A New Polymorph of Behenic Acid (bm) As a Promising Lipid Matrix for Controlled Drug Release: Structure Determination from Synchrotron XRD and Vibrational Analysis Supported by Theoretical Calculations

This paper reports on the structural, spectroscopic, and thermal characterization of a novel polymorph (Bm form) of behenic acid (docosanoic acid, C22), crystallized from dichloromethane. The crystal structure was solved from synchrotron single-crystal X-ray diffraction (100 K), revealing a monoclinic system with space group P21/c. Hirshfeld surface analysis quantified the dominant intermolecular interactions as H & ctdot;H (90.3 %) and H & ctdot;O/O & ctdot;H (7.6 %), which stabilize a compact supramolecular lattice with a low void volume of 3.28 %. Density functional theory (DFT) calculations, including an implicit solvation model using four different solvents (i.e., dichloromethane, acetone, ethanol, and hexane), confirmed the thermodynamic stability of the polymorph and provided key chemical reactivity descriptors, indicating high electronic stability (HOMO-LUMO gap ti11 eV) and low electrophilicity. Vibrational spectroscopy (infrared and Raman) combined with DFT assignments provided a complete mode interpretation, highlighting a pronounced solvent-permittivity effect for vibrations of the carboxyl group, directly linked to its role in intermolecular interactions. Thermal analysis showed the material's stability up to 464 K and two thermal events were observed, i.e., a solid-state polymorphic transition (Bm -> C) at 343 K (Delta H ti 4.54 kJ/mol) and melting at 355 K (Delta H ti 74.68 kJ/mol). Finally, an in silico pharmacokinetic assessment underscored a significantly promising physicochemical profile, characterized by high lipophilicity, low polarity and moderate molecular weight, strengthening the C22 (Bm) polymorph potential as an advanced excipient to develop lipid matrices for controlled-release drug delivery systems.