QUALITY CONTROL OF TABLETS IPQC stands for in process quality control. These are checks that are carried out before the manufacturing process is completed.

1. QUALITY CONTROL OF TABLETS
Dr. V. S. Kashikar
Asso. Prof., Head, Dept. of Pharmaceutics
PES Modern College of Pharmacy ( for ladies), Moshi Pune 412 105
An orientation lecture
For
M.Pharm
on

2. In Process Quality Control
 The development of a drug product is a lengthy process involving drug discovery, laboratory testing,
animal studies, clinical trials and regulatory registration.
 To further enhance the effectiveness and safety of the drug product after approval, many regulatory
agencies such as the United States Food and Drug Administration (FDA) also require that the drug product
be tested for its identity, strength, quality, purity and stability before it can be released for use.
 For this reason, pharmaceutical validation and process controls are important in spite of the problems
that may been countered. Process controls include raw materials inspection, in-process controls and target
so for final product.
 IPQC stands for in process quality control. These are checks that are carried out before the
manufacturing process is completed.
 The function of in-process controls is monitoring and if necessary adaption of the manufacturing
process in order to comply with the specifications. This may include control of equipment and environment
too.
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3. IPQC/Quality Control-Tablets
 DIAMETER AND SHAPE
 TABLET THICKNESS
 UNIQUE IDENTIFICATION MARKINGS (embossing, engraving
or printing)
 HARDNESS (CRUSHING STRENGTH)
 FRIABILITY TEST
 DISINTEGRATION TEST
 WEIGHT VARIATION TEST
 DRUG CONTENT
 DISSOLUTION
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4.  Diameter and shape depend on the die and punches selected for the compression of the tablet.
Tablet thickness should be controlled within a ± 5 % variation of standard value.
 Tablet thickness is the only dimensional variable related to the compression process and can be
measured by micrometer
 HARDNESS (CRUSHING STRENGTH) is a function of the die fill and compression force
 FRIABILITY TEST To study the effect of abrasion and shock during handling, packaging and
shipping operations
 DISINTEGRATION TEST is a measure of the time required for a tablet to break up into particles
under a given set of conditions
 WEIGHT VARIATION test would be a satisfactory method of determining the drug content
uniformity of tablets if the active ingredient is 90 to 95% of the total tablet weight.
 DRUG CONTENT The potency (drug content) of tablet is expressed in terms of gm, mg, or mcg
(for some potent drugs) of drug per tablet and is given as the label strength of the product
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5. WEIGHT VARIATION
Weigh individually 20 units selected at random and calculate the average weight. Not
more than two of the individual weights deviates from the average weight by more than
the percentage given in the pharmacopea and none deviates by more than twice that
percentage.
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IP/BP Limit USP
<80 mg ± 10% <130mg
80 mg to 250 mg ± 7.5% 130 mg to 324 mg
>250 mg ± 5% >324 mg

6. Friability Test As per USP
Friability is the phenomenon where the surface of the tablet is damage or shown a site of damage due to
mechanical shock.
PURPOSE : to evaluate the ability of the tablets to withstand the breakage during the transportation and
handling.
APPARATUS: ROCHE FRIABALITOR
CRITERIA :
 For the tablet with a unit equal to or less than 650 mg, take a sample of whole tablets corresponding
as near as possible to 6.5 gm.
 For tablets with a unit weight of more than 650 mg, take a sample of 10 whole tablets.
Friability = ((W1-W2)/W1) *100
Compress tablet that lose less than 0.5 to 1.0 % of the Tablet weight are consider acceptable.
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7. DRUG CONTENT
This test is applicable to tablets that contain less than 10 mg or less than 10% w/w of active
ingredient. For tablets containing more than one active ingredient carry out the test for each
active ingredient that corresponds to the aforementioned conditions. The test for Uniformity of
content is not applicable to tablets containing multivitamins and trace elements.
Determine the content (assay) of active ingredient(s) in each of 10 tablets/30 tablets.
Comply with the test if not more than one (9 out of 10) of the individual values thus obtained
is outside the limits 85 to 115 % of the labeled drug content and none is outside the limits 75
to 125 % of the labeled drug content. If these conditions are not met repeat the determination
using remaining 20 tablets. The tablets comply with the test if in the total sample of 30 tablets,
none is outside the limits 85 to 115 % range.
Note: Several samples of tablets should be taken from the various part of production run to satisfy
statistical procedure.
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8. DISINTEGRATION
TEST
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9. Sr.
No
Types of tablets Medium Temperature Limit
1 Uncoated Water/As specified in
monograph
37º± 2ºC Within 30 min/As per individual
monograph
2 Coated Water/As specified in
monograph
37º± 2ºC Within 30 min/ As per individual
monograph
3 Enteric-coated Tablets Simulated gastric fluid,
Simulated intestinal fluid
37º± 2ºC 01 hour in simulated gastric fluid : No
disintegration
As per individual monograph:
Simulated intestinal fluid should
disintegrate within 2 hour
4 Buccal Tablet Water/As specified in
monograph
37º± 2ºC Within 4 hour
Disintegration Testing Condition (USP)
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10. Sr.N
o
Types of tablets Medium Temperature Limit
1 Uncoated Water/ Buffer 37º± 2ºC Within 15 min/ As per individual
monograph
2 Film Coated Water 37º± 2ºC Within 30 min/ As per individual
monograph
3 Sugar coated Water/ 0.1N HCl 37º± 2ºC Within 60 min/ As per individual
monograph
4 Dispersible Tablets Water 20º± 5ºC Within 03 min/ As per individual
monograph
5 Effervescent Tablets Water 20º± 5ºC Within 05 min/ As per individual
monograph
6 Enteric-coated Tablet 0.1N HCl
Mixed phosphate
buffer pH 6.8
37º± 2ºC 02 hour in HCl: No disintegration
60 min in Buffer: Disintegrate
7 Soluble Tablet Water 20º± 5ºC Within 03 min.
Disintegration Testing Condition (IP)
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11. Dissolution Test
When solid particles come in contact with the GI tract, a
saturated layer of drug solution is created very quickly in
the surface of particles in the liquid immediately
surrounding them (called the diffusion layer). The drug
molecules then diffuse through the GI content to the
lipoidal membrane where diffusion across the gastro
intestinal membrane and absorption into the circulation
takes place.
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12. There are two possible scenarios for the drug dissolution
• Absorption from solution takes place following the rapid dissolution of
solid particles. In this case rate of absorption is controlled by rate of
diffusion (Rate limiting step) into the GI fluid.
• Absorption from solution takes place following the slow dissolution of
solid particles. In this case rate of absorption is controlled by rate of
dissolution (Rate limiting step) into the GI fluid.
Hence, Dissolution is a process in which a solid substance solubilises in a
given solvent i.e., mass transfer from solid surface to the liquid phase
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13. In the pharmaceutical industry, drug dissolution testing is routinely
used to provide critical in vitro drug release information for
both quality control purposes, i.e., to assess batch-to-batch
consistency of solid oral dosage forms such as tablets and drug
development, i.e., to predict in vivo drug release profiles.
The main objective of developing and evaluating an IVIVC is to
establish the dissolution test as a surrogate for human studies, as
stated by the Food and Drug Administration (FDA).
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14. Dissolution test is conducted for,
 Optimization of therapeutic effectiveness during product
development and stability assessment.
 Routine assessment of production quality to ensure uniformity
between production lots.
 Assessment of ‘bioequivalence’.
 Prediction of in-vivo availability, i.e. bioavailability (where
applicable).
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16. USP
Apparatus Type
NAME Rotator Speed Used for
I Rotating basket 50-120 rpm Immediate release, delayed release, chewable tablets,
delayed release suppositories, Extended release tablets
and floating dosage form
II Paddle 25-50 rpm Immediate release, orally disintegrating tablets, chewable
tablets, delayed release and Extended release tablets and
capsules and suspensions.
III Reciprocating cylinder
It enables the product to be
subjected to different dissolution
media and agitation speeds in a
single run
6-35 rpm Controlled release formulations, Chewable tablets and
beads
IV Flow through cell
To provide Sink conditions by
continually removing solvent and
replacing it with fresh solvent
- Drug products containing poorly soluble API, Powders
and granules, microparticles and Implants.
V Paddle over disk 25-50 rpm Transdermal Patches, Ointments and Emulsions
VI Rotating Cylinder
Basket being replaced by a stainless
steel cylinder
25-50 rpm Transdermal Patches
VII Reciprocating Holder
A sample holder that oscillates
up and down
30 rpm Controlled release formulations Transdedrmal
formulations & non disintegrating oral formulations
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21. Model Linear Equation Plot System that
follows the
model
On X- axis On Y-axis
Zero Order Qt = Qo +Kot Time Cumulative of
percentage of
drug release
Osmotic systems,
transdermal
system
First Order Log C = log Co – Kt /
2.303
Time Log cumulative
percentage of
drug remaining
Water soluble
drugs in a
porous matrix
Higuchi Model Qt = KHt1/2 Square root of
Time
Cumulative
percent amount of
drug release
Diffusion matrix
formulation
Hixon Crowell Wo1/3 – Wt1/3 = Kst Time Cube root of
percentage of
drug remaining
Erodible matrix
formulation
Korsmeyer-
peppas Model
Mt/Ma = Ktn Log Time Log cumulative
percentage of
drug release
Swellable
polymeric
devices
Some model with linear equation for graphical presentation
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22. Where, a = Scale parameter
b = Suface parameter
Qt = Fraction of dose released at time t
K,KH,K0,KS = Release rate constant characteristics to respective models
m & n = Release exponents
Mt = Amount released at time t
M∞ = Amount release at infinite time
Q0 = Drug amounts remaining to be released at zero hour
Qt = Drug amounts remaining to be released at time t
Ti = Lag time before the onset of dissolution
W0 = Initial amount of drug present in matrix
Wt = Amount of drug released at time t
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23. Korsmeyer-peppas Model
A plot of the log (cumulative percentage drug released ) vs log (time) yields
slope n (diffusion exponent) having value.
 n = 0.5 indicating pure fickian diffusion.
 n = 0.5-1 or n = 0.45-0.89 indicating anomalous non- fickian diffusion i.e
the rates of solvent penetration and drug release are in the same range. This deviation is
due to increased drug diffusivity from the matrix by the solvent induced relaxation of the
polymers.
 n=0.89 or n = 1 indicate zero order release which can be achieved when drug
diffusion is rapid compared to the constant rate of solvent induced relaxation and
swelling in the polymer (case II transport for swellable polymers).
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29.  First Step
Determine concentration of drug released by using formula
Y =mX +/- C
Y is absorbance, m is slope, C is intercept, X is concentration (mcg/ml)
 Second Step
Calculate amount of drug released
Amount of drug released (mg)= [Concentration X Dilution factor X Volume of Dissolution
medium] / 1000
 Final Step
% Drug release = Amt of drug released (mg) X 100 / Dose (mg)
Cumulative % drug Released (CDR) =
Volume of sample withdrawn(ml)/Bath volume (v) X P (t-1) +Pt
Where, Pt Percentage drug released at time t
P (t-1) = Percentage drug released previous to t
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31. BIOWAIVER
Biowaiver is an exemption granted by the US FDA to conduct in-vivo bioequivalence studies. It
implies that it is not necessary for generic products to conduct the in-vivo studies for product
approval. Instead a dissolution test can be adopted.
Biowaiver can be suggested only for solid, orally administered immediate release products (85%
release in 30 min), containing highly soluble drugs over a pH range of 1 to 7.5.
For a bioequivalence study of a waiver, the test and reference product should exhibit similar
dissolution profile (f2 >50). However, it is not applicable for buccal, sublingual, oral dispersion
and modified release formulations. Biowaiver reduces the cost of bringing new products to the
market. It has a major advantage in reducing the time for approval of a product.
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32. Fit factor:
Similarity factor f2: For comparison of in-vitro dissolution profiles, similarity and
difference factors are emphasized by US FDA. As the name specifies, similarity
factor (f2) stresses on the comparison of closeness of two comparative
formulations. The f2 parameter is commonly used to establish similarity of two
dissolution profiles The FDA defines Similarity factor as " the logarithmic
reciprocal square root transformation of one plus the mean squared (the average
sum of squares) differences of drug percent dissolved between the test and the
reference products".
f2 = 50 + log {[1+ (1/n) ∑t=1 * n (Rt-Tt) 2] -0.5 ×100}
Rt and Tt are the cumulative percentage dissolved at each of the selected n time points of the reference and test product
respectively
Two profiles are considered to be same when f2=100. f2 value results in 50 at an average difference of
10% for all measured time points. f2 value between 50-100 indicates similarity between two
dissolution profiles. In other words if difference at each sampling time is less than or equal to 10% f2
value will be between 50 and 100.
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33. Dissimilarity factor (f1):
Dissimilarity factor focuses on the difference in percent
dissolved between reference and test at various time intervals.
Therefore the factors directly compare the difference between
percent drug dissolved per unit time for a test and a reference
product. f1 factor is used to calculate the approximate % error
in drug release profile.
f1 should be between 0 and 15.
f1= {[Σ t=1 n |Rt-Tt|] / [Σ t=1 nRt]} ×100.
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34. The criteria stated by US FDA for dissolution profile
1. The dissolution profiles can be compared only when the number of dissolution unit used is equal to or greater
than 12. f2 should be computed from average mean dissolution data of 12 units.
2. For accurate calculation of similarity factor, statistical approach of establishment of confidence intervals to
determine whether the reference and test are statistically significant or not may be used.
3. The dissolution conditions should be identical for both reference and test products like the strength of dosage
form, test time intervals, temperature, rpm, total test time etc.
4. The literature also states to consider only one time after 85% dissolution of product, since f2 values are
sensitive to number of dissolution time points.
5. For rapid dissolving products, that may dissolve 85% in 15 minutes, comparison of dissolution profiles is not
mandatory.
6. Similarity factor of 50-100 ensures sameness of two products.
7. Difference factor of 0-15 ensures minor difference between two products.
Therefore prior to in-vivo study, comparison of in-vitro dissolution profiles using fit factors may be the promising
surrogate.
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