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

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 mu m), (75-125 mu m), and (180-250 mu m) 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 mu m). 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.