Internally generated seeding policy in anti-solvent crystallization of ceftriaxone sodium

A promising seeding strategy of internally generated seeds in producing ceftriaxone sodium with a uni-modal crystal size distribution (CSD) was experimentally investigated in batch anti-solvent crystallization. Effects of different seeding policies on product CSDs, both external seeding and internally generated seeding, were experimentally determined. A uni-modal product CSD was obtained without obvious nucleation at high external-seed loadings, while a bi-modal CSD was obtained with plenty of secondary nuclei at low external-seed loadings. The internally generated seeds, prepared by adding pure acetone into the non-seeded saturated solution of ceftriaxone sodium, were fine crystals with a uni-modal, narrow CSD, irrespective of the amount of the added diluent. These fine crystals were grown continuously as seeds by slowly adding a relatively low concentration diluent. The product CSD was uni-modal with relatively large mass-weighted mean size, and the product quality was as good as the one obtained by external seeding. Therefore, such an internally generated seeding policy is expected to be a favorable seeding technology to hopefully substitute for the external seeding policy in the pharmaceutical industry, where external seeding is not welcome because the external seeding policy would destroy the axenic conditions in crystallizer and lead to unstable quality of different batches.