Moisture Activated Dry Granulation

A low cost/high efficiency approach to wet granulation

Dr. Gerard Thone

North/Latin American Technical Services Manager

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Objectives for today’s discussion

Provide a basic understanding of the moisture activated dry granulation

(MADG) process

Explain what basic excipient needs are in MADG

Explain why Avicel PH-200 LM is an ideal excipient for use in MADG

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Standard granulation approaches

Direct Compression

Dry Granulation (Roller Compaction)

Wet Granulation
Standard approach
Moisture Activated Wet Granulation (MADG)

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Tableting process overview

100%
Granulation

Drug Dominant
Drug Loading

Direct Compression

Excipients Dominant
0.1%
Granulation
0%
Bad Drug Properties Good

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Wet granulation

Benefits
• Good particle size distribution, good flow
• Flexibility, broad applications
• Good uniformity

Drawbacks
• Requires multiple steps
• Requires milling step
• Less robust, risk of overgranulation
• Expensive drying step

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Traditional wet granulation process

Blending Dispensing
Granulating
Solution

Wet Massing
Blending Pre-mix

Screening Drying
Tabletting

Screening

Moisture Activated Dry Granulation

MADG granulation process

Blending
Active, Binder, Dispensing
Diluent
Water

Wet Massing Blending

Avicel PH-200 LM
Pre-mix

Screening Drying
Tabletting

Screening

Moisture Activated Dry Granulation

MADG process

As the name implies, this is a process where moisture is used to activate the
granule formation, but the granules are not heat dried

This process is comprised of two major steps:

• Agglomeration
• Moisture distribution

Moisture Activated Dry Granulation

Agglomeration

In this step, the drug is mixed with a filler and a dry binder

While mixing, a small (1-4%) amount of water is sprayed

Water droplets hydrate the dry binder and create tacky nuclei or tacky wet mass

Dry powder particles adhere to the wet nuclei or wet tacky mass to create moist
agglomerates

These are small moist agglomerates and not like the big wet lumps observed in
conventional wet granulation

Moisture Activated Dry Granulation

Moisture distribution

While mixing the agglomerates, remaining drug, if any, can be added.

Low Moisture Avicel® PH-200 LM is added and mixing continued

While mixing, disintegrant is added and mixing continued

Contents can be lubricated, sieved/sized and blended

Moisture Activated Dry Granulation

MADG process - stages
DRUG + FILLER + BINDER
Blend
DRY BLEND Agglomerates
After
Dry
Finalblend
Avicel
blend
Blend + Spray Water
MOIST AGGLOMERATES
Blend + Add Drying Agent
(drug/Avicel/Silica)

DRY-FREE FLOWING GRANULES

Blend + Add Disintegrant
UN-LUBRICATED GRANULES

Blend + Add Lubricant

LUBRICATED GRANULES
Sieve / Size
SIZED GRANULES
Blend
FINAL GRANULATION
Courtesy of Ishmat Ullah, BMS
“The process”
Stages of MADG process (overview)
Dry blend After Avicel® PH-200 LM
1 3

Agglomerates Final blend

2 4

Moisture Activated Dry Granulation Courtesy of Ishmat Ullah, BMS

Effect of agglomeration

Control - Ungranulated Powder

MADG Granules (PVP K-12 5% , water 1.4% )
60.0 54.4
47.1
Retained on Screen (%)

50.0
40.0 36.5
33.3
30.0
20.0
12.0 11.5
10.0 4.0 4.9
0.0
60 mesh 100 mesh 200 mesh < 200 mesh
Screen Size
250 µm 150 µm 75 µm < 75 µm

Moisture Activated Dry Granulation Courtesy of BMS

General granulation characteristics

Batch Size 400 g 400 g 400 g 30 kg 400 g 400 g 400 g

Lactose Lactose Lactose Lactose Mannitol Acetami- Lactose
Drug/Filler Hydrous Hydrous Hydrous Hydrous C-160 nophen Hydrous
PVP PVP PVP PVP PVP PVP
K-12 K-12 K-12 K-12 K-12 K-12 HPC EXF
Binder 5.0% 5.0% 9.0% 5.0% 5.0% 8.0% 5.0%
Water 0.0 1.4% 2.0% 1.4% 1.25% 2.0% 2.40%
LOD(%) 1.0 1.9 2.6 1.8 1.8 2.5 2.2
Bulk Density(g/mL) 0.56 0.55 0.58 0.58 0.53 0.50 0.58
Powder Flow(mL/sec) 1.9 8.3 10.0 7.7 7.9 7.7 7.4
Pellet Hardness(scu) * 21.8 19.7 20.9 19.9 24.1 20.4 15.1
Pellet Ejection
43 38 26 39 39 20 32
Force(lbs) *
Disintegration in
17 25 98 30 82 45 30
Water(sec)

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Example of low dose drug
(Drug A)
Ingredient (%)
Drug A 5.0
Lactose Monohydrate 65.0
PVP K-12 7.0
Water 2.0
Aeroperl 300 2.0
Avicel PH 200 LM 13.5
Crospovidone 5.0
Magnesium Stearate 0.5

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Example of Medium/High Drug Load Drug
Difficult to Granulate
(Drug B)
Ingredient (%)
Drug B 25.0
Mannitol C-160 40.0
PVP K-12 5.0
Water 3.0
Aeroperl 300 3.0
Avicel PH 200 LM 17.5
Crospovidone 6.0
Magnesium Stearate 0.5
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Example of High Drug Load Drug
Difficult to Granulate
(Drug C)
Ingredient (%)
Drug C 45.8
Lactose Monohydrate 5.2
PVP K-12 11.5
Crospovidone 2.1
Water 4.2
Drug C 16.7
Aeroperl 300 5.2
Avicel PH 102 5.2
Crospovidone 3.5
Magnesium Stearate 0.6
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Pictures of agglomerates from different binders
PVP HPC exf

Crospovidone Maltrin 180

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Pictures of final granules from different binders
PVP HPC exf

Crospovidone Maltrin 180

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Pictures of sieved agglomerates
On 60 mesh On 200 mesh

On 100 mesh Pass thru 200 mesh

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Pictures of agglomerates from different droplet sizes
Agglomerate coarse droplets Final blend from coarse droplets

Agglomerate fine droplets Final blend from fine droplets

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Effect of Agglomeration

Control - Ungranulated Powder

MADG Granules (PVP K-12 5% , water 1.4% )
60.0 54.4
47.1
Retained on Screen (%)

50.0
40.0 36.5
33.3
30.0
20.0
12.0 11.5
10.0 4.0 4.9
0.0
60 mesh 100 mesh 200 mesh < 200 mesh
Screen Size

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Effect of Binders
• PVP K-12 5.0% with water 1.4%
• HPC EXF 5.0% with water 2.4%
• Crospovidone 5.0% with water 1.8%
• Maltrin 180 5.0% with water 1.25%
60

50
Retained on Screen (%)

40

30

20

10

0
Pre-Screening 60 mesh 100 mesh 200 mesh < 200 mesh
30 mesh Screen Size
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Effect of Binder Level

PVP K-12 5.0% with water 1.4%

PVP K-12 7.0% with water 1.7%
PVP K-12 9.0% with water 2.0%
50
45
Retained on Screen (%)

40
35
30
25
20
15
10
5
0
Pre-Screening 60 mesh 100 mesh 200 mesh < 200 mesh
30 mesh
Screen Size

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Effect of Water Droplet Size
(with 5.0% PVP K-12 and 1.4% Water)

Water droplet size D90 at 200 microns

Water droplet size D90 at 110 microns
Water droplet size D90 at 60 microns
50
Retained on Screen (%)

40

30

20

10

0
Pre-Screening 60 mesh 100 mesh 200 mesh < 200 mesh
30 mesh
Screen Size

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Effect of drugs
Lactose monohydrate, PVP K-12 5.0%, water 1.4%
Mannitol, PVP K-12 5.0%, water 1.25%
Acetominophen, PVP K-12 8.0%, water 2.0%
50
Retained on Screen (%)

40

30

20

10

0
Pre-Screening 60 mesh 100 mesh 200 mesh < 200 mesh
30 mesh
Screen Size

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Process Reproducibility
(Lactose, PVP K-12 7.0%, Water 1.7%)

Replicate 1 Replicate 2 Replicate 3

50
Retained on Screen (%)

40

30

20

10

0
Pre-Screening 60 mesh 100 mesh 200 mesh < 200 mesh
30 mesh
Screen Size

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Process Scale-up
(Lactose monohydrate, PVP K-12 5.0%, Water 1.4%)

Batch size 0.4 kg (Diosna 2 L)

Batch size 30 kg (PMA 150 L)
50
Retained on Screen (%)

40

30

20

10

0
Pre-Screening 60 mesh 100 mesh 200 mesh < 200 mesh
30 mesh
Screen Size

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Test formulations
Component Percent Composition

Formulation 1 Formulation 2 Formulation 3 Formulation 4

APAP 34.01 31.85 35.91 36

PVP K- 12 5.44 5.1 0.17 0.2
Lactose, Hydrous
SD
27.21 44.59 28.73 29
Avicel PH 200 LM

31.29 16.56 33.04 33

Na
Croscarmellose
1.36 1.27 1.44 2
Mg Stearate 0.68 0.64 0.72 0.75
Water 3 5 2.8 5
Granule LOD 3.89 3.85 2.67 2.86

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Particle size distribution

Particle Size Distribution at Stages

40

35 Formulation 4 Powder Blend

Formulation 4 Granule Size

30
Percent on Screen

25

20

15

10

0
25 50 70 80 120 200

Mesh Size

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Particle size distribution

Particle Size Distribution of MADG Granules

35

Formulation 1, Particle Size

30 Formulation 2, Particle Size

Formulation 3, Particle Size
Formulation 4, Particle Size

25
Percent on Screen

20

15

10

0
25 50 70 80 120 200
Particle Size (Mesh)

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Summary of MADG benefits

MADG vs WG Primary Benefit Secondary Benefit

Faster process, increased
Lower amount of added
No drying efficiencies, lower
moisture (4% to 8% total)
production costs
Single production
Lower investments and Increased efficiencies,
equipment (high shear
maintenance lower production
Increased costs
efficiencies,
granulator)
lower production costs.
No equipment change Reduces process time Faster product
development, faster to
market.
No milling required No fines Higher yields, lower costs

Lower tablet capping

Lower tablet rejection rate Higher yields, lower costs
(common w/ low moist.)
No over or under- Higher asset utilization,
Fewer scrapped batches
granulation lower costs
Note: MADG benefits have not yet been demonstrated for moisture sensitive drugs

l Moisture Activated Dry Granulation

MADG - remarks

The resulting granules are very homogeneous and free flowing.

Demonstration was done using low-dose and high-dose APIs.

The amount of water remaining is typical for a direct compression

granulation.

The process to obtain granules is 20 minutes. A typical WG process

takes several hours.

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Other attributes of the MADG Process

A simple, clean and lean process

Economical, energy saving and environmentally friendly

Good content uniformity enables QbD

Useful for most pharmaceutical granulation needs

Reproducible and scalable

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The use of Avicel® PH-200 LM for MADG

MADG requires coarse, free flowing water-absorbent excipients to match the

wet granule morphology and bind free water.

Avicel PH-200 LM has a moisture level of NMT 1.5%.

• Absorbs 3-4 times as much water from the granule as conventional
Avicel PH-200
• Enables compression without further drying

The morphology of larger particle size of Avicel PH-200 LM (180µ APS) is ideal
for blending with the wet granulate.

Note: Avicel PH-200 LM can also be used effectively in direct compression for moisture
sensitive API’s

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Conclusions
Moisture Activated Wet Granulation (MADG) is a simple, clean process which
can be used in place of wet granulation to:
• increase manufacturing efficiencies
• achieve higher asset utilization
• decrease costs
• achieve higher yields with fewer fines

MADG is reproducible and scalable.

The introduction of low moisture, large particle Avicel® PH-200 LM enables the
pharmaceutical industry to take advantage of all that MADG has to offer.

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Acknowledgements:

BMS Pharmaceutical development

Ishmat Ullah, Sr. Prin. Scientist, BMS Co.