| dc.description.abstract | The rapid growth of the global population, aging and energy crisis have gradually captured the people’s attention. The concept of energy saving and waste reduction had been applied to process enhancement in the present study. In the literature, the original production of amantadine HCl included three steps: (1) hydrolysis of 1-acetamidoadamantane to synthesize amantadine, (2) steam distillation, and (3) salt formation. In this study, an intensified process of making amantadine HCl had been designed and developed. Firstly, the reaction time for the synthesis of amantadine by hydrolyzing 1-acetamidoadamantane was shortened from 24 to 16 h. The energy-intensive distillation step had been replaced by the direct separation of amantadine from sodium acetate, based on the difference in their solubilities in water. The intensified process for the synthesis of amantadine had been developed to get rid of a series of tedious and energy-intensive separation operations (i.e. steam distillation, extraction, and solvent removal). A much smaller E factor of 3.9 had been obtained, meaning that the intensified process was more sustainable with minimized waste generation. After the water addition in the crystallization step, it was observed that amantadine carbonate (AC) is produced when the primary amine of amantadine reacted with the atmospheric CO2. The formation of AC was investigated upon filtration, cake rinsing, and drying. Amantadine wet cake was dried under a nitrogen atmosphere to prevent the conversion of amantadine to AC. To increase the bioavailability of amantadine in an aqueous solution, it was further prepared as a HCl salt by slurry reactive crystallization and antisolvent crystallization, respectively. The slurry reactive crystallization was selected by achieving a lower E factor of 3.4. The overall E-factor became 7.7, much lower than the original method of 21.5. This intensified process has been scaled up in a 0.5 L-stirred tank, which showed an improved overall yield of 82.9%, and provided some significant features, such as the shortening of reaction time, saving of energy, and waste minimization. | en_US |