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End Point Determination in a Wet Granulation Process

What is Granulation end-point?
  • End-point can be defined by the formulator as a target particle size mean or distribution. The end-point can be defined in rheological terms. It has been shown that once you have reached the desired end-point, the granule properties and the subsequent tablet properties are very similar regardless of the granulation processing factors, such as impeller or chopper speed or binder addition rate.
  • The ultimate goal of any measurement in a granulation process is to estimate viscosity and density of the granules, and, perhaps, to obtain an indication of the particle size mean and distribution. One of the ways to obtain this information is by measuring load on the main impeller.
  • In addition to a possible end-point determination, it can be used to troubleshoot the machine performance (for example, help detect worn-out gears and pulleys or identify mixing and binder irregularities).

Endpoint can be defined as a target particle size mean or distribution.

  • Endpoint finding of wet granulation is very important to form good quality granules and retain the same quality when repeated batches are manufactured. The endpoint is regulated during wet granulation after addition of binder solution /solvent. Mixing time after addition of binder solution/solvent should be optimum because over mixing may develop hard granules and under mixing may generate more fine than granules.

The ultimate goal of end-point determination in a granulation process is to obtain an indication of formation of granules with the desired physical properties, such as acceptable mean particle size range and porosity.

The advantages of using an appropriate method to determine the granulation end point are listed below:

  • Process Optimization
  1. Evaluate raw material
  2. Determine optimal end point
  • Batch Reproducibility
  1. Use end point to achieve batch to batch consistency
  2. Document adherence to batch protocol
  • Process Troubleshooting
  1. Detect mechanical problems
  2. Identify mixing irregularities


👉   Different traditional methods and techniques are used to monitor endpoint some are described as follow

a)  Power Consumption:
  • Power consumption of the mixer motor for end-point determination and scale-up is widely used because the measurement is economical, does not require extensive mixer modifications and is well correlated with granule growth.
  • Intragranular porosity also shows some correlation with power consumption. Normalized work of granulation (power profile integrated over time) can accurately determine endpoints and is correlated well with properties of granulates.

b)  Impeller Torque:
  • Direct torque measurement requires installation of strain gauges on the impeller shaft or on the coupling between the motor and impeller shaft. Since the shaft is rotating, a device called a slip ring is used to transmit the signal to the stationary data acquisition system.

c)  Torque Rheometer:
  • A torque rheometer provides an off-line measurement of torque required to rotate the blades of the device and can be used to assess rheological properties of the granulation. It has been extensively used for endpoint determination. The torque values obtained have been termed a “measure of wet mass consistency”.

d)  Reaction Torque:
  • As the impeller shaft rotates, the motor tries to rotate in the opposite direction, but does not because it is bolted in place. The tensions in the stationary motor base can be measured by a reaction torque transducer.

e)  Other Possibilities:
  • When agglomeration is progressing very rapidly, neither power consumption nor torque on the impeller may be sensitive enough to adequately reflect material changes. Some investigators feel that other measurements, such as torque or force on the impeller blades, may be better suited to monitor such events. 
  • There are other ideas floating around—for example, use of neural networks to describe and predict the behavior of the wet granulation or control of the endpoint by a rapid image processing system. A technique for measuring tensile strength of granules, in addition to power consumption measurement, to facilitate optimal endpoint determination. 

f)  Solvent/Binder addition Time
  • To assure consistent endpoint addition of binder solution/solvent plays an important role. Binder addition rate control granules density. Slow binder solution addition rate is suggested to prevent local over-wetting.

g)  Kneading Time
  • Higher mixing time after binder solution addition results in a decrease in intra-granular porosity and increase in granules size and strength.

h)  Hand Squeeze Method/Banana Technique
  • It is an old and most commonly used method to determine the endpoint of granulation, in this method wet mass is squeezed in hand and then lumps are broken down to physically check the quality of granules, there should be no dry powder or fine powder. This method depends on operators skills and can not be validated.

How to determine an end-point?
  • A wet granulation end-point should be defined empirically in terms of wet mass density and viscosity, particle size distribution, flowability or tableting parameters (e.g., capping compression).
  • It is advisable to run a trial batch at a fixed speed and with a predetermined method of binder addition (for example, add water continuously at a fixed rate to a dry mix with a water-soluble binding agent).
  • Before adding the liquid, measure the baseline level of motor power consumption Po or impeller torque τo at the dry mix stage.
  • During the batch, stop the process frequently times to take samples and, for each sample, note the end-point values of power consumption Pe or impeller torque τe
  • For each of these “end-points”, measure the resulting wet mass density ρ. As a result, you will be able to obtain some data that will relate the “end-point parameters” listed above with the processing variables in terms of net motor power consumption ΔPm = (Pe - Po) or net impeller power consumption ΔPi = 2π x n x (τe - τo), where n is the impeller speed.

End-Point Reproducibility
  • For every blend and a fixed set of values for processing factors (such as mixer geometry, blade speed, powder volume, amount and method of addition of granulating liquid), a wet granulation process state (end-point) is completely characterized by rheological properties of the wet mass (density, viscosity), which are, in turn, a function of particle size, shape and other properties. 
  • The process can be quantified with the help of dimensionless Newton Power Number Np that will assume a certain numerical value for every condition of the granulate. Under fixed processing conditions, Np will be proportional to Net Power Consumption ΔP for any end-point. Thus, in order to reproduce an end-point, it is sometimes sufficient to monitor power of the impeller (or the motor) and stop when a predefined net level of the signal is reached. If, however, any of the processing variables or the rheological definition of the end-point has changed, a more sophisticated approach is required.
  • Once the desired end-point is determined, it can be reproduced by stopping the batch at the same level of net power consumption ΔP (for the same mixer, formulation, speed, batch size and amount/rate of granulating liquid). To account for changes in any of these variables, you have to compute the Newton power number Np for the desired end-point:
Np = ΔP / (ρ n3 d5)
  • In other words, if you have established an end-point in terms of some Net Impeller or Motor Power ΔP and would like to reproduce this end-point on the same mixer at a different speed or wet mass density, calculate Newton Power Number Np from the given Net Impeller Power ΔP, impeller speed n, blade radius d, and wet mass density ρ (assuming the same batch size), and then recalculate the target ΔP with the changed values of speed n or wet mass density ρ.
  • Wet mass viscosity η can be calculated from Net Impeller Power ΔP, blade radius d and impeller speed n, using the following equations:
ΔP = 2π Δτ x n
η = ϕ x Δτ / (n x d3)
where 
Δτ is the net torque required to move wet mass, 
n is the speed of the impeller, 
d is the blade radius or diameter,
ϕ is mixer specific “viscosity factor” relating torque and dynamic viscosity 
(note: the correlation coefficient ϕ can be established empirically by mixing a material with a known dynamic viscosity, e.g. water). 

  • Alternatively, you can use impeller torque τ as a measure of kinematic viscosity and use it to obtain a non-dimensionless “pseudo-Reynolds” number, based on the so-called “mix consistency” measure, that is, the end-point torque, as described in the case studies.
  • Fill Ratio h/d can be calculated from a powder weight, granulating liquid density (1000 kg/m3 for water), rate of liquid addition, time interval for liquid addition, and bowl volume Vb
  • The calculations are performed using the idea that the fill ratio h/d (wet mass height to blade diameter) is proportional to V/Vb, and wet mass volume V can be computed as
V = m / ρ

where 
m is the mass (weight) of the wet mass 
ρ is the wet mass density.
  • Now, the weight of the wet mass is computed as the weight of powder plus the weight of added granulating liquid. The latter, of course, is calculated from the rate and duration of liquid addition and the liquid density.
  • Finally, you can combine the results obtained at different end-points of the test batch or from different batches or mixer scales (assuming geometrical similarity).
  • Given wet mass density ρ, wet mass viscosity η, fill ratio h/d ~ m Vb / ρ, setup speed n, and blade radius or diameter d, you can calculate the Reynolds number Re (or the “pseudo-Reynolds” number) and the Froude number Fr
  • Then you can estimate the slope “a” and intercept “b” of the regression equation
Np = b ⋅ (Re ⋅ Fr ⋅ h/d)a
                         or
log Np = log b + a ⋅ log (Re ⋅ Fr ⋅ h/d)
  • Once the regression line is established, you can calculate Newton Power number Np (which is the target quantity for scale up) and Net Power ΔP (which can be observed in real time as a true indicator of the target end-point) for any point on the line.

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