IPQC TESTS FOR TABLETS

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What Do You Mean By “IPQC”…?

IPQC is concerned with providing accurate , specific, & definite descriptions of the

procedures to be employed, from, the receipt of raw materials to the release of the finished

dosage forms.

“INSPECTION”

“TESTING”

In process Quality Control  

In process Quality Control, IPQC tests are mostly performed within the production

area.

They should not carry any risk for the quality of product.

In process testing enables easier identification of problems. It some time identifies

a defective product batch that can be corrected by rework, whereas once that batch

has been completed, this may not be possible.

Failure to meet In process control specification indicates either that procedure were

not followed or some factor(S) out of control.

Various instrument used in IPQC department:  Disintegration apparatus

Dissolution apparatus

Analytical balance Muffle furnace

Friability testing apparatus

Bulk density apparatus

Tablet hardness tester

Infra red moisture content measuring apparatus

U.V Spectroscopy

Abbe Refractometer

T.L.C. kit

Karl fisher Titrimeter

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Official and unofficial tests for evaluation of tablets Official Tests: 1. Weight variation2. Disintegration 3. Dissolution 4. Drug content Non-Official Tests: 1. Hardness2. friability

Evaluation of Tablet

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1. General Appearance: The general appearance of a tablet, its identity and general elegance is essential for consumer acceptance, for control of lot-

to-lot uniformity and tablet-to-tablet uniformity. The control of general appearance involves the measurement of size,

shape, color, presence or absence of odor, taste etc.

2. Size & Shape:

It can be dimensionally described & controlled. The thickness of a tablet is only variables. Tablet thickness can be

measured by micrometer or by other device. Tablet thickness should be controlled within a ± 5 % variation of standard

value.

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3. Unique identification marking:

These marking utilize some form of embossing, engraving or printing. These markings include company name or symbol,

product code, product name etc.

4. Organoleptic properties:

Color distribution must be uniform with no mottling. For visual color comparison compare the color of sample against standard

color.

5. Hardness :

Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in

manufacture, packaging and shipping. Hardness generally measures the tablet crushing strength.

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Hardness (crushing strength):

It is the load required to crush the tablet when placed on its edge.

Why do we measure hardness?

To determine the need for pressure adjustments on the tableting machine. Hardness can affect the disintegration. So if the tablet is too hard, it may not disintegrate in the required period of time. And if the tablet is too soft, it will not withstand the handling during subsequent processing such as coating or packaging. In general, if the tablet hardness is too high, we first check its disintegration before rejecting the batch. If the disintegration is within limit, we accept the batch. If Hardness is high + disintegration is within a time accept the batch.

Factors Affecting the Hardness:

• Compression of the tablet and compressive force. • Amount of binder. (More binder à more hardness) • Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness).Limits: 5 kilograms minimum and 8 kilograms maximum. Make hardness test on 5 tablets and then take the average hardness.

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DIFFERENT HARDNESS TESTER

Erweka

Pfizer

Schleuniger

Monsanto

Strong-cobb

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6.Friability: Friability of a tablet can determine in laboratory by Roche friabilator. This consist of a plastic chamber that revolves at 25 rpm,

dropping the tablets through a Distance of six inches in the friabilator, which is then operate for 100 revolutions. The tablets are

reweighed. Compress tablet that lose less than 0.5 to 1.0 % of the Tablet weigh are consider acceptable.

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It is the tendency of tablets to powder, chip, or fragment and this can affect the elegance appearance, consumer acceptance of the tablet,

and also add to tablet’s weight variation or content uniformity problems.

Friability is a property that is related to the hardness of the tablet.

An instrument called Roche friabilator is used to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and

shipping.

Procedure:

1. Weigh 20 tablets together = W1

2. Put these tablets in the friabilator and adjust the instrument at 100 rpm (i.e. = 25 rpm for 4 min)

3. Weigh the 20 tablets (only the intact ones) = W2

Friability (% loss) = W1 - W2/100

It must be less than or equal to1 % but if more we do not reject the tablets as this test is non-official.

Perform this test using 20 tablets that were used first in the weight variation test.

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7. Thickness test

Thickness is an unofficial test .

Thickness of the tablet is inversely proportional to hardness i.e. increase in hardness decrease the thickness & vice

versa.

Thickness of tablet is measured by Vernier caliper/screw gauge.

It is determined for 10tablets.

Vernier caliper

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8.Weight variation test (uniformity of weight)

Weigh 20 tablet selected at random, each one individually . X1, X2, X3… Xz

Determine the average weight. X= (X1+X2 +X3+…+ Xz)/20

Limit:

Upper limit = average weight + (average weight * % error)

Lower limit = average weight - (average weight * % error)

The individual weights are compared with the upper and lower limits.

Not more than two of the tablets differ from the average weight by more than the % error listed, and no tablet

differs by more than double that percentage.

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Sr. No

Average wt. of tablet(mg) Max. % difference allowed

1 130 or Less 10%2 130-324 7.5%3 More than 324 5%

WEIGHT VARIATION TOLERANCES FOR UNCOATED TABLETS

USP XX-NF STANDARDS

IP STANDARDS

Sr. No

Average wt. of tablet(mg) Max. % difference allowed

1 84 or Less 10%2 84- 250 7.5%3 More than 250 5%

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9. Content Uniformity Test:

It is an official test.

Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must

contain not less than 85% and not more than 115% of the labeled drug content and the 10 th tablet may not contain

less than 75% and more than125 % of the labeled content. If these conditions are not met, remaining 20 tablet

assayed individually and none may fall out side of the 85 to 115 % range.

10. Disintegration test (U.S.P.) :

Disintegration test is an official test.

It is the time required for the tablet to break into particles, the disintegration test is a measure only of the time

required under a given set of conditions for a group of tablets to disintegrate into particles

It is performed to identify the disintegration of tablet in particular time period.

Disintegration test is not performed for controlled & sustained release tablets.

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The U.S.P. device to test disintegration uses 6 glass tubes that are 3” long; open at the top and 10 mesh screen at the bottom end. To

test for disintegration time, one tablet is placed in each tube and the basket rack is positioned in a 1-L beaker of water, simulated

gastric fluid or simulated intestinal fluid at 37 ± 20 C such that the tablet remain 2.5 cm below the surface of liquid on their upward

movement and not closer than 2.5 cm from the bottom of the beaker in their downward movement. Move the basket containing the

tablets up and down through a distance of 5-6 cm at a frequency of 28 to 32 cycles per minute. Floating of the tablets can be

prevented by placing perforated plastic discs on each tablet.

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According to the test the tablet must disintegrate and all particles must pass through the 10 mesh screen in the time

specified. If any residue remains, it must have a soft mass.

Liquids used in disintegration

Water,

Simulated gastric fluid (pH = 1.2 HCl),

or Simulated intestinal fluid (pH = 7.5, KH2PO4 (phosphate buffer) + pancreatic enzyme + NaOH)

Disintegration test apparatus

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Sr no. Type of tablets Medium Temperature limit

1 Compressed uncoated 37 ± 2 0C 15 minutes or as per individual monograph

2 Sugar coatedIf 1 or 2 tablets fail

Water0.1 N HCL

37 ± 2 0C 60 minutes or as per individual monograph

3 Film coated water 37 ± 2 0C 30 minutes or as per individual monograph

4 Enteric coated 0.1 N HCL &Phosphate buffer pH 6.8

37 ± 2 0C 1 hr or as per individual monograph

5 Dispersible/ Effervescent

water 37 ± 2 0C LST < 3 minutes or as per individual monograph

6 Buccal 37 ± 2 0C 4 hr or as per individual monograph

DISINTEGRATION TESTING CONDITIONS AND INTERPRETATION

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U.S.P. method for uncoated tablets:

Start the disintegration test on 6 tablets.

If one or two tablets from the 6 tablets fail disintegrate completely within 30min repeat the same test on another 12 tablet. (i.e. the whole

test will consume 18 tablets).

Not less then 16 tablets disintegrate completely within the time

if more then two tablets (from the 18) fail to disintegrate, the batch must be rejected.

For Coated tablets:

1. To remove or dissolve the coat, immerse the tablet in distilled water for 5min.

Put the tablet in the apparatus in water or HCL for 30 min at 37oC (according to the U.S.P). If not disintegrated, put in intestinal fluid.

If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the 18 must completely disintegrate within the time, if

two or more not disintegrated the batch is rejected.

U.S.P. and B.P Method for Enteric coated tablets:

1. Put in distilled water for five minutes to dissolve the coat.

2. Then put in simulated gastric fluid (0.1M HCL) for one hour.

3. Then put in simulated intestinal fluid for two hours.

If one or two tablets fail to disintegrate, repeat this test on another 12 tablets. So 16 tablets from 18 should completely disintegrate. If more

than two fail to disintegrate the Batch must be rejected.

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11. Dissolution Test

Dissolution is an official test.

Dissolution is performed to check the percentage release from the dosage forms.i.e.tablet.

Tablet breaks down into small particles which offers a greater surface area to the dissolving media.

Disintegration test does not give assurance that particles will release drug in solution at an appropriate rate, that’s

why dissolution tests & it’s specifications developed for all tablet products.

1. USP Dissolution apparatus I ( Basket method)

A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a variable

speed motor. The basket is immersed in a dissolution medium (as specified in monograph) contained in a 1000 ml

flask. The flask is cylindrical with a hemispherical bottom. The flask is maintained at 37 ± 0.50C by a constant

temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at

intervals to determine the amount of drug in solutions.

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2. USP Dissolution apparatus II ( Paddle method)

It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is allowed to sink to the bottom of

the flask before stirring. For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to

be used, rpm of the shaft, time limit of the test and assay procedure for. The test tolerance is expressed as a % of the

labeled amount of drug dissolved in the time limit.

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Sr.no. Quantity Stage/level

Number of tablets tested

Acceptance criteria

1 S1 6 Each unit is < D* + 5 percent**

2 S2 6 Average of 12 units (S1 +S2) is equal to or greater than (> )D, and no unit is less than D - 15 percent**

3 S3 12 Average of 24 units (S1+S2+S3) is equal to or greater than (> )D, not more than 2 units are less than d-15 percent** and no unit is less than d-25 percent**

DISSOLUTION TESTING AND INTERPRETATION IP STANDARDS

*D is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the labelled content. ** Percentages of the labelled content.

CONTENTS

Evaluation of Precompressional Characteristics of tabletsor

Rheological Characteristics of granules

1. Particle Size & Shape Determination.

2. Surface area.

3. Density

i. Bulk density

ii. True density

iii. Granular density

4. Granule strength & friability.

5. Flow properties.

i. Angle of repose

ii. Percentage Compressibility Index

iii. Hausner’s ratio

6. Moisture content.

7. Percentage fines(% fines).

EVALUATION OF COMPRESSIONAL CHARACTERISTICS OF TABLETS

1. General Appearance

2. Size & Shape

3. Unique identification marking

4. Organoleptic properties

5. Hardness test

6. Friability.

7. Thickness test

8. Weight variation.

9. Disintegration test.

10. Drug Content Uniformity

11. Dissolution test.

CHARACTERIZATION OF GRANULES

1) Particle Size & Shape Determination

Size affects the average weight of tablet, Disintegration Time, weight variation, friability, flowability & drying rate.

The size & shape depends upon processing requirements & during granulation.

The methods for determining size & shape are

1. Sieving

2. Sedimentation rate.

3. Microscopy (SEM)

4. By Light Scattering

2. SURFACE AREA

It is not commonly used for granules but generally used for drug substances.

If required particle size is measured & from this surface area is measured.

Most method used is gas absorption & air permeability.

In gas absorption, gas is absorbed as monolayer on particles this is in term of calculated & converted to surface area.

In air permeability method the rate of air permeates a bed of powder ,is used to calculate surface area of powder sample.

3. Density

Density may influence compressibility, tablet porosity & dissolution.

Dense hard granules may require higher load to produce cohesive compact to reduce free granules seen on the surface of tablets.

↑ compressibility ↑ DT, Dissolution, if DT is slower dissolution is indirectly hampered.

Dense granules have less friability but cause a problem in releasing the drug.

Three Methods to determine density

i. Bulk Density –

Bulk density is given by equation,

ρb = M / Vb

Where, ρb- bulk density of granules,

M is mass of granules in gm,

Vb – volume of granules in measuring cylinder in ml.

More compressible bed of particulate - less flowable powder or granules.

If less dense/compressible - more flowable powder or granules.

ii. True/tapped density –

Tapped/true density is given by equation,

ρt = M / Vb

Where, ρt- bulk density of granules,

M is mass of granules in gm,

Vt – volume of granules in measuring cylinder after tapping in ml.

iii. Granular density

It is determined by Pycnometer method.

Two methods are used to determined granular density.

In one intrusion fluid used-Mercury, and other

Any solvent of low surface tension e.g. Benzene

The accuracy of these method depends upon ability of intrusion fluid to penetrate the pores of granules.

Liquids should not masks granules solubilies in it, & having property to penetrate the pores.

Density is then determine from volume of intrusion fluid displaced in pycnometer by giving mass of granulation.

It is calculated by using equation,

Granular Density (D) = M / Vp -Vi

Where, Vp-Total volume of Pycnometer, Vi- Volume of intrusion fluid (ml) containing Mass (gm) (M) of granules required to fill pycnometer.

4. Granule Strength & Friability They are important because they affect:-

1.changes in particle size distributions of granulations.

2.compressibility into cohesive tablets.

Granule strength & friability are measured by:-

1.Compressive Strength/hardness.

2.Using Friability measurements/apparatus.

5. Flow properties.

It is an ability of the granule to flow from hopper to die cavity for tablet uniformity.

Flow property of granule are not uniform we are not getting tablet of uniform

size.

Flow property of material results from many forces

1.Frictional force

2.Surface tension force

3.Mechanical force caused by interlocking of irregular shape particles

4.Electrostatic forces

5.Cohesive/ vander Waals forces

Forces also affect granule property such as particle size, particle size distribution, particle shape, surface texture, roughness &

surface area.

If particle size of powder is ≤ 150 µm the magnitude of frictional & vander waals force predominate.

When particle size↑ mechanical & physical properties become more important with packing properties.

Flow properties of granules are determined by measuring three parameters-

i. Angle of repose – It is measured by two methods

a. Static angle of repose

b. Dynamic angle of repose.

Equation is , tan θ = h/r.

Where, θ - angle of repose, h – height of pile, r – radius of pile.

Fig(1)Fixed height

Fig(2)fixed base cone

Fig (3)Tilting angle

Fig (4)Rotating cylinder

Methods of determination of angle of repose

In fig.(1) height is constant & powder is added through the hopper until powder reaches tip of funnel.

In fig.(2) height is varied & base cone is fixed, powder is added until height reaches at max.

In fig.(3) rectangle box is filled with powder & tipped until content begins to slide.

In fig.(4) revolving cylinder with transparent end is made to revolve horizontally when half filled with powder.

The max. angle that the plane of powder makes with horizontal surface on rotation is taken as the angle of repose..

(1),(2) & (3) gives static angle of repose. While (4) gives kinetic or dynamic angle of repose.

Sr no. Angle of repose (o) Type of flow1 < 25 Excellent2 25-30 Good3 30-40 passable4 > 40 Poor

ii. Percentage compressibility Index It is directly related to the relative flow rate cohesiveness & particle size.

It is simple fast & popular method of presiding powder flow characters.

It can be obtained from bulk density measurements is the % Compressibility index (C).

% Compressibility index = Tapped density - Bulk density / Tapped density X 100.

OR

I = (1 – V/ Vo ) x 100

Where, I – % Compressibility index,

V – volume occupied by powder/ granules after tapping, Vo - volume of powder/granules before tapping.

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SR.NO. % Compressibility index Type of flow1 5-15 Excellent2 12-16 Very good3 18-21 Good4 23-25 Passable5 33-38 Poor6 > 40 Very poor

iii. Hausner's Ratio

• Hausner’s ratio was related to interparticulate friction and as such could be used to predict powder flow characteristics.

• It showed that powder with low particular friction such as coarse sphere had ratio of approximately 1.2, where as more as cohesiveness- less free flowing powders such as flaks have Hausner’s ratio greater than 1.6.

FORMULA:

Hausner’s ratio = Tapped density / Bulk density

6. Moisture content

The amount of moisture present in the granule is called moisture content.

Generally the granules contain 2% moisture. It is required for the binding of the powder or granules during compression in die cavity.

Percentage of moisture is calculated by using “moisture Balance” or “IR Balance”.

IR Balance consist of simple balance which is placed I to the casing in which the IR bulb is attached which produce heat inside the chamber.

The small amount of sample taken from oven to measure moisture content & place in the moisture balance..

Initial reading should be note down after that we are initiated the IR Bulb as IR bulb is initiated the moisture is removed from the granules via heating after that note down the reading.

% of moisture is calculated by,

% moisture content = Initial wt.- Final wt./ initial weight X 100

Moisture analyzerIR moisture balanceSarotorious MA-100

7. Percentage Fines (% Fines)

% fines means the amount of powder remain in the granule.

Generally the amount is 15% of fines.

It is necessary for the tablet compression because if we are using 100% granules then it is difficult to maintain hardness of tablet because they having free space in the die cavity after compression the tablet is crack due to air.

% fine can be calculated by using Sieve method.

% fine should not be more than 15%.

IPQC/Official Standards as per B.P. /I.P./ U.S.P. for tablets

COMPARISON OF DIFFERENT PHARMACOPOEIAL QUALITY CONTROL TESTS

BRITISH PHARMACOPOEIA

FOR ALL TABLETS:

Content of active ingredients

Disintegration

Uniformity of content

Labeling.

Uncoated tablet:-Disintegration test-Uniformity of weight

Effervescent tablet:

-Disintegration test

-Uniformity of weight

Coated tablet:-Disintegration test-Uniformity of weight

Gastro resistant tablet:

-Disintegration test

Modified release tablet:

-Uniformity of weight.

Dispersible tablet:

-Disintegration test

-Uniformity of dispersion

-Uniformity of weight

INDIAN PHARMACOPOEIA

Uncoated tablet:

-Uniformity of container content

-Content of active ingredient

-Uniformity of weight

-Uniformity of content

-Disintegration test

Enteric coated tablet:

-Disintegration test

Dispersible tablet:

-Uniformity of dispersion

-Disintegration

Soluble tablet:

-Disintegration test

Effervescent tablet:

-Disintegration/ Dissolution / Dispersion test.

UNITED STATES PHARMACOPOEIAPhysical tests applicable to tablet formulation:

-Bulk density / Tapped density of powder

-Powder fineness

-Loss on drying

-Disintegration test

-Tablet friability

-Dissolution test

-Drug release testing

-Uniformity of dosage form

-Container permeation test

-Labeling of inactive ingredients

References

1. Leon Lachman, The theory and practice of Industrial pharmacy,3rd edition, Varghese publishing house, page no.67-68,77-78,315-317,296-303.

2. Indian Pharmacopoeia-2010,Govt.Of India ministry of health & family welfare,6th edition, page no.187-198.

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Process control by means of in-process controls

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Example of an IPQC structure

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RESPONSIBILITIES

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EXAMPLES OF IN-PROCESS CONTROLS

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EXAMPLE OF APPROVAL FOR TABLET PRODUCTION

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CONTENTS OF A SAMPLING PROCEDURE

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DOCUMENTATION IN-PROCESS CONTROLS

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IN-PROCESS CONTROL AS MEANS OF CONTROLLING PRODUCTION

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“All the in-process controls, including those made in the production area by

production personnel, should be performed according to methods approved by

Quality Control and the results recorded.“ (6.18 EU-GMP-Guide, see chapter C.4).

AQL lists (AQL = Acceptance Quality Limit)

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The parameters and experiences

accumulated during the process validation determine the scope of the

tests as well as the limits.

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“In-process controls may be carried out within the production area provided they

do not carry any risk for the production.” (3.17 EU-GMP-Guide, see chapter C.4).

This means that particular care must be taken when carrying out sampling or testing.

Examples of possible influences of in-process control methods on production

are shown below:

• Particle measurements (influence on air flow pattern)

• Direct contact tests (matrix residues on surface)

• Disintegration tests (influence on room humidity)

• Leak test on blisters (blue bath with microbial contamination risk)

Tests are therefore normally carried out in a segregated area and not directly at

the manufacturing location.

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As a first step, a sampling plan has to be established, which identifies process steps and/or locations for sampling, as well as number and amount of samples. When defining the amount to be sampled, statistical criteria should be considered and justified, e.g.

• Component variability

• Confidence levels

• Degree of precision

• Quantity needed for analysis

• Reserve amount needed The sampling plan should also contain precise instructions on the sampling procedure,

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TESTING

Samples are tested to verify conformance with specifications:

• Identity

• Component conformity to written specifications

• Container/Closure conformity to written specifications

• Examination for contamination As a result, components, containers or closures will be approved or rejected. The tests to be performed and the methods to be used have to be defined. A list of specifications has to be established.

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CONCLUSION

In-process control not only provides a means of controlling production. It also performs a quality assurance function.

The in-process control group personnel may be assigned to production or quality control depending on the relevant company structure. In each case, autonomy in relation to the production process must be ensured.

The in-process control methods that are part of the manufacturing formula are compiled and validated under the supervision of quality control.

Statistical evaluation and periodic review of in-process data contributes to the general assessment of process performance and product quality.

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