the physical and materials chemistry division, led the project. The comprehensive study has appeared in the Royal Society of Chemistry journal CrystEngComm, which deals with crystal engineering and drug polymorphs.
Professor Nangia said, “The different hydrated forms of Entresto have 2.0 to 3.2% water and exhibit additional stability to temperature and moisture, which is vital for their long-term storage, shelf-life and drug bioavailability. This paper is a first-of-its-kind wherein investigators have shown that large supramolecular drug complexes pose unique challenges in the characterisation of polymorphs and hydrate structures by powder X-ray diffraction, thermal measurements and spectroscopic techniques. The next task for the team will be to understand the molecular packing arrangement and hydrogen bonding with water by determining its crystal structures.”
Entresto is different from other drugs of its ilk; it has a multi-drug supramolecular complex of Sacubitril and Valsartan as a trisodium hemi-pentahydrate salt cocrystal. Most drugs in the market are single-drug molecules while others are fixed-dose combinations (FDCs) or administered as a combination of multiple drugs (cocktail dosage) for treatment.
Gonnade said, “Entresto is a first-in-class drug designed and developed using crystal engineering principles, supramolecular synthons and pharmaceutical cocrystals published in academic literature starting in the early 2000s and patents filed in subsequent years. A drug can exist in solid state in more than one crystal form, referred to as polymorphs. These are important for tablet oral formulation and its bioavailability properties such as solubility, permeability, and absorption in the body. Entresto is different from other drugs in other aspects too. For example, the cocrystal-salt complex’s crystal structure comprises six Sacubitril and Valsartan molecules, each in their anionic form, along with 18 penta- and hexa-coordinated sodium cations and 15 water molecules.”
While commenting on the research, professor Gautam R Desiraju, emeritus professor, IISc, Bengaluru, and former president, International Union of Crystallography, said, “These results are important because it has come at the intersection of cutting-edge science, legal questions, and commercial viability. The utmost scrutiny from various quarters is needed to safeguard intellectual property (IP) from Indian laboratories and institutions; India is at the forefront of international crystal engineering research.”