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.
4 affiliations
- 1MolMod-CS - Instituto de Química, Universidade Federal Fluminense, Campus Valonguinho s/n, Centro, Niterói, Rio de Janeiro, 24020-14, Brazil.
- 2Laboratório de Cristalografia, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva, 700, Alfenas, MG, 37130-000, Brazil.
- 3Laboratório de Cristalografia, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva, 700, Alfenas, MG, 37130-000, Brazil. [email protected].
- 4MolMod-CS - Instituto de Química, Universidade Federal Fluminense, Campus Valonguinho s/n, Centro, Niterói, Rio de Janeiro, 24020-14, Brazil. [email protected].
Abstract
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.
Related
- Intermolecular Interactions, Proton Transfer, and Adatom Rearrangement during Cysteine Dimer Adsorption on Au(111)
- Modulating intermolecular interactions and high-order triplet states of anthracene host materials for efficient TTA-UC with a Naphtho[2,3-d][1,3,2]diazaborole scaffold and its N-substituents
- Intermolecular Bonding Interactions Within Acenaphthene Peri-Diselenide Radical Cations: Combining Chalcogen Bonding and Pancake Bonding
- Buffer-Dependent Micellization of Sodium N-Dodecanoyl Taurinate: Combined Experimental and Theoretical Insights
- Photoreactivity of E-N,N-bis(2-hydroxyethyl)cinnamamide in Methanol and Solid State: A Complementary Experimental and Theoretical Investigation
BibTeX
@article{singaravel2026relative,
title = {{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.}},
author = {Nathiya Singaravel and Jarede Da Silva Martins and Panneerselvam Murugesan and Juliana D M Silva and Leandro M Santos and Antônio C Doriguetto and Luciano T Costa},
journal = {Journal of molecular modeling},
year = {2026},
month = oct,
doi = {10.1007/s00894-026-07029-3},
url = {https://europepmc.org/article/MED/42961500},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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.
AU - Nathiya Singaravel
AU - Jarede Da Silva Martins
AU - Panneerselvam Murugesan
AU - Juliana D M Silva
AU - Leandro M Santos
AU - Antônio C Doriguetto
AU - Luciano T Costa
PY - 2026
DA - 2026/10/30
JO - Journal of molecular modeling
DO - 10.1007/s00894-026-07029-3
UR - https://europepmc.org/article/MED/42961500
AB - 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.
SN - 1610-2940
SN - 0948-5023
ER -