Microspheres are small spherical particles, with a diameter of 1µm to 1000 µm These are spherical free-flowing particles consisting of proteins or synthetic polymers which are biodegradable in nature. Microcapsules are those in which entrapped substance is distinctly surrounded by a distinct capsule wall. Micromatrices are those in which entrapped substance is dispersed throughout the matrix. Gelatin is a natural polymer obtained either by partial acid or alkaline hydrolysis or by thermal or enzymatic degradation of structural animal collagen protein. Gelatin is non-expensive and does not express antigenicity in vivo and could be readily dissolved in aqueous solutions. Gelatin’s crosslinking with several agents is essentially aiming to increase its mechanical and thermal stability. Therefore, based on its unique characteristics, gelatin is widely used in the preparation of depot microsphere formulations. Screening Plackett-Burman DoE trials were employed to identify materials attributes and process parameters. Morphological analysis via SEM revealed the formation of spherical particles with smooth surface, while FTIR analysis showed the presence of strong molecular interaction between API and gelatin matrix. Leading, to formation of amorphously dispersed drug-loaded microspheres (verified via DSC and pXRD). Finally, dissolution studies showed a biphasic release profile for optimum microsphere formulation , which extended API’s release for up to 30 days following a Fickian diffusion release mechanism.