Simvastatin: structure solution of two new low-temperature phases from synchrotron powder diffraction and ss-NMR

Abstract

Simvastatin is a substance used for the treatment of hypercholesterolemia. In addition to the already known room temperature structure of simvastatin (Č ejka et al. in Acta Cryst C59:o428, 2003) two new low-temperature polymorphs were found by X-ray powder diffraction with the phase transition at 261 and 223 K (later confirmed by DSC to be 272 and 232 K). The main differences among three polymorphs consist in the side-chains conformation only and the phase changes are fully reversible. The structures of the polymorphs were studied by the powder diffraction based on synchrotron radiation as well as by solid-state NMR spectroscopy.

Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia

“…Crystalline and amorphous samples of pure APIs, physical mixtures of the two crystalline APIs of the components and the amorphous binary systems were measured. Figure 4 a shows the diffraction pattern for crystalline SIM; diffraction peaks are in agreement with previous results, showing characteristic peaks at 9.3 , 10.8 , 17.2 , 18.7 , and 22.5 for , which correspond to reported values [ 25 ]; it is the only stable polymorph at standard conditions [ 30 ]. The PXRD pattern for crystalline NIF is shown in Figure 4 c, and the diffraction peaks coincide with the ones reported for the polymorph A [ 27 ], showing characteristic peaks at 7.9 , 10.3 , 11.6 , 16.0 , 24.5 and 25.7 for 2 .…”

Solution thermodynamics of simvastatin in pure solvents and binary solvent mixtures

“…SMV is widely used to treat hypercholesterolemia as a cholesterol-lowering agent due to its well proven efficacy and safety behavior [1][2][3][4].…”

Enantiotropy of Simvastatin as a Result of Weakened Interactions in the Crystal Lattice: Entropy-Driven Double Transitions and the Transient Modulated Phase as Seen by Solid-State NMR Spectroscopy

“…To better understand the molecular mechanisms of the phenomena that separate individual crystal phases of simvastatin and control phase transitions, we first analyzed the crystal structure of the low-temperature Form III ( Figure 9 ). Form III is distinguished by the presence of two symmetry-independent molecules (designated A and B below; see also reference [ 4 ]), which have different torsion angles in the ester parts C20-C21-C22-C23 and O4-C20-C21-C22 (A: −172° and −11°; B: −76° and −36°). Molecular packing is driven predominantly by hydrogen bonding involving ester-carboxyl groups C20 and hydroxyl groups of the lacton cycle [ 33 ].…”

“…A typical representative of such compounds is simvastatin ( Figure 1 ). Although active pharmaceutical ingredients (APIs) have long been used to control hypercholesterolemia, new low-temperature polymorphic APIs were serendipitously discovered in 2010 [ 4 ]. Later in 2018, Simões et al [ 5 ] investigated the three-fold polymorphism of simvastatin, exploiting X-ray, calorimetry and molecular-simulation methods to investigate the related structural, conformational and thermodynamic aspects.…”