Study of the Variation of the Electronic Distribution and Motional Dynamics of Two Independent Molecules of an Asymmetric Unit of Atorvastatin Calcium by Solid-State NMR Measurements

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 spinlattice 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.

Automated summary

Significant changes in the spin-lattice time and chemical shift anisotropy parameters have been observed in two independent molecules of atorvastatin calcium, indicating the coexistence of two different kinds of motional degrees of freedom. These changes enhance the solubility and bioavailability of the drug molecule. The use of solid-state NMR methodology quantifies for the first time the molecular dynamics of the two independent molecules in an asymmetric unit of atorvastatin calcium.