The crux of this research was the pragmatic investigation into the formulation of a reconstitutable multiparticulate anti-tuberculosis drug delivery system for facilitated administration for the attainment of segregated gastrointestinal (GI) delivery of rifampicin (RIF) and isoniazid (INH) in order to address issues of unacceptable RIF bioavailability on coadministration with INH. Ionotropically crosslinked polymeric enterospheres for delivery of INH to the small intestine were developed via a response surface methodology for the design and optimization of the formulation and processing variables. A 3(4) Box-Behnken statistical design was constructed. The concentration of zinc sulfate salting-out and crosslinking electrolyte, the crosslinking reaction time, the drying temperature (DT), and the concentration of triethyl citrate plasticizer were varied for determination of their effect on the molar amount of zinc (n(Zn)) incorporated in the crosslinked enterosphere, drug entrapment efficiency (DEE), and mean dissolution time (MDT) at t(2h) in acidic media (0.1 M HCl). Complexometric determination of zinc cations (Zn(2+)) revealed that 23.70-287.89 mol of Zn(2+) per mole of polymer were implicated in crosslink formation. DEE of 27.92% to 99.77% were obtained. Drug release at t(2h) ranged from 1.67% to 73.04%. The salting-out and crosslinking agent significantly affected n(Zn) (p = 0.034) and the DEE (p = 0.000), as did the concentration of plasticizer employed (p = 0.000 and 0.002, respectively). High DTs (>42.5 degrees C) also significantly improved DEE (p = 0.029). ZnSO(4) had a significant effect on the MDT (p = 0.000). A dry dispersible multiparticulate system incorporating the optimally designed INH-loaded enterospheres and RIF was developed. Bivariate regression analysis of UV spectrophotometric absorbance data allowed in vitro resolution of RIF and INH release at simulated gastric pH.