technical granulation binder

Wet and dry granulation binder

a teCHniCal reVieW

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

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:

VISCOSITY OF AQUEOUS SOLUTIONSCONTAINING METHOCELTM AT VARYING CONCENTRATIONAND MOLECULAR WEIGHTViscosity, mPa•s // Concentration, % Binder

0.05 0.1 0.25 0.5 1 1.5 2 2.5 5 10

100

200

300

400

500

1000

1500

2000

2500

3000

3500

METHOCELTM K3P LV @ 20°C

METHOCELTM E5P LV @ 20°C

METHOCELTM A15P LV @ 20°C

H immediat release

•Nowthat’sthetabletwe’relookingfor: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.

•Whateveryouneed,wecanhelp: 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 capsule-filling 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.

• Followtherulesforsuccess: 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.

We know what you need and can help you deliver.

When you’re developing immediate release tablet and capsule medicines, we know what you’re 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.

FOrMULATing THE MEDiCinES tHat proVide people WitH iMMEDiATE rELiEF

Wet and dry granulation binder 0201 Wet and dry granulation binder ®tMTrademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow

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.

MetHoCel™ Can Help you get tHere

H immediat release

HARDNESS OF COMPRESSED TABLETS CONTAININGACETAMINOPHEN AND GRANULATED WITH 6% DRY BINDER INLOW-SHEAR AND HIGH-SHEAR GRANULATORSHardness, strong-cobb units // Binder // Hardness, kiloponds

30 21.41

14.27

7.13

20

10

MET

HO

CEL

TM

A15

Pre

m L

V

Low ShearHigh Shear

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

PVP

DRUG RELEASE FROM COMPRESSED TABLETSCONTAINING ACETAMINOPHEN AND GRANULATED WITH3% DRY BINDER IN A HIGH-SHEAR GRANULATORDrug released, % // Time, min

20

40

60

80

100

METHOCELTM E5 Prem LV - 3%

HPC-EF - 3%

PVP - 3%

METHOCELTMA15 Prem LV - 3%

H immediat release

0 10 20 30 40 50

USPSpecifications

DRUG RELEASE FROM COMPRESSED TABLETSCONTAINING ACETAMINOPHEN AND GRANULATED WITH6% DRY BINDER IN SOLUTION IN A LOW-SHEAR GRANULATORDrug released, % // Time, min

20

40

60

80

100

H immediat release

0 10 20 30 40 50 60 70

USPSpecifications


HPC-EF - 3%

PVP - 3%


DRUG RELEASE FROM COMPRESSED TABLETSCONTAINING ACETAMINOPHEN AND GRANULATED WITH6% BINDER IN SOLUTION IN A FLUID-BED GRANULATORDrug released, % // Time, min

20

40

60

80

100

H immediat release

0

USPSpecifications

5 10 15 20 25 30 35 40


HPC-EF - 3%

PVP - 3%


H immediat release

HARDNESS OF COMPRESSED TABLETS CONTAININGACETAMINOPHEN AND GRANULATED WITH 6% DRY BINDER INLOW-SHEAR AND HIGH-SHEAR GRANULATORSHardness, strong-cobb units // Binder // Hardness, kiloponds

30 21.41

14.27

7.13

20

10

Low Shear

High Shear

Fluid Bed

MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

PVP

acetaminophen: high-dose, loW-solubility 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.

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.


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 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 high-shear 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.

HARDNESS OF COMPRESSED TABLETS CONTAININGASCORBIC ACID AND GRANULATED WITH 6% DRY BINDER INLOW-SHEAR AND HIGH-SHEAR GRANULATORSHardness, strong-cobb units // Binder // Hardness, kiloponds

15 10.70

7.13

3.56

10

5

Low ShearHigh Shear

H immediat release

MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

PVP

HARDNESS OF COMPRESSED TABLETSCONTAINING ASCORBIC ACID AND GRANULATED WITH6% BINDER IN SOLUTION IN FLUID-BED, LOW-SHEAR,AND HIGH-SHEAR GRANULATORSHardness, strong-cobb units // Binder // Hardness, kiloponds

30 21.41

14.27

7.13

20

10

H immediat release

Low Shear

High Shear

Fluid Bed

MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

PVP

DRUG RELEASE FROM COMPRESSED TABLETSCONTAINING ACETAMINOPHEN AND GRANULATED WITH6% BINDER IN SOLUTION IN A FLUID-BED GRANULATORDrug released, % // Time, min

20

40

60

80

100

METHOCELTM K3 Prem LV - 6%

HPC-EF - 6%

PVP - 6%


H immediat release

0 10 20 30 40 50 60

DRUG RELEASE FROM COMPRESSED TABLETSCONTAINING ASCORBIC ACID AND GRANULATED WITH3% BINDER IN SOLUTION IN A HIGH-SHEAR GRANULATORDrug released, % // Time, min

20

40

60

80

100

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


H immediat release

0 5 10 15 20 25 30

FRIABILITY OF COMPRESSED TABLETSCONTAINING ASCORBIC ACID AND GRANULATED WITH 6%DRY BINDER IN LOW-SHEAR AND HIGH-SHEAR GRANULATORSFriability, % weight loss // Binder

0.6

0.4

0.2

Low Shear

High Shear

0.8

H immediat release

MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

PVP

METHOCEL™ MEETS yOUr FOrMULATiOn nEEDS

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 drug-release 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.


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.

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 friability—less 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.

MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

PVP

FRIABILITY OF COMPRESSED TABLETSCONTAINING METHAZOLAMIDE AND GRANULATED WITH3% OR 6% BINDER IN SOLUTION IN A FLUID-BED GRANULATORTablet friability, % weight loss // Binder

3%

6%

0.1

0.3

0.5

H - Immediate release

0 10 20 30 40 50 60 70 80

DRUG RELEASE FROM COMPRESSEDTABLETS CONTAINING METHAZOLAMIDE AND GRANULATEDWITH 6% DRY BINDER IN A HIGH-SHEAR GRANULATORDrug released, % // Time, min


40

60

100

80

20

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


PVP - 6%

USPSpecifications

DRUG RELEASE FROM COMPRESSED TABLETSCONTAINING METHAZOLAMIDE AND GRANULATED WITH 3% DRY BINDER IN A HIGH-SHEAR GRANULATORDrug released, % // Time, min

20

40

60

80

100

HPC-EF - 3%

PVP - 3%METHOCELTM A15 Prem LV - 3%

H immediat release

0

USPSpecifications

10 20 30 40 50 60 70





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 6–8 minutes for the lower molecular weight products (E5 Premium LV and K3 Premium LV) to 5–12 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 16–18 minutes for E5 Premium LV and K3 Premium LV to 19–40 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.


METHOCELTM A15 Prem LV

HPC-EFPVP K90

METHOCELTM E5 Prem LV

METHOCELTM K3 Prem LV

PVP 29-32METHOCELTM E15 Prem LV

0 5 10 15 20 25 30 35 40 45 50 55 60

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

10

15

25

20

5


MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

E15

Prem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

-EF

PVP

29-3

2

PVP

K90

HARDNESS OF COMPRESSED TABLETS CONTAINING NIACINAMIDEAND PREPARED USING ROLLER COMPACTION AT 1 TON PRESSUREHardness, strong-cobb units // Binder // Hardness, kiloponds

7.13

14.27

12,5% Binder

25% Binder

6,25% Binder

10

15

25

20

5


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

10 7.13

14.27

15

20

5

12,5% Binder

25% Binder

6,25% Binder


MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

E15

Prem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

-EF

PVP

29-3

2

PVP

K90


FRIABILITY OF COMPRESSED TABLETS CONTAINING NIACINAMIDEAND PREPARED USING ROLLER COMPACTION AT 3 TONS PRESSUREFriability, % weight loss // Binder

3

4

5

6

2

1

12,5% Binder

25% Binder

6,25% Binder

CA

PPIN

G

MET

HO

CEL

TM

A15

Pre

m L

V

MET

HO

CEL

TM

E5 P

rem

LV

MET

HO

CEL

TM

E15

Prem

LV

MET

HO

CEL

TM

K3

Prem

LV

HPC

-EF

PVP

29-3

2

PVP

K90

METHOCELTM

A15 PremLV

METHOCELTM

E5 PremLV

METHOCELTM

E15 PremLV

METHOCELTM

K3 PremLV

HPC-EF PVP 29-32 PVP K90

290

142

118

TIME TO 90% DRUG RELEASE FROM COMPRESSEDTABLETS CONTAINING NIACINAMIDE AND PREPARED USING ROLLERCOMPACTION AT 3 TONS PRESSURETime to 90% drug release, minutes // Binder

30

40

50

60

70

20

10

12,5% Binder

25% Binder

6,25% Binder



Wet and dry granulation binder

north America: +1 800 258 2436Europe: +31 11 567 2626 Pacific: +60 3 7965 5392Latin America: +55 11 5188 [email protected]

®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 Customer’s use and for ensuring that Customer’s 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.

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