Category: Formulation and Quality
Purpose: Amorphization is an effective way to improve the solubility/dissolution of poorly soluble drugs. Unexpectedly, the BCS class II drug lurasidone hydrochloride (LH) in amorphous state shows a much lower dissolution than crystalline LH due to its gelation during dissolution. The current study aims to explore the gelation mechanism of amorphous LH and the internal relationship with its chemical structure, and external factors including temperature and ionic strength on gelation and hence the dissolution of amorphous LH.
Methods: Dissolution tests of amorphous LH were performed under different temperatures (30, 37 and 45 oC) and buffer ionic strengths (salt concentrations: 0.025, 0.05 and 0.1 M at 37 oC). The formed gels were characterized by rheology study, texture analysis, PLM, SEM, DSC, XRPD and FTIR.
Results: During dissolution, amorphous LH powders quickly aggregated upon contacting water, and formed a viscous soft mass (“gel”) adhering on the paddle, which is responsible for its lower dissolution than crystalline LH (Fig.1). However, no such gelation phenomenon of amorphous lurasidone (the base form of LH) was observed under the same dissolution condition. Interestingly, the gel would reform when dropping concentrated hydrochloric acid slowly into the bottom of medium during dissolution of amorphous lurasidone, and XRPD/DSC/FTIR results indicated that the regenerated gel was consisted of crystalline LH (Fig.2). On the other hand, effects of two important factors for dissolution, temperature and ionic strength, on the formation and strength of gel have been investigated. With the increase of temperature (from 30 to 45 oC) and salt concentrations (from 0.025 to 0.1 M) of medium, the dissolution of LH decreased, while the strength, hardness and adhesiveness of in situ formed gel from amorphous LH enhanced (Fig.3).
Conclusion: The charge-assisted bond N+-H in the structure of LH mediated the gel formation of amorphous LH during dissolution, resulting in an unconventional dissolution behavior with a much lower dissolution than its crystalline LH. With increase of temperature and ionic strength, the gel strength of in situ formed gel from amorphous LH enhanced with more compact microstructure, subsequently leading to decreased dissolution profiles.
References: 1. Qian et al, Cryst Growth Des. 2015;15(6):2920-2928. 2. Qian et al, Int J Pharm. 2017;518(1-2):335-341. 3. Heng et al, Pharm Res. 2019;36(5):72.
Yuanfeng Wei– Nanjing, Jiangsu, China (People's Republic)
Shanshan Wang– Nanjing, Jiangsu, China (People's Republic)
Shengyan Zhou– Nanjing, Jiangsu, China (People's Republic)
Di Ma– Nanjing, Jiangsu, China (People's Republic)
Yuan Gao– Nanjing, Jiangsu, China (People's Republic)
Jianjun Zhang– Nanjing, Jiangsu, China (People's Republic)
Shuai Qian– Nanjing, Jiangsu, China (People's Republic)