When producing APIs via crystallisation, the combination of radially-pumping and axially-pumping impellers in the glass-lined reaction vessel has its benefits, argues Chris Drysdale, process engineer at Pfaudler Balfour
Many pharmaceutical and chemical manufacturers have processes that involve crystallisation (the process of obtaining a solid by precipitating crystals from a solution). More specifically, crystallisation is used in the manufacture of active pharmaceutical ingredients (APIs), where glass-lined vessels are frequently used as batch reactors in the crystallisation process.
The crystallisation process consists of the following steps:
- supersaturated liquid is added to the vessel
- small seed. crystals are distributed into the solution
- the solids are fully suspended
- the vessel contents are cooled to induce crystallisation
- the solution is drained out of the vessel
- the solids are recovered from the mother liquor by filtration.
The draining of the solution from the vessel is often carried out in batches, due to the solid/ liquid separation equipment (i.e. a filter or centrifuge) often having a smaller capacity than the discharging vessel. This process can lead to several problems.
Crystals that are in suspension must stay this way at all times, which can prove difficult at low volume levels within the vessel. If suspension is poor, this creates a potential for solids to settle on the bottom dish of the vessel, leading to batch-to- batch contamination if solids are left over; or bottom dish glass abrasion due to solids swirling on the surface of the bottom dish.
Historically, conical bottom vessels have been used as they are useful for low level mixing. However, although superior for liquid blending applications at low levels, these types of vessel have proven to be inferior when compared with standard torispherical bottom vessels for solid suspension duties.
To solve the problem of keeping solids in suspension at low volumes we need first to define and then prioritise the process issues:
1. Solid suspension.
2. Low level solid suspension.
3. Heat transfer from vessel walls
Solid suspension is important in the process as the seed crystals need to be mixed well in the supersaturated liquid for maximum process efficiency.
top-to-bottom mixing
The general solution for solid suspension processes is to supply an axially pumping impeller. This draws the fluid from directly above the impeller and then pumps it down to the bottom dish of the tank and up around the vessel's walls, thus promoting top-to-bottom mixing. This flow pattern is effective for keeping solids in suspension and is also efficient in heat transfer applications with the fluid flowing up the vessel walls.
However, axial impellers are not suitable for low-level applications because there must be space below the blades for the impeller to pump to. In these cases, radially pumping impellers are required as the fluid is pumped out towards the vessel walls with no space required below.
So, a solution has been devised that combines both impellers without compromising any of the priorities. Using a radially pumping impeller close to the bottom and an axially pumping impeller further up the shaft creates both a top-to-bottom flow pattern and the low level mixing that would be required. This solution has been validated and is being used increasingly by pharmaceutical companies and engineering houses.
Although Pfaudler Balfour can produce 2-dimensional computational fluid dynamics (CFD) in-house, to validate the equipment fully the company consulted ANSYS, a leading provider of engineering simulation software and consulting services. Taking a typical full-scale production reactor, engineers at Pfaudler worked with ANSYS to model and validate the crystallisation process at 100% volume (4000 litres) and 25% volume (1000 litres).
ANSYS was supplied with theAutoCAD files of the vessel, both impellers, agitator shaft and the baffle and the conditions of the process, i.e. impeller speed, solids vol%, density, etc. A computational model (mesh) was then built and the 3D studio was used to model the particle motion and interaction with the liquid.
ANSYS produced three-dimensional pictures and animations showing solids distribution, velocities and fluid strain. The processing operating conditions are given in Table 1.
As a result of its simulations, ANSYS has shown that for the full vessel (4000 litres):
a) The dual flight agitator fully suspends all solids (volume fraction 4.64%) with only 0.04% variation across the vessel.
b) There is good top-to-bottom mixing across the bottom dish and vessel walls, maximising heat transfer from the vessel walls.
Both of these points are essential for controlled crystal production.
For the 25% full vessel (1000 litres), ANSYS has shown that with one radially pumping impeller, all solids (volume fraction 20.45%) are fully suspended with only 0.38% variation. This highlights that no solids are settled on the bottom dish.
The results show that a dual-flight agitation system with both an axial and radial impeller gives the required solid suspension at both high and low volumes while also promoting a good fluid flow regime which is needed for the required heat transfer from the vessel walls. This system has been independently validated by ANSYS to show that it is suitable for crystallisation processes in API manufacture.