NMR Crystallographic Investigation Coupled with Molecular Dynamics Simulations Reveals the Nature of Disorder in Chlorpromazine Hydrochloride Solvatomorphs

Chlorpromazine, a widely used antipsychotic medication formulated as a hydrochloride salt, has been a significant active pharmaceutical ingredient (API) for the treatment of schizophrenia for much of the last century. This work presents a comprehensive investigation into the nature of the structural disorder of chlorpromazine hydrochloride solvatomorphs using a combination of nuclear magnetic resonance (NMR) crystallography and molecular dynamics simulations. We focus on understanding the structural characteristics and stability of chlorpromazine hydrochloride and its hydrate, particularly the disorder in the dimethylaminopropyl side chain. This work provides a detailed analysis of the structural characteristics influencing this disorder, advancing the understanding of drug development and the design process for APIs that exhibit similar types of disorder.