An unexpected aerobic oxidation of α-amino boronic acid part of Borteomib, leading to (thermal) decomposition of this very expensive anti-cancer API

Abolghasem Beheshti,Meghdad Payab,Seyyed Amir Siadati,Vahid Seyyed-Ali-Karbasi

doi:10.5267/j.ccl.2021.12.001

Abstract

This project was started when an unknown peak was being detected in the organic volatile impurity (OVI) analysis (using the head-space vapor sampling procedure) of bortezomib (BZB) active pharmaceutical ingredient (API), in pharmaceutical companies. During the OVI analysis of the API of BZB, a huge-area peak with an unknown source appeared in the chromatograms of the gas chromatography with flame ionization detector (GC-FID). The data prepared by GC-MAS revealed that the considered huge peak was 3-methylbutanal (3MBut). But, investigating the synthesis procedures showed that during all the synthesis steps, 3MBut or any other solvent containing this impurity was not being applied. Thus, we had concluded that there is a possibility for emergence of this aldehyde from bortezomib itself. To find out which part of bortezomib might turn into 3MBut, we began to investigate all its molecular structure, and hypothesized that the α-amino-boronic acid part of the molecule turned into 3MBut. The experimental analysis and theoretical quantum chemical calculations confirmed that the α-amino-boronic acid center of bortezomib molecule undergoes a rare and unexpected aerobic oxidation by O2 molecule, even in catalyst and solvent-free conditions. The result of this project not only might make clear the passive source of the 3MBut peak of the OVI of bortezomib, but also, it would suggest to store this API in an inert oxygen-free atmosphere to improve the long-term and accelerated (thermal) stability of this very expensive anti-cancer drug.

Highlights

Bortezomib (BZB), as a very expensive anti-cancer active pharmaceutical ingredient (API), is one of the most important chemotherapy medications which have been widely used for treatment of multiple myeloma and mantle cell lymphoma.[1]
The Organic Volatile Impurities (OVI) and the Related Impurity (RI) analysis are of the most important parameters in passing and releasing an API for further use
While the GC-MAS, and gas chromatography with flame ionization detector (GC-FID) chromatogram data showed us that this mechanism could not be true in the case of BZB; because, the carbon center of this (α-amino) boronic acid undergoes an oxidation process to give an aldehyde (3MBut; m/z: 29,44,58,71,86; similarity index based on Wiley Library=95%)

Summary

Introduction

Bortezomib (BZB), as a very expensive anti-cancer API, is one of the most important chemotherapy medications which have been widely used for treatment of multiple myeloma and mantle cell lymphoma.[1]. Due to the high cost of chiral precourses, difficult synthesis schemes, and low total yield, the final product of BZB (and a number of boron derivative anticancer drugs) are very expensive.[2]. Many researchers such as pharmacologists, chemists, and biologists, hardly try to design[3] and synthesize[4-6] vast number of molecules which are derived from previously confirmed bioactive molecules, in order to introduce cheaper and more effective cures. It may contain theoretical drug design,[7] synthesis new derivatives, or optimizing the synthesis methods.[8,9]. The methods which are being used for those two analyses, must be valid, and trustable.[16]

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Results

Conclusion