M. S. Thesis Colloquium: Atomic Level Investigation of Pharmaceutical Compounds During  Co-crystallization Procedure

The physicochemical properties of pharmaceutical solid dosage forms are  fundamentally governed by their molecular packing and non-covalent  interactions.  For drugs suffering from poor aqueous solubility, such as  those in Biopharmaceutics Classification System (BCS) Class-II,  co-crystallization serves as a powerful crystal engineering technique to  improve these properties without altering the core chemical structure. A  complete mechanistic account of the intricate structural reorganizations  and non-covalent interactions that govern the co-crystallization  process, however, remains contingent on investigation at atomic  resolution.

This thesis examines the structural dynamics of pharmaceutical materials  undergoing co-crystallization, with Niflumic acid, a fluorinated  Non-Steroidal Anti-Inflammatory Drug (NSAID), as the API and Gallic acid  and Vanillic acid as the two co-formers of interest. The atomic-scale  assemblies formed between these components are interrogated through a  combination of solid-state NMR (ssNMR) spectroscopy and Powder X-ray  Diffraction (PXRD), exploiting the complementary sensitivity of these  techniques to local molecular environments and long-range crystalline  order, respectively.

The experimental approach follows a deliberate progression.  One-dimensional 1H and 13C ssNMR spectra of the pure starting ma= terials first establish the peak assignments necessary for interpreting the more complex spectral signatures of the co-processed  mixtures. Given the well-recognized resolution constraints of 1D  experiments in multi-component systems, 2D Double Quantum–Single Quantum  (DQ-SQ) correlation NMR is subsequently employed to explicitly resolve  and map the intra- and intermolecular hydrogen-bonding networks that  develop between the API and each co-former.

The integrated spectroscopic and diffraction evidence exposes a  pronounced divergence in the operative formation mechanisms. Dry gri= nding yields predominantly disordered molecular aggregation, whereas liquid-assisted grinding drives the system toward well-defined  molecular packing arrangements and the unambiguous formation of a new  crystalline phase. Atomic-resolution assessment of molecular integration  across both co-former systems converges on Gallic acid as the superior  choice of co-former for Niflumic acid. Overall, this work demonstrates  the crucial capability of advanced ssNMR to track intermediate  structural dynamics and map critical non-covalent interactions in  pharmaceutical crystal engineering.