Strategy to Assess and Control Nitrosamine Formation in API during Storage: A Sitagliptin Case Study

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-08-06 DOI:10.1021/acs.oprd.4c00088

Laura Badia, Helena Camps, Isabel Lloveras, Norbert Handler, Helmut Buschmann, Jordi Valls, Michal Poznik

引用次数: 0

Abstract

A new strategy to identify, assess, and mitigate the nitrosamine formation in APIs during storage was developed and demonstrated on sitagliptin hydrochloride monohydrate, in which an increase in nitrosamine content was observed during stability studies. Comprehensive stress tests and stability assessments were carried out to evaluate the influence of various internal and external stimuli. Air exposure, secondary amine content, and optimum pH conditions emerged as the principal trigger factors. The results were consistent across all four distinct types of sitagliptin hydrochloride monohydrate tested, which were synthesized at different manufacturing sites and via diverse synthetic routes. A mitigation strategy was developed in which the secondary packaging material was modified to effectively prevent the ingress of air. This change yielded a clear reduction in nitrosamine formation, confirmed by 6-month stability studies at 40 °C.

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评估和控制原料药在储存过程中亚硝胺形成的策略：西他列汀案例研究

在对盐酸西格列汀一水合物进行稳定性研究时，发现亚硝胺含量有所增加，因此开发了一种新策略来识别、评估和减轻原料药在储存过程中亚硝胺的形成。进行了全面的压力测试和稳定性评估，以评估各种内部和外部刺激的影响。空气暴露、二级胺含量和最佳 pH 值条件成为主要的触发因素。测试的所有四种不同类型的盐酸西他列汀一水合物的结果都是一致的，这些产品是在不同的生产基地通过不同的合成路线合成的。我们制定了一项缓解策略，对二级包装材料进行改良，以有效防止空气进入。这一改变明显减少了亚硝胺的形成，40 °C下6个月的稳定性研究证实了这一点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.