Crystal Agglomeration and Microscopic Molecular Exchange Mechanism in Antisolvent Crystallization

Agglomeration is a significant challenge in antisolvent crystallization, especially when it comes to crystallizing insoluble drugs. This study aimed to address this issue by taking a unique, dynamic molecular perspective and proposing a solution based on microscopic molecular exchange. Atorvastatin calcium, a widely prescribed medication for lowering blood lipids, was used as a case for antisolvent crystallization, which is also prone to agglomeration. Kinetic experiments revealed the rapid exchange between solvent and antisolvent, leading to precipitation occurring within a mere 0.0333 s. Thermodynamic investigations further showed that each droplet had the potential to generate an astonishing equivalent nucleation rate of up to 5 billion nuclei per second. The rapid precipitation and small nucleation region, coupled with a large number of nuclei, worsened the crystal agglomeration problem. However, it was found that this molecular exchange process can be slowed by the solvent composition. Specifically, when the methanol mole fraction in the crystallization system reached approximately 50%, the equivalent nucleation rate decreased significantly to about 100 million per second. Armed with this crucial finding, a strategy was devised to overcome agglomeration by simultaneously adding the solution and antisolvent to maintain a lower exchange rate, which effectively avoided agglomeration and promoted the purification of atorvastatin calcium.