Issue 6, 2017

Mass spectrometric directed system for the continuous-flow synthesis and purification of diphenhydramine

Abstract

A highly integrated approach to the development of a process for the continuous synthesis and purification of diphenhydramine is reported. Mass spectrometry (MS) is utilized throughout the system for on-line reaction monitoring, off-line yield quantitation, and as a reaction screening module that exploits reaction acceleration in charged microdroplets for high throughput route screening. This effort has enabled the discovery and optimization of multiple routes to diphenhydramine in glass microreactors using MS as a process analytical tool (PAT). The ability to rapidly screen conditions in charged microdroplets was used to guide optimization of the process in a microfluidic reactor. A quantitative MS method was developed and used to measure the reaction kinetics. Integration of the continuous-flow reactor/on-line MS methodology with a miniaturized crystallization platform for continuous reaction monitoring and controlled crystallization of diphenhydramine was also achieved. Our findings suggest a robust approach for the continuous manufacture of pharmaceutical drug products, exemplified in the particular case of diphenhydramine, and optimized for efficiency and crystal size, and guided by real-time analytics to produce the agent in a form that is readily adapted to continuous synthesis.

Graphical abstract: Mass spectrometric directed system for the continuous-flow synthesis and purification of diphenhydramine

Supplementary files

Article information

Article type
Edge Article
Submitted
27 Feb 2017
Accepted
10 Apr 2017
First published
19 Apr 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2017,8, 4363-4370

Mass spectrometric directed system for the continuous-flow synthesis and purification of diphenhydramine

B. P. Loren, M. Wleklinski, A. Koswara, K. Yammine, Y. Hu, Z. K. Nagy, D. H. Thompson and R. G. Cooks, Chem. Sci., 2017, 8, 4363 DOI: 10.1039/C7SC00905D

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