Effect of Chirality on the Compression of 2-(2-Oxo-1-pyrrolidinyl)butyramide: A Tale of Two Crystals

Abstract

Understanding polymorphism in chiral systems for drug manufacturing is essential to avoid undesired therapeutic effects. Generally, polymorphism is studied through changes in temperature and solution concentration. A less common approach is the application of pressure. The goal of this work is to investigate the effect of pressure on levetiracetam (pure enantiomer) and etiracetam (racemic compound). Anisotropic compressions of levetiracetam and etiracetam are observed to 5.26 and 6.29 GPa, respectively. The most compressible direction for both was identified to be perpendicular to the layers of the structure. Raman spectroscopy and an analysis of intermolecular interactions suggest subtle phase transitions in levetiracetam (∼2 GPa) and etiracetam (∼1.5 GPa). The stability of etiracetam increases with respect to levetiracetam on compression; hence, the chiral resolution of this system is unfavorable using pressure. This work contributes to the ongoing efforts in understanding the stability of chiral systems.

Figure 1

Molecular structures and numbering schemes for (a) the S enantiomer of Lev (chiral carbon C6) and (b) the R enantiomer present in the racemic compound Eti (chiral carbon C5) taken from reference structures deposited with the CSD (OMIVUB and OFIQUR). It is not ideal that the numbering schemes are different in both compounds; however, to be consistent with the references we are following the CSD numbering schemes.

Figure 2

Crystal structures of Lev and Eti. (a) The crystalline structure of Lev is formed through two infinite chains, NH···O(py) (in dark blue) and NH···O(CNH₂) (in light blue) following the b direction. (b) The structure of Lev is packed through van der Waals interactions along the a-axis (view of two layers in the element colors and a green layer). (c) In Eti infinite enantiopure chains (S enantiomer (in element colors) and R enantiomer (in orange)) formed through NH···O(CNH₂) hydrogen bonds (in dark blue); the chains are linked by NH···O(py) hydrogen bonds (in light blue), creating a centrosymmetric dimer. (d) In Eti chains are parallel to the (1 0 –1) plane and are linked by an inversion center. The stepped layers are depicted in green.

Figure 3

Raman spectra of commercial (a) Lev and (b) Eti at atmospheric pressure.

Figure 4

(a) Raman spectra of a powder sample of Lev during the compression to 5.26 GPa. The effect of pressure could be observed in several peaks such as at (green ●) ∼345 cm^–1, (purple ▼) ∼690 cm^–1, (blue ▼) ∼700 cm^–1, and (brown ◆) ∼3360 cm^–1. (b) Raman spectra of a single crystal of Eti during the compression to 6.29 GPa. The effect of pressure could be observed in several peaks such as at (blue and green ●) ∼345 cm^–1, (green ▼) ∼700 cm^–1, and (brown ◆) ∼3180 cm^–1.

Figure 5

(a–c) Evolution of the center position of a specific Raman peak for Lev at (green ●) ∼345 cm^–1, (purple ▼) ∼690 cm^–1, (blue ▼) ∼700 cm^–1, and (brown ◆) ∼3360 cm^–1.during compression to 5.26 GPa. The peaks are observed in Raman spectra of powder (solid symbols) and single-crystal samples (open symbols) upon compression of the samples. At 1.25 and 2.1 GPa the data points of the single crystal and powder overlap; hence, they are shown in a lighter color (light color symbols); (d–f) Evolution of the center position of a specific Raman peak for Eti at (blue and green ●) ∼345 cm^–1, (green ▼) ∼700 cm^–1, and (brown ◆) ∼3180 cm^–1 during compression to 6.29 GPa.

Figure 6

X-ray diffraction compression data of (a–c) Lev and (d–f) Eti: (a, d) unit cell axis; (b, e) variation of the β angle; (c, f) volume fitted to the third-order Birch–Murnaghan equation of state for Lev and third-order Murnaghan equation of state for Eti. The compression of LEV was performed using three crystals illustrated by solid symbols (crystal 1), open symbols (crystal 2) and right half solid symbols (crystal 3) in compression data of (a) the unit cell axis and by different shapes of symbols in the (b) variation of the β angle and (c) volume: squares in crystal 1, circles in crystal 2, and triangles in crystal 3.

Figure 7

Compressibility indicatrix for (a) Lev and (b) Eti calculated by PASCal together with a vector applied to the crystal structure to show how the crystal compresses.

Figure 8

Representation of voids in the crystal structure of Lev and Eti: (a) view along the b axis in the crystal structure of Lev; (b) view along the b axis in the crystal structure of Eti. Parameters used for void calculations: probe radius of 0.5 Å and grid spacing 0.2 Å.

Figure 9

Molecular volume (V/Z) for Eti (orange plot) and Lev (blue plot) as a function of pressure. The lines are only a guide to the eye.

Figure 10

Variation of unit cell lengths as a percentage change together with the adjusted total lattice energies for (a) Lev (all data) and (b) Eti as a function of pressure. The discontinuities in the regions of 2 and 1.5 GPa can be seen in Lev and Eti, respectively. Lines are polynomials as a guide to the eye.

Figure 11

Energy of molecular interactions in Lev illustrated by (a) a molecular packing diagram surrounding the element-colored molecule with (b) red molecule interaction energies (amide-oxopyrrolidine hydrogen bond), (c) purple-molecule interaction energies (amide–amide hydrogen bond), and (d) blue molecule interaction energies (interlayer interaction). Color code: green, repulsion energy; blue, dispersion energy; red, polarization energy; violet, total energy.

Figure 12

Energy of molecular interactions in Eti illustrated by (a) a molecular packing diagram surrounding the element-colored molecule with (b) green-molecule interaction energies (amide–oxopyrrolidine hydrogen-bonded dimer), (c) purple-molecule interaction energies (amide–amide hydrogen bond) and (d) blue-molecule interaction energies (interlayer interaction). Color code: green, repulsion energy; blue, dispersion energy; red, polarization energy; violet, total energy.