Self-Assembled Monolayers as Nucleating Surfaces to Study Early Formation Pathways of Crystallographic Polymorphs

SUMMARY
Understanding and control of crystallographic polymorphism and crystal habit
of organic compounds is scientifically and technologically important to several
industries. Since a polymorph is determined at the early stages during crystallization,
methods that lead to an advanced understanding of early crystal formation pathways and
mechanisms are highly desirable. In this project, we used a combination of selfassembled
monolayers (SAMs) in conjunction with varying solvents or solvent mixtures
in order to control crystal polymorphs. To that end, either alkane-thiol based SAMs on
gold or silanes on glass, each with different terminal (omega) functional groups, were
used to control nucleating surface chemistry. Both polar and nonpolar solvents were
chosen to study their effects on polymorph selection in concert with SAMs. In the first
part of the project, a pharmaceutical compound, acetaminophen (ACM), with two
predominant crystal forms, Form I and Form II, was investigated. In this part, nucleation
and growth were induced by simple solvent evaporation, i.e. without control of the
degree of supersaturation. Under these conditions, we first demonstrated that both SAM
surface chemistry and solvent conditions work together to control crystal polymorph.
We then introduced time-resolved in situ wide-angle X-ray scattering (WAXS) at
Cornell’s High Energy Synchrotron Source (CHESS) to study the early formation stages
of Form I and II crystallization events of ACM under these conditions. Studying
crystallization of Form II by seeded nucleation, we verified that crystals grow faster at
the substrate-solution interface than in the bulk above, and that a PTS
(trichloro(phenyl)silane) terminated SAM surface has a strong influence over
crystallographic orientation, directing the (002) planes from slightly out-of-plane to a
totally in-plane orientation. Studying crystallization of Form I by spontaneous
nucleation, we identified unusual shifts along scattering vector, q, of the earliest peaks
occurring. Further analysis and corroboration via additional data sets pointed to the
possible existence of structural transformations at these early stages. These results
suggested, that our methodologies are effective to gain insights into the earliest
formation stages of the crystallization of ACM and may be used to extend to studies of
other model compounds. In the second part of the project, to that end a more complex
organic model system, 5-methyl-2-[(2-nitrophenyl) amino]-3-thiophenecarbonitrile
(ROY), was chosen for in depth studies. Alkane-thiols based SAMs on gold with
different terminal (omega) functional groups were used to control nucleating surface
chemistry, and both polar and nonpolar solvents were again chosen to study their effects
on polymorph selection in concert with SAMs. To that end, solubility curves for ROY
in toluene and benzyl alcohol were determined. In this part of the project, in order to
control the level of supersaturation, crystallization experiments upon cooling were
conducted instead of the solvent evaporation-based crystallization employed in the first
part of the project. SAMs were placed vertically in the solution and the nucleation was
induced on the SAM surface by generating temperature jumps. Raman microscopy was
applied for polymorph characterization of the resulting nucleated crystals. For ROY in
benzyl alcohol, Y was the dominant polymorph, irrespective of SAM. Secondary
polymorphs were not frequently observed, even at higher supersaturation levels
(exception: phenyl SAMs). The growth possibility showed an overall increasing trend
with longer incubation time. When the solvent changed to toluene, Y was still the
dominant polymorph, irrespective of SAM. However, secondary polymorphs were
observed as a function of SAM chemistry. The possibility of occurrence of these
secondary polymorphs typically increased with increasing supersaturation (exception:
phenyl SAMs). The growth possibility dropped as supersaturation increased, which was
likely caused by crystals falling off of the substrate into the solution. Furthermore, all
crystallization experiments reported with ROY on SAMS were also plagued by the fact
that only a small amount of ultrapure ROY was available (in part as a result of the
Covid-19 shutdown). This may have led to variations in the solubility curves, which
were the basis for the designs of all experiments conducted and associated
interpretations. Overall, the two-part project clearly established, however, that under
appropriate conditions, nucleation and growth on SAMs can function as a model system
to study polymorph selectivity in different solvents or solvent mixtures as well as to
look at early formation stages of crystallization.