(64b) Evaluation of Mechanical Properties of Organic Crystals for the Prediction of Breakage during Isolation Processes

Fragkopoulos, I. S. - Presenter, University of Leeds
Hallac, F. S. - Presenter, University of Leeds
Connell, S. D., University of Leeds
Muller, F. L., University of Leeds
Crystal breakage during the isolation of active pharmaceutical ingredients (API) is an issue of great concern to the pharmaceutical industry. Conservation of the desired particle size distribution (PSD) throughout downstream processing is extremely important as changes are known to affect properties such as bioavailability, flowability and bulk density [1]. APIs are commonly produced by batch crystallisation as high aspect ratio crystals, usually needle-shaped, and they are separated from the mother liquor through pressure filtration. At industrial scale, isolation of the material is prone to significant changes in the PSD. This is typically attributed to agitation during drying [2]. In contrast, MacLeod and Muller [3] showed that the filtration process itself can have a profound impact on the PSD of needle-shaped crystals. The main objective of this work is to elucidate the phenomenon of crystal fracture under pressure filtration. To achieve this, mechanical properties, such as yield stress, elasticity and hardness, need to be determined at the single crystal level.

Namazu et al. [4] conducted 3-point bending test experiments using an inorganic single crystal (Si) fixed beam in order to evaluate the size effect on the mechanical properties of crystals. It was found that reduction of the crystal size leads to an increase in bending strength. Our group developed a single crystal 2-point bending test by fixing one edge of single microscopic needle-shaped crystals and applying a force at the other edge using Atomic Force Microscopy [5]. We employed this method to determine the micro-mechanical properties of β-L-glutamic acid (β-LGA), a needle-shaped organic crystal. Similar to [4], a high number of experiments demonstrated that the yield stress is a strong function of the crystal size. Using a derivative from Bernoulli’s beam theory [3], it was found that the critical stress leading to β-LGA crystal snapping is equal to 13.8 MPa. As the crystals are by nature not identical, a Weibull analysis was also performed to model the distribution of the experimental observations. The Weibull’s distribution function shape (k) and scale (λ) parameters were estimated and are equal to 2.07 and 1.896x107 respectively. The median of the Weibull distribution is equal to 15.9 MPa, meaning that 50% of the crystals would break under such a stress [6].

A solid mechanics model, implemented in COMSOL Multiphysics, was used to simulate the single crystal fixed beam bending. The model can very accurately predict the crystal deflection and stress profiles under the application of varying forces. The extension of such a model to carry out simulations at the filter bed scale, in conjunction with yield stress experimental findings, could be ultimately used as a predictive tool towards the evaluation of the propensity for particle breakage during API isolation at scale, and the improvement of the process design as well as operating conditions.


1. Kougoulos, E., C.E. Chadwick, and M.D. Ticehurst, Impact of agitated drying on the powder properties of an active pharmaceutical ingredient. Powder Technology, 2011. 210(3): p. 308-314.

2. Lekhal, A., K.P. Girard, M.A. Brown, S. Kiang, J.G. Khinast, and B.J. Glasser, The effect of agitated drying on the morphology of L-threonine (needle-like) crystals. International Journal of Pharmaceutics, 2004. 270(1-2): p. 263-277.

3. MacLeod, C.S. and F.L. Muller, On the fracture of pharmaceutical needle-shaped crystals during pressure filtration: Case studies and mechanistic understanding. Organic Process Research and Development, 2012. 16(3): p. 425-434.

4. Namazu, T., Y. Isono, and T. Tanaka, Evaluation of size effect on mechanical properties of single crystal silicon by nanoscale bending test using AFM. Journal of Microelectromechanical Systems, 2000. 9(4): p. 450-459.

5. Sohi, S.S., S.D. Conell, D. Harbottle, and F.L. Muller, A method for the determination of mechanical properties of needle shaped crystals using Atomic Force Microscopy. Master's Report, University of Leeds, 2016.

6. Hallac, F.S., I.S. Fragkopoulos, S.D. Connell, and F.L. Muller, Micro-mechanical properties of needle-shaped organic crystals. Organic Process Research and Development, 2017. To be submitted.