无定形固体
喷雾干燥
降水
材料科学
聚合物
工艺工程
色散(光学)
化学工程
玻璃化转变
纳米技术
化学
有机化学
复合材料
物理
工程类
气象学
光学
作者
Marina A. Solomos,Ashish Punia,Sugandha Saboo,Christopher T. John,Christopher W. Boyce,A. H. Chin,Robert V. Taggart,Daniel T. Smith,Matthew S. Lamm,Luke Schenck
标识
DOI:10.1016/j.xphs.2023.02.011
摘要
Amorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (Tg) can pose challenges to this approach. This study addresses multiple routes towards overcoming issues encountered with a low Tg (∼ 12 °C) API during manufacture of a spray dry intermediate (SDI). Even once formulated as an amorphous solid dispersion (ASD) with HPMCAS-LG, the Tg of the ASD was sufficiently low to require the use of non-ideal solvents, posing safety concerns and ultimately resulting in low yields with frequent process interruptions to resolve product build-up. To resolve challenges with spray drying the HPMCAS-L SDI, higher Tg polymers were assessed during spray drying, and an alternative antisolvent precipitation-based process was evaluated to generate co-precipitated amorphous dispersions (cPAD) with either HPMCAS-L or the additional higher Tg polymers. Both approaches were found to be viable alternatives to achieve single phase ASDs while demonstrating comparable in vitro and in vivo bioperformance compared to the SDI. The results of this effort offer valuable considerations for future early-stage activities for ASDs with low Tg APIs.
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