Multiparticulate drug delivery systems offer advantages in controlled release, dose flexibility, and personalized medicine. Fusion prilling, a process that produces spherical lipid-based microparticles through vibrating nozzles, is gaining interest in the field. This study aims to explore the use of fusion prilling to encapsulate crystallizable water-in-oil emulsions, enabling the incorporation of hydrophilic active pharmaceutical ingredients (APIs) within lipid matrices. Urea (highly water-soluble) and Erythromycin (poorly water-soluble) were selected as model compounds, solubilized in the aqueous and lipid phases, respectively. The first phase of the study evaluated lipid excipients for their suitability in prilling, ensuring microparticle consistency in shape, size, and stability. The second phase focused on characterizing microparticles notably in terms of structural organization and integrity. Results demonstrated successful encapsulation of both model compounds, with high efficiency, by omitting an additional emulsification step. Despite concerns over water evaporation during processing, microparticles remained stable for up to 14 months when stored at room temperature in a hermetically sealed container. This work highlights the potential of fusion prilling for multiparticulate drug delivery systems, even for formulating APIs with different solubility profiles. Future research should focus on optimizing the process for broader API incorporation.