Tablet Evaluation

[ ]
.

Outline
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z
z
z (USP 20)
z Uniformity of dosage unit (USP 27)
z Uniformity of weight or mass (BP)
z Uniformity of content (BP)
z
z
z

Learning Objectives

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Suggested Readings
|

Ansel, H.C. (1985). Introduction to Pharmaceutical Dosage Forms.

4th ed. Philadelphia: Lea & Febiger.
Ansel, H.C., Allen, L.V. and Popovich, N.G. (1999). Pharmaceutical
Dosage Forms and Drug Delivery Systems. 7thed. New York:
Lippincott Williams & Wilkins.
Banker, G.S. and Chalmer, R.K. (1982). Pharmaceutics and
Pharmacy Practice. Philadelphia: J.B. Lippincott.
Gennaro, A.R. (2000). Remingtons Pharmaceutical Sciences.
20thed. Pennsylvania: Mack Publishing Company.
Hoover, J.E. (1987). Dispensing of Medication. 8thed.
Pennsylvania: Mack Publishing Company.
Rhodes, M.J. (1990). Principles of Powder Technology. New York:
John Wiley & Sons.

Introduction
|

Introduction
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(evaluation)

(specification) (quality control)

Quality Control for Tablets

(Raw Materials)
| (In-Process)
|

(Granules)
z (Tablets)
z

(Finished Products)

Quality Control for Tablets

In-process Control for Tablets
|

weight variation

Quality Control for Tablets

Finished Products
|

weight variation, content uniformity, amount of active
ingredient, loss on drying
(bioavailability)

Tablet Evaluation
(Physical properties)
|



z
z
z
z
z
z

(weight variation)
(thickness)
(hardness)
(friability)
(disintegration)
(dissolution)

Tablet Evaluation
(Chemical properties)
|

(identification)
(uniformity of content)
(assay)
(Biological properties)
|

(bioavailability) (toxicity test)
(clinical test)

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|
|

|
|

Thickness ()
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5%

Thickness ()
|

Thickness ()

Mechanical properties
|

(mechanical properties)

(mechanical strength)
fracture resistance, bending strength, crushing
strength, tensile strength, hardness friability

Mechanical properties
|

2
particle porosity
(density) crushing strength
(compression force)

diametrical compression force horizontal crushing
strength test Brazilian test

(hardness)
(friability)

Hardness ()
|

(porosity)


particle

Hardness ()
|
|

|
|

4 .

(Rule of thumb)

(axial)
(radial)

Hardness ()
Stokes-Monsanto hardness tester

10

Hardness ()
Erweka hardness tester (portable)

Friability ()
|

11

Friability ()
z

z
z

Friability ()
|

1%

12

Friability ()
|

Erweka abrasion tester
z

plexiglass
20
25 /

Roche friabilator
z

12 1
100 /4

Friability ()
Roche friabilator

13

Friability ()
Roche friabilator

Friability ()
|

For tablets with a unit mass equal to or less than 650 mg, take
a sample of whole tablets corresponding to 6.5 g. For tablets
with a unit mass of more than 650 mg, take a sample of 10
whole tablets.
The tablets should be carefully dedusted prior to testing.
Accurately weigh the tablet sample, and place the tablets in
the drum. Rotate the drum 100 times, and remove the tablets.
Remove any loose dust from the tablets as before, and
accurately weigh.

14

Friability ()

% friability =

Wo W
x 100
Wo

Weight of Tablets
| Weight variation

(USP 20)
| Uniformity of dosage unit (USP 27)
| Uniformity of weight or mass (BP)

15

Weight variation (USP 20)

|

(> 50 mg)

(< 50 mg)

(content uniformity)

Weight variation (USP 20)

|

USP20

(mg)
USP20
X < 130
130 < X < 324
X > 324

(%)
10
7.5
5

2
2

16

Uniformity of dosage unit

|

Uniformity of dosage unit

2
z (weight variation)
z (content uniformity)

Uniformity of dosage unit

(weight variation USP27)
|
|

USP 20

> 50
. > 50% (
)

|
|
|
|
|

30
10

10
content uniformity monograph
4

17

Uniformity of dosage unit

(weight variation USP31)
|
|

USP 27

> 25
. > 25% (
)

|
|
|
|
|

30
10

10
content uniformity monograph
4

Uniformity of dosage unit

(weight variation)

| 10 85.0-115.0%
RSD < 6.0%
| 1
85.0-115.0%
75.0-125.0% RSD>
6.0% 2 20
| 1 30 85.0-115.0%
75.0-125.0%
RSD 30 7.8%

18

Uniformity of dosage unit

(content uniformity USP27)
|

> 50 . > 50%

|
|

30
10
monograph

Uniformity of dosage unit

(content uniformity USP31)
|

USP 27

> 25 . > 25% (

)

|
|

30
10
monograph

19

Uniformity of dosage unit

(content uniformity)

|
10 85.0-115.0%
RSD < 6.0%
|
1 85.0-115.0%
75.0-125.0% RSD >
6.0% 2 20
|
1 30 85.0-115.0%
75.0-125.0%
RSD 30 7.8%

Uniformity of weight (BP)

|

(BP2001)

|
|
|
|

20

()

20

Uniformity of weight (BP)

2

2

(mg)
BP2001
X < 80
80 < X < 250
X > 250

(%)
10
7.5
5

Uniformity of content (BP)

|

|
|

10
10
monograph

21

Uniformity of content (BP)

85.0-115.0%

1 85.0-115.0% 75.0-125.0%
20
1
30 85.0-115.0%
75.0-125.0%

1 85.0-115.0%
1 75.0-125.0%

Disintegration
|

(solution)
(disintegration)
(dissolution)

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Disintegration
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Disintegration
|

USP BP

USP27

BP2001

Uncoated tablets
Plain-coated tablets
Delayed-release (enteric coated) tablets
Buccal tablets
Sublingual tablets

Uncoated tablets
Enteric-coated tablets
Effervescent tablets
Coated tablets
Soluble tablets
Dispersible tablets
Vaginal tablets

(lozenges) (chewable tablets) sustainedrelease tablets

23

Disintegration
Disintegration apparatus

Disintegration
Disintegration apparatus

24

Disintegration
|

2
z

basket rack

basket rack

Disintegration

USP27
monograph 1 2 12
16 18

BP2001 6

25

Dissolution
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(Tablet Dissolution)

Dissolution
|

Tablet Dissolution is a standardized method for measuring

the rate of drug release from a dosage form. The principle
function of the dissolution test may be summarized as
follows:
z

Optimization of therapeutic effectiveness during product

development and stability assessment.

Routine assessment of production quality to ensure uniformity

between production lots.

Assessment of bioequivalence, that is to say, production of the

same biological availability from discrete batches of products
from one or different manufacturers.

Prediction of in-vivo availability, i.e. bioavailability (where

applicable).

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Dissolution
|

( )

USP
BP
USP27 BP2001

dissolution apparatus
USP BP

Dissolution
Dissolution apparatus

apparatus 1
apparatus 2
apparatus 3
apparatus 4
apparatus 5
apparatus 6
apparatus 7

USP (/)
BP (/)
rotating basket
rotating basket
paddle
paddle
reciprocating cylinder flow-through cell
flow-through cell
paddle over disk
cylinder
reciprocating holder

27

Dissolution
Dissolution apparatus

Dissolution
Dissolution apparatus

USP Dissolution Apparatus 1

(Basket)

USP Dissolution Apparatus 2

(Paddle)

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Dissolution
1 (Apparatus 1; Basket)
|

(covered vessel)
160-175 mm 98-100 mm 1000 mL
(cylindrical basket)
316 36.8 3 mm 25.4 3 mm
425 micron (40 mesh)
(motor) (drive shaft) basket
monograph
(drive shaft)

(medium) medium
monograph 36.5-37.5 oC
(thermostat) 36.5-37.5 oC

Dissolution
Dissolution apparatus 1

(a)

(b)

(c)

(d)

Baskets for dissolution apparatus:

(a) standard 40-mesh basket, (b) 20-mesh
basket, (c) 10-mesh basket and
(d) suppository basket

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Dissolution
2 (Apparatus 2; Paddle)
|

apparatus 1 paddle
basket

Dissolution
Dissolution apparatus 2

Paddles for dissolution apparatus;

PTFE coated paddle (left) and solid PTFE paddle (right)

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Dissolution

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|

|
|
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36.5-37.5 oC (37 0.5 oC)
monograph

37 0.5 oC

1 basket (apparatus 1) vessel (apparatus 2)

monograph

basket paddle 1 cm
1

monograph

Dissolution

BP2001
|

6
45 ()
70%
monograph 1
6

USP27
|

3
1 1
2 3

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Dissolution
Acceptance table for dissolution (USP 27)

Stage
S1
S2
S3

Number tested
Acceptance criteria
6
Each unit is not less than Q-5%
6
Average of 12 units (S1+S2) is equal to or
greater than Q and no unit is less than Q-15%
12

Average of 24 units (S1+S2+S3) is equal to or

greater than Q, not more than 2 unit are less
than Q-15% and no unit is less than Q-25%

Dissolution
Dissolution apparatus 3

32

Dissolution
Dissolution apparatus 4

Dissolution
Dissolution apparatus
Flow-through cell

33

Dissolution
Dissolution apparatus 6 (cylinder)

In-vivo Dissolution

Source: Bnlkke et al. (1997). A new approach for direct in vivo dissolution studies of poorly
soluble drugs. Pharmaceutical Research, 14 (10), 1490-1492.

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Stability study
|

Stability study
|

35

Acetaminophen Tablets USP27

Acetaminophen Tablets contain not less than 90.0 percent and not more than 110.0 percent of the labeled amount of
acetaminophen (C8H9NO2).
Packaging and storage Preserve in tight containers, and store at controlled room temperature. ( USP27 )
Labeling Label Tablets that must be chewed to indicate that they are to be chewed before swallowing.
USP Reference standards < 11 > USP Acetaminophen RS .
Identification
A: The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the
chromatogram of the Standard preparation, as obtained in the Assay.
B: Triturate an amount of powdered Tablets, equivalent to about 50 mg of acetaminophen, with 50 mL of methanol, and
filter: the clear filtrate (test solution) responds to the Thin-layer
Chromatographic Identification Test < 201 >, a solvent system consisting of a mixture of methylene chloride and
methanol (4:1) being used.
Dissolution < 711 >
Medium: pH 5.8 phosphate buffer (see Buffer Solutions in the section Reagents, Indicators, and Solutions); 900 mL.
Apparatus 2: 50 rpm.
Time: 30 minutes.
Procedure Determine the amount of C8H9NO2 dissolved by employing UV absorption at the wavelength of maximum
absorbance at about 243 nm on filtered portions of the solution under test, suitably diluted with Dissolution Medium, if
necessary, in comparison with a Standard solution having a known concentration of USP Acetaminophen RS in the same
Medium.
Tolerances Not less than 80% (Q) of the labeled amount of C8H9NO2 is dissolved in 30 minutes.
FOR TABLETS LABELED AS CHEWABLE
Medium: pH 5.8 phosphate buffer (see Buffer Solutions in the section Reagents, Indicators, and Solutions); 900 mL.
Apparatus 2: 75 rpm.
Time: 45 minutes.
Procedure Proceed as directed for Procedure for Acetaminophen Tablets.
Tolerances Not less than 75% (Q) of the labeled amount of C8H9NO2 is dissolved in 45 minutes.

Acetaminophen Tablets USP27

Uniformity of dosage units < 905 >: meet the requirements.
Assay
Mobile phase, Standard preparation, and Chromatographic system Proceed as directed in the Assay under
Acetaminophen Capsules.
Assay preparation Weigh and finely powder not fewer than 20 Tablets. Transfer an accurately weighed portion of the
powder, equivalent to about 100 mg of acetaminophen, to a 200-mL volumetric flask, add about 100 mL of Mobile phase,
shake by mechanical means for 10 minutes, sonicate for about 5 minutes, dilute with Mobile phase to volume, and mix.
Transfer 5.0 mL of this solution to a 250-mL volumetric flask, dilute with Mobile phase to volume, and mix. Pass a portion
of this solution through a filter having a 0.5-m or finer porosity, discarding the first 10 mL of the filtrate. Use the clear
filtrate as the Assay preparation.
Procedure Proceed as directed for Procedure in the Assay under Acetaminophen Capsules. Calculate the quantity, in
mg, of acetaminophen (C8H9NO2) in the portion of Tablets taken by the formula: 10,000 C (rU / rS), in which C is the
concentration, in mg per mL, of USP Acetaminophen RS in the Standard preparation; and rU and rS are the
acetaminophen peak responses obtained from the Assay preparation and the Standard preparation, respectively.
Auxiliary Information
Staff Liaison : Clydewyn M. Anthony, Ph.D., Senior Scientific Associate
Expert Committee : (PA2) Pharmaceutical Analysis 2
USP27NF22 Page 19
USP27NF22 Supplement : No. 1 Page 3037
Pharmacopeial Forum : Volume No. 27(3) Page 2495
Phone Number : 1-301-816-8139

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Paracetamol Tablets BP2001

Definition
Paracetamol Tablets contain Paracetamol.
With the exception of the requirements for shape, the tablets comply with the requirements stated under Tablets and with the
following requirements.
Content of paracetamol, C8H9NO2 95.0 to 105.0% of the stated amount.
Identification
Extract a quantity of the powdered tablets containing 0.5 g of Paracetamol with 20 ml of acetone, filter, evaporate the filtrate
to dryness and dry at 105o. The residue complies with the following tests.
A. The infrared absorption spectrum, Appendix II A, is concordant with the reference spectrum of paracetamol (RS 258).
B. Boil 0.1 g with 1 ml of hydrochloric acid for 3 minutes, add 10 ml of water and cool; no precipitate is produced. Add 0.05 ml
of 0.0167M potassium dichromate; a violet colour is produced slowly which does not turn red.
C. Melting point, about 169o, Appendix V A.
Dissolution
Comply with the dissolution test for tablets and capsules, Appendix XII D, using Apparatus II. Use as the medium 900 ml of
phosphate buffer pH 5.8 and rotate the paddle at 50 revolutions per minute. Withdraw a sample of 20 ml of the medium and
filter. Dilute the filtrate with 0.1M sodium hydroxide to give a solution expected to contain about 0.00075% w/v of
Paracetamol. Measure the absorbance of this solution, Appendix II B, at the maximum at 257 nm using 0.1M sodium
hydroxide in the reference cell. Calculate the total content of paracetamol, C8H9NO2, in the medium taking 715 as the value
of A(1%, 1 cm) at the maximum at 257 nm.
4-Aminophenol
Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Solution (1) contains 0.001%
w/v of 4-aminophenol in methanol (15%). For solution (2) shake a quantity of the powdered tablets containing 1.0 g of
Paracetamol with 15 ml of methanol, dilute to 100 ml with water and filter.
The chromatographic procedure may be carried out using (a) a stainless steel column (20 cm 4.6 mm) packed with stationary
phase C (10 m) (Nucleosil C18 is suitable), (b) 0.01M sodium butanesulphonate in a mixture of 0.4 volume of formic acid, 15
volumes of methanol and 85 volumes of water as the mobile phase with a flow rate of 2 ml per minute and (c) a detection
wavelength of 272 nm.

Paracetamol Tablets BP2001

In the chromatogram obtained with solution (2) the area of any peak corresponding to 4-aminophenol is not greater than the
area of the peak in the chromatogram obtained with solution (1). In the chromatogram obtained with solution (2) peaks with a
long retention time may occur due to excipients (0.1%).
Related substances
Carry out the method for thin-layer chromatography, Appendix III A, using silica gel GF254 as the coating substance and a
mixture of 10 volumes of toluene, 25 volumes of acetone and 65 volumes of chloroform as the mobile phase. Pour the mobile
phase into an unlined tank, immediately place the prepared plate in the tank, close the tank and allow the solvent front to
ascend 14 cm above the line of application. Apply separately to the plate 200 l of solution (1) and 40 l of each of solutions
(2), (3) and (4). For solution (1) transfer a quantity of the finely-powdered tablets containing 1.0 g of Paracetamol to a groundglass-stoppered 15-ml centrifuge tube, add 5 ml of peroxide-free ether, shake mechanically for 30 minutes, centrifuge at 1000
revolutions per minute for 15 minutes or until a clear supernatant liquid is obtained and use the supernatant liquid. For
solution (2) dilute 1 ml of solution (1) to 10 ml with ethanol (96%). Solution (3) contains 0.0050% w/v of 4-chloroacetanilide in
ethanol (96%). For solution (4) dissolve 0.25 g of 4-chloroacetanilide and 0.10 g of paracetamol in sufficient ethanol (96%) to
produce 100 ml. After removal of the plate, dry it in a current of warm air and examine under ultraviolet light (254 nm). Any
spot corresponding to 4-chloroacetanilide in the chromatogram obtained with solution (1) is not more intense than the spot
in the chromatogram obtained with solution (3). Any secondary spot in the chromatogram obtained with solution (2) with an
Rf value lower than than that of 4-chloroacetanilide is not more intense than the spot in the chromatogram obtained with
solution (3). The test is not valid unless the chromatogram obtained with solution (4) shows two clearly separated principal
spots, the spot corresponding to 4-chloroacetanilide having the higher Rf value.
Assay
Weigh and powder 20 tablets. Add a quantity of the powder containing 0.15 g of Paracetamol to 50 ml of 0.1M sodium
hydroxide, dilute with 100 ml of water, shake for 15 minutes and add sufficient water to produce 200 ml. Mix, filter and dilute
10 ml of the filtrate to 100 ml with water. Add 10 ml of the resulting solution to 10 ml of 0.1M sodium hydroxide, dilute to 100
ml with water and measure the absorbance of the resulting solution at the maximum at 257 nm, Appendix II B. Calculate the
content of C8H9NO2 taking 715 as the value of A(1%, 1 cm) at the maximum at 257 nm.
Storage
Paracetamol Tablets should be protected from light.

37

Summary
TABLETS (USP27)
|

Tablets are solid dosage forms containing medicinal substances with

or without suitable diluents. They may be classed, according to the
method of manufacture, as compressed tablets or molded tablets.

The vast majority of all tablets manufactured are made by

compression, and compressed tablets are the most widely used
dosage form in this country. Compressed tablets are prepared by the
application of high pressures, utilizing steel punches and dies, to
powders or granulations. Tablets can be produced in a wide variety of
sizes, shapes, and surface markings, depending upon the design of
the punches and dies.

............

Summary
WEIGHT VARIATION and CONTENT UNIFORMITY (USP27)
|

Tablets are required to meet a weight variation test (see Uniformity of

Dosage Units < 905 >) where the active ingredient comprises a major
portion of the tablet and where control of weight may be presumed to
be an adequate control of drug content uniformity.

Weight variation is not an adequate indication of content uniformity

where the drug substance comprises a relatively minor portion of the
tablet, or where the tablet is sugar-coated. Thus, the Pharmacopeia
generally requires that coated tablets and tablets containing 50 mg or
less of active ingredient, comprising less than 50% by weight of the
dosage-form unit, pass a content uniformity test (see Uniformity of
Dosage Units < 905 >), wherein individual tablets are assayed for
actual drug content.

38

Summary
DISINTEGRATION and DISSOLUTION (USP27)
|

Disintegration is an essential attribute of tablets intended for

administration by mouth, except for those intended to be chewed
before being swallowed and for some types of extended-release
tablets. A disintegration test is provided (see Disintegration < 701 >),
and limits on the times in which disintegration is to take place,
appropriate for the types of tablets concerned, are given in the
individual monographs.

For drugs of limited water-solubility, dissolution may be a more

meaningful quality attribute than disintegration. A dissolution test (see
Dissolution < 711 >) is required in a number of monographs on
tablets. In many cases, it is possible to correlate dissolution rates with
biological availability of the active ingredient. However, such tests are
useful mainly as a means of screening preliminary formulations and as
a routine quality-control procedure.

Summary
< 701 > DISINTEGRATION (USP27)
|

This test is provided to determine compliance with the limits on

Disintegration stated in the individual monographs except where the
label states that the tablets or capsules are intended for use as
troches, or are to be chewed, or are designed as modified-release
dosage forms (see Drug Release < 724 >). Determine the type of units
under test from the labeling and from observation, and apply the
appropriate procedure to 6 or more dosage units.

For the purposes of this test, disintegration does not imply complete
solution of the unit or even of its active constituent. Complete
disintegration is defined as that state in which any residue of the unit,
except fragments of insoluble coating or capsule shell, remaining on
the screen of the test apparatus is a soft mass having no palpably firm
core.

39

Summary
< 711 > DISSOLUTION (USP27)
|

This test is provided to determine compliance with the dissolution

requirements where stated in the individual monograph for a tablet or
capsule dosage form. Of the types of apparatus described herein, use
the one specified in the individual monograph. Where the label states
that an article is enteric-coated, and a dissolution or disintegration test
that does not specifically state that it is to be applied to enteric-coated
articles is included in the individual monograph, the test for DelayedRelease Articles under Drug Release < 724 > is applied unless
otherwise specified in the individual monograph.
For hard or soft gelatin capsules and gelatin-coated tablets that do not
conform to the Dissolution specification, repeat the test as follows.
Where water or a medium with a pH of less than 6.8 is specified as the
Medium in the individual monograph, the same Medium specified may
be used with the addition of purified pepsin that results in an activity
of 750,000 Units or less per 1000 mL. For media with a pH of 6.8 or
greater, pancreatin can be added to produce not more than 1750 USP
Units of protease activity per 1000 mL.

Summary
TABLETS (BP2001 / Ph.Eur. 3rd Ed.)
|

Tablets are solid preparations each containing a single dose of one or

more active substances and usually obtained by compressing uniform
volumes of particles. Tablets are intended for oral administration.
Some are swallowed whole, some after being chewed, some are
dissolved or dispersed in water before being administered and some
are retained in the mouth where the active substance is liberated.

The particles consist of one or more active substances with or without

excipients such as diluents, binders, disintegrating agents, glidants,
lubricants, substances capable of modifying the behaviour of the
preparation in the digestive tract, colouring matter authorised by the
competent authority and flavouring substances.

Tablets are usually solid cylinders, the end surfaces of which are flat
or convex and the edges of which may be bevelled. They may have
lines or break-marks and may bear a symbol or other markings.
Tablets may be coated.

40

Summary
TESTS FOR TABLETS (BP2001 / Ph.Eur. 3rd Ed.)
|

Uniformity of content (2.9.6). Unless otherwise prescribed or justified

and authorised, tablets with a content of active substance less than 2
mg or less than 2 per cent of the total mass comply with test A for
uniformity of content of single-dose preparations. If the preparation
has more than one active substance, the requirement applies only to
those substances which correspond to the above conditions.

Uniformity of mass (2.9.5). Uncoated tablets and, unless otherwise

justified and authorised, film-coated tablets comply with the test for
uniformity of mass of single-dose preparations. If the test for
uniformity of content is prescribed for all the active substances, the
test for uniformity of mass is not required.

Summary
TESTS FOR TABLETS (BP2001 / Ph.Eur. 3rd Ed.)
|

Disintegration Uncoated tablets comply with the test for Disintegration

of tablets and capsules (2.9.1). Use water R as the liquid medium. Add
a disc to each tube. Operate the apparatus for 15 min, unless
otherwise justified and authorised, and examine the state of the
tablets. If the tablets fail to comply because of adherence to the discs,
repeat the test on a further six tablets omitting the discs. The tablets
comply with the test if all six have disintegrated. Chewable tablets are
not required to comply with the test.

Dissolution A suitable test may be carried out to demonstrate the

appropriate release of the active substance(s), for example one of the
tests described in Dissolution test for solid dosage forms (2.9.3).
Where a dissolution test is prescribed, a disintegration test may not be
required.

41