Role of Hydrogen Bonds in Formation of Co-amorphous Valsartan/Nicotinamide Compositions of High Solubility and Durability with Anti-hypertension and Anti-COVID-19 Potential.

Marika Turek,Piotr Bałczewski,Marek Koprowski,Bernard Marciniak,Ewa Różycka-Sokołowska

doi:10.1021/acs.molpharmaceut.0c01096

Abstract

Physicochemical properties, in particular solubility and the associated bioavailability, are key factors in determining efficacy of poorly water-soluble drugs, which constitute 40% of new drugs in the market, and improving them is an important challenge for modern pharmacy. A recent strategy to achieve this goal is formation of stable co-amorphous solid dispersions with co-formers of low molecular weight. Here, the amorphization strategy was applied for low-soluble anti-hypertensive valsartan (VAL), an angiotensin II receptor blocker, and nicotinamide, which exhibits lung- and cardio-protective effects. Through interactions with the renin–angiotensin–aldosteron system, VAL may be used to treat both hypertension and the current pandemic coronavirus SARS-CoV-2 infection. Using mechanochemical and liquid- and solid-state approaches, solvated co-amorphous solid dispersions of VAL with nicotinamide were obtained. They were characterized by spectroscopic, thermal, and X-ray analyses. The density functional theory, quantum theory of atoms in molecules, and non-covalent interaction index calculations revealed the presence of two types of hydrogen bonds between VAL and NIC (i.e., N–H···O and O–H···O). One of them had a partially covalent character, which caused conformational changes in the flexible VAL molecule, restricting contribution of the tetrazolyl N–H donor and thus limiting the possibility of co-crystal formation. The recognized VAL/NIC1- and VAL/NIC2-type heterodimeric interactions were responsible for the excellent durability of the solid compositions and up to 24-fold better solubility than VAL alone. The synthesized dispersions constitute a new class of dually acting drugs, containing an active pharmaceutical ingredient (VAL) and supporting nutraceutical (nicotinamide).

Highlights

Valsartan (VAL) is an anti-hypertensive drug belonging to the angiotensin II receptor blockers (ARBs), which according to the recommendations of the European Cardiac Society (2016) provide alternative treatment for patients intolerant of angiotensin-converting enzyme inhibitors (ACE inhibitors) or aldosterone receptor blocker therapies.[1]
As our solid dispersions are ethanol-solvated, we investigate the possible intermolecular interactions of ethanol with the VAL/NIC heterodimer by designing the (VAL/NIC1)EtOH system and doing the calculations in the framework of quantum theory of atoms in molecules (QTAIM) and non-covalent interactions index (NCI) methods as in the case of earlier structures
The VAL/NIC slurry and VAL/NIC ball mill dispersions revealed full amorphization and the best solubility. These compositions could be used to treat two seemingly unrelated diseases, such as hypertension and the COVID-19 disease.[82]. This is due to the fact that SARS-CoV-2 enters host cells by utilizing angiotensin-converting enzyme 2 (ACE2), an enzyme which is a target for treatment of hypertension

Summary

Introduction

Valsartan (VAL) is an anti-hypertensive drug belonging to the angiotensin II receptor blockers (ARBs), which according to the recommendations of the European Cardiac Society (2016) provide alternative treatment for patients intolerant of angiotensin-converting enzyme inhibitors (ACE inhibitors) or aldosterone receptor blocker therapies.[1]. No wonder that pharmaceutical industry is intensively looking for solutions that will allow them to reduce the dose of the drugs by enhancing solubility, which improves their bioavailability. Several strategies have been used to improve the oral bioavailability of VAL, such as co-crystallization,[4−7] formation of host−guest β-cyclodextrin complexes,[8,9] synthesis of microcapsules,[10] nanoparticles,[11] and polymeric solid dispersions.[12−14] It is worth noting that the solid dispersion strategy leading to amorphization of pharmaceutical components is especially important in the case of pharmaceuticals, such as VAL, which are difficult to crystallize, and attempts to crystallize them usually lead to a sticky solid, amorphous film, or loose powder.[15]

Methods

Results

Conclusion