Robert T. Forbes

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.

Purpose. The formulation and processing of protein drugs requires the stabilization of the native, biologically active structure. Our aim was to investigate the thermal stability of a model protein,...

One theory suggests that by maintaining the protein in an amorphous glassy sugar matrix, the physical hindrance encountered by the protein functions to stabilize it. Thus, the nature of the sugar/protein interaction is important as is the maintenance of the sugar in an amorphous form without any recrystallization. Moisture is known to function as a plasticizer and facilitate crystallization and thus loss of the amorphous state. We report the effect of cospray-drying with different proteins on the physical stability of lactose and mannitol. Particle sizing showed their suitability for inhalation, and the effect of exposure of the spray-dried products to moisture vapor was monitored gravimetrically. Bovine liver catalase, bovine pancreatic insulin, and bovine pancreatic ribonuclease A when individually cospray-dried with lactose showed no extensive initial crystallinity by powder X-ray diffraction, but proteins cospray-dried with mannitol generally showed evidence of mannitol component crystallinity. Catalase appeared to inhibit lactose crystallization from an amorphous matrix to a greater extent than insulin when exposed to short-term elevated humidity, but this difference was a kinetic feature. The hygroscopicities of the cospray-dried materials differed and indicated that each protein/sugar system required individual characterization to identify an optimal formulation.