Use of Differential ScanninTableg Calorimetry as a Rapid, Effective In-process Check Method for Impurity Quantitation of an Early Clinical Batch of Giredestrant (GDC-9545)

杂质 差速器(机械装置) 过程(计算) 差示扫描量热法 色谱法 计算机科学 化学 物理 热力学 有机化学 程序设计语言
作者
Paroma Chakravarty,Karthik Nagapudi
出处
期刊:Journal of Pharmaceutical Sciences [Elsevier]
标识
DOI:10.1016/j.xphs.2024.09.003
摘要

Giredestrant (GDC-9545) is a selective estrogen receptor degrader (SERD) that was developed for treatment of ER+/HER2- metastatic breast cancer. An anhydrous crystalline tartrate salt was identified as the solid form suitable for clinical development. An early clinical batch of the active pharmaceutical ingredient (API)/drug substance failed to pass the GMP purity specifications owing to the presence of a substantial amount of high molecular weight impurities (oligomers), as determined by size exclusion chromatography. Several trial rework batches were manufactured using various re-slurry and recrystallization conditions to purge impurities in the drug substance to adhere to purity specifications. Based on the melting point depression of the API in presence of oligomers in these rework batches, a differential scanning calorimetry method was developed to quantify impurity content as a function of melting point onset of the API. This thermal analysis method was used as a surrogate for chromatography as a rapid, effective in-process check method for impurity quantitation to enable the timely release of the final reworked clinical batch. Post release, the % w/w oligomer value determined by calorimetry was in excellent agreement to that obtained by size exclusion chromatography.

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