Bubble-induced fast crystal growth of indomethacin polymorphs in a supercooled liquid

Abstract

Physical stability is one of the main challenges when developing robust amorphous pharmaceutical formulations. This article reports fast crystal growth behaviors of the γ and α forms of indomethacin (IMC) initiated by bubbles in the interior of a supercooled liquid. Bubble-induced crystal growth of γ-IMC exhibits approximately the same kinetics as its surface crystal growth, supporting the view that bubble-induced crystal growth is a surface-facilitated process. In contrast, the rates of bubble-induced crystal growth of α-IMC are much faster than those of its surface crystal growth. These results indicate that the bubble-induced crystal growth not only depends on the interface created by the bubble but also strongly correlates with the true cavitation of the bubble. Moreover, bubble-induced fast crystal growth of γ- and α-IMC can be terminated at different temperatures by cooling. These outcomes are meaningful for the in-depth understanding of physical stability and pre-formulation study of amorphous pharmaceutical solids showing surface-facilitated crystal growth.

Effects of polyvinylpyrrolidone on the crystallization of amorphous griseofulvin: fracture and molecular mobility

“…These results support the view that crystal nucleation can be significantly enhanced by cooling the liquid to cause fracture (Su et al, 2019). Fracture was expected to generate a free surface, providing the sites for heterogeneous nucleation and enhanced molecular mobility (Shi, Tao et al, 2020;Shi et al, 2021;Su et al, 2019).…”

“…Bubble-induced crystal growth in the interior of amorphous pharmaceuticals was first reported in griseofulvin at temperatures from 130 to 150 � C (Shi, Tao et al, 2020;Shi & Cai, 2016). In subsequent studies, these interesting growth behaviors have also been found in the crystal growth of nimesulide and in the �-form and �-form of indomethacin (Shi et al, 2021;. This enhanced crystallization through the air-liquid interface was mainly attributed to the fast molecular diffusion at the surface and interface (Yu, 2016;Huang, Ruan et al, 2017).…”

“…In addition, the velocity of needle-like crystal growth was comparable to that of bubble-induced crystal growth. Recent studies proposed that bubble-induced growth was a surface-facilitated process (Shi, Tao et al, 2020;Shi et al, 2021;. Bubbles generated from the crystallization provided an air-liquid interface to accelerate the crystal growth, taking advantage of the high surface mobility (Yu, 2016).…”

“…It is well accepted that drug molecules at a free surface or interface exhibit different degrees of freedom in comparison with those in the interior of amorphous pharmaceutical solids (Shi, Tao et al, 2020;Yu, 2016;. As a result, crystal growth and nucleation at the free surface and interface can be much faster compared with those in the interior (Shi, Tao et al, 2020;Zhang, Xu et al, 2023;Shi et al, 2021;Shi & Cai, 2016; For instance Zhang, Xu et al (2023) investigated the effects of proximity to the surface on the nucleation of clotrimazole polymorphs by using a two-stage method. Compared with bulk nucleation, nucleation rates at the surface of clotrimazole polymorphs were vastly accelerated by 5-6.5 orders of magnitude (Zhang, Xu et al, 2023).…”