How to Identify the Crystal Growth Unit

Abstract

The structure and composition of the crystal growth unit are of huge fundamental and practical consequence. We propose a method to identify the solute species that incorporates into the growth site on crystal surfaces, the kinks, which rests on the kinetics of the elementary reaction at the kinks. We use as model crystals olanzapine, an antipsychotic medication, and etioporphyrin I, a field-effect transistor. We combine time-resolved in situ atomic force microscopy with Raman and absorption spectroscopies, complemented by density functional theory and all-atom molecular dynamics modeling of the solutions. We show that the structure of the growth unit cannot be deduced neither from the solute oligomers nor from the crystal structure. Chemical kinetics analyses reveal that if the dominant solute species is the one that incorporates into the crystal growth sites, then the kinetics of layer growth complies with a monomolecular rate law. By contrast, if the crystal growth unit assembles from two units of the dominant solute form, a bimolecular rate law ensues. Solutions of both olanzapine and etioporphyrin I are dominated by solute monomers, which exist in equilibrium with a minority of dimers. Whereas numerous olanzapine crystal structures incorporate dimer motifs, etioporphyrin I crystals organize as stacks of monomers. Olanzapine crystal grow by incorporation of dimers. One of the studied face of etioporphyrin I grows by incorporation of the majority monomers, whereas the other one selects the minority dimers as a growth unit. The results highlight the power of the crystallization kinetics analyses to identify the growth unit and illuminate one of the most challenging issues of crystal growth.

The elementary reactions for incorporation into crystals

“…400 nm, and four Q bands in the wavelength range 475 to 630 nm ( Fig. 1 C ) attributed to distinct transitions of the conjugated π electron systems of the constituent pyrroles ( 44 – 46 ). The Soret and the Q bands are similarly structured in the three alcohols and DMSO ( Fig.…”

Modeling Morphologies of Organic Crystals via Kinetic Monte Carlo Simulations: Centrosymmetric Growth Units

“…Olanzapine (pictured in Figure ) is a benzodiazepine agent used for treatment of psychoses such as schizophrenia . Prior studies have investigated the crystal growth of olanzapine from solution and demonstrated that growth occurs by incorporation of dimers into the crystal surface. , The growth unit is thus considered to be a centrosymmetric olanzapine dimer. Previous research further describes how the dimer growth unit is constructed and treated within ADDICT .…”

Pharmaceutical Digital Design: From Chemical Structure through Crystal Polymorph to Conceptual Crystallization Process

“…Succinic acid is a centrosymmetric molecule, and it has been established that the growth unit in olanzapine is the centrosymmetric dimer (Figure ), ,− and so these cases can both be treated as centrosymmetric growth units. Figure shows the predicted morphologies of succinic acid grown from water and olanzapine grown from ethyl acetate.…”