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.

Fig. 1. Representation of (A) accelerated droplet reactor system, and (B) microfluidic reactor system. The droplet reactor is used to rapidly screen routes, whilst the microfluidic reactor is used to optimize favorable routes. Two explored routes are illustrated.

Scheme 1. Synthesis of diphenhydramine from chloro/bromo diphenylmethane.

Fig. 2. MS quantitation of DPH synthesis from chlorodiphenylmethane.

Fig. 3. Byproduct formation (A) MS/MS of m/z 272 shows presence of isomeric ions; (B) MS follows the effect of residence time on byproduct formation.

Fig. 4. (A) Sample mass spectra collected on-line. (B) Calculated conversions from MS data collected on-line demonstrate temperature dependence of the reaction. S.M. refers to DMAE.

Fig. 5. Engineering details for the integrated synthesis and purification system. Orange lines represent a tubular heater (Fig. S8†).

Fig. 6. (A) Droplet train from microreactor. (B) Droplet detection using LED phototransistor, (C) droplet size distribution.

Scheme 2. Synthesis of DPH from benzhydrol.