Recent regulations regarding water quality motivated research in reverse osmosis (RO) technology for water desalination especially under boron restrictions. Boron control in the permeate products by reverse osmosis technology comprises several mitigation options which impose capital and operation costs. In our study, we investigate the design of RO system under the design concept of split partial second pass reverse osmosis (SPSPRO) in order to allow extraction of permeate streams along the RO pressure vessels. The design approach is based on superstructure optimization which allows the identification of optimal process layout and optimal operation conditions of the process units. pH adjustment of the network streams is also included in the model to control boron species distribution during the separation process. A mixed integer nonlinear program (MINLP) model is subsequently formulated based on the superstructure representation. The mathematical programming formulation is demonstrated on a case study to show the application of the mathematical programming model. The results show lower treatment cost through the proposed mathematical programming model. (C) 2015 Elsevier B.V. All rights reserved.