Scholarlink

Purpose <p>This study intended to investigate two unknown impurity peaks (DP-1 and DP-2, at 0.29% and 0.20%, respectively) observed during the stability testing of brexpiprazole drug substance, which exceeded the unspecified impurity threshold (≤ 0.10%) and triggered an out-of-specification (OOS) investigation in a GMP environment. The objectives are to identify their structures, determine whether they are true impurities or artificial degradants, and establish appropriate control procedures for the pharmaceutical analysis of brexpiprazole.</p> Methods <p>The impurities were initially characterized using LC-UV/PDA high-resolution MS<sup>n</sup> (<i>n</i> = 1 to 3), which identified DP-1 as an isomer of brexpiprazole and DP-2 as a dimer. Further structural elucidation of DP-1 was performed using semi-preparative HPLC and 1D/2D NMR spectroscopy. Forced degradation studies were conducted under photolytic conditions to confirm the formation of DP-1 and DP-2, with freshly prepared solutions kept in the dark as controls.</p> Results <p>DP-1 and DP-2 are both photo-degradants of brexpiprazole in solution. DP-1 is confirmed as an intramolecular [2 + 2] cycloaddition product of brexpiprazole, which is a novel and unreported impurity found in the product of brexpiprazole. DP-2 is identified as an intermolecular [2 + 2] cycloaddition product and consistent with a prior literature [<CitationRef CitationID="CR1">1</CitationRef>]. Both impurities formed only under light exposure and were absent in the light-protected samples, confirming their photodegradation origin rather than inherent impurities.</p> Conclusion <p>Both DP-1 and DP-2 are photo-induced degradants of brexpiprazole, rather than real impurities. These findings enhance understanding of brexpiprazole’s degradation chemistry and emphasize the need for light-protected sample preparation to prevent artifactual peaks in pharmaceutical analysis of brexpiprazole drug substance and its formulations.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Isolation and Characterization of a Novel Photo-Degradant of Brexpiprazole Due to an Intramolecular [2 + 2] Cycloaddition Via High Resolution MSn (n = 1 To 3) Analysis and Multi-Dimensional NMR Measurement

  • 期刊论文

  • 发表日期：

    2025年11月5日

查看全文
  • Jinsheng Lin,
  • Qilin Wu,
  • Xueyang Liu,
  • Renjian Cao,
  • Qiyun Yong,
  • Dan Li,
  • Wenbin Chen,
  • Min Li,
  • Weiyang Shen

摘要

Purpose

This study intended to investigate two unknown impurity peaks (DP-1 and DP-2, at 0.29% and 0.20%, respectively) observed during the stability testing of brexpiprazole drug substance, which exceeded the unspecified impurity threshold (≤ 0.10%) and triggered an out-of-specification (OOS) investigation in a GMP environment. The objectives are to identify their structures, determine whether they are true impurities or artificial degradants, and establish appropriate control procedures for the pharmaceutical analysis of brexpiprazole.

Methods

The impurities were initially characterized using LC-UV/PDA high-resolution MSn (n = 1 to 3), which identified DP-1 as an isomer of brexpiprazole and DP-2 as a dimer. Further structural elucidation of DP-1 was performed using semi-preparative HPLC and 1D/2D NMR spectroscopy. Forced degradation studies were conducted under photolytic conditions to confirm the formation of DP-1 and DP-2, with freshly prepared solutions kept in the dark as controls.

Results

DP-1 and DP-2 are both photo-degradants of brexpiprazole in solution. DP-1 is confirmed as an intramolecular [2 + 2] cycloaddition product of brexpiprazole, which is a novel and unreported impurity found in the product of brexpiprazole. DP-2 is identified as an intermolecular [2 + 2] cycloaddition product and consistent with a prior literature [1]. Both impurities formed only under light exposure and were absent in the light-protected samples, confirming their photodegradation origin rather than inherent impurities.

Conclusion

Both DP-1 and DP-2 are photo-induced degradants of brexpiprazole, rather than real impurities. These findings enhance understanding of brexpiprazole’s degradation chemistry and emphasize the need for light-protected sample preparation to prevent artifactual peaks in pharmaceutical analysis of brexpiprazole drug substance and its formulations.