Development of sustainable reaction and separation processes for amantadine and amantadine hydrochloride

The concept of sustainable development has been applied for process intensification and optimization in the present study. One of the original methods of making amantadine hydrochloride (amantadine HCl) included [1] the hydrolysis of 1-acetamidoadamantane to form amantadine, [2] its separation by steam distillation, and [3] the formation of amantadine HCl salt. Firstly, the reaction time for the synthesis of amantadine at 100ºC was shortened. Secondly, the energy-intensive distillation step was replaced by the direct separation of amantadine from an impurity-containing mother liquor upon water addition thanks to the solubility difference. As a result, a series of tedious separation operations, such as extraction and solvent removal, could be avoided in our intensified process for the synthesis of amantadine. Unexpectedly, amantadine carbonate (AC) was formed when amantadine was reacted or in contact with carbon dioxide dissolved into the solution. The formation of AC was investigated upon filtration, cake rinsing, and drying steps. Lastly, amantadine HCl could successfully be prepared by slurry reactive crystallization and antisolvent crystallization with 4 M HCl (aq). In addition, the whole process has been scaled up in a 0.5 L-stirred tank with an improved overall yield of 82.9%. This study provided some significant features, such as the shortening of reaction time, saving of energy, and avoidance of waste generation.