Continuous crystallisation

Although crystallisation in pharmaceutical manufacturing is traditionally carried out as a batch operation, with the drive towards implementing continuous manufacturing of pharmaceuticals there is increased interest in developing and applying approaches for continuous crystallisation [1, 2]. Indeed, the potential to directly connect multiple process stages as part of an integrated end-to-end process chain including a continuous crystallisation step has been demonstrated for the manufacture of aliskiren hemifumarate tablets [3] and in a compact reconfigurable platform for a range of liquid dosage APIs [4]. Crystallisation is a key operation for the purification and isolation of active pharmaceutical ingredients (APIs) from solution mixtures to produce pure drug substance in a stable, solid form suitable for subsequent formulation and processing. Crystallisation is therefore a critical stage in controlling the physical properties of the solid material [5, 6]. For pharmaceuticals, achieving high levels of chemical purity of crystallised or precipitated particles is an essential requirement. However, a given API can also show a range of variability in crystalline form (polymorph, solvate, salt, co-crystal), crystal size, size distribution and shape that can have significant effects on processing performance and product stability [7]. Consequently, robust continuous crystallisation processes are required that can achieve the target particle attributes consistently and avoid uncontrolled variation in quality and performance. However, despite the widespread application of crystallisation in fine chemical and pharmaceutical production, it still remains relatively poorly understood. Hence the development of consistent and robust continuous crystallisation processes requires systematic and rigorous approaches to identify and control the complex physical transformations that take place within a multicomponent, multiphase process environment.