Probing NMR chemical shifts in a pharmaceutical compound

GRAD, GABRIELA; CHATTAH, KARINA; BUENO, MARIA SOLEDAD; GARNERO, CLAUDIA; BONZI, EDGARDO

Munich

Encuentro; 8th ORCA User Meeting; 2022

By using ORCA [1] we compute the NMR chemical shifts and IR spectra a pharmaceutical antibiotic of the tetracycline family, the oxytetracycline (OTC), a polymorphic drug that evidences erratic absorption in oral administration. The results performed within Density Functional Theory were compared with the experimental NMR spectra for oxytetracycline hydrochloride (OTC.HCl) [2] .We built the OTC molecule by geometry optimization with Avogadro code [3], then DFT energy minimizations were performed with ORCA quantum chemistry program in vacuum and D2O solvent [1]. After the geometry was optimized we calculated the chemical shifts of 1H, 13C and 15N and compared our calculations with NMR experimental results in solution (1H) and solid state (13C and 15N ). Geometry optimizations and vibrational frequency calculations of the molecule were performed with the ORCA 4.2 program [2] at the DFT level with the PBE0 exchange-correlation functional and def2–TZVP basis set. The NMR parameters of the studied complexes were investigated for the isolated molecule and in solution with deuterated water at the DFT level, and compared with experimental results. The calculations of the absolute nuclear magnetic shielding constants σ were carried out with the PBE0 exchange-correlation functional with the def2–TZVP def2/JK tightscf NMR basis set.The compound with pharmaceutical use (and commercially available) is the OTC.HCl (oxytetracycline hydrochloride). Previously we have characterized the OTC.HCl system with different solution and solid state techniques. From NMR we have obtained 1H, 13C and 15N spectra. The 1H spectrum was obtained in solution with deuterated water (remember that in solution some protons are not visible, for example OH protons). 13C and 15N spectra were obtained with the technique called CP-MAS (Cross polarization magic angle spinning)The project aims to explore conformations and hydrogen bonds in solids, where this compound can exist in different polymorphic forms. The study of the solid forms is important for developing strategies of repositioning and the use of known compounds in new therapeutic alternatives [2].We determined the configuration of the OTC.Hcl system with Avogadro and ORCA calculations.We project to analyse different hydrogen bonds or interactions that appear in solid state. Our plan is to optimize the configuration with two molecules in different arrangements to emulate some otherinteractions or hydrogen bonds that are present in solid state. We will compare with the 1H NMR spectra that was obtained from HETCOR correlation spectra.We should analyse the discrepancies appearing in some proton and nitrogen chemical shifts.