A Structured Approach To Cope with Impurities during Industrial Crystallization Development

Abstract

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…Methods for preventing aggregate formation are widely available in the literature and fall out of the scope of this work. [44][45][46][47][48][49] Similarly, when the mother liquor is filtered from the solids, adequate washing steps must be in place to wash out the adhering liquid while preventing the precipitation of impurities by anti-solvent effects. 20,40 In this area, impurity precipitation (either during crystallization, or during washing) is driven by the generation of a supersaturated state for those impurities.…”

“…A similar impurity incorporation mechanism emanates from solution entrapment, and commonly occurs for systems with porous or large crystals, where a portion of the liquid phase is entrapped in the solid product and is not easily washed away. 42,44 Inclusions stem from non-equilibrium processes and may be categorized as primary (those formed during crystal growth) or secondary (those formed after crystal growth). One probable account for primary inclusion formation could be due to the disproportionate growth rates at the surface of crystals, mostly with the edges and corners growing quicker than the centre of the faces, leading to cavities formation which are ultimately sealed as growth proceeds.…”

“…Similarly, impurities dissolving towards the later steps would indicate that they are predominantly inside the crystal, in areas that are sometimes not accessible during the early dissolution steps. 44,51 It is important to note that these methods rely on the assumption that crystal faces dissolve evenly and that the presence of impurities does not affect the dissolution rate of the impure crystal faces. Wang et al conducted dissolution studies of crystallized salicylic acid, which presented elongated crystals with an impure crystal core.…”

The Behaviour of Rare Earth Elements from South African Coal Fly Ash during Enrichment Processes: Wet, Magnetic Separation and Zeolitisation

“…This was likely due to the exclusion of these elements from the Si extract material during the process of precipitation. This phenomenon occurs during the crystallization of thenardite from the Si-rich filtrate solution whereby solvated silicate species are incorporated into the crystalline material that precipitates out of the solution, while other soluble impurities were excluded from the crystalline material or largely remained in solution [68,69].…”

Switching Polymorph Stabilities with Impurities: A Thermodynamic Route to Benzamide Form III

“…As the synthetic routes are improved and the compounds are subjected to crystallization development, their purity increases which may lead to new crystal forms. 6 Whilst crystallization is a very selective process (thus widely used as a purification technique), sometimes the tiniest amount of impurities can have a significant impact on the outcome. This is especially true when the impurity has a close molecular similarity with the compound under development.…”