Effect of Solution Composition on the Crystallization of Multicomponent Forms of Carbamazepine beyond Crystal Form and Shape: Surface as a Source of Diversity in the Solid-Form Landscape

Abstract

This paper reports on the solution growth of carbamazepine dihydrate and discusses the relative development of the {h00} and {0k0} faces as a function of the crystallization conditions. While the overall shape of the obtained crystals remains lathlike, it is shown that from ethanol/water mixtures and at high water content (91 mol %) the dominant faces are {0k0}, whereas at lower water content (52 mol %) they are the {h00} faces. Our computational and systematic analyses suggest that the relative development of these faces is likely related to the anisotropic nature of the crystal structure and the existence of hydrophobic {0k0} and hydrophilic {h00} faces and as a consequence the importance of the ethanol/water composition in the crystallization mixture. The results of this solvent effect on crystal growth are further probed by assessing the characteristics and behavior of other multicomponent forms of carbamazepine, including one cocrystal and two solvates which are structurally related to the dihydrate. The kinetic effect of solution composition in the crystallization outcome appears to be more pronounced in CBZ·2H2O, although the 2:1 cocrystal with 1,4-benzoquinone and the formamide solvate also seem to vary as a function of solution composition. The results provide an illustration of how the crystal surface serves as an additional source of diversity in the solid-form landscape of pharmaceuticals, going beyond the crystal form and shape.