Seminars Archive

Relaxation and crystallization of amorphous drugs: anomalies and open questions

Abstract
The improved bioavailability of amorphous pharmaceuticals is achieved thanks to their metastable state, leading to the drawback of enhanced tendency to crystallize, limiting broad applications. Although vitrification and crystallization of supercooled liquids are very well studied phenomena, the recently reported anomalous behavior of crystallization with significant decoupling from diffusion has opened new perspectives of investigation [1, 2]. In particular, some molecular pharmaceutical amorphous solids have shown two kinds of anomalies: (i) a fast crystal growth (FCG) near and below the glass transition temperature [2]; (ii) surface crystal growth much faster than in bulk, reflecting fast surface mobility [3]. From the experimental evidence it is clear that a new theory is needed to rationalize the molecular mechanism originating fast crystal growth near the arrested state (an unpredicted fact, in principle, by diffusion theories). Although some extensive studies have recently been performed on some polymorphic pharmaceuticals and some theories proposed to explain the fast mode of crystal growth, the mechanism is far to be understood [2,4,5]. Its presence was correlated to (i) high fragility, i.e. the T-dependence of structural relaxation time, (ii) strong translational/rotational decoupling, (iii) broadness of relaxation time distribution, (iv) excess thermodynamic quantities of the metastable state with respect to the crystalline one. High pressure paths might yield amorphous materials with higher stability, due to less excess of free energy, reduced fragility, less decoupling, and larger activation energy for local processes. The effect of density over thermal fluctuations in favoring fast crystallization has been also proposed [4] but with controversial experimental validations [6]. In fact, isochronal crystallization kinetics measurements, i.e. in the same mobility conditions, have been demonstrated to be able to single out the role of thermodynamic variables [7]. Some studies report that also the local secondary beta-relaxation may control the FCG, so that the suppression of local mobility, due to some specific interaction, can stabilize amorphous drug against crystallization [8]. In this study we will present our recent results about the relation between crystallization kinetics and dynamics under temperature and pressure variations. Isochronal crystallization kinetics at different T-P conditions have shown a negative correlation of some excess thermodynamic quantities with the stability against crystallization. Moreover, we will illustrate the role of JG β-relaxation in determining: (i) the fast crystal growth in supercooled systems near the arrested state, (ii) the fast nanoscale mobility observed at the free surface [9], (iii) the onset of cage dynamics (over the time scale from ps to ns) occurring on heating above some temperature Tgβ deep in the glassy state [10]. These phenomena may have a fundamental importance in controlling the stability of amorphous pharmaceuticals. In particular, it appears that Tgβ could mark the lower limit between stability and instability range of amorphous systems. [1] A. Lindsay Greer, Nature Materials, 114, 542 (2015). [2] Y. Sun, L. Zhu, T. Wu, T. Cai, E. M. Gunn, and L. Yu, The AAPS Journal 14, 380-388 (2012). [3] C.W. Brian, L. Yu, J. Phys. Chem. A 117, 13303 (2013). [4] T. Konishi, H.Tanaka, Phys. Rev. B 76, 220201(R) (2007); J. Russo, H. Tanaka, Sci. Rep. 2, 505 (2012). [5] D. Musumeci et al J.Phys.Chem.Lett. 5, 1705 (2014). [6] K. Adrjanowicz et al J.Chem.Phys. 136, 234509 (2012). [7] K. Adrjanowicz, A.Grzybowski, K.Grzybowska, J. Pionteck, M. Paluch, Cryst. Growth Des. 13, 4648 – 4654 (2013). [8] S. Capaccioli, M. Paluch, D. Prevosto, Limin Wang, K.L. Ngai, J. Phys. Chem. Lett. 31, 735-743 (2012). [9] S. Capaccioli, K.L. Ngai, M. Paluch, D. Prevosto, Phys. Rev. E. 86, 051503 (2012). [10] S. Capaccioli, K.L. Ngai, M.Shahin Thayyil, D.Prevosto, J. Phys. Chem. B 119, 8800 (2015); K. L. Ngai, S. Capaccioli, D. Prevosto, L-M. Wang, J. Phys. Chem. B, 119, 12502 (2015); J. Phys. Chem. B, 119, 12519 (2015).