Background: Literature reports various methods for the synthesis of diphenhydramine hydrochloride
each of these has one or the other drawback such as low as ~39% atom efficiency or high
reaction temperature, usage of corrosive bromine and formation of hazardous by product or else it requires
strong scrubbing system which generates huge amounts of inorganic waste, in some cases molar
equivalents of P-toluenesulfonic acid was used which was further eliminated as waste with low
product output and thus not economically viable, literature also reports continuous flow process which
requires PFA tube reactor with very high temperature ~175°C addition to this it also uses IPA-HCl for
salt preparation which is prone for the formation of genotoxic impurity 2-chloropropane.
Methods: Objective of present work is to overcome the limitations studied in literature to improve the
process in terms of atom efficiency, cost effectiveness, robust, commercially viable, industrially scalable,
minimum environmental hazards considering principles of green chemistry. We have developed
the process in such as way that atom efficiency at halogenation stage is enhanced by ~93% compared
to ~39% when diphenylmethane reacts with bromine. HCl gas generated in-situ or if needed supplied
to prepare diphenhydramine hydrochloride salt instead of using IPA-HCl to eliminate chances of formation
of genotoxic impurity if any.
Conclusion: In order to achieve the continuous improvement process, we have developed modified
process for the synthesis of diphenhydramine hydrochloride which elimination of use of corrosive
bromine, overall time cycle reduced by ~40%, overall process atom efficiency enhanced by ~45%,
eliminated chance of formation of genotoxic impurity by avoiding use of IPA-HCl solvent for final
stage, by carrying out reaction in either water as a universal green solvent or solvent free conditions
with high yield to obtain pharmacopeial quality of the final active pharmaceutical ingredient. We assert
to have a better process in terms of atom efficiency, minimal wastage, operability and quality.