A FORMULATION STRATEGY FOR SOLVING OVER-GRANULATION PROBLEM IN

HIGH SHEAR WET GRANULATION

Frederick Osei-Yeboah

Granulation is a processing technique in which smaller particles are clustered together to form
larger semi-permanent masses where the original particles can still be identified. [1, 2]It has been
used to improve the flow properties, compressibility and content uniformity of a formulation.
Additional benefits of a granulated powder include increased bulk density and reduced dust during
handling. Granulation can be a wet process (wet granulation), which requires a granulating fluid,
or a dry process (dry granulation), where particle aggregation is attained by applying compressive
stress.[3]

In the wet granulation, the level of agitation (shear stress) that causes agglomeration ranges from
low to very high. When high shear stress-generating mixers are used, the process is referred to as
High Shear Wet Granulation (HSWG). In a typical HSWG process, powdered components are
mixed in a vessel using rotating impellers at high speed. Once a homogeneous mixture is obtained,
granulation liquid is added at a controlled rate with mixing by the impellers at relatively low speed.
When granulating liquid addition is complete, the wet mass is further mixed at high impeller
speeds for a period of time (termed massing time) until a perceived endpoint is reached.[2, 4, 5]
The wet granules are then dried and sieved, if needed, to obtain the final granules for subsequent
unit operations such as capsule filling or tableting.[6]

Granulation is a form of particle design. Properties of granulated powders are affected by both
formulation compositions, i.e. choice of excipients; and process parameters, e.g. impeller speed.
Extensive understanding in several areas of wet granulation is required to fully predict product
properties and performance.[3, 7] HSWG granules have been observed to undergo substantial loss
of the ability to be compressed into tablets of sufficient strength, a phenomenon called “over-
granulation”. [8, 9] Studies on the compaction properties of microcrystalline cellulose (MCC), a
commonly used pharmaceutical excipient, have shown that granule size enlargement, surface
rounding, decreased granule porosity and densification all contribute to reduction in tabletability
by reducing granule deformability and intergranular bonding area.[10, 11] One effective approach
to address the overgranulation problem is the granule size reduction.[8, 9, 12, 13] Brittle excipients
predominantly undergo brittle fracture when deformed during ordinary powder compaction
process. [14, 15] Since granule size reduction can effectively improve powder tabletability through
creation of larger surface areas available for bonding in a tablet,[16] we hypothesize that the
incorporation of a brittle excipient in an otherwise plastic powder can enhance brittleness of
HSWG granules, which will lead to more extensive granule fragmentation, hence overcoming the
overgranulation problem. In this study, we test the stated hypothesis by incorporating brittle
excipients (lactose monohydrate and dibasic phosphate calcium) in a plastic MCC matrix.

The results show that tabletability of MCC granules deteriorated rapidly with increasing
granulating water as expected.[9] Intact tablet could not be made for MCC granules prepared with
55% granulating water or higher. However, the rate of granules tabletability reduction by water
addition was lower with increasing amount of lactose. For mixtures containing 20% lactose or
more, tabletability improved with increasing amount of granulating water after passing a minimum.
We conclude that the addition of brittle excipient to an otherwise plastic powder is effective in
reducing or even eliminating the over-granulation propensity in HSWG.
References:
1. Iveson, S.M., et al., Nucleation, growth and breakage phenomena in agitated wet
granulation processes: a review. Powder Technology, 2001. 117(1-2): p. 3-39.
2. Parikh, D.M., Handbook of pharmaceutical granulation technology. 2007, New York,
N.Y.: Informa Healthcare.
3. Augsburger, L.L. and S.W. Hoag, Pharmaceutical dosage forms - tablets. 2008, London:
Informa Healthcare.
4. Leuenberger, H., et al., Manufacturing pharmaceutical granules: Is the granulation end-
point a myth? Powder Technology, 2009. 189(2): p. 141-148.
5. Parker, M.D., P. York, and R.C. Rowe, Binder-substrate interactions in wet granulation.
1 : The effect of binder characteristics. International Journal of Pharmaceutics, 1990. 64(2-
3): p. 207-216.
6. Gibson, M., Pharmaceutical preformulation and formulation : a practical guide from
candidate drug selection to commercial dosage form. 2009, New York: Informa Healthcare.
7. Knight, P., Challenges in granulation technology. Powder technology., 2004. 140(3): p.
156.
8. Badawy, S., D. Gray, and M. Hussain, A Study on the Effect of Wet Granulation on
Microcrystalline Cellulose Particle Structure and Performance. Pharmaceutical Research,
2006. 23(3): p. 634-640.
9. Shi, L., Y. Feng, and C.C. Sun, Roles of granule size in over-granulation during high shear
wet granulation. Journal of Pharmaceutical Sciences, 2010. 99(8): p. 3322-3325.
10. Sun, C.C., Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity.
Journal of Adhesion Science and Technology, 2011. 25(4-5): p. 483-499.
11. Habib, Y., et al., Is Silicified Wet-Granulated Microcrystalline Cellulose Better than
Original Wet-Granulated Microcrystalline Cellulose? Pharmaceutical Development and
Technology, 1999. 4(3).
12. Shi, L., Y. Feng, and C.C. Sun, Origin of profound changes in powder properties during
wetting and nucleation stages of high-shear wet granulation of microcrystalline cellulose.
Powder Technology, 2011. 208(3): p. 663-668.
13. Shi, L., Y. Feng, and C.C. Sun, Massing in high shear wet granulation can simultaneously
improve powder flow and deteriorate powder compaction: A double-edged sword.
European Journal of Pharmaceutical Sciences, 2011. 43(1-2): p. 50-56.
14. Roberts, R.J. and R.C. Rowe, Brittle/ductile behaviour in pharmaceutical materials used in
tabletting. International Journal of Pharmaceutics, 1987. 36(2-3): p. 205-209.
15. Duncan-Hewitt, W.C. and G.C. Weatherly, Evaluating the Fracture Toughness of Sucrose
Crystals Using Microindentation Techniques. Pharmaceutical Research, 1989. 6(5): p. 373-
378.
16. Wu, S.-J. and C. Sun, Insensitivity of compaction properties of brittle granules to size
enlargement by roller compaction. Journal of Pharmaceutical Sciences, 2007. 96(5): p.
1445-1450.