The basic configuration of glucocorticoid consists of four-fused rings associated with one cyclohexadienone ring, two cyclohexane rings, and one cyclopentane ring. The ways the structure and dynamics of five glucocorticoids (prednisone, prednisolone, prednisolone acetate, methylprednisolone, and methylprednisolone acetate) are altered because of the substitution of various functional groups with these four-fused rings are studied thoroughly by applying sophisticated solid-state nuclear magnetic resonance (NMR) methodologies. The biological activities of these glucocorticoids are also changed because of the attachment of various functional groups with these four-fused rings. The substitution of the hydroxyl group (with the C11 atom of the cyclohexane ring) in place of the keto group enhances the potential of the glucocorticoid to cross the cellular membrane. As a result, the bioavailability of prednisolone (the hydroxyl group is attached with the C11 atom of the cyclohexane ring) is increased compared to prednisone (the keto group is attached with the C11 atom of cyclohexane rings). Another notable point is that the spin–lattice relaxation rate at crystallographically distinct carbon nuclei sites of prednisolone is increased compared to that of the prednisone, which implies that the motional degrees of freedom of glucocorticoid is increased because of the substitution of the hydroxyl group in place of the keto group of the cyclohexane ring. The attachment of the methyl group with the C6 atom of cyclohexane rings further reduces the spin–lattice relaxation time at crystallographically distinct carbon nuclei sites of glucocorticoid and its bioactivity is also increased. By comparing the spin–lattice relaxation time and the local correlation time at crystallographically different carbon nuclei sites of three steroids prednisone, prednisolone, and methylprednisolone, it is observed that both the spin–lattice relaxation time and the local correlation time gradually decrease at each crystallographically distinct carbon nuclei sites when we move from prednisone to prednisolone to methyl-prednisolone. On the other hand, if we compare the same for prednisolone, prednisolone acetate, and methylprednisolone acetate, then we also observe that both the spin–lattice relaxation time and the local-correlation time gradually decrease from prednisolone to prednisolone acetate to methylprednisolone acetate for all chemically different carbon nuclei. It is also noticeable that both the spin–lattice relaxation time and the local-correlation time gradually decrease from prednisone to prednisolone to prednisolone acetate to methylprednisolone to methylprednisolone acetate for most of the carbon nuclei sites. From in silico analysis, it is also revealed that the bioavailability and efficacy of the glucocorticoid increase from prednisone to prednisolone to prednisolone acetate to methylprednisolone to methylprednisolone acetate. Hence, it can be concluded that the biological activity and the motional degrees of freedom of the glu...

The structure and dynamics of quinine and its quasienantiomer quinidine were studied at the atomic resolution by measuring the chemical shift anisotropy (CSA) tensor and site-specific spin–lattice relaxation time. For quinine, there are three crystallographically independent molecules “a”, “b”, and “c” in an asymmetric unit since its 13C CP-MAS SSNMR spectrum features three distinct resonance peaks for certain carbon nuclei. The 13C assignments are fulfilled by DFT calculations. The experimental 13C isotropic chemical shifts well match the calculated values. These variations of isotropic chemical shift for three independent molecules are also observed by two-dimensional 13C–1H heteronuclear correlation spectroscopy (HETCOR) of quinine. The spin–lattice relaxation time, and the principal components of CSA parameters are also varied substantially for certain carbon nuclei of “a”, “b”, and “c” molecules. For quinidine, its 13C CP-MAS SSNMR spectrum is remarkably different from that of quinine despite, their almost identical solution NMR spectra. Furthermore, the remarkable change in the structure and dynamics of quasienantiomers are also observed including the steric effect of the substituent vinyl group, the variation of helical motifs, and the variation of the strength of the intermolecular hydrogen bonds. The variation of the structure and dynamics of quasienantiomers are thoroughly studied by solid-state NMR measurements. These types of studies will enrich the field of NMR crystallography.

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Significant changes in the spin-lattice time and chemical shift anisotropy (CSA) parameters are observed in two independent molecules of an asymmetric unit of atorvastatin calcium (ATC-I) (which is referred to as “a”- and “b”-type molecules by following Wang et al.). The longitudinal magnetization decay curve is fitted by two exponentialsone with longer relaxation time and another with shorter relaxation time for most of the carbon nuclei sites. The local correlation time also varies significantly. This is the experimental evidence of the coexistence of two different kinds of motional degrees of freedom within ATC-I molecule. The solubility and bioavailability of the drug molecule are enhanced due to the existence of two different kinds of dynamics. Hence, the macroscopic properties like solubility and bioavailability of a drug molecule are highly correlated with its microscopic properties. The motional degrees of freedom of “a”- and “b”-type molecules are also varied remarkably at certain carbon nuclei sites. This is the first time the change in the molecular dynamics of two independent molecules of an asymmetric unit of atorvastatin calcium is quantified using solid-state NMR methodology. These types of studies, in which the chemical shift anisotropy (CSA) parameters and spin-lattice relaxation time provide information about the change in electronic distribution and the spin dynamics at the various crystallographic location of the drug molecule, will enrich the field “NMR crystallography”. It will also help us to understand the electronic distribution around a nucleus and the nuclear spin dynamics at various parts of the molecule, which is essential to develop the strategies for the administration of the drug.

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