Mechanosynthesis of cocrystals and coamorphous binary drug–drug systems with apremilast core: structural and biological studies

Abstract

In this paper, we discuss an issue important for understanding the mechanism of forming pharmaceutical binary systems and their safety in specific therapies. The main aim of this article is to answer the question of whether, in mechanochemical processes, the crystallographic form of the starting substances (substrates) affects the course of the reaction and the nature of the products obtained. Two crystallographic forms of the apremilast (APR), which is a drug used in the treatment of psoriasis and psoriatic arthritis, were utilized. As co-formers, medicines from the nonsteroidal anti-inflammatory drug (NSAID) group were used, including salicylic acid (SA), ethenzamide (ET), and paracetamol (PA) which is classified as an analgesic antipyretic drug (AAD). Each of them has a well-defined crystal structure determined by X-ray diffraction. During the course of the studies, it was found that ball milling of the physical mixture produces cocrystals of APR:SA and APR:ET, whereas APR:PA does not. The difference in reactivity is discussed in the context of the preorganization mechanism and the propensity to disrupt the dimeric structure present in the crystal lattice. The disruption of dimers in the ball mill allows the formation of isolated molecules (SA, ET), which complement the cocrystal structure by positioning themselves in the aromatic pocket of APR. Such a process is not observed in the case of PA. For testing the biological properties of new products, we selected the APR:ET cocrystal as a representative sample. Importantly, biological studies showed that the resulting binary system is cytotoxically safe and does not exhibit any undesirable effects.