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).
【저자키워드】 COVID-19, anti-hypertensive, co-amorphization, nicotinamide, solid dispersion, valsartan, 【초록키워드】 Efficacy, coronavirus, SARS-COV-2 infection, drugs, lung, drug, nicotinamide, valsartan, hypertension, Bioavailability, Density functional theory, X-ray, ingredient, receptor, molecules, Donor, Angiotensin II, Hydrogen bond, Interaction, pandemic coronavirus, angiotensin, conformational change, Physicochemical properties, low molecular weight, hydrogen, receptor blocker, quantum theory, (nicotinamide), approaches, market, treat, key factor, active pharmaceutical ingredient, conformational changes, hydrogen bonds, liquid, Effects, flexible, responsible, caused, applied, characterized, functional, analyses, exhibit, acting, heterodimeric, NIC, 【제목키워드】 solubility, role, bond, Potential, Formation,