A stable amorphous statin: solid-state NMR and dielectric studies on dynamic heterogeneity of simvastatin.
Statins have been widely used as cholesterol-lowering agents. However, low aqueous solubility of crystalline statins and, consequently, reduced biovailability require seeking for alternative forms and formulations to ensure an accurate therapeutic window. The objective of the present study was to evaluate the stability of amorphous simvastatin by probing molecular dynamics using two nondestructive techniques: solid-state NMR and dielectric relaxation spectroscopy. Glassy simvastatin was obtained by the melt quench technique. (13)C cross-polarization/magic-angle-spinning (CP/MAS) NMR spectra and (1)H MAS NMR spectra were obtained from 293 K up to 333 K (Tg ≈ 302 K). The (13)C spin-lattice relaxation times in the rotating frame, T1ρ, were measured as a function of temperature, and the correlation time and activation energy data obtained for local motions in different frequency scales revealed strong dynamic heterogeneity, which appears to be essential for the stability of the amorphous form of simvastatin. In addition, the (1)H MAS measurements presented evidence for mobility of the hydrogen atoms in hydroxyl groups which was assigned to noncooperative secondary relaxations. The complex dielectric permittivity of simvastatin was monitored in isochronal mode at five frequencies (from 0.1 to 1000 kHz), by carrying out a heating/cooling cycle allowing to obtain simvastatin in the supercooled and glassy states. The results showed that no dipolar moment was lost due to immobilization, thus confirming that no crystallization had taken place. Complementarily, the present study focused on the thermal stability of simvastatin using thermogravimetric analysis while the thermal events were followed up by differential scanning calorimetry and dielectric relaxation spectroscopy. Overall, the results confirm that the simvastatin in the glass form reveals a potential use in the solid phase formulation on the pharmaceutical industry.
Centro de Química Estrutural and ‡Centro de Química-Física Molecular and IN-Institute of Nanoscience and Nanotechnology, Instituto Superior Técnico/Universidade de Lisboa , Avenida Rovisco Pais, 1049-001 Lisboa, Portugal.
Teresa G
TG
Nunes
M Teresa
MT
Viciosa
Natália T
NT
Correia
F
F
Danède
Rita G
RG
Nunes
Hermínio P
HP
Diogo
D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D058266:Dielectric Spectroscopy; D004355:Drug Stability; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D019821:Simvastatin / Q000737:chemistry*; D013816:Thermodynamics; D013818:Thermogravimetry
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
DRS; DSC; TGA; amorphous simvastatin; solid-state NMR