New method for cocrystallization in the solid state


Pharmaceutical cocrystals have been effectively prepared through the solid-state co-grinding method. It is a combination of one or more cocrystal formers and an active pharmaceutical ingredient formed through the interaction of the molecules. Despite the several cocrystallization techniques available, the numerous limitations associated with them undermines their application. For example, solubility differences between the co-formers make solution crystallization an ineffective method as it does not produce cocrystals. Therefore, researchers have identified mechanical grinding as an effective method for eliminating the solubility differences between the co-formers thereby resulting in the screening of the cocrystals. Presently, the need to increase the cocrystal formation rate in the solid state has resulted in different grinding methodologies. This includes co-grinding at temperatures close to glass transition temperature and under cryogenic conditions.

Recently, researchers at Northwest University (Dr. Xiaorui Li, Dr. Min Qi, Professor Qiushuo Yu, Professor Xiaoxun Ma) investigated accelerated cocrystallization through a two-step co-grinding technique. The steps involved compaction of the raw materials mixtures followed by motion and collision between its particles. The authors used succinic acid and cytosine as the model compounds owing to their suitable properties. The former is a dicarboxylic acid thus favorable coformer in the cocrystals preparation while the latter is widely used in pharmaceutical industries. They purposed to increase the rate of cocrystallization process as well as investigate the effects of compression time and pressure level on the powder properties. Their research work is currently published in the research journal, Crystal Research and Technology.

The authors observed that pretreatment through compaction of the raw materials mixture before neat grinding was an efficient method of increasing the rate of cytosine-succinic acid crystallization process as compared to that without compaction. The results of the measured flake thickness under different compression conditions indicated an increase in the compressibility of the mixture from 20-80% that also represented the mole percentage increase in the cytosine.

Grinding of cocrystallization do not only accelerate the rate of crystallization but also increase the crystallinity and yield of the product. Grinding has significant physical effects on molecular particles such as removing the coating layers and increasing the surface area through breaking down of the particles. This ensures intimate mixing of the reactants, frictional heating, and amorphization of the material. Furthermore, the pressure level greatly influenced the rate of cocrystallization. For instance, a high compression ratio resulted in a long distance between the particles which favored long-distance motion of the particles. This ensured high frequent contact among the particles thereby escalating the formation of cocrystals.

The accelerated cocrystallization presented in the study will, therefore, advance the high-throughput cocrystal screening and formation. For instance, the authors suggested poor material compressibility and low pressure in tableting to minimize the risk of phase shifts in active pharmaceutical ingredients.

cocrystallization in the solid state-Advances in Engineering

About the author

Qiu shuo Yu gained his Ph.D degree in Chemical Technology from Tianjin University in 2010. His tutor is Prof. Hong yuan Wei. He started his academic career at Northwest University (China) since 2010, and was promoted to Associate Professor in 2014. He joined in Zoltan K. Nagy group at the Purdue University as a visiting scholar from 2017 to 2018.

His research interests are focused on the industrial crystallization, including the control of crystal structure, shape and size during solution crystallization, sublimation and cocrystallization.


Li, X., Qi, M., Yu, Q., & Ma, X. (2018). Accelerated Cocrystallization of Cytosine and Succinic Acid Through Compaction+Grinding. . Crystal Research and Technology, 53(3), 1700118.

Go To Crystal Research and Technology

Check Also

Numerical Representation of the Operating Behavior of a Crossflow Friction Turbomachine - Advances in Engineering

Numerical Representation of the Operating Behavior of a Crossflow Friction Turbomachine