01/10/2019
Experimental Setup for kinetic studies and sample spectra

Experimental Setup for kinetic studies and sample spectra

Source: BAM, Structure Analysis Division

The solid form of a molecule plays a definitive role in deciding its physical properties. The dissolution of a pharmaceutical material, for example, is intimately related to the orientation of molecules in the solid state. In turn, the biological activity of a pharmaceutical molecule also depends on its solid structure. Tuning the physical properties of solids has therefore captured the interest of both industry and academia. A popular approach for altering solid state structure is by combining multiple, different molecules into the same solid form: cocrystals. Unfortunately, traditional cocrystal synthesis strategies are solvent-intensive. A modern, alternative approach – mechanochemistry – instead allows cocrystal formation by grinding together dry materials, without the addition of bulk solvent. Unfortunately, mechanochemistry appears to defy many rules of textbook chemistry, greatly limiting its predictability and hence industrial application.

Using advanced analytical techniques, the mechanochemical syntheses of two pharmaceutically relevant three-component cocrystals were investigated in real time. Seemingly subtle changes in the mechanochemical procedure were shown to introduce important mechanistic changes in the mechanochemical syntheses. When conducted at high energy, or under completely solvent-free conditions, the three-component cocrystals formed directly from the starting materials. Unexpectedly, at lower energy or with the addition of microliters of liquid, a competitive cocrystal product was formed. The unpredictable formation of competitive products represents a major issue for developing robust and reliable processing strategies, particularly in the fine chemicals industry. Both the reaction rate and product integrity can be adversely affected by the presence of alternative reaction pathways, often in unpredictable ways. Identifying how subtle processing parameters affect reaction mechanisms is critical for the a priori assessment and design of new manufacturing technologies of crucial industrial importance.

Combination of advanced analytical techniques (X-ray diffraction and Raman spectroscopy) reveal the evolution of solid material during grinding. This methodology allows to follow the kinetics of environmentally benign, solvent-free reactions in real time.

Manipulating the dynamics of mechanochemical ternary cocrystal formation
Hannes Kulla, Adam Michalchuk, Franziska Emmerling
published in Chemical Communications 2019, Volume 55, Issue 66, Pages 9793 - 9796
BAM, Structure Analysis Division