Mechanically induced amorphization of small molecule organic crystals

YF Zeng and L Alzate-Vargas and CY Li and R Graves and J Brum and A Strachan and M Koslowski, MODELLING AND SIMULATION IN MATERIALS SCIENCE AND ENGINEERING, 27, 074005 (2019).

DOI: 10.1088/1361-651X/ab234a

Milling and micronization are commonly used to reduce the particle size of active pharmaceutical ingredients and excipients. During these processes the materials are subjected to extensive deformation that may result in defect nucleation, polymorphic transformations, and amorphization. Current amorphization models require parameters that demand extensive number of experiments. We present a multiscale framework to predict mechanically induced amorphization without experimental information. The model requires as input only the molecular structure and starts with molecular dynamics simulations to determine elastic constants, melting temperature, crystal-amorphous interface energy, and the energy density difference between the amorphous and crystalline phases. This information is used in a phase field model that includes defect nucleation and solid state amorphization. At each scale, the components of the model are validated by performing simulations of sucrose, lactose, acetaminophen, and gamma-indomethacin. The multiscale framework is exercised to predict the response of two pharmaceutical compounds F1 and F2, without any experimental information. The model indicates that F1 is resistant to disorder while F2 tends to be amorphized, in agreement with the experimental results.

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