GS-2278的游離堿形式存在很多晶型，包括溶劑化物，其鹽形式包括各種酸基，綜合研究后，選擇鹽酸鹽二水合物的晶型。
特性鑒定
DSC-TGA1-HCl 2H2O is a dihydrated form (Karl Fischer =5.8% water, TGA weight loss = 5.8%) with a desolvation endotherm around 82 °C, followed by endotherms around 143 and 166 °C, attributed to HCl loss and decomposition, respectively.
DSC，熱，三個(gè)吸熱峰，分別是失去水，失去氯化氫和分解。
TGA，重，先失去水，再失去氯化氫，再分解，然后恒重。
單晶
hydrochloric acid salt of 1, and it contains one freebase cation, one chloride anion, and two water molecules.
手性問題，原文有，這里沒有搬運(yùn)，單晶是證明絕對構(gòu)型的最好證據(jù)。
穩(wěn)健性研究
原料藥粉碎工序?qū)偷挠绊?/span>
As the clinical program progressed, a batch of 1-HCl 2H2O was jet-milled, and the resulting data confirmed that there was no change in crystalline form or water content
原料藥干燥工序?qū)偷挠绊?/span>
原料藥加熱到100度，粉末衍射數(shù)據(jù)發(fā)生了變化，但是當(dāng)冷卻到35度時(shí)，粉末衍射數(shù)據(jù)和35度干燥的樣品粉末衍射數(shù)據(jù)一樣，就是目標(biāo)晶型數(shù)據(jù)。
數(shù)據(jù)說明，加熱條件水分會(huì)丟失，晶型發(fā)生變化，但是冷卻后缺水或者無水晶型會(huì)從環(huán)境中吸收水分變成2水合物。
基于加熱，溫度過高，水分會(huì)丟失的風(fēng)險(xiǎn)，干燥工序溫度未超過40度。
生產(chǎn)環(huán)境濕度對原料藥水合物的影響
春夏秋冬，不同時(shí)間點(diǎn)濕度不一樣，不一樣的車間濕度也不一樣。制劑生產(chǎn)過程，原料藥暴露環(huán)境也涉及不同濕度環(huán)境。
Dynamic vapor sorption (DVS) data can be used to gauge the robustness of a hydrate as a function of relative humidity conditions.
This indicates that 1-HCl
2H2O is resistant to desolvation/form change when exposed to nonhumid conditions and provides evidence of no conversion to a higher hydrate when exposed to very humid conditions.
參考文獻(xiàn)
https://doi.org/10.1021/acs.oprd.5c00065
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