tableting manufacturing-2011lecture 3

8/13/2019 Tableting Manufacturing-2011Lecture 3

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Tableting : Tablet manufacturing

Wet granulation method

Dry granulation method (slugging)

Direct compression


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Powder properties to make

tablet The powder must be compressible and

compactible

The particles must flow well (tablet

uniformity)

The particle surfaces must wet well


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Granulation

Two main advantages do granules show,

That of compressibil i ty and good powder

flow!


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Wet granulation

Compressibility is improved by the addition

of a binder

Flowability is attained due to a particle size

increase

Hydrophobic surfaces are made hydrophilic

by use of a hydrophilic binder


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Manufacture of granules

Blend

powders

Moist

massMoist agglomerates

Dried granulesProperly sized

Dry granules

Add binder

solution

Pass through

screen

dry

Pass throughscreen

-large cohesion force

-low viscosity

-Inert

-Should blend easily

-High solubility

-Non-hygroscopic


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Wet granulation: BindersSugars / Natural binders

Sucrose

Liquid glucose

Acacia Tragacanth

Gelatin

Starch paste

Pregelatinized starch

Alginic acid

Cellulose

Synthetic / Sem isyn thetic

polymers

Methyl cellulose (MC)

Ethyl cellulose (EC)

Hydroxypropylmethyl cellulose(HPMC)

Hydroxypropyl cellulose (HPC)

Na-carboxymethyl cellulose

(CMC)

Polyvinyl pyrrolidone (PVP)

Polyethylene glycol (PEG)

Polyvinyl alcohol (PVA)

Polymethacrylates (PMA)


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Granule formation

pendular funicular

capillary droplet

Nucleation Transition Ball growth


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Why granules

Flow better than powder

Less surface area per unit weight than

powders (more stable, less likely to cake inthe container than powders)

Wet granulation provides content

uniformity Wet granulation may improve drug

dissolution


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Disadvantages of Wet Granulation Quality: Effects on disintegration times

Cost:Granulation is an expensive process becauseof labor, time, equipment, energy and spacerequirements

Loss of material during various stages ofprocessing

Stability may be major concern for moisturesensitive or thermo labile drugs

Multiple processing steps add complexity and

make validation and control difficult Incompatibilitiesbetween formulation components

can be aggregated


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High shear mixture granulation

Blending and wet massing is carried out using animpeller and a chopper. Mixing, densification andagglomeration are achieved through shear andcompaction force exerted by the impeller.

Advantages:

Short processing time

Less liquid binder is required

compared with fluid bed

granulation

Highly cohesive material can

be granulated


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Fluid bed granulationFluid bed granulation is a process by which

granules are produced in a single step by sprayinga binder solution onto a fluidized powder bed.

Advantages:

Single step process

Fine, homogenous particles

Free flowing powders

Disadvantages:

Producing too much dust

Segregation and loss of fine particles

Generation of static electricity charges


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Spray drying granulation

A granulation technique that converts liquids into

dry powders in a single step. This method removes

moisture instantly.

Advantages:

Rapid process

Ability to be operated

continuously

Suitable for heat sensitive

products


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Drying

Important process - last stage before packaging

moisture low enough - prevent degradation, allow

free flow pharmaceutical powders contain some moisture -

vary with air they are exposed to

drying -removal of all or most of the liquid by

supplying latent heat to cause thermal vaporization


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To dry a material following points

should be considered Heat sensitivity of the material being dried

Physical characteristics of the material

The necessity for asepsis

Nature of the liquid to be removed

The scale of the operation Available sources of heat


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Drying problems (solute migration)Air flow

drug

On compression


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Consequences of solute migration

Loss of active ingredient Mottling of coloured tablets

Intragranular migration of colour

To reduce mottling, use insoluble colour

(aluminum lake) use small granules for tableting

Migration of soluble binders

To make harder granules

Binder-binder interaction rather than drug-drug ordrug-excipient contact

this can be beneficial


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Dry granulation

Advantages I deal for moisture sensitive

material

I deal for heat sensitive mater ial

I deal for improved disintegration(no binder)

Disadvantages

Requires a specialized heavy dutytablet press to form slug

Poor color distr ibution uni formity

Tends to create more dust,increasing the potential of

contamination

Blend powders

Slug

Granules

Sized granules

Mill

Sieve

Compression


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Operations in tablet manufacturing

Wet granulation Dry granulation Direct compression

1. Weighing 1. Weighing 1. Weighing

2. Sizing 2. Sizing 2. Sizing

3. Blending 3. Blending 3. Blending

4. Wet massing 4. Slug compression -

5. Wet screening 5. Milling -

6. Drying - -

7. Dry screening 6. Dry screening -

8. Blending w/ lubricant

& disintegrant

7. Blending w/ lubricant

& disintegrant

-

9. Tablet compression 8. Tablet compression 4. Tablet compression


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Choice of Method Depends on

Several Factors Size of Dose

Compactibility and/or Fluidity of Drug

Stability Characteristics of the Drug


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A Consideration of the Dose of Drug

is the Starting Point

LOW DOSE (250 mg)

(Most of the tablet will be drug)

Compactibility

Fluidity


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Lower Dose Drugs Generally can

Be Directly Compressed

Can compensate for any lack of compactibility

and/or lack of flowability by the use of specialdirect compression fillers (filler-binders).

Can provide lubricity by addition of die walllubricant.

Can help fluidity by adding a glidant Can assure rapid disintegration by adding

disintegrant.

Blend Compress


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Advantages of direct compression

Efficient and economical

Elimination of heat and moisture = increased stability

Particle size uniformity

Increased particle dissolution rate (each primary

particle is released upon tablet disintegration asopposed to granules)

Batch-to-batch variation is negligible (fewer processsteps)

Fewer excipients = less chance of chemicalinteraction between API and excipient

No aging effects


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Direct compression limitations

Uniform blending and prevention of unblending oflow-dose drugs

Fillers often are more expensive than filler used ingranulation

Limitation in producing coloured tablets

Dust problems

Limitations in the dilution capacity of excipients More sensitive to lubricant softening and

overmixing than granulations


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Requirements for a directly

compressible filler Good flowability

Good blending properties

Low lubricant sensitivity

High compactibility

Inertness

Constant quality

Relatively cost effective


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Examples of Direct Compression

Filler-Binders Microcrystalline Cellulose (MCC)

Most compactible material available for

pharmaceutical use.When made from mostly MCC, tablets self

disintegrate and require little lubricant.

Spray processed lactose (Fast Flo Lactose)Minigranulation of lactose crystals glued

together by small amount amorphous lactose.


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POTENTIAL PROBLEMSIN TABLETING


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Manufacturing problems

Capping and Laminating or Splitting

Sticking, Picking and Filming

Chipping and Cracking Binding


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Potential problems in tableting

Tablet presses have become more complex, however,the compaction of material between punches remainsessentially the same

The main differences in speed of compaction,

mechanical feeding of the materials from the hopper intothe die and electronic monitoring of the press

Large presses can produce as many as 10000tablets/min

All these advancements and innovations have notdecreased the problems often encountered inproduction, and in fact have increased the problemsbecause of the complexities of the presses and the

greater demands on quality


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Capping

Capping occurs when the upper segment of the

tablet separates from the main portion of the tabletand comes off as a cap.

Top tablet falls off

Elasticity in combination with poor bonding


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Capping: reasons

Due to air entrapped in the granulation and thenexpands when the pressure is released

Due to a large amount fine particles in thegranulation

Due to a lack of sufficient clearance between thepunch and the die wall

It is often due to new punches and dies that aretight fitting

Due to too much or too little lubricant

Due to an excessive moisture

Causes and remedies of capping related to formulation


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Causes and remedies of capping related to formulation

CAUSES REMEDIES

1. Large amount of fines in the

granulation

Remove some or all fines

2. Too dry (leading to loss of

proper binding action).

Moisten the granules or add a

hygroscopic substance e.g.:

sorbitol, methyl cellulose or PEG-

4000

3. Granules not dry enough Dry the granules properly

4. Insufficient amount of binder or

improper binder.

Increase the amount of binder or

add a dry binder such as acacia,

sorbitol, PVP

5. Insufficient or improper

lubricant

Increase the amount of lubricant or

change the type of lubricant

6. Granular mass too cold to

compress firmly

Compress at room temperature

Causes and remedies of capping related to


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Causes and remedies of capping related to

the machinery

CAUSES REMEDIES

1. Poorly finished dies Polish dies properly, investigate

other steels or materials

2. Deep concave punches or

beveled-edge faces of

punches

Use flat punches

3. Lower punch remains below the

face of die during ejection

Make proper setting of lower

punch during ejection

4. Incorrect adjustment of sweep-off blade

Adjust sweep-off blade correctlyto facilitate proper ejection

5. High compression speed Reduce speed of compression

(increase dwell time)


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Lamination

Lamination is the separation of the

tablet into two or more distinct layers.

Elasticity in combination with poor bonding


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Causes and remedies of lamination

related to formulation

CAUSES REMEDIES

1. Oily or waxy materials

in granules

Modify mixing process. Add

adsorbent or absorbent.

2. Too much of

hydrophobiclubricant e.g.:

Magnesium-stearate.

Use a lower amount of

lubricant or change thetype of lubricant.


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Causes and remedies of lamination

related to the machineryCAUSES REMEDIES

1. Rapid relaxation of the

peripheral regions of a

tablet, on ejection from a

die.

Use tapered dies, i.e. upper part

of the die bore has an

outward taper of 3 to 5.

2. Rapid decompression Use pre-compression step.

Reduce turret speed and

reduce the f inal

compression pressure.

Sticking picking and filming


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Sticking, picking and filming Sticking is usually due to improperly dried or lubricated

granulations causing the tablet surface to stick to the punchfaces

Picking is a form of sticking in which a small portions ofgranulations sticks to the punch face and grows with eachrevolution of the press, picking out a cavity on the tabletface

Filming is a slow form of picking and is largely due toexcess moisture in the granulation, high humidity, hightemperature or loss of highly polished punch faces due towear


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Causes and remedies of

sticking/filming related to formulationCAUSES REMEDIES

1. Granules not dried

properly

Dry the granules properly. Make

moisture analysis to determine

limits.

2. Too little or improperlubrication

Increase or change lubricant.

3. Too much binder Reduce the amount of binder or use a

different type of binder.

4. Hygroscopic granular

material

Modify granulation and compress

under controlled humidity.

5. Oily or waxy materials Modify mixing process. Add an

absorbent.

6. Too soft or weak granules Optimize the amount of binder and

granulation technique.


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Causes and remedies of sticking/filming

related to the machinery

CAUSES REMEDIES

1. Concavity too deep forgranulation.

Reduce concavity tooptimum.

2. Too little pressure. Increase pressure.

3. Compressing too fast. Reduce speed.


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Causes and remedies of picking related to

formulation

CAUSES REMEDIES

1. Excessive moisture in granules. Dry the granules properly

2. Too little or improper lubrication. Increase lubrication; use colloidal

silica as an antiadherant

3. Low melting point substances may

soften from the heat of

compression

Add high melting-point materials. Use

high meting point lubricants.

4. Low melting point API in a high

concentration.

Refrigerate granules and the entire

tablet press

5. Granules too warm during

compression

Compress at room temperature. Cool

sufficiently before compression.

6. Too much binder Reduce the amount of binder, change

the type or use dry binders.


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Causes and remedies of picking related to the

machinery

CAUSES REMEDIES

1. Rough or scratched punch faces Polish faces to high luster.

2. Embossing or engraving letters

on punch faces such as B, A,

O, R, P, Q, G

Design lettering as large as

possible. Plate the punch faces

with chromium to produce a

smooth and non-adherent face.

3. Bevels or dividing lines too deep Reduce depths and sharpness.

4. Pressure applied is not enough;

tablets too soft

Increase pressure to optimum.


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Chipping and cracking Chipping = The breaking of tablet edges as the tablet

leaves the press or during subsequent handling and coating

operations

Cracking = Small, fine cracks observed on the upper and

lower central surface of tablets, or very rarely on the side

walls

C d di f


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Causes and remedies of

chipping/cracking related to formulation

CAUSES REMEDIES

1. Sticking to

punch faces

Dry the granules

properly or

increase

lubrication.

2. Granules too

dry

Moisten the granules.

Add hygroscopic

substances.

3. Too much

binder

Optimize binding, or

use dry binders.

CAUSES REMEDIES

1. Large size of

granules

Reduce granule

size. Add fines.

2. Granules toodry

Moisten thegranules and add

binder.

3. Tablet

expansion

Improve

granulation. Adddry binders.

4. Granules too

cold

Compress at room

temp.

Causes and remedies of chipping/


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Causes and remedies of chipping/

cracking related to the machinery

CAUSES REMEDIES

1. Groove of die

worn

Polish to open end,

reverse or

replace the die.

2. Barreled die

(center of the

die wider

than ends)

Polish the die to

make it

cylindrical

3. Edge of punch

face turned

inward

Polish the punch

edges

4. Concavity too

deep to

compress

properly.

Reduce concavity

of punch faces.

Use flat punches.

CAUSES REMEDIES

1. Tablet expands

on ejection due

to air

entrapment.

Use tapered die.

2. Deep concavities

cause cracking

during tablet

removal

Use special

removal

equipment

C d di f bi di


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Causes and remedies of binding

related to formulation

CAUSES REMEDIES

1. Granules too moist, extrudes

around lower punch

Dry the granules properly

2. Insufficient or improper

lubricant

Increase the amount of lubricant or use a

more effective lubricant.

3. Granules too coarse Reduce granule size, add more fines, and

increase the quantity of lubricant.

4. Granules too hard for the

lubricant to be effective

Modify granulation. Reduce granule size.

5. Granules are very abrasiveand are cutting into dies

Reduce granule size. Use wear-resistantdies.

6. Granules too warm, they stick

to the die

Reduce temperature.

C i f i i


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Causes and remedies of binding

related to the machinery

CAUSES REMEDIES

1. Poorly finished dies Polish the dies properly.

2. Rough dies due to abrasion,

corrosion

Investigate other steels or other

materials or modify granulation.

3. Undersized dies. Too little

clearance

Rework to proper size.

Increase clearance.

4. Too much pressure in the tablet

press

Reduce pressure OR

modify granulation.


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Mottling

Mottling = an unequal distribution of color

with light or dark spots standing out in anotherwise uniform surface

Causes: Use of colored drug with neutral

excipients, dye migration to the surface during

granule drying process, improper mixing


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Tablet testing (uncoated tablets)

Uniformity of weight

Hardness

Disintegration time

Friability

Dissolution test (similarity factor)

Content uniformity


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Weight control is based on a sample of 20 tablets[B.P 1998].

The USP needs 10 Tablets

Danish and Switzerland require 100 tablets

The USP XXII: has made content uniformity theprincipal attribute. Weight uniformity still

applies, where the product contains > 50mgactive or where the drug constitutes >50% of thecompression weight.


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(Continued) Uncoated tablets comply with the following test:

Weigh 20 tablets selected at random and determineaverage weight.

Not more than 2 of the individual weights deviate

from the average weightby more than thepercentage deviation shown in table I and none

deviates by more than twice that percentage.


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Table I: Permitted weight variation

Average weight of tablet [mg] Acceptable Percentage

of deviation

80

80< tablet weight


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Average tablet weight

Tablet weight (mg) tablet weight (mg) Tablet weight (mg)

310 83 210

310 80 200

315 83 210

288 82 220289 88 185

310 73 176

305 75 191

305 74 200

268 82 219

300 80 189

300 mg 80 mg 200 mg

285-315 mg 72-88 mg 185-215 mg

REJECTED

ACCEPTEDREJECTED

300 x 5%=15 mg x 2 = 30mg


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Uniformity of content

Determine the content of active ingredient of each of 10tablets taken at random using a suitable analyticalmethod.

The requirement is met if the individual values obtainedare all within the range [85-115%] of the average value.

The test fails if more than one individual value is

outside the limits 85 to 115% of the average value or ifany individual value is outside the limits 75 to 125% ofthe average value.

Paracetamol (mg) paracetamol (%)500 100

P l ( ) P l (%)


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500 100

510 102

520 104

505 101

490 98

470 94

480 96

530 106

475 95

520 104

mean 500

Content uniformity

85%-115%

ACCEPTED REJECTED

REJECTED

Content uniformity

Outside 75%-125%

Paracetamol (mg) Paracetamol (%)

500 98.23

545 107.07

520 102.16

505 99.21

490 96.27

420 82.51

480 94.30

590 115.91

530 104.13520 102.16

Mean 509

Paracetamol (mg) Paracetamol (%)

500 100

490 98

480 96

505 101

490 98

480 96

480 96

630 126

470 94

480 96Mean 500.5


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Only 1 individual outside of 85-115% but within 75-125%

More tablets

should be

tested

paracetamol tablets

(mg) paracetamol (%)

500 96545 104

520 100

505 97

490 94

510 98

480 92

620 119

530 102

520 100Mean 522


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Uniformity of content

(Continued) If one individual value is outside the limits 85-115%

but within the limits 75-125% of the average value,

repeat the determination using another 20 tablets taken

at random.

The requirement is met if in the total sample of 30

tablets not more than one individual value is outside thelimits 85-115% and none is outside the limits 75-125%

of the average value.

Paracetamol (mg) paracetamol (%)

1 500 97 81


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1 500 97.81

2 545 106.61

3 520 101.72

4 505 98.79

5 490 95.85

6 510 99.76

7 480 93.

89

8 600 117.37

9 530 103.68

10 520 101.72

11 518 101.33

12 500 97.81

13 520 101.72

14 530 103.68

15 515 100.

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16 480 93.89

17 480 93.89

18 460 89.98

19 485 94.87

20 530 103.68

21 500 97.81

22 525 102.70

23 550 107.59

24 535 104.65

25 485 94.87

26 520 101.72

27 495 96.83

28 510 99.76

29 500 97.81

30 500 97.81

mean 511.27

Outside of 85-115%Within 75-125%

Previous 10 tablets

ACCEPTED


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Disintegration

The process of disintegration is characterised by twosimultaneous processes:

Fluid penetration and

Particle separation

The method uses a 2.8 cm diameter tube which has a10 (1700 m) sieve fitted at the base and which isvertically raised and lowered 30 times a minute, 7.5 cmthrough water at 37C.

Disintegration apparatus


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Disintegration apparatus


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Method

Introduce one tablet or capsule in each tube and, if

prescribed in the appropriate general monograph, add a

disc to each tube.

Suspend the assembly in the beaker containing the

specified liquid.

Operate the apparatus for the specified time.

Remove the assembly from the liquid.

The tablets pass the test if all six have disintegrated.


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Mechanical properties of tablets


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p p

robustness & capping propensity Crushing strength: defined as the compressional force

applied diametrically to a tablet which just fractures it.Tablet diameter and thickness affect the force

necessary to break it.

Tensile strength:

Where is the tensile strength, P the crushingstrength, D the diameter and H tablet thickness.

DH

P

2


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Hardness or Tensile strength

hardness (kg) diameter (mm) Thickness (mm) TS (Mpa)

5 5 3 2

.08068

7 8 4 1.36545

11 10 5 1.37325


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Hardness tester

Schleuniger hardness tester: calibrated in

Strong Cobb units [SCU] as well as

kiloPonds [kP].

1 kP = 9.807N and 1 SCU = 0.714kP.

Tensile strength is expressed in N/m2 or

Pa, MPa.

Resistance to abrasion or


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Resistance to abrasion or

Friability 20 tablets are dedusted, weighed [W0] and

placed in a perspex drum (Roche Friabilator)and tumbled (rotated 100 times [4min]). Afterdedusting they are reweighed [W].

Limits of 1% friability are often set but


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Friabilator

Drop

The % Weight loss due to chipping, abrasion and erosion

is reported as % F riabil i ty.

i l i


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Dissolution tester

Concern :


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Versus

In-vitro versus in-vivo dissolution

Reasons for dissolution test:

1. To evaluate the potential effect of formulation

2. To ensure that preparations comply with product specification

3. To indicate the performance of the preparation under in vivo

condition

USP Dissolution Apparatus


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USP Dissolution Apparatus

Apparatus 1 - Basket (37) Apparatus 2 - Paddle (37)

Apparatus 3 - Reciprocating Cylinder(37)

Apparatus 4 Flow-Through Cell (37)

Apparatus 5

Paddle over Disk (32), TransdermalDelivery System, use paddle and vessel from Apparatus2 with a stainless steel disk assembly to hold thetransdermal on the bottom of vessel.

Apparatus 6, Cylinder(32), Transdermal Delivery

System, use Apparatus 1 except replace the basketshaft with a stainless steel cylinder element.

Apparatus 7, Reciprocating Holder, for transdermaldelivery systems and also a variety of dosage forms


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Dissolution specifications


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Dissolution specifications

Known drug New chemicals

Highly

soluble

Poorly

soluble

Single

point

two

points

NLT 80%

In 30 min15 and 30 min

(carbamazepine)

Highly

soluble

Poorly

soluble

Single

point

two

points

NLT 80%

In 30 min15 and 30 min

Mildconditions

:

Ba

sket50/100r

pm

Pa

ddle50/75rp

m


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Dissolution Profile comparison

Similarity factorDifference factor

Time (min)

Dissolved9%)

5 10 20 30

reference

Test

Difference Factor


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Difference Factor

where n is the number of time points, Rt is the dissolution value of

the reference batch at time t, and Tt is the dissolution value of the

test batch at time t.

Similarity Factor

f2 > 50 similar

f2 < 50 different

f1 0-15 similar

f1 > 15 different

tableting manufacturing-2011lecture 3

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