Relative stability of chlorthalidone (CTD) Forms I and II: integrated experimental and theoretical insights into the superior thermodynamic stability of CTD-I driven by intra- and intermolecular interactions

Context Chlorthalidone (CTD), an antihypertensive drug, crystallizes in racemic polymorphic forms (Forms I and III) and as a conglomerate form (Form II). Understanding the relative stability of these crystal forms is essential for pharmaceutical solid-state characterization. Theoretical and experimental results consistently demonstrate the superior thermodynamic stability of Form I over Form II. Equilibrium solubility, thermogravimetric, and differential scanning calorimetry analyses support the computational findings. Calculated Raman and infrared spectra reproduce the main experimental features and reveal differences arising from distinct crystal packings. The results show that crystal stability is governed by a balance between intra- and intermolecular interactions, highlighting that the most stable crystal form does not necessarily correspond to the most stable isolated molecular conformer. These findings emphasize the importance of considering both molecular and packing effects in studies of pharmaceutical solids. Methods All gas-phase calculations were performed in Gaussian09 using density functional theory (DFT) at the M06-2X/6–311 + G(d,p) level. Solid-state calculations were carried out with periodic DFT using the PBE-D3 functional in Quantum ESPRESSO. Crystal structures were modeled using plane-wave basis sets and projector augmented-wave pseudopotentials to investigate molecular conformations, crystal packing effects and relative stabilities. The bonding and intramolecular interactions were analyzed using QTAIM 2000 and Multiwfn software.