Final DG Application Bulletin.pdf - FMC BioPolymer

THE SCIENCE OF FORMULATION 

APPLICATION BULLETIN 

Avicel® DG 

Specialty Binder for Dry Granulation 

Avicel® DG is an MCC-based binder that produces high quality tablets post-dry granulation. It is a coprocessed excipient 

containing microcrystalline cellulose and anhydrous calcium phosphate. 

Key differentiating features of Avicel®DG over other excipients commonly used in dry granulation include: 

• Higher initial compactibility – potential benefits when used with poorly compactible API’s, i.e. robust ribbons in roller 

compaction and improved tablet strength in direct compression 

• Improved recompactibility – significant benefits in tabletting properties post-dry granulation 

• Much improved flow vs. other highly compactible binders such as Avicel® PH-105 or PVP-based materials 

• Reduced lubricant sensitivity (particularly to magnesium stearate) – offers opportunity to reduce processing steps and 

hence overall ‘cost-in-use’ 

Avicel® DG is similar to other MCC-based binders in: 

• Dissolution properties 

• Manufacturing consistency 

• Long-term stability 

Contents 

Superior compactibility and robustness of Avicel® DG 2 

Superior recompactibility of Avicel® DG vs. common excipients 3 

Performance of Avicel® DG is validated across diverse formulations 4 

Flowability of Avicel® DG 5 

Dissolution of Avicel® DG 6 

Manufacturing process capability of Avicel® DG 7 

Lubricant sensitivity of Avicel® DG 8 - 9 

Stability of Avicel® DG 10 

Sales Offices 12

Superior compactibility and robustness of Avicel® DG 

Formulation 

• 30% Ascorbic Acid (Vitamin C) 

• 69.5% Excipient 

• 0.5% Magnesium Stearate 

Roller Compactor settings 

• Compactor: Chilsonator IR‐520/D6A, Fitzpatrick 

• Pressure: 30 bars 

• Mill type: Bar rotor 

• Mill speed: 500 rpm 

• Rasping screen: 1.0 mm 

Tabletting settings 

• ESH Compaction Simulator 

• Dwell time: 6 ms (high tabletting speed) 

Excipient 

69.5% 

Blend 10 min 

Intermediate 

Blend 

Blend 2 min 

Final Blend 

Roller 

AscorbicAcid 

30% 

Sieve 1mm 

Pre-blend 

Sieve 1mm 

Magnesium 

Stearate 0.5% 

DirectCompression 

Comparison of tablet strength (initial and retained) at a certain tabletting pressure 

3.5 

3.0 

Direct Compression 

Dry 

and 

2.5 

Loss of 

2.0 

1.5 

59% 

78% 

1.0 

47% 67% 

0.5 

0.0 

Avicel®DG 

Avicel® 

PH-102 

Avicel® PH-102 + 

Lactose Monohyd. 

DC (50:50) 


DCP Dihyd. DC 

(65:35) 

The improved compactibility of Avicel® 

DG – initial and retained – over physical 

blends of MCC and a secondary (brittle) 

excipient offers benefits in Direct 

Compression and Dry Granulation. 

Improved compactibility of 

Avicel® DG over physical 

blends of MCC and brittle 

excipients 

Improved robustness, 

i.e. minimized loss of 

compactibility due to reworking, 

of Avicel® DG over MCC 


enhances 

tablet strength 

in direct 

compression 


enables the 

production of 

quality ribbons 

and tablets 

2

Superior recompactibility of Avicel® DG vs. common excipients 

Formulation 


3.5 




• Compactor: Chilsonator IR‐220/ 

L1A, Fitzpatrick 





Tablet tensile strength (MPa) 

3.0 

2.5 

2.0 

1.5 

1.0 

0.5 

Common TS target 

Avicel® PH-101 




• Dwell time: 6 ms 

0.0 

0 50 100 150 200 250 

Tabletting presssure (MPa) 

The use of Avicel® DG enables the production of robust tablets at lower tabletting forces, which in turn minimizes equipment wear. Other 

common excipients (or blends of) may fail to yield satisfactory tablet strength and that may plateau at higher tabletting forces. 

Comparison of tablet strength, post‐granulation, at a certain tabletting pressure 

2.5 

Bars = 2 standard 

n = 14 (9 Avicel DG lots) 


at 150 MPa tabletting pressure 

2.0 

1.5 

1.0 

0.5 

0.0 


Avicel® 

PH-101 

Avicel® 

PH-102 

Avicel® 

PH-101 + 

An. DCP 

(75:25) 

Avicel® 

PH-101 

+ An. 

Lactose 

(50:50) 

Avicel® 

PH-102 + 

An. DCP 

(75:25) 

Avicel® 

PH-102 

+ An. 

Lactose 

(50:50) 

3

Performance of Avicel® DG is validated across diverse formulations 

Ascorbic Acid model with Magnesium Stearate 

Formulation 

• 3 0 % Ascorbic Acid (Vitamin C) 




• Compactor: Chilsonator IR‐220/L1A, Fitzpatrick 







• Dwell time: 6 ms (high tabletting speed, closer 

reflection of the actual production environment) 

APAP model with Alubra® PG‐100 

Formulation 

• 4 0 % Acetaminophen (Paracetamol) 


• 2% Ac‐Di‐Sol 

• 0.5% Alubra® PG‐100 


• Compactor: Chilsonator IR‐220/L1A, Fitzpatrick 








Comparison of compaction properties across multiple formulations 


at 150MPa tabletting pressure 

2.5 

2.0 

1.5 

1.0 

0.5 

AscorbicAcid high speed 

APAP low speed 

0.0 


Avicel® PH-101 Avicel® PH-101 + 

An. DCP (75:25) 


An. Lactose (50:50) 

The superior performance of Avicel® DG was observed in various models, with different API’s at different levels, different lubricants, compacted 

at various pressures and tabletted at various speeds. 

4

Flowability of Avicel® DG 

Carr’s index & FT4 Powder Rheometer – Flowability of Avicel® DG is similar to that of Avicel® PH-101 

Product 

LOD 

(%) 

LBD 

(g/cc) 

D50 

(µm) 

Hausner 

Carr’s index 

(%) 

FT4 Powder Rheometer Results 

FRI SE (mJ/g) UYS (kPa) 

Avicel® DG 4.3 

0.32 

42 

1.6 

37 

1.4 

7.9 

1.8 


4.2 

0.30 

49 

1.6 

38 

1.5 

8.3 

3.9 


4.1 

0.29 

105 

1.5 

34 

1.2 

6.8 

3.1 


3.7 

0.24 

20 

2.0 

50 

2.2 

18.1 

4.5 

LOD: loss on drying (%) 

LBD: loose bulk density (g/cc) 

D50: median particle size determined by laser diffraction (μm) 

Hausner ratio: tapped density at 2500 taps / loose bulk density 

Carr’s index: (tapped density at 2500 taps – loose bulk density) / 

tapped density at 2500 taps x 100 (%) 

FRI: flow rate index, higher FRI indicates flow rate sensitive and very 

cohesive powder 

SE: specific energy, energy needed to displace the powder 

UYS: unconfined yield strength, stress at which a bridge will collapse in 

a hopper outlet 

Hausner ratio – Avicel® DG flows similarly to Avicel® PH-101 and significantly better than Avicel® PH-105 

2.2 

Hausner ratio 

Tapped density / loose bulk density 

2.0 

1.8 

1.6 

1.4 

1.2 

1.0 

0.8 





0 500 1000 1500 2000 2500 

Number of taps 

The flowability of Avicel® DG is comparable to that of Avicel® PH-101, but significantly better than that of Avicel® PH-105. Indeed Avicel® DG 

and Avicel® PH-101 share several physico‐chemical properties, such as loss on drying (moisture content), loose bulk density and particle size. 

The presence of Calcium Phosphate in Avicel® DG may minimize unconfined yield strength and potentially reduce bridging in hoppers and 

feeding units. 

5

Dissolution of Avicel® DG 

Avicel® DG demonstrated similar dissolution rates to other binder substitutes across different formulations. 

APAP model 

Formulation 

• 40% APAP (Paracetamol 



• 0.5% Alubra® PG‐100 


• Compactor: Chilsonator IR‐ 

220/L1A, Fitzpatrick 





Metformin HCl model 

Formulation 

• 50% Metformin 



• 0.5% Alubra® PG‐100 


• Compactor: Chilsonator IR‐ 

220/L1A, Fitzpatrick 





HCTZ model 

Formulation 

• 10% Hydrochlorothiazide 



• 0.5% Alubra® PG‐100 


• Compactor: Chilsonator IR‐ 220/L1A, 

Fitzpatrick 





HCTZ Model, poorly soluble API, lowest release rate of the three models considered 

100 

90 

HCTZ Percent release (%) 

80 

70 

60 

50 

40 

30 

20 




Avicel® PH-101 + An. Lactose (50:50) 

Avicel® PH-101 + An. DCP (75:25) 

0 10 20 30 40 50 60 

Time (min) 

APAP HCl HCTZ 

USP acceptance criteria > 80% (Q) in 30 min > 70% (Q) in 45 min > 60% (Q) in 60 min 


95 ± 2.4 

100 

99 ± 0.5 


97 ± 1.2 

100 

98 ± 0.4 


100 ± 0.5 

100 

95 ± 0.8 

Avicel® PH-101 + An. DCP (75:25) 

84 ± 7.1* 

99 ± 0.5 

96 ± 0.6 

Avicel® PH-101 + An. Lactose (50:50) 

99 ± 0.8 

100 

93 ± 0.8 

Mean of 6 tablets ± standard deviation 

* 2 tablets out of 6 released less than 85% of APAP in 30 minutes. This formulation failed the stage 1 acceptance criteria, i.e. each unit is not less 

than Q + 5%, where Q is the amount of dissolved active ingredient specified in the individual monograph. 

6

Manufacturing process capability of Avicel® DG 

Formulation 





• Compactor: Chilsonator IR‐220/L1A, 

Fitzpatrick 






3.5 

3.0 

2.5 

2.0 

1.5 

1.0 

0.5 

--- 2009 (3 lots) 

--- 2011 (3 lots) 

--- 2012 (3 lots) 




0.0 

0 50 100 150 200 250 

Time (min) 

Mean tensile strength = 2.03 MPa (standard deviation ± 0.08 MPa) 

2.5 


at 150 MPa tabletting pressure 

2.0 

1.5 

1.0 

0.5 

0.0 

Manufacturing year – Lot number 

A total of 9 Avicel® DG lots, produced over a period of three years, confirm the excellent production and lot‐to‐lot consistency. 

7

Lubricant sensitivity of Avicel® DG 

Formulation 





• Compactor: Chilsonator IR‐220/ 

L1A, Fitzpatrick 







• Dwell time: 6 ms (high tabletting 

speed) 

Process A – Two blending steps 

1. API & Excipient 

2. Lubrication 

Process B – One blending step 

1. API & Excipient & Lubricant 

Excipient 

69.5% 

AscorbicAcid 

30% 

Excipient 

69.5% 

Magnesium 

Stearate 0.5% 

AscorbicAcid 

30% 

Sieve 1mm 

Pre-blend 

Sieve 1mm 

Blend 10 min 

Intermediate 

Blend 

Magnesium 

Stearate 0.5% 

Sieve 1mm 

Pre-blend 

Blend 10 min 

Sieve 1mm 


Blend 2 min 

Roller 


Roller 

Impact of blending steps on tablet strength 


3.5 

3.0 

2.5 

2.0 

1.5 

1.0 

0.5 

Avicel® DG + 0.5% MgSt 

One blending step, Process B 

Avicel® DG + 0.5% MgSt 

Two blending steps, ProcessA 

Avicel® PH-101 + 0.5% MgSt 

Two blending steps, Process A 


One blending step, Process B 

Standard MCC is more lubricant 

sensitive than Avicel® DG and would 

therefore show signs of lamination 

and capping if the lubricant is 

incorporated in the initial blend. 

Therefore, a secondary and final 

lubricant blending step would be 

required. Avicel® DG yields highquality 

tablets in formulations 

blended in a single step, offering 

significant benefits from process 

simplification and cycle‐time 

reduction. 

0.0 

0 50 100 150 200 250 

Tabletting pressure (MPa) 

8

Lubricant Sensitivity of Avicel® DG (continued) 

Formulation 



Excipient 

69.5% 

AscorbicAcid 

30% 

• 0.5% Magnesium Stearate or Alubra® 

Sieve 1mm 

PG‐100 


Blend 10 min 

• Compactor: Chilsonator IR‐520/D6A, 

Fitzpatrick 

Intermediate 

Blend 

Lubricant 

0.5% 



Pre-blend 


Sieve 1mm 



Blend 2 min 




Roller 

Comparison of tablet strength using different lubricants 

4.5 

4.0 

3.5 


3.0 

2.5 

2.0 

1.5 

1.0 

0.5 

Common TS target 


0.0 

0 50 100 150 

200 250 

Tabletting pressure (MPa) 

Avicel® DG can significantly improve tablet strengths over standard MCC. This benefit is accentuated with the use of Alubra® PG‐100 (Sodium 

Stearyl Fumarate), which may assist in formulating with poorly compactible and/or poorly soluble API’s. 

9

Stability of Avicel® DG 

Long term storage at 25°C and 60% RH 

N/A: not available, Lot #1: XN09820884, Lot #2: XN09820885, Lot #3: XN09820886 

Long term storage at ambient conditions, Brussels, Belgium 

Mean temperature: 21°C (min: 15°C, max: 25°C), Mean relative humidity: 43% (min: 16%, max: 76%) 

0 

N/A: not available, Lot #1: XN09820884, Lot #2: XN09820885, Lot #3: XN09820886 

Avicel® DG is less hygroscopic than MCC 


* 25°C and 60% RH simulate long term storage conditions 

10

Notes 

11

Sales Offices 

United States 

Philadelphia, PA 

Sales/Technical Assistance: 

Tel: 1-215-299-6534 

Fax: 1-215-299-6669 

Customer Service: 

Tel: 1-800-526-3646 

Fax: 1-215-299-6475 

Europe 

Brussels, Belgium 

Sales/Technical Assistance: 

Tel: +32-2-775-8311 

Fax: +32-2-775-8300 

Customer Service: 

Tel: +353-21-4354-133 

Fax: +352-21-4353-057 

Asia-Pacific 

Shanghai 

Tel: +86-21-5427-1177 

Fax: +86-21-5427-0193 

Tokyo, Japan 

Tel: +81-3-3402-3739 

Fax: +81-3-3402-3700 

Singapore 

Tel: +65-6430-0383 

Fax: +65-6430-0399 

Latin America 

Montevedeo, Uruguay 

Tel/Fax: +5982-604-3030 

Tel/Fax: +5982-604-3104 

Middle East 

Amman, Jordan 

Tel: +962-5-4618150 

Fax: +962-5-4618156 

Visit our website at www.fmcbiopolymer.com 

E-mail: pharm_info@fmc.com 

Patents 

FMC Corporation is owner and/or licensee of several patents related to its products. The products, processes and uses of such products referred to in this document 

may be covered by one or more patents or pending applications in the United States and/or other countries. FMC does not warrant against any infringement claim 

arising from the sale and/or use of any FMC product in combination with other materials; the use of any FMC product in the operation of any process; any FMC 

product manufactured to a customer’s designs or specifications; or any FMC product manufactured by any process requested by a purchaser. 

Product Suitability 

The information contained in this document (as well as any advice or assistance) is provided by FMC only as a courtesy and is intended to be general in nature. Any 

uses suggested by FMC are presented only to assist our customers in exploring possible applications. FMC makes no warranty, express or implied, as to its accuracy 

or completeness, or the results to be obtained from such information, advice or assistance. Each customer is solely responsible for determining whether the FMC 

products are suitable for such customer’s intended use, and for obtaining any necessary governmental registrations and approvals for such customer’s production, 

marketing, sale, use and/or transportation of finished goods using or incorporating the FMC products. 

FMC logo, Alubra and Avicel are trademarks of FMC Corporation. ©FMC Corporation 2012. All rights reserved. 

Chilsonator is a trademark of The Fitzpatrick Company.

Final DG Application Bulletin.pdf - FMC BioPolymer

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