Kilian Kobl*, Lucrèce Nicoud, Edouard Nicoud, Anna Watson, John Andrews, Edward A. Wilkinson, Muhid Shahid, Christopher McKay, Benjamin I. Andrews, Batool Ahmed Omer, Olga Narducci, Edward Masson, Suzanne H. Davies and Tobias Vandermeersch,
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引用次数: 0
Abstract
Oligonucleotides have emerged as a promising class of pharmaceuticals, leading to significantly increased demand. Oligonucleotides are typically produced by solid-phase synthesis and then purified by ion exchange or reverse-phase chromatography. Predictive simulation is a valuable tool to help reduce process development times, secure scale-up, and decrease waste generation. In this paper, we disclose for the first time a cutting-edge mechanistic model describing oligonucleotide purification by ion exchange chromatography. The novel aspect of the model and focus of this paper is the thermodynamic description of large, highly charged molecules, which includes both solution chemistry and the ion exchange mechanism with the chromatographic medium. The different retention of such molecules depending on their sequence length, charge state, and interaction strength with the resin is accurately predicted. Thanks to a meaningful description of the underlying physical and chemical phenomena, the model also has highly predictive capabilities outside of the experimentally studied parameter ranges. It can be used to predict the outcome of changes to the operating conditions and experimental protocol, like the pH or ionic strength of buffer solutions, the number of washing steps, the loaded sample quantity, and more. The model can also account for a change of configuration from a single column to a multicolumn system. The step-by-step methodology to implement this model is presented and illustrated with examples from three leading pharmaceutical companies in the field. This methodology has been shown to lead to a significant process understanding with minimal experimental effort.
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.