Spontaneous crystal growth of co-crystals: the contribution of particle size reduction and convection mixing of the co-formers

Abstract

Previously reported methods for co-crystal synthesis have employed a variety of strategies and these include co-grinding, co-precipitation, growth from the solution, melt and slurry (M. Zaworotko, Polymorphism in Co-crystals and Pharmaceutical Co-crystals, XX Congress of the International Union of Crystallography, Florence, 2005) and spontaneous co-crystal formation without pre-milling activation (C. Maheshwari, J. Jayasankar, N. A. Khan, G. E. Amidon and N. Rodriguez-Hornedo, CrystEngComm, 2009, 11, 493–500). In this contribution the impact of particle size and pre-milling of the components on spontaneous co-crystal formation is described. This report builds on concepts outlined in a perspective by the authors on future developments in co-crystal formation (N. Blagden, D. J. Berry, A. Parkin, H. Javed, A. Ibrahim, P. T. Gavan, L. L. Dematos and C. C. Seaton, New. J. Chem., 2008, 32, 1659–1672) in this area. In particular, the opportunity for spontaneous co-crystal formation utilizing a solid component mixing process with a separate pre-milling step to activate the process is presented. Previously reported systems known to form co-crystals were examined, namely caffeine and urea as the model drug, and malonic acid and 2-methoxybenzamide (2-MB) as well-documented molecular complex formers. The synthesis approach adopted for this study involves pre-milling of the solid components to a particular particle size range and subsequent tracking of any co-crystal formation in a physical mixture during a solid-state convection mixing of the components. For both systems, three different size fractions (20–45 µm), (75–125 µm), and (180–250 µm) were examined. An assessment of transformation from component phase to molecular complex indicated that, typically, the co-crystals started to form after 30 min, as reflected in the evolution of co-crystal powder X-ray diffraction peaks with time. Notably, the rate of co-crystal formation rapidly increased for the smallest size fraction (20–45 µm). No buried eutectic or extensive amorphous intermediate phase was identified and this outcome suggests that the propensity for crystallization was associated with inter-particle contact and that this is linked to an increase in contact areas with decreasing particle size.