# Impact of Halogen Substituent Nature and Position on the Structural and Energetic Properties of Carbamazepine Cocrystals with Meta‐Halobenzoic Acids: A Two‐Pathway Synthesis Study

## TL;DR

This study examines how halogen atoms in benzoic acid affect the structure and stability of carbamazepine cocrystals, revealing insights for drug development.

## Contribution

The study reveals isostructurality and enhanced lattice stability with heavier halogens in carbamazepine cocrystals.

## Key findings

- Cocrystals with meta-halobenzoic acids show isostructurality despite varying halogen substituents.
- Heavier halogens increase lattice stability due to larger atomic radii.
- Mechanochemical synthesis is efficient and eco-friendly for cocrystal formation.

## Abstract

Crystal engineering provides effective strategies to produce pharmaceutical cocrystals, aimed at enhancing the physicochemical properties of active pharmaceutical ingredients. Herein, the structural and energetic properties of carbamazepine cocrystals with meta‐chlorobenzoic, meta‐bromobenzoic, and meta‐iodobenzoic acids are examined in depth, with particular focus on the influence of halogen substitution. A comparative assessment of solution‐based crystallization and mechanochemical synthesis via liquid‐assisted grinding provides insight into the viability of different synthetic methodologies. The crystallographic analysis reveals isostructurality among the three cocrystals, with lattice stability being modulated by the increasing atomic radius of the halogen substituent. Complementary techniques, including thermogravimetry, differential scanning calorimetry, Fourier transform infrared spectroscopy, and Hirshfeld surface analysis, further elucidate the intermolecular forces driving the formation of these crystalline phases. The lattice energy calculations offer a quantitative perspective on the role of halogen substitution in stabilization, enriching the understanding of fundamental crystal engineering principles relevant to pharmaceutical development.

This study explores how halogen substitution in benzoic acid coformers affects the structure and stability of carbamazepine cocrystals. Isostructurality and enhanced lattice stability with heavier halogens are revealed, highlighting key supramolecular interactions. Mechanochemical synthesis proves efficient and eco‐friendly, offering insights for pharmaceutical crystal design.© 2025 WILEY‐VCH GmbH