Wet and dry granulation binder

a teCHniCal reVieW

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

FOrMULATing THE MEDiCinES tHat proVide people WitH iMMEDiATE rELiEF

We know what you need and can help you deliver.

When youre developing immediate release tablet and capsule medicines, we know what H immediat release youre looking for: good tablet hardness at low concentration, versatility and compliance with applicable government requirements. Producing a tablet with a high concentration of the active drug requires a binder that is highly effective at low concentrations. For this, choose METHOCEL Premium products from Dow Wolff Cellulosics, which deliver the necessary tablet hardness without increasing friability and without negatively impacting the release of the drug.

Why Wait When We can help you deliver noW METHOCEL products provide important binding and adhesive properties during the granulation step of the manufacturing process for immediate release tablet and capsule products. They offer several important benefits for every formulator:

Now thats the tablet were looking for: METHOCEL polymers produce hard tablets at very low concentrations as low as 3% when used in formulations for wet granulation processes (low shear, high shear, and fluid bed) and between 6% and 12% for dry granulation (roller compaction) without increasing friability. With METHOCEL, minimize tablet size while maximizing the ability to use other excipients to optimize other tablet characteristics, which makes these polymers ideal in formulations with high active drug concentrations. Whatever you need, we can help: METHOCEL products offer flexibility when manufacturing tablets. Wet and dry granulation processes provide important characteristics to the finished product, including better product flow on tablet presses and capsulefilling equipment, better compressibility and overall improved physical characteristics of tablets, uniform drug content within the dosage form, and fewer industrial hygiene constraints. METHOCEL is highly effective in both granulating technologies. These polymers also are compatible with virtually all active ingredients and other excipients, and hydrate quickly in process liquids to minimize mixing and preparation time. At the appropriate concentration, METHOCEL can be used to add needed viscosity to the granulating liquid to minimize mixing and preparation time. METHOCEL products also can be used in solutions or dry-blended into the powder mass that is to be granulated and then hydrated by spraying water. Follow the rules for success: METHOCEL Premium grades comply with the compendia specifications of the Pharmacopoeia of the U.S., Europe, and Japan (current editions) and the Food Chemicals Codex, third edition.

VISCOSITY OF AQUEOUS SOLUTIONS CONTAINING METHOCELTM AT VARYING CONCENTRATION AND MOLECULAR WEIGHT
Viscosity, mPas // Concentration, % Binder

3500 3000 2500 2000 1500 1000 500 400 300 200 100 0.05
TM

0.1

0.25

0.5

1.5

2.5

10

METHOCEL A15P LV @ 20C METHOCELTM E5P LV @ 20C METHOCELTM K3P LV @ 20C

01 Wet and dry granulation binder

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Wet and dry granulation binder 02

MetHoCel Can Help you get tHere

H immediat release

H immediat release

H immediat release

Below we provide the results of several studies included in our extensive testing program. These provide representative examples of the effects of METHOCEL binders on tablet properties.

acetaminophen: high-dose, loWsolubility drug in the Wet-granulation in a formulation with 50% acetaminophen, METHOCEL demonstrated good hardness at concentrations of 3% and 6% of total tablet weight. in some formulations, METHOCEL polymers can even provide optimum tablet properties at concentrations of 1% and lower. This ability to provide good hardness at low concentrations makes METHOCEL ideal for formulations that contain a high percentage of active drug or other excipients.
HARDNESS OF COMPRESSED TABLETS CONTAINING ACETAMINOPHEN AND GRANULATED WITH 6% DRY BINDER IN LOW-SHEAR AND HIGH-SHEAR GRANULATORS Hardness, strong-cobb units // Binder // Hardness, kiloponds

DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING ACETAMINOPHEN AND GRANULATED WITH 3% DRY BINDER IN A HIGH-SHEAR GRANULATOR
Drug released, % // Time, min

DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING ACETAMINOPHEN AND GRANULATED WITH 6% BINDER IN SOLUTION IN A FLUID-BED GRANULATOR
Drug released, % // Time, min

100

100

80

USP Specications

80

USP Specications

60

60

40

40

H immediat release

H immediat release
METHOCELTM K3 Prem LV HPC PVP

20

20

30
METHOCELTM A15 Prem LV METHOCELTM E5 Prem LV

21.41
0 10 20 30 40 50 0
TM

10

15

20

25

30

35

40

20

14.27

METHOCELTMA15 Prem LV - 3% PVP - 3% HPC-EF - 3%

METHOCEL A15 Prem LV - 3% PVP - 3% HPC-EF - 3% METHOCELTM E5 Prem LV - 3%

10

7.13

METHOCELTM E5 Prem LV - 3% DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING ACETAMINOPHEN AND GRANULATED WITH 6% DRY BINDER IN SOLUTION IN A LOW-SHEAR GRANULATOR
Drug released, % // Time, min

Low Shear High Shear

HARDNESS OF COMPRESSED TABLETS CONTAINING ACETAMINOPHEN AND GRANULATED WITH 6% DRY BINDER IN LOW-SHEAR AND HIGH-SHEAR GRANULATORS Hardness, strong-cobb units // Binder // Hardness, kiloponds
METHOCELTM E5 Prem LV

100

80

USP Specications

METHOCELTM A15 Prem LV

30

METHOCELTM K3 Prem LV

21.41
HPC PVP

The desirable hardness characteristics of METHOCEL also result in friability performance that is well within acceptable limits at both 3% and 6% binder levels. The drug-release performance represents an average of six test runs. in all cases performance of METHOCEL binders was within the USP specifications and comparable to that of PVP binders.

60
14.27

20

40
10 7.13

20

Low Shear High Shear Fluid Bed

0
TM

10

20

30

40

50

60

70

METHOCEL A15 Prem LV - 3% PVP - 3% HPC-EF - 3% METHOCELTM E5 Prem LV - 3%

03 Wet and dry granulation binder

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Wet and dry granulation binder 04

H immediat release

H immediat release

METHOCEL MEETS yOUr FOrMULATiOn nEEDS

vitamin c (ascorbic acid): high-dose, high-solubility drug in the Wet-granulation in a formulation with 75% ascorbic acid, the hardness values of METHOCEL products were equivalent or superior to those achieved with another polymer, polyvinylpyrrolidone (PVP), for H immediat release all granulating techniques and at both binder levels. Low-shear and high-shear granulations demonstrated comparable hardness values, except for PVP formulations. For PVP, low-shear processing resulted in harder tablets than highshear processing for dry binder. At 6% binder level in solution, fluid-bed granulations from all products demonstrated excellent tablet hardness, in all cases better than low-shear or high-shear granulations.

FRIABILITY OF COMPRESSED TABLETS CONTAINING ASCORBIC ACID AND GRANULATED WITH 6% DRY BINDER IN LOW-SHEAR AND HIGH-SHEAR GRANULATORS
Friability, % weight loss // Binder

0.8
METHOCELTM A15 Prem LV METHOCELTM E5 Prem LV METHOCELTM K3 Prem LV

HPC

0.6

0.4

0.2

METHOCEL at 3% binder level achieved good tablet hardness, though not as consistently high as at 6%. regardless of the granulation process used, tablets prepared using METHOCEL cellulose ethers had friability values below 0.7%. METHOCEL A15 Premium LV, E5 Premium LV and K3 Premium LV all demonstrated friability performance that was superior to PVP. The drugrelease performance again represents an average of six test runs. in all cases using binders in solution, at least 80% of the active ingredient is released within 15 minutes. For dry binder additions, at least 80% of the active ingredient is released within 30 minutes.

DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING ASCORBIC ACID AND GRANULATED WITH 3% BINDER IN SOLUTION IN A HIGH-SHEAR GRANULATOR
Drug released, % // Time, min

PVP

100

80

60

40

Low Shear High Shear

H immediat release

20

0
TM

10

15

20

25

30

HARDNESS OF COMPRESSED TABLETS CONTAINING ASCORBIC ACID AND GRANULATED WITH 6% BINDER IN SOLUTION IN FLUID-BED, LOW-SHEAR, AND HIGH-SHEAR GRANULATORS
Hardness, strong-cobb units // Binder // Hardness, kiloponds
METHOCELTM A15 Prem LV METHOCELTM E5 Prem LV METHOCELTM K3 Prem LV

METHOCEL E5 Prem LV - 3%
HARDNESS OF COMPRESSED TABLETS CONTAINING ASCORBIC ACID AND GRANULATED WITH 6% DRY BINDER IN LOW-SHEAR AND HIGH-SHEAR GRANULATORS
Hardness, strong-cobb units // Binder // Hardness, kiloponds
METHOCELTM E5 Prem LV METHOCELTM A15 Prem LV METHOCELTM K3 Prem LV

PVP - 3% HPC-EF - 3% METHOCELTM K3 Prem LV - 3%

HPC

HPC

30

21.41
PVP

15

10.70
PVP

DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING ACETAMINOPHEN AND GRANULATED WITH 6% BINDER IN SOLUTION IN A FLUID-BED GRANULATOR
Drug released, % // Time, min

20

14.27

10

7.13

100
10 7.13
5 3.56

80

Low Shear High Shear Fluid Bed

Low Shear High Shear

60

40

20

0
TM

10

20

30

40

50

60

METHOCEL E5 Prem LV - 6% PVP - 6% HPC-EF - 6% METHOCELTM K3 Prem LV - 6%

05 Wet and dry granulation binder

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Wet and dry granulation binder 06

H - Immediate release
METHOCEL MEETS yOUr FOrMULATiOn nEEDS

methazolamide: loW-dose, loW-solubility drug in the Wet-granulation in a formulation of 7.1% methazolamide, METHOCEL K3 Premium LV produced the best tablet hardness values at a binder level of 3% using a high-shear granulation process. At 6% binder level, hardness values were essentially equivalent for all binder materials, although low-shear granulation processes tended to perform better than high-shear processes.

FRIABILITY OF COMPRESSED TABLETS CONTAINING METHAZOLAMIDE AND GRANULATED WITH 3% OR 6% BINDER IN SOLUTION IN A FLUID-BED GRANULATOR
Tablet friability, % weight loss // Binder

0.5
METHOCELTM A15 Prem LV

0.3

Fluid-bed granulation offered even less differentiation between the three METHOCEL products, with performance again equivalent to the PVP binder. The binder level was not a factor for fluid-bed granulation as additional binder did not consistently result in harder tablets. All binders used in this portion of the study produced tablet with low friabilityless than 0.6% and well below the 1% industry norm. in terms of drug release from the tablet, all tablets surpassed USP specifications by a significant margin.

DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING METHAZOLAMIDE AND GRANULATED WITH 6% DRY BINDER IN A HIGH-SHEAR GRANULATOR
Drug released, % // Time, min

METHOCELTM E5 Prem LV

METHOCELTM K3 Prem LV

100

80
USP Specications

HPC

PVP

60

40

0.1

H immediat release

20

10

20

30

40

50

60

70

80

3% 6%

METHOCELTM E6 Prem LV - 6% HPC-EF - 6% METHOCELTM A16 Prem LV - 6%

METHOCELTM K3 Prem LV - 6% PVP - 6%

DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING METHAZOLAMIDE AND GRANULATED WITH 3% DRY BINDER IN A HIGH-SHEAR GRANULATOR
Drug released, % // Time, min

100

80

USP Specications

60

40

20

0
TM

10

20

30

40

50

60

70

METHOCEL A15 Prem LV - 3% METHOCELTM E5 Prem LV - 3% METHOCELTM K3 Prem LV - 3%

HPC-EF - 3% PVP - 3%

07 Wet and dry granulation binder

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Wet and dry granulation binder 08

H - Immediate release

H - Immediate release

H - Immediate release

METHOCEL MEETS yOUr FOrMULATiOn nEEDS

niacinamide: high-dose, high-solubility drug in the roller-compaction A study looked at three formulations with niacinamide (88.5%, 82.5% and 70.75%) plus METHOCEL. The level of pressure applied to the compactor rolls was important to the quality of the finished tablets. in general, low roller pressures resulted in tablets with higher hardness. At the lowest binder level (6.25%), hardness values of tablets produced at 1- and 3-ton pressures were marginal, and friability was excessive. At the highest binder level (25%), hardness was generally improved and friability (with the exception of PVP) was good. At most binder levels and roller pressures, hardness and friability values for the METHOCEL products were better than PVP. Tablet drug-release times were primarily a function of binder concentration and molecular weight rather than roller pressure. For the METHOCEL products, the time required to release 90% of the drug at the lowest binder level ranged from 68 minutes for the lower molecular weight products (E5 Premium LV and K3 Premium LV) to 512 minutes for the higher molecular weight products (E15 Premium LV and A15 Premium LV). The time required to release 90% of the drug at the intermediate binder concentration increased to 1618 minutes for E5 Premium LV and K3 Premium LV to 1940 minutes for E15 Premium LV and A15 Premium LV. The highest binder concentration required 44 and 59 minutes for K3 Premium LV and E5 Premium LV, respectively, and 290 and 142 minutes for A15 Premium LV and E15 Premium LV, respectively, for 90% drug release. Times to 90% release for PVP were generally lower than the METHOCEL products at the lowest concentration, but the release times were not as sensitive to increases in binder concentration. However, the physical properties of these tablets were poor; i.e, the tablets exhibited capping. Times to 90% release for the nisso HPC-EF were between the low and high molecular weight METHOCEL products.

FRIABILITY OF COMPRESSED TABLETS CONTAINING NIACINAMIDE AND PREPARED USING ROLLER COMPACTION AT 3 TONS PRESSURE
Friability, % weight loss // Binder
HPC-EF

HARDNESS OF COMPRESSED TABLETS CONTAINING NIACINAMIDE AND PREPARED USING ROLLER COMPACTION AT 3 TONS PRESSURE
Hardness, strong-cobb units // Binder // Hardness, kiloponds

HARDNESS OF COMPRESSED TABLETS CONTAINING NIACINAMIDE AND PREPARED USING ROLLER COMPACTION AT 1 TON PRESSURE
Hardness, strong-cobb units // Binder // Hardness, kiloponds
METHOCELTM A15 Prem LV METHOCELTM K3 Prem LV

METHOCELTM E15 Prem LV

METHOCELTM K3 Prem LV

METHOCELTM A15 Prem LV

6 5
METHOCELTM E5 Prem LV

20
PVP 29-32

14.27
METHOCELTM K3 Prem LV HPC-EF

25

METHOCELTM E5 Prem LV

METHOCELTM E15 Prem LV

HPC-EF

METHOCELTM E5 Prem LV

PVP 29-32

4
METHOCELTM A15 Prem LV

METHOCELTM E15 Prem LV

15
PVP K90

20
PVP K90

14.27
PVP 29-32

3 2 1

15 7.13 10

CAPPING

10

PVP K90

H - Immediate release
5

H - Immediate release

7.13

6,25% Binder 12,5% Binder 25% Binder

6,25% Binder 12,5% Binder 25% Binder

6,25% Binder 12,5% Binder 25% Binder

TIME TO 90% DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING NIACINAMIDE AND PREPARED USING ROLLER COMPACTION AT 3 TONS PRESSURE
Time to 90% drug release, minutes // Binder

290

RATE OF DRUG RELEASE FROM COMPRESSED TABLETS CONTAINING NIACINAMIDE WITH 12.5% BINDER AND PREPARED USING ROLLER COMPACTION AT 3 TONS PRESSURE
Drug released, % // Time, min

142

70 60

118

25

20

50 40 30 20 10
5 15

10

METHOCELTM METHOCELTM METHOCELTM METHOCELTM HPC-EF PVP 29-32 A15 Prem E5 Prem E15 Prem K3 Prem LV LV LV LV

PVP K90

10

15

20

25

30

35

40

45

50

55

60

METHOCELTM A15 Prem LV HPC-EF PVP K90 METHOCELTM E5 Prem LV

METHOCELTM K3 Prem LV PVP 29-32 METHOCELTM E15 Prem LV

6,25% Binder 12,5% Binder 25% Binder

09 Wet and dry granulation binder

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Wet and dry granulation binder 10

Wet and dry granulation binder

north America: +1 800 258 2436 Europe: +31 11 567 2626 Pacific: +60 3 7965 5392 Latin America: +55 11 5188 9000 dow.contact@dowwolff.com www.dowwolff.com

tMTrademark of The Dow Chemical Company (Dow) or an affiliated company of Dow

Form no. 198-02258 - 10/11 EST

nOTiCE: no freedom from infringement of any patent owned by Dow or others is to be inferred. Because use conditions and applicable laws may differ from one location to another and may change with time, Customer is responsible for determining whether products and the information in this document are appropriate for Customers use and for ensuring that Customers workplace and disposal practices are in compliance with applicable laws and other government enactments. The product shown in this literature may not be available for sale and/or available in all geographies where Dow is represented. The claims made may not have been approved for use in all countries. Dow assumes no obligation or liability for the information in this document. references to Dow or the Company mean the Dow legal entity selling the products to Customer unless otherwise expressly noted. nO WArrAnTiES ArE giVEn; ALL iMPLiED WArrAnTiES OF MErCHAnTABiLiTy Or FiTnESS FOr A PArTiCULAr PUrPOSE ArE EXPrESSLy EXCLUDED.