A Multidisciplinary Investigation to Determine the Structure and Source of Dimeric Impurities in AMG 517 Drug Substance

Maria Victoria Silva Elipe,Zhixin Jessica Tan,Tracy Bostick,Michael Ronk

doi:10.1155/2009/768743

Maria Victoria Silva Elipe, Zhixin Jessica Tan + Show 2 more

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https://doi.org/10.1155/2009/768743

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Abstract

In the initial scale-up batches of the experimental drug substance AMG 517, a pair of unexpected impurities was observed by HPLC. Analysis of data from initial LC-MS experiments indicated the presence of two dimer-like molecules. One impurity had an additional sulfur atom incorporated into its structure relative to the other impurity. Isolation of the impurities was performed, and further structural elucidation experiments were conducted with high-resolution LC-MS and 2D NMR. The dimeric structures were confirmed, with one of the impurities having an unexpected C-S-C linkage. Based on the synthetic route of AMG 517, it was unlikely that these impurities were generated during the last two steps of the process. Stress studies on the enriched impurities were carried out to further confirm the existence of the C-S-C linkage in the benzothiazole portion of AMG 517. Further investigation revealed that these two dimeric impurities originated from existing impurities in the AMG 517 starting material, N-acetyl benzothiazole. The characterization of these two dimeric impurities allowed for better quality control of new batches of the N-acetyl benzothiazole starting material. As a result, subsequent batches of AMG 517 contained no reportable levels of these two impurities

Highlights

In the early stages of new drug development, understanding the impurity profiles of the drug substance is critical when interpreting the data from toxicology and clinical studies
A commonly used framework used in the pharmaceutical industry is Q3A(R2), the International Conference on Harmonization (ICH) guidance for controlling impurities in new drug substance [1]
The organic impurities are of major concern for a new drug substance produced by chemical synthesis because the potential toxicity of most of these impurities is unknown

Summary

Introduction

In the early stages of new drug development, understanding the impurity profiles of the drug substance is critical when interpreting the data from toxicology and clinical studies. Knowledge of impurity structures can provide important insight into the chemical reactions responsible for forming these impurities as well as understanding potential degradation pathways [2] Such information is essential in establishing critical control points in the drug substance synthetic process and eventually ensuring its overall quality and safety. These HPLC-UV methods are frequently used to track impurity profiles across various batches of drug substance which are often produced by different synthetic routes and at different scales This is especially important in the earlier phases of clinical development when, due to resources and time. The desire to understand the origin of these impurities in the drug substance led to investigation of starting materials using HPLC-UV and LC-MS Information compiled from these studies allowed us to work back through the synthetic scheme for AMG 517 to determine the source of the dimeric impurities. (a)Data from 400 MHz NMR instrument; (b)data from 600 MHz instrument; (c)overlapping signals

Experimental

Results and Discussion

Conclusion