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45242-G5
Self-Assembled Monolayers as Nucleating Surfaces to Screen Rapidly for Polymorphs of Organic Crystals
Motivation: The understanding and control of crystallographic polymorphism of small organic molecules is scientifically and financially important to the pharmaceutical industry. The identification of all possible polymorphs (crystalline solids with different arrangements of the same molecules) of a given compound is, however, experimentally difficult. Since the polymorph is determined at the nucleation of the crystal, to scan for polymorphism, we require a method that can create a large number of different substrates for nucleation.
Experimental Design: Towards this aim, we have investigated the use of arrays of self-assembled monolayers (SAMs) of alkanethiols, with different terminal (omega) functional groups, on metallic substrates in 96-well plates. These arrays of SAMs provide nucleating surfaces with diverse chemical functionality. We have used these arrays to screen for different physical forms (polymorphs, solvates, and amorphous structures) of organic compounds important to the pharmaceutical industry.
Outcomes: The worked completed so far on this project has focused on optimizing the crystal growth conditions in the 96-well plates. For these initial experiments, we have focused on acetaminophen which has three different polymorphic forms. The monoclinic form is the thermodynamically stable form that is commercially used. The orthorhombic form is less stable, but has more desirable properties for processing. We have compared the nucleation of acetaminophen on methyl-terminated SAMs, carboxylic-acid terminated SAMs, and bare gold. During the course of this work, we have identified the evaporation rate as a critical variable in determining the polymorph selectivity. Consistent with Ostwald's Rule of Stages, faster evaporation rates yield more of the less stable (orthorhombic) polymorph. Using fast evaporation rates, we have determined that the surface also plays a significant role in determining polymorph selectivity. For example, in a trial with 20 wells with each functionality, the orthorhombic form was observed in 50% of the methyl wells, 0% of the acid wells, and 5% of the bare gold wells. We are currently working to improve the nucleation conditions and understand the mechanistic origin of the growth of the orthorhombic form on hydrophobic surfaces. This result is consistent with a recent report by Heng and Williams that the dominant faces of the orthorhombic form are more hydrophobic than the dominant faces of the monoclinic form. In the coming year, this work will be extended to other organic compounds. We will report the results in due course.
Career Impact: This PRF Type G grant was my first grant. It allowed me to take on an additional graduate student, who was supported by the PRF grant in the spring semester (in the Fall semester, he was supported by a TA-ship). This graduate student has mentored an URM undergraduate student who has also contributed significantly to this project. She was funded for the summer (2007) by the Cornell College of Engineering Undergraduate Learning Initiatives. She recently applied for, and received, an extension of this grant for the 2007-2008 school year.
