(569bm) Kinetics, Solvent Effects, and at-Line Monitoring of Diphenhydramine Synthesis

Academia, government, and industry are working towards the future of continuous pharmaceutical manufacturing. Continuous flow chemistry can enable the rapid development of processes, utilizing less material, and are easier to scale up than their batch process counterparts. However, implementing continuous strategies requires thorough understanding of transport and kinetics to ensure technical and legal obligations are met.

Diphenhydramine (DPH) is the most widely used antihistamine, and production follows one of two batch processes.[1] The first step of DPH synthesis involves the halogenation of diphenylmethanol (DPM) using concentrated HCl. In this study, we have developed a systematic methodology wherein NMR spectra (Figure 1A) enabled offline quantification of the species, while in-line Raman spectra (Figure 1B) bridged the gaps, with enhanced fidelity. These experiments show a strong dependence of chlorodiphenylmethane (DPC) rate formation on the mixing rate and the pH of the system, showing that the reaction is primarily mass-transfer limited.

The second reaction step is the etherification of DPC to yield DPH. We have investigated the effect of (a) reactant ratio, (b) temperature and (c) solvents to the rate of formation of DPH by utilizing a microfluidic reaction system coupled with an at-line low-field NMR. This reaction is shown to follow second order rate behavior with a strong dependence on the nature of the solvent used. In the case of a nonpolar solvent, e.g. toluene, excess dimethylethanolamine is needed to maintain the solubility of DPH. In polar solvents, the reaction rate was found to increase in the following order: NMP< DMF<ACN. The entropy and enthalpy of reaction through transition-state-theory was calculated, supporting a bimolecular transition state and the second order S_N2-type mechanism. The reaction rate was found to increase as the Gutmann acceptor number of the solvent increases and decreases with solvent volume.

1. Snead,D.R. and Jamison,T.F. Chem.Sci. 4, 2822 (2013)