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From Solution to Sublimation: Thermodynamic Evaluation of Iproniazid Multicomponent Crystals for Robust
Ksenia V Drozd1, Anna G Ramazanova1, Liudmila E Shmukler1
1G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya St., Ivanovo, 153045, Russian Federation.
Pharmaceutical Research
|August 7, 2026
Summary
The study reveals how the structure of dihydroxybenzoic acid isomers affects the stability of iproniazid co-crystals. This thermodynamic understanding aids in selecting optimal coformers for pharmaceutical development.
Area of Science:
- Physical Chemistry
- Materials Science
- Pharmaceutical Science
Background:
- Understanding the thermodynamics of multicomponent crystals is crucial for pharmaceutical development.
- Iproniazid (IPN) is an antidepressant drug whose solid-state properties can be modulated by co-crystallization.
- Dihydroxybenzoic acids (DHBAs) are potential coformers for pharmaceutical salts and co-crystals.
Purpose of the Study:
- To characterize the solution and sublimation thermodynamics of iproniazid (IPN) with six dihydroxybenzoic acid (DHBA) positional isomers in acetonitrile.
- To establish structure-thermodynamic relationships for coformer selection in pharmaceutical development.
Main Methods:
- Temperature-dependent solubilities were measured using the shake-flask method (293.15–313.15 K).
- Activity coefficients were calculated using the Schrӧder-van Laar equations.
- Sublimation parameters were indirectly determined via a thermodynamic cycle.
Main Results:
- Most systems showed positive deviations from ideality, except for 2,5-DHBA and 3,5-DHBA, indicating favorable solute-solvent interactions.
- Stable multicomponent crystals formed spontaneously via an enthalpy-driven mechanism.
- High sublimation enthalpies (233.2–266.5 kJ·mol⁻¹) correlated with lattice energies, reflecting crystal lattice strength.
Conclusions:
- Positional isomerism of DHBA significantly influences the thermodynamic stability of IPN multicomponent crystals.
- An integrated thermodynamic cycle approach provides a practical method for evaluating sublimation parameters.
- This research offers guidance for coformer selection, solid form screening, and predicting physical stability in drug development.
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