Rapid coprecipitation is a novel method for assembling common pharmaceutical ingredients such as proteins, nanoparticles and nucleic acids onto the surface of crystals [1-3]. The microparticles obtained are typically monodisperse and form free-flowing dry powders that have attractive properties for a range of alternate drug-delivery application. Here we report studies aimed at better determining the mechanism of formation of these microcrystals. The material chosen for this study was D,L-valine (an amino acid) because the kinetics of precipitation of this material were found to be sufficiently slow to allow the process to be monitored in real time. The precipitated microcrystals are generally plate-like with a very high aspect ratio, typically 5-10 microns diameter with a thickness of about 0.2 microns. The basic process involves well controlled rapid mixing of an aqueous solution of valine and an active pharmaceutical ingredient with a water miscible solvent, such as isopropanol, which is a poor solvent for both solutes. This was carried out either in a batch process using a dynamic mixer or in a continuous process using a static mixer, producing particles of very similar morphology. Formation of valine microcrystals and their precursors was monitored in situ using turbidimetry, static and dynamic light scattering over a range of solution compositions at constant temperature [4]. It was found that mixing of isopropanol with an excess aqueous solution resulted in gradual precipitation of stable valine nanoparticles with a constant diameter with a value depending on the solution composition. Subsequently, few large valine crystals grew slowly from these transparent nanoparticle dispersions, while nanoparticle size as detected by dynamic light scattering stayed unchanged. However, mixing of aqueous solutions with an excess isopropanol resulted in liquid-liquid demixing, followed by a sudden appearance of micron-size valine crystals, as observed by fluorescence and small angle static light scattering. In this work we show how careful experimental characterisation of particle formation processes through light scattering, fluorescence and microscopy can be used to identify non-trivial physico-chemical pathways leading to formation of crystals and ordered assemblies of organic molecules, thus providing fundamental understanding crucial for a better design and control of crystallisation processes in pharmaceutical industry.

[1] Kreiner, M.; Moore, B.D.; Parker, M.C. Chem. Comm., 2001, 1096-1097.

[2] Kreiner, M.; Fuglevand, G.; Moore, B.D.; Parker, M.C. Chem. Comm., 2005, 2675-2676.

[3] Murugesan, M.; Cunningham, D.; Martinez-Albertos, J.L.; Vrcelj, R.M.; Moore, B.D. Chem. Comm., 2005, 2677-2679.

[4] Variny M.; Jawor-Baczynska, A., Moore, B.D.; Sefcik, J. J. Disp. Sci. Technol. (in press).