Mechanochemical synthesis and 35Cl NMR crystallography of ionic cocrystals of phenothiazine drugs

Abstract

The solid forms of active pharmaceutical ingredients (APIs), such as polymorphs, cocrystals, and hydrates, possess unique physicochemical properties, including stability, bioavailability, and solubility. These properties are closely tied to their structures, which can be specifically tailored through rational design of novel forms. HCl salts are among the most common solid forms of APIs; however, the formation of pharmaceutical cocrystals of HCl APIs with pharmaceutically acceptable coformers, while relatively rare, can vastly expand the landscape of solid forms. This study explores the mechanochemical synthesis of known cocrystals of promethazine HCl and novel cocrystals of promethazine HCl and chlorpromazine HCl, along with the use of ³⁵Cl solid-state NMR (SSNMR) spectroscopy and density functional theory (DFT) calculations for their structural characterization. Mechanochemical synthesis methods were employed, offering higher yields and better scalability than conventional methods. However, the nature of the products of mechanochemical reactions, which are often powders, presents significant challenges for crystal structure determination. ³⁵Cl SSNMR experiments were used to reveal the chloride environments with distinct hydrogen bonding networks in each solid form, identified through unique quadrupolar interaction parameters. Experimental ³⁵Cl electric field gradient (EFG) tensor data were compared with those from DFT calculations, and used to identify a series of unique chloride ion hydrogen bonding configurations. This work highlights the potential of NMR crystallography for advancing the rational design of cocrystals, improving synthetic methodologies, and providing deeper insights into their solid-state properties.