A numerical optimization technique using the desirability approach was used to develop tropicamide-loaded CMTKP nanoparticlulate formulation with the desired responses. The optimization was done to locate the optimal concentrations of polymer and cross-linker under the constraints of minimizing the particle size and maximizing the % encapsulation. The numerical optimization tool provided us with different sets of optimal solutions. Using these solutions, an optimal batch of tropicamide-loaded CMTKP nanoparticulate formulation was prepared and analyzed for particle size and % encapsulation efficiency. The optimal calculated parameters were concentrations of CMTKP-0.10% (w/v) and calcium chloride-0.11% (w/v). The optimized batch of tropicamide-loaded CMTKP nanoparticulate formulation was found to have the particle size (Y1) of 339 nm (predicted 317.69 nm), and % encapsulation efficiency (Y2) of 15.57% (predicted-16.25%). The lower value of % prediction error (−1.09% for Y1 and 3.12% for Y2) indicates the reliability of developed mathematical models.