Multi-phase polymeric microspheres containing a molecular compound dispersed in a polymeric matrix are described. Methods for preparing the multi-phase microspheres are also described, which includes a multiple emulsion solvent evaporation technique. Drug loading efficiencies between 80 to 100% were achieved using the described methods. Particular ratios of the W/O emulsion to polymer, and concentration of surfactant and dispersion media (mineral oil) provide highly efficient multi-phase microspheres. In particular embodiments, the multi-phase microspheres feature a high loading efficiency of water-soluble drugs, and also eliminates partitioning of the water soluble agent into the polymer acetonitrile (solvent) phase, thus preventing low encapsulation efficiency. The described multi-phase microspheres possess efficient drug loading, release properties, and drug stability, and also provide a vehicle for long term therapeutic release of a biologically active molecule for therapeutically effective periods of time. Molecular compounds which may be incorporated within the multi-phase microspheres include both water-soluble and water-insoluble drugs, proteins (e.g. TNF), peptides, and chemicals. The molecular compound is protected within an oily droplet, and contact with polymer, surfactant, organic solvents, and other potentially denaturing agents is prevented.