Development and Structure Analysis of Crystal Forms of Apabetalone: Solvates and Polymorphs

Apabetalone is a drug for treating cardiovascular and cerebrovascular diseases, which has been recently recognized as a breakthrough therapy designation (BTD) by the FDA. In the present work, five novel forms of apabetalone (a polymorph, a hydrate, and three 1,4-dioxane solvates) were obtained and characterized by various analytical techniques. The single-crystal structures of two new solvates (1,4-dioxane and water) and two reported polymorphs (forms CS1 and CS4) were solved for the first time to give information about the molecular assembly and the role of solvent molecules within the lattice. The results revealed that apabetalone molecules are mainly self-assembled through two types of hydrogen-bond dimers (dimers I and II) and expanded through π stacking. Nevertheless, the water molecules could disturb the more encountered dimer I and lead to a special packing mode. The relationship between crystal structure and molecular conformations was also discussed. Furthermore, the thermal behavior and phase transformation process were investigated in detail. A novel solvent-free polymorph was obtained in this process through desolvation of the dioxane solvates, indicating a feasible way to develop novel polymorphs.