Mechanochemical Behaviour of Solid Pharmaceuticals during Milling: Experimental and Modelling Studies

Milling is a commonly used technique in the processing of active pharmaceutical ingredients (APIs) or excipients to control the size and dissolution rate of poorly soluble drugs. However, one of the major challenges of the milling process is the physical and chemical changes arising from the mechanical treatment (mechanochemistry) of the material which might adversely impact the pharmaceutical performances. The common practice to optimise the milling of a specific solid pharmaceutical is to conduct extensive trial and error experiments. However, this method is costly and ineffective, particularly in the early drug development stage, where, a limited amount of API is available. Hence, a methodology that allows anticipating the milling behaviour of particular pharmaceutical solids would be highly desirable. The review section is set to identify the knowledge gap to enable designing a methodology that can address the lack of understanding of the mechanistic behaviour of solid pharmaceutical during milling including the extent of particles size reduction (comminution), and potential mechanochemistry (i.e. amorphisation). This is achieved through determining the key material properties that influence the milling behaviour of the sample, such as the mechanical properties which are controlled by their underlying crystal structure and molecular properties. And through evaluating the critical milling parameters that control the level of the energy available for the treatment of particles during milling, including the type of mill, speed, and time of milling. The material properties influencing the mechanistic behaviour of solid pharmaceuticals were predicted using computational chemistry through studying the sample intrinsic characteristics at the molecular level. The key predicted properties include crystal habit, mechanical properties, and any potential slip plane/system. Two solid pharmaceutical candidates were used in the modelling work, L-Glutamic Acid (β-LGA) and Diaqua-bis(Omeprazolate)-magnesium(II) dihydrate (DABOMD) which are employed for cancer inhibition and stomach acid reflux applications respectively. The outcome of the properties prediction indicates that DABOMD is anticipated to experience large comminution and amorphisation due to its propensity to brittle failure and plastic deformation owed to its moderate elastic modulus and hardness, presence of slip plane and the allocation of water molecules near its slip system. Whereas β-LGA is expected to experience larger comminution and lower amorphisation compared to DABOMD which is related to the prevailing hydrogen network holding its crystal structure, higher elastic modulus and hardness values, and to the lack of slip planes in its structure. To verify the results of the predicted work, milling was performed on DABOMD using a planetary ball mill and a single ball mill and on β-LGA using a planetary ball mill at different times. The outcome of the empirical work shows that DABOMD undergoes a prominent comminution and amorphisation processes that occur parallel to each other, with planetary ball mill causing slightly higher comminution and amorphisation compared to the single ball mill. Whereas, milling of β-LGA shows that it undergoes larger dominant comminution followed by partial amorphisation and recrystallisation. To establish a relationship between the degree of comminution, amorphisation, and the intensity of milling. The energies of planetary ball mill and a single ball mill were quantified using a collision model derived from the literature, and through tracking the milling jar with high speed-camera respectively and were validated through the DEM simulations of the mills. It was found that the planetary ball mill produces higher energy than single ball mill which explains the difference in the comminution and amorphisation obtained in the two mills. The energy produced using DEM simulation of the planetary ball mill agrees with the calculated energies from the collision model. However, the energy calculated from the DEM simulation is lower than that generated from tracking the milling jar in the single ball using a high-speed camera since the DEM tracks the movement of the ball and the powder instead of the movement of the jar. This methodology will enable determining the type and amount of changes that raise with the milling of a solid (i.e. comminution, amorphisation), the time at which it occurs, and the energy required to cause this change.