(74j) On the Interplay between Conformational Complexity, Solution Structure, and Polymorphism in Succinic Acid Nucleation from Solution.

Polymorphism, i.e. the existence of different crystal phases for the same molecule, is ubiquitous in nature and is key in defining mechanical, physical, chemical, and functional properties of crystalline materials. Understanding and controlling polymorphism is therefore of outmost importance for the rational development of efficient industrial crystallization processes. Organic molecules are often characterised by conformational flexibility; crystal structures including different conformers of the same molecule are known as conformational polymorphs. [1]

Obtaining an insight into the interplay between conformational transitions, the structure of the liquid parent phase, and the nucleation process leading to the appearance of a specific polymorph, is thus key in order to improve our overall understanding of nucleation of complex materials from a liquid solution.

In this work we investigate the relation between conformational transitions of succinic acid (1,4-Butanedioic acid), its solution structure, and the nucleation of two conformational polymorphs. The first polymorph is the notorious β form, stable at ambient temperature, in which succinic acid is in a planar conformation. The second is the recently discovered γ polymorph, in which succinic acid appears in a non-planar conformation. The γ polymorph has been serendipitously discovered during a co-crystallization experiment with Leu-Leu dipeptide, and was produced in concomitance with the β form. Despite CSP studies have shown that the γ form is indeed stable and thermodynamically plausible[2], extensive attempts at reproducing γ were not successful, classifying this system as a case in which disappearing polymorphism is observed. It is not uncommon in literature to encounter this phenomenon for molecules with conformational freedom[3].

We begin our work by analysing the stability at finite temperature and pressure of the bulk β and γ phases. As the stability of polymorphs changes at finite-temperature and pressure, molecular dynamics (MD) simulations are performed on β and γ crystals at 300K. These simulations show that while β is stable and the results are in reasonable agreement with experiments and CSP predictions, γ displays an incipient deformation of the cell shape. To further investigate such a structural relaxation, we perform metadynamics (MetaD)[4] and well-tempered metadynamics (WTMetaD)[5] simulations on γ. As a result, we observe that the fluctuation of an angle of the supercell induces firstly the formation of local defects accompanied by conformational transitions of individual succinic acid molecules, then local melting, which ultimately leads to the irreversible melting of the entire cell.

We move then to analyse the conformational behaviour of succinic acid in solution. We initially carry out a metadynamics simulation of a single molecule in aqueous solution, biasing three characteristic dihedral angles. From the resulting free energy surface, we identify 10 distinct conformers, including the folded isomer found in γ and the planar one found in β. A Markov State Model (MSM), informed by 18 100ns-long unbiased simulations allowed us to evaluate the equilibrium distribution of the conformers as well as the relaxation time of their population. The equilibrium distribution obtained from the MSM is in agreement with that obtained from metadynamics. Most notably we observe that γ conformer is dominant in solution (~70% probability), while the β planar conformer has a probability lower than 10%. The relaxation time for the conformer population is however fast, with a characteristic time of the order of 200 ps, hinting that in this case the conformational rearrangement does not represent a rate determining step in the nucleation process.

By repeating this analysis for increasing concentrations of succinic acid in water, we note that both the equilibrium probability and the relaxation time are affected by the transient formation of spatial domains locally dense in solute molecules.

To further investigate the interplay between conformational transitions and the nucleation process we study the homogeneous nucleation of both β and γ succinic acid crystals from solution through WTMetaD simulations. We expect such simulations to lead predominantly to the formation of β crystals, as it is well-known that this polymorph forms spontaneously even at low supersaturations; however, uncovering the mechanism of nucleation can shed a light upon possible role of γ as a metastable intermediate according to Ostwald’s rule of stages.

In conclusion, we present a simulation work motivated by the discovery of a new elusive polymorph of succinic acid, γ[6]. This disappearing polymorph is compatible with the CSP potential energy landscape, which identify it as plausible; MD simulations point towards the interpretation of γ as a labile structure, possibly prone to melting as seen with metadynamics simulations. In addition, the conformer found in γ is the most abundant in solution. Nucleation studies will possibly uncover the mechanism followed and thus lead to a better understanding of the role of γ in this scenario.

References

[1] A. J. Cruz-Cabeza and J. Bernstein, “Conformational Polymorphism,” Chem. Rev., vol. 114, no. 4, pp. 2170–2191, Feb. 2014.

[2] S. L. Price, “Why don’t we find more polymorphs?,” Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater., vol. 69, no. 4, pp. 313–328, Aug. 2013.

[3] J. D. Dunitz and J. Bernstein, “Disappearing Polymorphs,” Acc. Chem. Res., vol. 28, no. 4, pp. 193–200, Apr. 1995.

[4] A. Laio and M. Parrinello, “Escaping free-energy minima,” Proc. Natl. Acad. Sci., vol. 99, no. 20, pp. 12562–12566, Oct. 2002.

[5] A. Barducci, G. Bussi, and M. Parrinello, “Well-tempered metadynamics: A smoothly converging and tunable free-energy method,” Phys. Rev. Lett., vol. 100, no. 2, pp. 1–4, 2008.

[6] P. Lucaioli, E. Nauha, I. Gimondi, L. S. Price, R. Guo, L. Iuzzolino, I. Singh, M. Salvalaglio, S. L. Price, N. Blagden, submitted, 2018