Development of a High Shear Wet Granulation Process
Through the Use of Design of Experiments
Darren Gob, Shawn McConnell, Sanjay Konagurthu Ph.D.
darren.gob@thermofisher.com | shawn.mcconnell@thermofisher.com | sanjay.konagurthu@thermofisher.com

Thermo Fisher Scientific

PURPOSERESULT(S)Compound X is a micronized BCS class 2 drug substance with a very low bulk density (less than 0.2 g/mL),
formulated at 75% drug load as an immediate release capsule. High shear wet granulation was selected as themethod of manufacture to achieve sufficient densification to fit the required dose into a capsule shell. Water wasused as the granulation medium and the process was successfully scaled up from prototype batch size
(approximately 1.1 kg in a PMA-10 granulator) to Phase 3 clinical batch size (approximately 7 kg in a PMA-65)
by keeping granulator fill volume, water quantity, and mixing times constant. Impeller speed for scale-up wasdetermined via constant Froude number.

A summary of the DoE trial settings and their corresponding response factors is presented inTable 2 below.

To meet estimated commercial projections it was necessary to increase granulator fill volume by approximately
50%. Since a change in fill volume often leads to changes in mixing efficiency within a granulator, it wasnecessary to completely re-evaluate wet granulation parameters. A DoE study was conducted at the increased
fill volume to examine the effects of water quantity, impeller speed, and wet massing time on capsule dissolution(to target the Phase 3 clinical batch dissolution profile) and granulation flowability via Hanson Flodex for
information purposes to provide an indication of potential weight variation during encapsulation.
From the DoE, it was determined that dissolution was impacted by wet massing time > impeller speed > waterquantity. Granulation flowability was impacted by wet massing time > water quantity > impeller speed.

Table 2: Dissolution and Flowability Rankings (lower number is better) from
Wet Granulation DoE Trials at Increased Granulator Fill Volume.

Input
Variable

ResponseFactor

Water Quantity
Impeller Speed
Wet Massing Time
Dissolution Rank
Flowability Rank

Trial 1CenterCenterCenter43

Trial 2HighLow
High31

Trial 3HighHighLow
24

Trial 4Low
Low
Low
1*5Trial 5Low
HighHigh52

A summary of the wet granulation input variables
and their relative effect on dissolution andflowability is presented in Table 3.
Table 3: Effect of Water Quantity, Impeller Speed,
and Wet Massing Time on Dissolution andFlowability for Compound X (lower number
means greater magnitude of effect).
Input Variable
Water Quantity
Impeller Speed
Wet Massing Time

Relative Effect Relative Effecton Dissolution on Flowability
322311*Matched the dissolution profile of Phase 3 clinical capsules

METHOD(S)The DoE trials were manufactured in a 3 L high shear granulator (KG-3). The Phase 3 clinical batch served as areference for the DoE study, where water quantity (Phase 3 ± 10%), wet massing time (Phase 3 ± 2 minutes),and impeller speed were examined for their impact on dissolution profile and granulation flowability. The
fractional factorial study consisted of 4 trials (2 3-1) where high and low settings for each parameter were used incombination, plus one center point trial for a total of 5 trials.
It was determined that commercial scale batches would be manufactured in either a PMA-600 or PMA-1200, so
the Froude number equivalents of the maximum and minimum achievable impeller speeds on the PMA-600
served as the high (530 rpm) and low (280 rpm) settings for the study, respectively. Since the impeller speed
used for the Phase 3 clinical batch was already very close to the high setting for the study, it was not used as thecenter point for the study. Instead, the Froude number equivalent of maximum achievable impeller speed on thePMA-1200 (360 rpm) was selected as a more appropriate center point, though not perfectly in the middle of thehigh and low settings. Kneading times, drying endpoint, and milling parameters remained consistent across thestudy. A summary of the DoE trial settings is presented in Table 1.

Table 1: High, Center, and Low Settings used for Compound X Wet Granulation
DoE trials.
SettingHighCenterLow

Relative Water Quantity+10-1

Relative Impeller Speed+10-0.7

Relative Wet Massing Time+10-1

Phase 3 clinical capsules exhibited rapid dissolution and served as the target dissolution profile. Flowability wasassessed via Hanson Flodex (critical orifice diameter) for information purposes to provide an indication ofencapsulation performance. Each DoE trial was ranked for how closely their dissolution profile matched thePhase 3 clinical capsules and for their granulation flowability. Based on the dissolution and flowability rankings,
each wet granulation parameter was weighted for their impact.

Dissolution rate is typically inversely related to water quantity, impeller speed, and wet
massing time. Higher values for these input variables typically give rise to larger, less porous
particles. Trial 4, which used all low settings, had the fastest dissolution and was the only trialthat had a dissolution profile that resembled Phase 3 clinical capsules.
Wet massing time appeared to have the strongest influence on dissolution, as Trial 3 (highwater quantity, high impeller speed, and low wet massing time) had the second fastest
dissolution despite the use of high water quantity and impeller speed.

Impeller speed appeared to be the next most influential parameter as Trial 2 (high waterquantity, low impeller speed, high wet massing time) had the next highest dissolution rank.
Water quantity appeared to have the weakest influence on dissolution, where Trial 5 (lowwater quantity, high impeller speed, high wet massing time) had the slowest dissolution.
Wet massing time appeared to also have the greatest influence of flowability, followed bywater quantity, and then finally by impeller speed. Although Trial 4 (all low settings) had thepoorest flowability of all the trials, priority was given to matching the dissolution profile ofPhase 3 clinical capsules, and Trial 4 was the only trial to achieve this benchmark. In addition,
the poor flowability of Trial 4 was still deemed to be sufficient to attain acceptable weightvariation during encapsulation on an automatic encapsulator.
The dissolution and flowability rankings of the center point batch may have changed if impeller
speed was the midpoint of the high and low settings; however, the rankings of the other DoE
trials would remain the same relative to one another other.

CONCLUSION(S)DoE was used to evaluate the effects of wet granulation
parameters of water quantity, impeller speed, and wet
massing time for their effect on response factors ofcapsule dissolution and granulation flowability for
Compound X. From the study it was determined that
dissolution was affected by wet massing time > impeller
speed > water quantity. Granulation flowability wasaffected by wet massing time > water quantity > impeller
speed.
Learnings from the wet granulation DoE study (low water
quantity, impeller speed, and wet massing time) wereapplied to further development batches for Compound X.
Granulations were ultimately scaled up in a PMA-600
granulator and used in the successful manufacture ofcapsules for Registration.