(M1430-01-04) Shear-Induced Crystallization of Amorphous Indomethacin

Purpose: Improving the dissolution of BCS class-II drugs is a big challenge in pharmaceutical industry. Benefiting from rapid dissolution, amorphous state of drugs has received extensive attention. However, thermodynamic instability of amorphous drugs is the most worrisome issue. Indomethacin (IDM) is a clinically classic non-steroidal anti-inflammatory drug with rich polymorphism, and often used as a model drug for solid-state chemistry studies. Shear is a force that is common in pharmaceutical manufacturing processes such as hot melt extrusion and grinding. In this work, we reported the discovery that shear force dramatically accelerates the nucleation of amorphous indomethacin, including the supercooled liquids and the glass.

Methods: Shear force was applied on supercooled liquid of IDM by pulling fibers and scraping with needles. The nucleation of amorphous IDM was monitored by hot-stage microscope and differential scanning calorimetry (DSC).

Results: First, as we buried a polymeric fiber in the IDM melts and kept the sample at 110 ℃, no nuclei can be observed after 24 h, indicating this fiber has no heterogeneous nucleation effect on the IDM supercooled liquids (Figure 1a). If we pull this fiber horizontally for 10 s (9 mm/s, 110 ℃), a string of small crystals was observed along the track of fiber after the pulling is complete (Figure 1b). This result indicates that even weak shear can significantly shorten the nucleation induction time of the IDM undercooled melts. Then, we applied small amplitude oscillatory shear on the IDM supercooled liquids using a stainless-steel needle to investigate the influence of shear duration and shear temperature on the nucleation. As shown in Figure 2a-d, the longer the oscillatory shear is applied, the faster the nucleation, and this accelerating effect reaches its peak between 100-120 ℃ and then decreases with the increasing shear temperature (Figure 2e). We speculate that shear force may generate precursors that promotes the nucleation of IDM and that these precursors relax more rapidly at higher temperatures. To verify the existence of shear-induced precursors in the IDM supercooled liquids, we gave an oscillatory shear to the IDM melts using a needle at 92 ℃ (above its glass transition temperature, T_g) without inducing immediate nucleation after shearing. These samples were stored at 32 ℃ (below the T_g of IDM). All of 19 sheared glass sample nucleated along the shear direction within 24 h, while for the glass sample without being sheared, only 1 of 19 nucleated after 7 d (Figure 3a-d). Then, we further employed DSC to detect thermal events of IDM glass samples with different force history during heating process, and the results demonstrate that the sheared glass samples recrystallized, while the quiescent samples kept amorphous as being heated at 10 ℃/min (Figure 3e). Based on the above results, we suggested shear force can generate the precursors at high temperature, which are kept in the glass and triggered the nucleation of glass IDM.

Conclusion: This work reported that shear force can accelerate the nucleation of both supercooled liquids and glass of IDM. This shear-enhanced nucleation may be attributed to the generation of precursors. These shear-generated precursors relax more rapidly at high temperature. In proper conditions, the precursors can be kept in the supercooled liquids or glass and triggered the nucleation of IDM molecules. These results suggest that the influence of strong shear on nucleation should be given full attention in the manufacturing of amorphous drugs.

Polarized optical microscopy (POM) images of IDM supercooled liquids sandwiched between two coverslips at 110 ℃. (a) After standing for 24 h under quiescent condition. (b) After being sheared by pulling a fiber at a speed of 9 mm/s for 10 s.

Morphology (a-d) and nucleation landscape (e) of IDM supercooled liquids as a function of shear temperature and shear duration. An oscillatory shear was applied using a stainless-steel needle. The samples were observed under POM immediately after shearing is complete. A cycle refers to the needle scraping back and forth once in a fixed direction. The scraping frequency is about 4 cycles per second. The shear temperature in a-d is 110 ℃.

POM images (a-b) and DSC curves (e) of IDM supercooled liquids and glass. a-d) the IDM melts were kept under quiescent condition (a) or sheared (b) at 92 ℃ and then stored at 32 ℃. e) The samples were melted in a crucible at 170 ℃ and then cooled to 120 ℃ for 10 s under quiescent condition (1) or being sheared (2), followed by quenching at ambient condition without the occurrence of nucleation.