Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals

Abstract

In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through the successful combination of the drug with the positional isomers of acetamidobenzoic acid. The structural and energetic features of the CBZ cocrystals with 3- and 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. The ability of three fundamentally different virtual screening methods to predict the correct cocrystallization outcome for CBZ was assessed based on the new experimental results obtained in this study and data available in the literature. It was found that the hydrogen bond propensity model performed the worst in distinguishing positive and negative results of CBZ cocrystallization experiments with 87 coformers, attaining an accuracy value lower than random guessing. The method that utilizes molecular electrostatic potential maps and the machine learning approach named CCGNet exhibited comparable results in terms of prediction metrics, albeit the latter resulted in superior specificity and overall accuracy while requiring no time-consuming DFT computations. In addition, formation thermodynamic parameters for the newly obtained CBZ cocrystals with 3- and 4-acetamidobenzoic acids were evaluated using temperature dependences of the cocrystallization Gibbs energy. The cocrystallization reactions between CBZ and the selected coformers were found to be enthalpy-driven, with entropy terms being statistically different from zero. The observed difference in dissolution behavior of the cocrystals in aqueous media was thought to be caused by variations in their thermodynamic stability.

How Molecular Packing Affects the Thermodynamic Parameters of Cocrystal Formation: The Case of Carbamazepine Cocrystals

“…21 As shown in our previous studies, acetonitrile is one of the appropriate solvents for the investigation of the CBZ cocrystal formation thermodynamics. 20,21 Therefore, preliminary experiments were carried out to verify the stability of the CBZ cocrystals studied in the present work in acetonitrile. For this purpose, the phase-pure CBZ cocrystals were suspended in acetonitrile at a constant temperature within 24 h, and the bottom phase was then analyzed by PXRD.…”

“…The crystal structure set was limited to 11 CBZ cocrystals, including those studied in the present work and those for which the thermodynamic parameters were previously determined (cocrystals with benzamide (BZA), 4hydroxybenzamide (4-OH-BZA), isonicotinamide (INAM), 3acetamidobenzoic acid (3-AcAmBA), and 4-acetamidobenzoic acid (4-AcAmBA)). 20,21 As for [CBZ + 4-OH-BA] (1:1), the crystal structures of both polymorphs (forms A and C) were analyzed. 29 First, the crystal structures of the CBZ cocrystals were compared using the hierarchical clustering technique, 29,30 performed with a Python script deposited in the official CSD GitHub repository (https://github.com/ccdc-opensource) and the CSD Python API.…”

“…This work is a continuation of our systematic investigation of the thermodynamic aspects of the CBZ cocrystal formation. , The aim of the current study is the experimental determination of the standard thermodynamic parameters of the carbamazepine (CBZ) cocrystal formation with benzoic acid derivatives, including salicylic acid (SA), 4-hydroxybenzoic acid (4-OH-BA), 2,4-dihydroxybenzoic acid (2,4-diOH-BA), 2,6-dihydroxybenzoic acid (2,6-diOH-BA), cinnamic acid (CinnAc), and dipicolinic acid (DPA) (Figure ). In the present work, the specific features of the molecular packing in the cocrystal lattices were involved in the discussion of the formation thermodynamic parameters.…”

Cocrystal formation by anti-solvent slurry

“…The concept of cocrystal formation by anti-solvent slurry was tested here with the model compound carbamazepine (CBZ), which is a BCS class II active pharmaceutical ingredient with low aqueous solubility and is known to form four polymorphs 19 and a number of solvates and cocrystals. [20][21][22][23][24] Heptane is a non-polar organic solvent and is generally employed in the synthesis of pharmaceuticals. The solubility of a large number of different compounds in heptane is negligible, which is applied as a "universal" antisolvent for our anti-solvent slurry experiments.…”

“…These CBZ cocrystals have already been reported previously in the literature. [22][23][24][25][26] For each cocrystal system, a stoichiometric ratio mixture of CBZ and co-former (with a total mass of 20 mg) was added to 1 mL of anti-solvent (n-heptane) with the addition of 10-100 μL of solvent (MeOH/MeCN/EtOAc/ACE). The obtained slurries were then equilibrated under ambient conditions for 24 h to 48 h. The solid phases were isolated and examined by powder X-ray diffraction (PXRD) and compared to the reported or calculated PXRD patterns.…”