Stability of amorphous pharmaceutical solids: crystal growth mechanisms and effect of polymer additives

Abstract

We review recent progress toward understanding and enhancing the stability of amorphous pharmaceutical solids against crystallization. As organic liquids are cooled to become glasses, fast modes of crystal growth can emerge. One such growth mode, the glass-to-crystal or GC mode, occurs in the bulk, and another exists at the free surface, both leading to crystal growth much faster than predicted by theories that assume diffusion defines the kinetic barrier of crystallization. These phenomena have received different explanations, and we propose that GC growth is a solid-state transformation enabled by local mobility in glasses and that fast surface crystal growth is facilitated by surface molecular mobility. In the second part, we review recent findings concerning the effect of polymer additives on crystallization in organic glasses. Low-concentration polymer additives can strongly inhibit crystal growth in the bulk of organic glasses, while having weaker effect on surface crystal growth. Ultra-thin polymer coatings can inhibit surface crystallization. Recent work has shown the importance of molecular weight for crystallization inhibitors of organic glasses, besides "direct intermolecular interactions" such as hydrogen bonding. Relative to polyvinylpyrrolidone, the VP dimer is far less effective in inhibiting crystal growth in amorphous nifedipine. Further work is suggested for better understanding of crystallization of amorphous organic solids and the prediction of their stability.

Fig. 1

a Crystal growth rate u and self-diffusion coefficient D of liquid and glassy o-terphenyl. Tg = 246 K. b Photomicrographs of GC growth at 248 K

Fig. 2

a Fibers of YT04 (a ROY polymorph) emerging at 270 K in 250 min from a spherulite previously grown at 267 K. Crossed polarizers were used to reveal the fibers and resulted in dark background. b Same as a, but after returning to 267 K for 30 min, allowing GC growth to occur. One polarizer was used, resulting in bright background and low visibility of the fibers seen in a

Fig. 3

a Crystal growth rates of γ IMC in the bulk and at the free surface. b Photographs of γ IMC growing at the free surface. The sample is on a circular cover glass. The fast surface crystal growth can be inhibited by a thin coating of gold (10 nm) or polymer (3–20 nm) (34,35)

Fig. 4

Light microscopy (LM) a and b and atomic force microscopy (AFM) c images of α IMC crystals grown at the surface of a 15 μm thick glass at 40°C. The AFM scan in c covered the square in b. Arrow indicates advance direction of crystal growth front. d Height profile along line AB in c. The crystals can be hundreds of nanometers above the glass surface

Fig. 5

u _s/u _b vs. crystal density for three CBZ polymorphs at 303 and 313 K (open and closed symbols, respectively)

Fig. 6

Surface and bulk diffusion coefficients of IMC liquid and glasses

Fig. 7

Different dependences of bulk and surface crystal growth rates in an NIF glass on PVP-K15 concentration

Fig. 8

Effect of PVP on crystal growth in an NIF glass at 313 K. a Pure NIF. b NIF containing 1 % w/w PVP-K15. u _b: bulk growth rate; u _s: surface growth rate. t ₀ is the time to start tracking crystal growth. a and b share the same scale bar