Investigation of the structural, thermal, vibrational, and thermodynamic properties of olanzapine and risperidone crystals

• The combined experimental–theoretical framework elucidate olanzapine and risperidone's solid-state behavior. • Dispersion-corrected DFT accurately reproduces experimental crystal structures. • Crystal lattice dynamics provide a solid-state basis for drug stability. • Low-frequency lattice modes govern thermal behavior of olanzapine and risperidone. • Hydrogen-bond topology controls lattice thermodynamics in both drugs. Olanzapine and risperidone are widely used antipsychotics whose solid-state properties are governed by crystal packing and low-energy lattice dynamics. Here, we combine powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and infrared/Raman spectroscopy with dispersion-inclusive periodic density functional theory (DFT) and density-functional perturbation theory (DFPT) calculations to establish a consistent vibrational, phonon, and thermodynamic description of their crystalline forms. Bulk structure optimizations performed at LDA, GGA-PBE, and GGA+TS levels support the importance of van der Waals interactions for accurate molecular-crystal geometries, while simulated IR/Raman spectra enable mode assignments based on phonon eigenvectors across three spectral windows (0–900, 900–1800, and 2750–3250 cm −1 ). Phonon dispersion relations are computed along selected high-symmetry directions, with emphasis on the 0–100 cm −1 region to highlight lattice modes most relevant to thermal behavior. From the phonon spectrum, we derive temperature-dependent thermodynamic functions, including Debye temperature ΘD(T), constant-volume heat capacity CV(T), vibrational enthalpy Hvib(T), Helmholtz free energy Fvib(T), and the entropic contribution TSvib(T) over 0–1000 K. The results reveal systematic differences between olanzapine and risperidone consistent with distinct low-frequency mode distributions and vibrational phase space, providing a microscopic basis for comparative thermal trends. Risperidone exhibits a higher density of low-frequency lattice modes and, consequently, larger phonon-derived entropic and heat-capacity responses than olanzapine across the investigated temperature range. Overall, this study delivers an integrated experimental–theoretical framework that advances solid-form identification, packing-sensitive vibrational fingerprinting, and phonon-based thermodynamic interpretation in pharmaceutical molecular crystals.