Uncovering Molecular Details of Urea Crystal Growth in the Presence of Additives

Abstract

Controlling the shape of crystals is of great practical relevance in fields like pharmacology and fine chemistry. Here we examine the paradigmatic case of urea which is known to crystallize from water with a needle-like morphology. To prevent this undesired effect, inhibitors that selectively favor or discourage the growth of specific crystal faces can be used. In urea the most relevant faces are the {001} and the {110} which are known to grow fast and slow, respectively. The relevant growth speed difference between these two crystal faces is responsible for the needle-like structure of crystals grown in water solution. To prevent this effect, additives are used to slow down the growth of one face relative to another, thus controlling the shape of the crystal. We study the growth of fast {001} and slow {110} faces in water solution and the effect of shape controlling inhibitors like biuret. Extensive sampling through molecular dynamics simulations provides a microscopic picture of the growth mechanism and of the role of the additives. We find a continuous growth mechanism on the {001} face, while the slow growing {110} face evolves through a birth and spread process, in which the rate-determining step is the formation on the surface of a two-dimensional crystalline nucleus. On the {001} face, growth inhibitors like biuret compete with urea for the adsorption on surface lattice sites; on the {110} face instead additives cannot interact specifically with surface sites and play a marginal sterical hindrance of the crystal growth. The free energies of adsorption of additives and urea are evaluated with advanced simulation methods (well-tempered metadynamics) allowing a microscopic understanding of the selective effect of additives. Based on this case study, general principles for the understanding of the anisotropic growth of molecular crystals from solutions are laid out. Our work is a step toward a rational development of novel shape-affecting additives.

Molecular-dynamics simulations of urea nucleation from aqueous solution

“…The metadynamics production runs were carried out for 0.26, 0.34, and 0.35 μs, respectively. Consistently with our previous works (9,26,38), generalized Amber force field (GAFF) (39,40) was chosen for urea together with the TIP3P water model. Each system was at first minimized with the conjugate gradient algorithm with a tolerance on the maximum force of 200 kJ·mol −1 ·nm −1 , and then a 100-ps NVT equilibration with a time step of 0.5 fs was performed to relax the system at the temperature assigned.…”

“…Such CVs can be decomposed in single-molecule contributions that account for the density of the local molecular environment surrounding each solute molecule, as well as the degree of orientation order of the molecules belonging to the coordination sphere of that solute molecule. The orientation order is defined with respect to an intramolecular vector (26,38,45). In the following, we shall define Γ CO , the molecular degree of order associated to the relative orientation of urea molecules with respect to the CO axis, and Γ NN , the degree of order associated to the relative orientation with respect to the NN axis.…”

In Silico Prediction of Growth and Dissolution Rates for Organic Molecular Crystals: A Multiscale Approach

“…Most investigations of crystallization processes using MD consider the distinct faces of the crystal in contact with the solvent [11,12,[14][15][16]33,35,[96][97][98]. However, time scales accessible in regular MD simulation are often not sufficient to resolve dissolution from the perfectly flat interfaces.…”

“…However, MD can, at most, only probe behavior on the nanometer and nanosecond scale. Thus, most investigations of growth and dissolution processes using MD are reported for relatively small and simple molecules like, e.g., urea [11][12][13] and glycine [14][15][16][17], or even for simple model systems, such as hard spheres and Lennard-Jones particles [18][19][20][21], whereas most organic molecules, especially those used as active pharmaceutical ingredients (APIs), form more complex crystal structures, and it is extremely challenging to capture their crystal growth using fully-atomistic simulations [22]. Replacing atomistic details with lower resolution, coarse-grained (CG) beads, in which groups of co-localized atoms are treated as a single interaction site, allows one to overcome the complexity of molecules and the long time scale associated with the crystallization [22,23].…”

A study on the effect of the polymeric additive HPMC on morphology and polymorphism of ortho-aminobenzoic acid crystals

“…While growth kinetic in the presence of impurities is a relatively well-understood phenomenon [11]- [12] the effect on nucleation is still being studied [13]- [15]. Impurities can induce nucleation of a different polymorphic form [16]- [18] and have an effect on the time of polymorphic transformation [19].…”