Model-based experimental design and parameter estimation, coupled with in situ infrared and laser backscattering instrumentation, was applied to the cooling crystallization of a drug compound to construct a model for use in the design of an optimal operating procedure. Because the model was constructed completely from in situ sensor data, with no sampling procedures, the amount of pharmaceutical compound required for batch process development was significantly reduced. Modeling issues involving the selection of the expressions for the supersaturation and nucleation rate, as well as the electronics mode in the laser backscattering instrument, were explored. All but one of the kinetic parameters from the gray-box model constructed using laser backscattering data were close to the kinetic parameters for a first-principles model constructed from data from off-line particle size measurements. The model was used to design batch operating procedures to minimize nucleation and maximize the sharpness of the crystal size distribution. This appears to be the first time that the procedure of model-based experimental design, parameter estimation, model selection, and optimization has been applied to the crystallization of a pharmaceutical, as well as the first time that this procedure has been applied to a crystallization process that forms loosely bound aggregates.