An efficient spherical agglomeration technology for high melting point drugs was developed by designing a two-step oiling-out (TSOO) mechanism, and spherical particles of 13 high melting point drugs were successfully prepared in water.

This work aims at developing a green and highly-efficient technique, which enables co-crystallization and co-agglomeration of drugs, or the crystallization of one drug and simultaneous agglomeration with another drug, in pure water taking advantage of oiling-out. By establishing the phase diagram and making use of the oil droplets formed in an oiling-out system, spherical co-agglomerates containing desired ratios of drugs, ibuprofen (IBU) with a second active pharmaceutical ingredient (API), including L-menthol (MT), praziquantel (PZQ), rivaroxaban (RXB) and lenalidomide (LDM), were successfully prepared, simply relying on a heating–quenching operation. Forming processes of the spherical co-agglomerates involved two kinds of mechanisms: co-oiling-out and single-oiling-out mechanisms, making the oiling-out co-agglomeration (OOCA) technique suitable for a wide range of applications in pharmaceuticals. Particularly, the co-oiling-out mechanism, which was proposed and designed, for the first time in this work based on ternary phase diagrams of (API₁–API₂–water), uniform oil droplets of two APIs were generated, guaranteeing a high degree of content uniformity in the co-agglomerate products. The OOCA technique developed in this work can not only incorporate crystallization and granulation into one unit operation, but also help in achieving drug combination (polypills). An effective screening strategy for drugs applicable to the OOCA technique was established by simulation and computation, greatly reducing the utilization of chemical substances and helping save time in the promotion process of OOCA.