Abstract
Polymorphism studies were conducted on elacestrant dihydrochloride (RAD1901-2HCl) to identify the existence of hydrates, solvates, and non-solvated forms and investigate their solid-state properties and relative thermodynamic stabilities. Two batches (denoted Form 1 and Form 2/3) of elacestrant dihydrochloride were extensively characterized, revealing that Form 1 exists as a stable anhydrous polymorphic form at 0-90% RH but converts irreversibly to a hydrate (Form 3) at greater than 90% RH. In contrast, Form 2/3 exhibits lower stability and is a dynamic mixture of anhydrous (Form 2) and hydrated states (Form 3) influenced by ambient RH. Analyzing humidity behavior, utilizing custom GVS and variable humidity XRPD methods, found that Form 1 is the preferred crystalline form, with stable properties and low hygroscopicity. Comprehensive polymorph screens, including heating, cooling, evaporation, and maturation cycles in diverse solvent systems, produced the known crystalline forms (Forms 1, 2, and 3). The prevalence of anhydrous Form 1 suggests its suitability for development, while the hydrate (Form 3) is generated in the presence of water or water/solvent mixtures. Water activity experiments with elacestrant dihydrochloride recrystallization solvents indicate that anhydrous Form 1 can be reliably obtained at and below 5% v/v water. These studies demonstrate that Form 1 (‘desired form’) is stable, has low hygroscopicity and good thermal properties, and is the most appropriate crystalline form for development and commercialization. However, careful control of water content (below 5% v/v) and room humidity is crucial during drug development, commercialization and storage to prevent the formation of the less stable Form 3 (hydrate).