Through a systematic search, we first selected a solvent system with a higher saturated gradient to guarantee the initial yield of metastable crystal form S2 through rapid crystallization. After further study, we discovered that S2 would be trans-crystallized after extended exposure to the air. It was necessary to reduce the surface area of the product to inhibit trans-crystallization. Since the metastable crystal in a solution system couldn't be acquired by crystal growth, we used spherical crystallization technique to reduce the particle’s specific surface area. This approach not only successfully solved the crystal form S2 transformation problems, but also increased the product particle size and reduced the difficulty of the suction filter.
The key technologies
- The composite solvent system with a higher saturated gradient of metastable crystal form was screened for crystallization
- The influence of sensitive factors on the trans-crystallization process was investigated and quantified
- Spherical crystallization technique was used to inhibit the trans-crystallization process