Q: What is the safety reason which prevents the elimination of downstream milling?
A: No safety reason, I was speaking about risk. The risk that all actions taken to control particle size can not guarantee some coarse won’t still be generated.
Q: What is the amount of force applied in the compression zone?
A: Sizable, we have reported pressures of 2.5 MPa at half the flow rate capacity of our extruder.
Q: What all pre-studies for materials would be suggested before going for wet granulation via Twin screw? Like DSC, rheology?
A: The environment is unique, but formulation considerations like liquid-to-solids ratio and weight fractions of excipient don’t differ a lot from high shear batch mixing or powder rheometer.
Q: I have seen screws where the kneading elements are spread along the screw with 2, 3 and even 5 kneading zones for wet granulation! what is the rational?
A: Poor wetting. Sometimes the physical limitations of the equipment available prevent even modest spreading of the liquid over the solds. More work, gently, is needed to solve the problem then.
Q: What kind of pre-formulation studies you suggest for reducing the workload while screening excipients for hot melt granulation?
A: If working on a smaller extruder is not possible, then something small, is heatable and rotates, like a rotovap might work.
Q: How we can explore twin screw granulation for continuous Manufacturing?
A: I feel this is a question about the granule structure based on the different methods available to granulate. TSG will create a denser, less friable particle than other methods with an aspect ratio closer to 1.5 and bimodal size distribution.
Q: Is there a way to reduce the extent of bimodal distribution observed?
A: Optimization of the formulation will help. But it is related to how the screws intermesh. It is possible a counter-rotating machine won’t produce this problem.
Q: Would the density of the material play a role during wet/foam granulation in the twin screw granulator?
A: Yes, but less so than in a high shear batch mixer where too much segregation may occur.
Q: Would the shear generated by the kneading blocks result in some physical degradation of the API?
A: If the powder is well wetted, I would say ‘no’. Heat is the damaging variable here and we have found no damage in most instances, probably because of the short residence time.
Q: Please comment on the position of the mixing zone in case of wet granulation.
A: Only as far as necessary to agitate the powder sufficiently that the bulk of it can be considered wetted.
Q: Can it be an alternative to fluid hot melt granulation? And if there what measures could be taken for temperature variation around the kneading zone?
A: TSG will generate a denser particle than a fluidized bed – which may or may not be preferred. Heat in the kneading block arises from how well wetted are the powders and the viscosity of the binder used. Variability within the bed can be diminished with more conveying sections between kneading zones to agitate and spread out the powders over the barrel surface.
Q: What types of granules will we get? I mean dense or light? and how’s the compressibility?
A: Tend to be denser and a bit more oval in shape compared to batch mixer or fluidized bed approaches.
Q: Does offset angle of kneading blocks have any impact on granule formation and associated particle size distribution? Please advice.
A: Yes, but it is affected by formulation and by the % fill inside the screws.
Q: What liquid to solid ratio do you usually start with in Twin screw wet granulation?
A: Successful ratios from a high shear batch mixer or fluidized bed are a good start but also a little bit high.
Q: Are there any predicted models available to match granules properties between high shear granulation and twin screw granulation?
A: None that I’m aware of.
Q: What would be the effect of differing heating zones on the process?
A: Due to the short residence time of the process only extremely different zones will have any effect at all. For melt granulation, high heating early is best to melt the binder but doing so at the feed zone is not possible without damaging the gear box. So a ramped heat is used normally.
Q: It looks like that the need for drying may make the wet granulation discontinuous. What do you think of increasing the processing temperature such that the material will dry after granulation without a separate drying step?
A: We have studied this quite a bit. We have only found drops in moisture by ~10% of what it was originally in the powder. The residence time is just too short for any effective drying to occur.
Q: How to determine the %fill?
A: Easiest way. Take an element and immerse it in a graduate cylinder to find its volume. Calculate its cylindrical volume based on the outer diameter of the flight and length of the element. The difference is the free volume. Using the bulk density and mass/rev you should know the occupied volume. % fill – occupied volume/free volume.
Q: What is the relation between the screw configuration and granules strength?
A: More compression, more strength. More compression can be produced by longer compression zones or high process throughput rates.
Q: Have you worked on similar processes with polymers like HPMC-AS/Eudragits?
A: Yes, for hot melt granulation and a heat-assisted dry granulation we devised.
Q: How to improve the shape (round is the target) of intermediate?
A: Choose a compression element with a higher ‘chopping’ nature. Distributive elements are better than kneading elements in this regards.