Hollow Crystal Formation through a Novel Ripening Mechanism in Crystallization

A novel ripening mechanism in crystallization is presented that allows for crystals to undergo morphological changes over time at seemingly constant conditions. This ripening phenomenon is different from Ostwald ripening in terms of its thermodynamic driving force and applicability across different particle sizes. Salicylic acid was crystallized in the presence of simulated structurally similar impurities, which resulted in formation of solid solutions. The impurity entrapment was elevated initially as a result of secondary nucleation and decreased during the course of the crystallization. The final crystals were thus comprised of impurity gradients having dirty cores and cleaner outer edges. Confocal Raman imaging was used to confirm the variable impurity entrapment in individual crystals showing enrichment in the center and interior of the crystals. As higher impurity levels corresponded to elevated solubility, dissolution took place from the impure center of the crystals when the solution concentration approached the solubility of pure salicylic acid. This in turn led to formation of macrotubular crystals with clearly distinguishable holes and cavities. The ripening mechanism is demonstrated experimentally at different stages in a crystallization relevant to a typical pharmaceutical isolation process. The results show not only that hollow crystals can be designed and challenging impurities can be better rejected, but more importantly it demonstrates the fundamental and dynamic interplay between impurity entrapment, solubility and desaturation kinetics that takes place throughout a real crystallization process.