Estimation of release profiles of drugs normally requires time-consuming trial-and-error experiments. Feed-forward neural networks including multilayer perceptron (MLP), radial basis function network (RBFN), and generalized regression neural network (GRNN) are used to predict the release profile of betamethasone (BTM) and betamethasone acetate (BTMA) where in situ forming systems consist of poly (lactide-co-glycolide), N-methyl-1-2-pyrolidon, and ethyl heptanoat as a polymer, solvent, and additive, respectively. The input vectors of the artificial neural networks (ANNs) include drug concentration, gamma irradiation, additive substance, and type of drug. As the outputs of the ANNs, three features are extracted using the nonlinear principal component analysis technique. Leave-one-out cross-validation approach is used to train each ANN. We show that for estimation of BTM and BTMA release profiles, MLP outperforms GRNN and RBF networks in terms of reliability and efficiency.