Experimental and Computational Insights into the Relative Stability of Ramipril-Analog Polymorphs through Quantum Mechanical Calculations and Molecular Dynamics Simulations

Polymorphism presents critical challenges in pharmaceutical development and assessing stability becomes particularly complex when crystals contain multiple independent molecules (Z′ > 1) and exhibit dynamic disorders. Compound I, a Ramipril cyclization product, crystallizes in two polymorphic forms: Form A with Z′ = 1 and Form B with Z′ = 3, both displaying temperature-dependent disorder. Across all lattice-energy evaluations, Form A is consistently identified as the thermodynamic minimum relative to Form B, with lower relative lattice energies for structures resolved at both 100 and 295 K. Both polymorphs are stabilized chiefly by intermolecular hydrogen bonding between neighboring molecules, with π–π stacking providing additional support; the contribution of π–π interactions is moderately reduced at room temperature. Additionally, MD simulations of crystallographic supercells reveal that both forms maintain structural integrity at 100 K, while exhibiting higher positional deviations at 295 K, with void volume changes observed exclusively in Form B. To assess whether the Form A and Form B structures resolved at 100 K could evolve toward their respective forms at 295 K, NPT MD simulations at 295 K starting from the 100 K models were performed. These simulations were designed primarily to investigate the development of voids and other temperature-induced structural changes. The results showed that Form B evolved toward the characteristic void structure observed experimentally at 295 K, while Form A retained its structural robustness without significant void formation. These multiscale computational findings align with experimental competitive slurry results, confirming that the elusive Form B is less thermodynamically stable than Form A. This new integrated approach provides valuable insights into polymorphic stability assessment when limited material availability precludes comprehensive traditional characterization.