The separation of tetrahydrofuran (THF)/ethanol/water mixtures from the norgestrel production is a challenging work due to the presence of multiple azeotropes, for which several pressure-swing distillation sequences are proposed in this paper, including heat-integrated schemes. Meanwhile, the potential benefits of those options with crossing curved-boundary are investigated and for this reason, a THF-rich feed composition is assumed. These sequences are optimized based on the minimal total annual cost (TAC) by using the sequential iterative search method coupled with heuristic pressure decision rules. The comparison results show that the proposed processes with boundary crossing have great economic and energy saving advantages, apart from one configuration based on the non-azeotropy property of THF/ethanol at a pressure. Also, a qualitative assessment of operational and control implications for energy integration schemes is made to draw recommendations.