Spherical agglomeration of high melting point drugs in water at low temperature by developing a two-step oiling-out mechanism and the design strategy

The current oiling-out spherical agglomeration technology overcomes the shortcomings of biohazardous solvents and complex equipment of the traditional spherical granulation technologies in the pharmaceutical industry. However, it is difficult for high melting point drugs to oil-out in water, so this novel green technology is only applicable to low melting point drugs, which severely limits its application. This work developed a two-step oiling-out (TSOO) mechanism suitable for high melting point drugs thereby increasing the number of potentially applicable substances for this technology by about 150%. In the TSOO mechanism, the high melting point drug first undergoes co-oiling-out with a specific oiling-out mate in an aqueous solution (first step), followed by the removal of the oiling-out mate forming single-oiling-out droplets of the high melting point drug (second step), which eventually forms spherical particles of the high melting point drugs. Process analytical technology tools including IR spectroscopy, FBRM and PVM were applied to monitor the preparation process in real time, which verified the TSOO mechanism experimentally. Based on the proposed mechanism, spherical particles of 13 drugs (melting point range is 385.15-526.15 K) with good powder properties, high yield and adjustable particle size distribution were successfully prepared in water at a low temperature. This demonstrates that the TSOO mechanism allows more drugs to be spherically granulated in a green way. Furthermore, the molecular simulation-based design strategy of TSOO spherical agglomeration significantly saves the time required and reduces the use of chemicals for the TSOO mechanism promotion.