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.
Experimental Design: In the first year of the project, we 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. We used these arrays to screen for different physical forms (polymorphs, solvates, and amorphous structures) of organic compounds important to the pharmaceutical industry.
In the second year of the project, we have begun to investigate the effect of additives, in conjunction with surfaces, on polymorph selectivity. For example, we have used peptide additives in conjunction with different surfaces to control the polymorphism of calcium carbonate.
Outcomes: In the first year of the project, we compared the nucleation of acetaminophen on methyl-terminated SAMs, carboxylic-acid terminated SAMs, and bare gold. We determined that the surface plays a significant role in determining polymorph selectivity. For example, in a trial with 20 wells with each functionality, the orthorhombic form of acetaminophen was observed in 50% of the methyl wells, 0% of the acid wells, and 5% of the bare gold wells. In the second year of the project, we have investigated different high-throughput analysis techniques to determine rapidly what polymorph forms on the different surfaces. Towards this end, we have used both Raman microscopy and x-ray powder diffraction. While Raman is a faster technique, it is less accurate than x-ray powder diffraction.
In the second year, in parallel with the studies of organic crystals and surfaces, we have also been investigating inorganic polymorphism in the calcium carbonate system. Calcite, the thermodynamically stable polymorph, is formed at room temperature and in the absence of any additives. Aragonite, a less stable polymorph, is difficult to form synthetically, but is often observed in biological systems (e.g., mother-of-pearl in mollusk shells). We have explored the following hypothesis: the polymorph selectively for aragonite observed in biological systems results from a synergistic interaction between functionalized surface and soluble additives. To test this hypothesis, in collaboration with John Evans (NYU), we have grown calcium carbonate crystals in the presence of soluble peptides and different surfaces. We tested the following surfaces: b-chitin, a-chitin, and hydroxyl-, carboxyl-, and methyl-terminated SAMs of alkanethiols on gold. We identified one peptide, n16N, which is a fragment of a protein isolated from pearl oysters, that could promote the growth of aragonite when used in combination with b-chitin. When n16N was combined with other surfaces, only calcite crystals grew. Similarly, when other peptides were combined with b-chitin, only calcite crystals grew. We are currently investigating what interaction(s) exist between n16N and b-chitin that lead to the polymorph selectivity. The results will be reported in due course. In future work, we will apply this concept, that soluble additives in conjunction with functionalized surfaces can influence polymorph selectivity, to organic crystals.
Career Impact: This PRF Type G grant was my first grant. In the second year of the grant, I was able to support a new graduate student, Debra Lin, in my lab for one semester. During the semester in which she was supported by the PRF grant, Debra applied for and received and NSF Predoctoral Fellowship, which will now support her for the rest of her PhD program. The preliminary results obtained with the PRF grant were included in my NSF-CAREER proposal, which is currently under review by the NSF.
