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

Abstract

In crystalline molecular solids, in the absence of strong intermolecular interactions, entropy-driven processes play a key role in the formation of dynamically modulated transient phases. Specifically, in crystalline simvastatin, the observed fully reversible enantiotropic behavior is associated with multiple order-disorder transitions: upon cooling, the dynamically disordered high-temperature polymorphic Form I is transformed to the completely ordered low-temperature polymorphic Form III via the intermediate (transient) modulated phase II. This behavior is associated with a significant reduction in the kinetic energy of the rotating and flipping ester substituents, as well as a decrease in structural ordering into two distinct positions. In transient phase II, the conventional three-dimensional structure is modulated by periodic distortions caused by cooperative conformation exchange of the ester substituent between the two states, which is enabled by weakened hydrogen bonding. Based on solid-state NMR data analysis, the mechanism of the enantiotropic phase transition and the presence of the transient modulated phase are documented.

Keywords: dynamics; enantiotropy; entropy; polymorphism; solid-state nuclear magnetic resonance (NMR); transient modulated phase.

Figure 1

Chemical structure and numbering of simvastatin, C₂₅H₃₈O₅.

Figure 2

DSC (A) and DDSC (B) thermograms measured for simvastatin at temperatures ranging from −60 to +30 °C and from −60 to +100 °C, respectively.

Figure 3

Comparison between theory and experiment for the ¹H–¹³C HETCOR spectrum of Form I of simvastatin. The measured and predicted data are marked with squares and circles, respectively (the atom numbering is detailed in Supplementary Materials, Tables S1 and S2). Statistical parameters, which are shown in the inset, are specified in the Section 5.

Figure 4

Expanded part of the variable temperature ¹³C CP/MAS NMR spectra of simvastatin, measured in the temperature range 231–298 K. Asterix * indicates position of a broadened signal.

Figure 5

Temperature dependences of ¹³C NMR chemical shifts of carbons of the ester tail, measured in the temperature range of 300 to 220 K.

Figure 6

Temperature dependences of T₁(¹³C) relaxation times of the selected units (CH—No. 3 and 10, CH₂—No. 6 and 22 and CH₃—No. 21, 22, and 25), measured in the temperature range of 330 to 220 K. These dependences are expressed as ln(R₁) vs. inverse temperature 1/T, where the relaxation rate is defined as R₁ = 1/T₁(¹³C).

Figure 7

Temperature dependences of the T_1ρ (¹³C) relaxation times of the selected units (CH—No. 3 and 10, CH₂—No. 6 and 20 and CH₃—No. 21, 22, and 25), measured in the temperature range of 330 to 220 K. These dependences are expressed as ln(R_1ρ) vs. inverse temperature 1/T, where the relaxation rate is defined as R_1ρ = 1/T_1ρ(¹³C).

Figure 8

Expanded parts of ¹H–¹³C PILGRIM NMR spectra of crystalline simvastatin measured at 310, 257 and 231 K (A); the corresponding ¹H–¹³C dipolar profiles extracted for methylene CH₂ unit C22 (B); the plot of selected order parameters S² vs. temperature (C); and the molecular structure of simvastatin displaying different segmental motions (D). The corresponding full range ¹H–¹³C PILGRIM NMR spectra are presented in Supplementary Materials Figures S5–S7.

Figure 9

The crystal structure of the low-temperature Form III (150 K, CSD Entry: EJEQAL01) (A); Hirshfeld surface mapped over d_norm, using a color scale of red (shorter than vdW separation), white (equal to vdW separation), and blue (longer than vdW separation) for the symmetry independent A and B molecules (B); and the corresponding 2D fingerprint plot (C).

Figure 10

Crystal structure of the intermediate Form II (258 K; CSD Entry: EJEQAL02).

Figure 11

The crystal structure of the high-temperature Form I (300 K, CSD Entry: EJEQAL); (A); Hirshfeld surface mapped over d_norm, using a color scale of red (shorter than vdW separation), white (equal to vdW separation) and blue (longer than vdW separation) for the single molecule (B); and the corresponding 2D fingerprint plot (C).

Figure 12

Free volume calculated for low-temperature Form III (A), intermediate Form II (B) and high-temperature Form I (C). Specifically, the empty spaces in the crystal unit cells large enough to hold spherical probes with radii of 0.8 or 0.6 Å are displayed.