Combining X-ray diffraction, solid-state NMR, and computational chemistry for structural insights and performanceevaluation of GIPAW/GIAO 13C chemical-shift calculationsfor lamivudine and three pharmaceutical salts

Abstract

The increasing prevalence of polymorphism and multicomponent crystal forms in active pharmaceutical ingredients demands rigorous structural characterization tools for quality control. Here, lamivudine and three pharmaceutical salts, hydro-chloride, salicylate monohydrate, and hydrogen phthalate, were investigated by combining powder X-ray diffraction, 13C solid-state NMR spectroscopy, and two DFT-based methods for theoretical chemical-shift prediction: gauge including projected augmented wave (GIPAW) and gauge including atomic orbital (GIAO). In statistical comparison of experimental and theoretical chemical shifts, the GIPAW method consistently outperformed GIAO for all four crystalline forms, as evidenced by lower median errors and higher Kendall’s τ correlation coefficient values, a rank-order metric that proved more discriminating than Pearson’s R alone. The superior performance of GIPAW is attributed to its explicit treatment of periodic boundary conditions, which faithfully reproduces the crystallographic environment of the solid state. In addition, QTAIM topological analysis and natural bond orbital (NBO) second-order perturbation theory were used to characterize all inter- and intramolecular hydrogen bonds in each form. Two strong, nearly symmetric O···H···O interactions in the hydrogen phthalate salt are reported here for the first time, consistent with the anomalously low pKa2 of ortho-phthalic acid. These results demonstrate that the combined use of periodic GIPAW NMR calculations with QTAIM/NBO analysis constitutes a powerful, generally applicable strategy for the unequivocal structural characterization of pharmaceutical solid forms, with direct implications for the physicochemical quality control of drug substances.