Morphology Design of Organic Crystals Grown from Solution

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1159746DohertyThis work is funded by the Chemical and Biological Separations Program of the Chemical, Bioengineering, Environmental, and Transport Systems (CBET) and the Chemical Measurements and Imaging Program of the Chemistry Division.Over ninety percent of all pharmaceutical products are formulated in particulate, generally crystalline form. Similarly, over seventy percent of the products from the chemical industry are sold as solids. Solution crystallization is the most common operation in these industries for the separation and purification of products that are solids at room temperature and pressure. During crystallization, many physical-chemical characteristics of the substance are defined, including crystal polymorph, shape and size, chemical purity and stability, bioavailability, solubility and dissolution rate. Accordingly, solution crystallization is a very important field of research. However, control over the physical form of organic crystals has remained poor, mainly due to inadequate understanding of the basic growth and dissolution mechanisms, and the influence of impurities, additives and solvents on the growth rate of individual crystal faces. A key aspect of this research is to develop and test a crystal growth model for non-centrosymmetric (noncentric) solute and/or impurity molecules of realistic complexity, which will provide a platform for designing crystal systems of defined shape. Crystal growth is a surface-controlled phenomenon in which solute molecules are incorporated stereo-specifically into surface lattice sites in order to yield the bulk long range order that characterizes crystalline materials. Such surface processes are naturally highly susceptible to the presence of small concentrations of other surface active molecules. These may be deliberately added to a crystallization process or may be inherent as reaction by-products - either way their activity is based on their stereo-chemical similarity to the desired solute and they are known to play havoc with the crystallization of organic crystalline materials. For fifty years, crystal growth models of this effect have assumed that adsorbed immobile impurities decrease the perpendicular growth rate of a crystal face by reducing the velocity (rate of solute uptake) at an edge. Specifically, the immobile impurities partition the edge into a collection of segments and the growth of those segments whose length is less than or equal to some critical length is arrested, thus decreasing the edge velocity. However, we argue here that under dilute imposter conditions (the normal situation) this is not expected. Rather, we argue the distances travelled by edges during the first turn of a growth spiral on a crystal face are increased, thereby decreasing the density of steps across the face and reducing the perpendicular growth rate of the crystal face. Research is proposed to test and extend this new predictive model so that it becomes a useful tool for process scientists and engineers. Model test systems will include paracetamol (acetaminophen) grown from aqueous solution in the presence of p-acetoxyacetanilide impurity (solute and impurity are both noncentric); adipic acid (centric solute) grown out of aqueous solution in the presence of hexanoic acid and octanoic acid (both noncentric) additives, and selected API systems in collaboration with our industrial partners. The intellectual merit of the new approach to crystal growth rests entirely on the fact that the models provide a predictive method for anticipating the shape, and shape evolution, of faceted crystals. This will greatly reduce the number of experiments needed to define the design space for crystals with an engineered shape. The broader impacts of this work include (a) providing undergraduate research experiences in my laboratory for students from UCSB, from universities across the USA more broadly, and for undergraduates from international universities, (b) dissemination of the research results through workshops, invited lectures and with industrial collaborators at Eli Lilly, Abbott Labs, and others, (c) tech transfer of the results through the creation and dissemination of software tools that will enhance the productivity of US pharma companies.