Crystal Structure of Salcaprozoic Acid (HNAC), the Free Acid of Salcaprozate Sodium (SNAC)

What is it about?

This study presents the first comprehensive crystallographic characterization of salcaprozoic acid (HNAC), the free acid form of salcaprozate sodium (SNAC), using single-crystal X-ray diffraction. The scope includes elucidation of molecular conformation, hydrogen-bonding networks, and crystal packing features, supplemented by powder X-ray diffraction (PXRD), Rietveld refinement, and IR spectroscopy. HNAC was found to crystallize in the monoclinic space group P2₁/c with two molecules in the asymmetric unit, stabilized by a robust network of intra- and intermolecular hydrogen bonds, forming planar two-dimensional networks. Comparison with related structures in the Cambridge Structural Database revealed that HNAC shares extended aliphatic chain conformations with other medium-chain fatty acids but is distinguished by the presence and orientation of an aromatic amide fragment. The Rietveld refinement of PXRD data confirmed consistency between the bulk material and the single-crystal model, ruling out impurities or additional polymorphs. IR spectroscopy corroborated the presence of key functional groups and highlighted the influence of hydrogen bonding on vibrational modes. Overall, the findings provide a detailed structural foundation for understanding the physicochemical properties of HNAC and inform future development of SNAC-based permeation enhancers.

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Photo by Seyed Ahmadreza Abedi on Unsplash

Photo by Seyed Ahmadreza Abedi on Unsplash

Why is it important?

This study addresses a gap in the structural understanding of salcaprozoic acid (HNAC), the free acid form of the widely used drug permeation enhancer salcaprozate sodium (SNAC), by providing the first comprehensive crystallographic characterization of HNAC. Structural insights into HNAC are directly relevant for the development and optimization of SNAC-based drug delivery systems, as molecular conformation and solid-state interactions influence physicochemical properties and in vivo behavior. Key Takeaways: 1. The research demonstrates that HNAC crystallizes in the monoclinic space group P2₁/c, with two molecules in the asymmetric unit stabilized by an extensive network of intra- and intermolecular hydrogen bonds, resulting in robust crystal packing and thermal stability. 2. Findings reveal that the molecular conformation of HNAC features an extended aliphatic chain and an aromatic amide fragment, distinguishing it from structurally simpler medium-chain fatty acids and highlighting differences in hydrogen-bonding networks compared to related compounds. 3. The study confirms the crystalline phase and structural consistency of HNAC through Rietveld refinement of powder X-ray diffraction data, establishing a solid foundation for future investigations into SNAC and related permeation enhancers at the molecular level.