Amide Pyramidalization in Carbamazepine:  A Flexibility Problem in Crystal Structure Prediction?

Abstract

Carbamazepine is known to exist in various polymorphic forms. Here we report on crystal structure prediction calculations for carbamazepine in an attempt to examine the predictability and relative stability of the various polymorphs. Hypothetical crystal structures generated in 10 of the most common space groups were compared to the observed polymorphs. Particular attention has been given to the influence of amide pyramidalization on the relative energies of the predicted structures. While the actual generation of possible crystal structures was found to be independent of the degree of deformation of the amide group, their final ranking in energy was greatly affected by pyramidalization of the amide nitrogen. This effect was examined in detail through systematic variation of the NH 2 geometry for each of the low-energy crystal structures; different amide geometries were favored in the various low-energy crystal structures. The results demonstrate that energetically feasible deformation of the amide group may occur in order to optimize hydrogen-bond interactions, and we conclude that neglect of amide pyramidalization introduces significant errors in crystal structure prediction for carbamazepine and similar molecules.

Carbamazepine polymorphs: Theoretical and experimental vibrational spectroscopy studies

“…Cruz Cabeza et al [34] performed calculations based on crystal structure of carbamazepine in order to examine the relative stability of various polymorphs. They found that carbamazepine exhibits a certain degree of conformational flexibility, due to the pyramidalization of the amide group nitrogen.…”

Insight Into the Intermolecular Factors Responsible for theZ,ZConfiguration of Ar–X–N=S=N–X–Ar (X = S, Se) Derivatives in the Solid State

“…[31] Molecular structures calculated on higher levels of theory therefore often provide a good approximation to the structures observed in the crystal, and crystal structure predictions based on rigid calculated molecular structures is generally assumed to be reasonable. [32,33] Also in the case of the parent Ph-S-N=S=N-S-Ph (1), the calculated gas-phase geometry of the Z,Z-anti,anti configuration seems to provide a useful model for the experimental geometry. [3] Therefore, the calculated molecular geometries of both configurations of 1 in the anti,anti conformation (i.e., Z,Z-anti,anti and Z,E-anti,anti, see Figure 1) were used in the OPiX calculations.…”

A computationally inspired investigation of the solid forms of (R)‐1‐phenylethylammonium‐(S)‐2‐phenylbutyrate

“…Lattice energies are notoriously sensitive to the positions of the hydrogen atoms. [9][10][11] The lower density of the P4 1 form also suggested the possibility of solvent inclusion that had not been detected in the previous determination. Recent studies of carbamazepine form II 12,13 discovered disordered solvent within the structure, which had previously been viewed as the least dense polymorph with an anomalous lattice energy.…”