PROBING EARLY FORMATION PATHWAYS OF CRYSTAL POLYMORPHS AND THE ROLE OF SUBSTRATE USING IN-SITU X-RAY SCATTERING TECHNIQUES

Abstract

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 in crystallization, methods that lead to an advanced understanding of early crystal formation pathways and mechanisms are highly desirable. In this work, we have 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 the Form I and II crystallization events of a pharmaceutical compound, acetaminophen (ACM), based on the knowledge we learned from previous work that both self-assembled monolayers (SAMs) surface chemistry and solvent conditions work together to control crystal polymorph. 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 PTS (trichloro(phenyl)silane) 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 peak occurring. The further analysis and corroboration of other data sets pointed to the possible existence of structural transformations at these early stages. These results indicate 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 other model compounds studies.