QUALITY

CONTROL II
Drug Testing Assay/Instrumentation
 MODULE 1 LESSON 1 - Introduction to
Quality Control II (Quality relationship)

MODULE 2 LESSON 1 - Quality Control

Documents
Course
Outline MODULE 2 LESSON 2- Quality Control of
Products

MODULE 3 LESSON 1- Sampling and

Errors
 MODULE 3 LESSON 2 -
Sampling Plans

Course
Outline
MODULE 4 LESSON 1 - Stages
in Quality Control (Raw
Material Quality Control)
 MODULE 5 LESSON 1 - Stages in
Quality Control (In-process Quality
Control)
Granules & Powders
Course
Outline MODULE 5 LESSON 2 - Stages in
Quality Control (In-process
Quality Control)
Tablets & Capsules
 MODULE 5 LESSON 3 - Stages in Quality
Control (In-process Quality Control)
Parenterals

MODULE 6 LESSON 1 - Stages in Quality

Control (Finished Goods Quality
Control)
Course
Outline MODULE 7 LESSON 1 - Stages in Quality
Control (Packaging Materials Quality
Control)

MODULE 8 LESSON 1- Statistical Quality

Control
MODULE 5 LESSON
1
Stages in Quality Control
(In-process Quality Control)
Granules & Powders
 Uniformity of
Mixtures
Criteria: Should contain
98-102% of the API
(depending on the
requirement in the USP-
NF)
Method: Coning and
Quartering, Thief Sampler
 Adequacy of Wetness
Criteria: Wet Granulation → Qualitative testing to check if the
binder added is enough
Method: Damp mass → Press thumb → Ball crumbles under
moderate pressure → next stage
Implication:
oUnderwetting – not enough binder, too many fines → Produce soft
tablets
oOverwetting – may clog the screen, prolong processing (drying),
forms very hard aggregates.
 Moisture Content
Criteria: Acceptable Limit – 0.5 to 1%
Method:
oGravimetric Method (Weigh → oven → weigh → oven → until
constant weight is achieved)
oMoisture Balance/Analyzer
Implication:
Increase Moisture Sticking Adhesion of the granules to the die wall
Picking Adhesion of the granules to the punch

Decrease Moisture Capping Complete/partial separation of the top or bottom

part of the tablet.
Chipping Separation of small portions of the tablets
Lamination Separation into two or more layers of the tablet.
 Particle Size Distribution
Criteria: 25 grams or more sample (not applicable for oil or
other cohesive powders or granules that tend to clog the sieve
openings)
Method:
Use a sieve machine
Mesh # - refers to the number of linear openings per square
inch
Implication:
oGood Granules – 85 to 90%
oFines – 10 to 15%
 Particle Size Distribution
Techniques:
1. Sieving (range: 40 - 9500μm ) – most rapid
• Standard sized sieves are designed to sit in a stack so that
material falls through smaller and smaller meshes until it
reaches a mesh which is too fine for it to pass through.
• The result achieved will depend on the duration of the
agitation and the manner of the agitation.

2. Optical Microscopy  (range: 0.2 -100 um)

•  The microscope eyepiece is fitted with a micrometer by
which the size of the particles may be estimated.

3. Electron Microscopy (0.001µm - 5µm)

• Particles are individually examined
• Visual means to see sub-micron specimens
• Particle shape can be measured
 Particle Size Distribution
Techniques:
4. Sedimentation (range:0.8 -300μm)
•  by measuring the terminal settling velocity of
particles through a liquid medium in a
gravitational centrifugal environment using
Andreasen apparatus.
• Methods depend on the fact that the terminal
velocity of a particle in a fluid increases with size.

5. Light scattering technique

Distribution of scattered intensity is analysed by
computer to yield the particle size distribution.
• Laser Diffraction Particle Size Analysis
(Particle size range 0.02-2000µm)
• Photon Correlation Spectroscopy
(Particle size range :1nm to 5µm)
 Angle of Repose
Criteria: Characterize the flow property of granules/powders
Method:
−1 h
𝐴𝑛𝑔𝑙𝑒 𝑜𝑓 𝑅𝑒𝑝𝑜𝑠𝑒=tan ( )
0.5 × 𝐷

Where,
h is the height of the heap of powder
D is the diameter of the base of the heap of powder
 Bulk Density
Criteria: Measurement of the density (depending on the
requirement in the USP-NF)
Method:

Where,
m is the mass of the sample
Vo is the bulk volume (USP 39-NF34)
 Tapped Density
Criteria: Measurement of the density (depending on the
requirement in the USP-NF)
Method:

Where,
m is the mass of the sample
Vf is the final tapped volume
 Compressibility Index and Hausner Ratio
Criteria: Characterize the compressibility of the powder/granules.
Method:

Where,
Vo = unsettled apparent volume or bulk volume
Vf = final tapped volume

𝑉𝑜
𝐻𝑎𝑢𝑠𝑛𝑒𝑟 ′ 𝑠 𝑅𝑎𝑡𝑖𝑜=
𝑉𝑓
Where,
Vo = unsettled apparent volume or bulk volume
Vf = final tapped volume
37
MODULE 5 LESSON 2
-Stages in Quality Control
(In-process Quality Control)
Tablets & Capsules
Objectives
At the end of the discussion, the student will be
able to:
• Discuss the different evaluation or control test of
tablet preparation
• Know the importance of performing the control test
• Tablets are flat or biconvex discs of unit dosage forms
containing one or more active ingredients,
compressed along with necessary additives.

Ingredients used in tablet formulations

o Drugs (API)

o Excipients
Properties of excipients:
oThey must be non-toxic & physiologically inert.
oThey must be free from all microbial
contamination.
oThey do not alter the bioavailability of drug.
 EXCIPIENTS
 Binders and Adhesives: These materials are added
either dry or in wet- form to form granules or to form
cohesive compacts for directly compressed tablet.

Example: Acacia, tragacanth, Cellulose derivatives-

Methyl cellulose, Hydroxy propyl methyl cellulose,
Hydroxy propyl cellulose, Starch paste,etc.,
 EXCIPIENTS
 Disintegrants
To promote breakup of the tablets
To promote rapid release of the drug
Example: Starch- 5-20% of tablet weight,
Starch derivative – Primogel and Explotab (1-8%) ,
Cellulose derivatives .
 EXCIPIENTS
• Glidants
• Reducing friction between the particles
• To improve the flow properties of the granulations

Example: - Corn Starch – 5-10% conc., Talc-5% conc., Silica

derivative - Colloidal silicas such as Cab-O-Sil, Syloid,
Aerosil in 0.25-3% conc.
 EXCIPIENTS
• Antiadherants
• To prevent adherence of the granules to the
punch faces and dies.
Examples: Talc ,corn starch
 EXCIPIENTS
Lubricants
• To reduce the friction during tablet ejection
between the walls of the tablet and the walls of
the die cavity
Example: Stearic acid, Magnesium stearate, Talc, PEG
(Polyethylene glycols), Surfactants
ORGANOLEPTIC AGENTS
Sweetening Agents: Sugar, mannitol. Saccharine (artificial): 500
times sweeter than sucrose

Coloring agents:
The use of colors and dyes in a tablet has three purposes:
o Masking of off color drugs
o Product Identification
o Production of more elegant product
Example: FD & C yellow 6-sunset yellow, FD & C yellow 5-
Tartrazine

Flavoring agents: These are mostly used in Chewable Tablets

Tablet production
Granulation Properties:

Particle size & shape: Particle size of granulation affect the average tablet
weight, weight variation, disintegration time, friability, granule flow ability.

Surface area:
Dissolution of a drug depends on surface area of powder materials or
granules.

Density: Granule density may influence compressibility, tablet porosity,

dissolution and other properties.
Tablet production
Granulation Properties:

Strength : Granules are aggregation of component particles that is

held together by bonds of infinite strength.

Flow properties: For the movement of granules from hopper to die

cavity sufficient flow properties are essential.
 Quality Control of Tablets
To design tablets and later monitor tablet production quality, quantitative
evaluations and assessments of a tablet’s chemical, physical, and bioavailability
properties must be made.
NON-OFFICIAL TESTS
General Appearance:
•Its visual identity and overall “elegance,” essential for:
1) Consumer acceptance
2) Control of lot-to-lot uniformity
3) Monitoring trouble-free manufacturing.
-Size, shape, and thickness:
This is important to facilitate packaging and to decide which tablet
compressing machine to use.
-Organoleptic properties:
which include color and odor of the tablets.
Official and unofficial tests:

oOfficial Tests: Weight variation, disintegration,

dissolution, drug content.
oNon-Official Tests: Hardness, friability, General
Appearance
Official Standards as per B.P. /I.P./ U.S.P.
COMPARISON OF DIFFERENT PHARMACOPOEIAL QUALITY CONTROL TESTS

BRITISH PHARMACOPOEIA
FOR ALL TABLETS:
• Content of active ingredients
• Disintegration
• Uniformity of content
• Labeling
BRITISH PHARMACOPOEIA INDIAN PHARMACOPOEIA
Uncoated tablet: Uncoated tablet:
-Disintegration test -Uniformity of container
-Uniformity of weight content
Effervescent tablet: -Content of active ingredient
-Disintegration test -Uniformity of weight
-Uniformity of weight -Uniformity of content
Coated tablet: -Disintegration test
-Disintegration test Enteric coated tablet:
-Uniformity of weight -Disintegration test
Gastro resistant tablet: Effervescent tablet:
-Disintegration test -Disintegration/ Dissolution /
Modified release tablet: Dispersion
test
-Uniformity of weight.
UNITED STATES PHARMACOPOEIA
Physical 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
THE CONTROL OF THE GENERAL APPEARANCE OF
A TABLET INVOLVES:

I. Tablet’s size
II. Tablet’s shape
III. Tablet’s color
IV. Presence or absence of an odor
V. Presence or absence of a taste
VI.Surface texture
VII.Physical flaws
VIII.Consistency
IX.Legibility of any identifying markings.
 I. SIZE AND SHAPE
A compressed tablet’s are determined by the tooling during the
compression process.

THICKNESS OF A TABLET:is the only dimensional variable related to the

process.

a) At a constant compressive load, b) while with a constant die fill,

tablet thickness varies with changes thickness varies with variations in
in die fill, with particle size compressive load.
distribution and packing of the
particle mix being compressed, and
with tablet weight.
NOTE:
Tablet thickness is consistent batch to batch or within a batch only if:

1. The tablet granulation or powder blend is adequately consistent in

particle size and size distribution.
2. The punch tooling is of consistent length
3. The tablet press is clean and in good working order.

Tablet thickness should be controlled within a ±5% variation

of standard value.
 MEASUREMENT OF THICKNESS

A. The crown thickness of individual

tablets may be measured with a
micrometer

1) Permits accurate
measurements
2) Provides information on
the variation between
tablets.
B.
techniques involv
Other
e
placing 5 or 10 tablets in a holding tray (total
crown thickness may be measured with a
sliding caliper scale).

Adv.:
1. more rapid than a micrometer in providing an overall
estimate of tablet thickness in production operations.
2. Used only if the punch and die tooling standardizes and
the tablet machine is functioning properly.

Disadv.: does not as readily provide

information on variability between tablets.
 IMPORTANT NOTES
A. Thickness control to facilitate packaging.

Problems:
a) Difficulties in the use of unit dose and other types of
packaging equipment (if the volume of the material being
packaged is not consistent).
b) Variable thickness of tablets (relates to consistent fill levels of
the same product container with a given number of dosage
units).
B. Weight of the tablet effected by:
i. The physical dimensions of the tablet
ii. Density of the materials and their proportion.

C. The size and shape of the tablet can influence:

1. Choice of tablet machine
2. Particle Size for the granulation
3. Production lot sizes
4. Packaging operations
5. Cost to produce the tablet.
D. The shape of the tablet alone can influence the choice of
tablet machine used.

Ex: Shaped tablets requiring “slotted punches” must be run at slower

speeds than are possible round tablets using conventional punches?
Because of the nonuniform forces involved within a tablet during
compression

The more convex the tablet surface, the more likely it is to cause
capping problems

Forcing the use of a slower tablet machine or one with

precompression capabilities.
II. UNIQUE IDENTIFICATION MARKINGS.
Technique: unique marking on the tablet in addition to color, to aid in the rapid
identification of products (embossing , engraving, or printing).

Types of informational marking placed on a tablet:

a. Company name or
Product
symbol b. code (e.g. National Drug Code
(NDC) number)
c. Product name
d. Product
potency.
III. ORGANOLEPTIC PROPERTIES.
a) Color (rapid identification and consumer acceptance).
Adv.: The color of a product must be uniform within a single
tablet also from tablet to tablet, and from lot to lot.

Disadv.: 1- Nonuniformity (“mottling”) of color can lacks

esthetic appeal.
2- Consumer can recognize nonuniformity of content and
general poor quality of the product.
HOW TO DISTINGUISH THE DIFFERENCE IN COLOR?

A. Eye: cannot discriminate small differences in color nor can it precisely

define color.

Visual color comparisons against some color standard.

Color standards are subject to change with

time Frequent redefinition or modification

Gradual and significant change in acceptable color.

B. Machines like:
i. Reflectance spectrophotometry
ii. Tristimulus colorimetric measurements,
iii. Microreflectance photometer (measure the color
uniformity and gloss on a tablet surface).
b) Odor (indicate a stability problem)

Examples:
1. Odor of acetic acid (degrading aspirin tablets).
2. Odor of the drug (vitamins have a characteristic
odor).
3. Added ingredients (flavoring agents
have pleasant odors).
4. The dosage form (film-coated tablets
usually have a characteristic odor).
c) Taste (important in consumer acceptanceof chewable tablets).

Many companies utilize taste panels to judge the preference of

different flavors and flavor levels in the development of a product.
A tablet’s level of flaws such as:
Chips, cracks, Contamination from foreign solid substances (e.g., hair, drops of oil,
and “dirt”), surface texture (“smooth” versus “dull”)
Method of detection:
1. Visual inspection techniques
2. Electronic devices.
 Tablet Thickness
Apparatus/Equipment:
Micrometer Caliper
Vernier Caliper

Acceptable Condition:
NMT 5% variation
 Tablet Hardness
Hardness (crushing strength):
It is the load required to crush the tablet when placed on its edge.

o Stoke’s Hardness Tester (Monsanto) – uses a spring applied diametrically to a

tablet
o Strong-Cobb hardness tester – force produced by a manually operated air
pump
o Pfizer tester – makes use of hand pliers as aid.
o Erweka tester – use of suspended weight.
o Schleuniger – horizontally positioned, eliminated operator variance.
 Tablet Hardness
Type of Tablet Acceptable
Hardness
Ordinary Compressed tablet 4-10 kgf
Buccal tablet 7-10 kgf
Chewable tablet 2-3 kgf
Sublingual Tablet 2-3 kgf
Sustained release Tablet 10-20 kgf
 The hardness of a tablet, like its thickness, is a function
of the die fill and compression force:

• At constant die fill, the hardness values increase and thickness decrease
as additional compression force is applied.

Tablet laminate or cap

Destroying the integrity of the tablet.

• At a constant compression force (fixed distance between upper and lower
punches

Hardness increases with increasing die fills and decreases with

lower die fills.
GENERAL NOTES
I. Tablets are harder several hours after compression than
they are immediately after compression.
II. Lubricants can affect tablet hardness when they are used in
too long a period.

Large tablets require a greater force to cause fracture and are

III.
therefore “harder” than small tablets.
IV. For a given granulation, a flat beveled tool produces
a tablet harder than a deep cup tool.
V. Tablet hardness is not an absolute indicator of strength? Since some
formulations, when compressed into very hard tablets, tend to “cap” on attrition, losing
their crown portions.

Another measure of a tablet’s strength (friability) is often measured.

VI. Tablets that tend to powder, chip, and fragment when

handled
Lack elegance and consumer acceptance, and can create excessively dirty processes in
such areas of manufacturing as coating and packaging.

Tablet’s weight variation or content uniformity problems.

 Friability
Friability is a property that is related to the
hardness of the tablet.
Ability of the tablet to withstand abrasion in
packaging, handling, and shipping.
oEquipment: Roche Friabilator
oSetting: 25 rpm
oTime: 4 minutes (100 revolutions)
oNo. of sample:
o 650mg or greater: min. of 10 tablets
o Less than 650mg: 20 tablets or sum of tablets equal to or
near to 6.5 grams.
 Friability Test
• Percentage lost by tablet in packaging and transport
• Reflects ability to withstand rigors of packaging and transport

Friability:
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
% weight loss = initial weight-final weight x 100
initial weight

• Procedure: Dedust tablets using air pressure. Take the weight and load into
friabilator. Expose tablets to required test parameters. Unload tablets and
remove any loose particles. Take the weight.
• Acceptance criteria:
– NMT 1% weight loss (average of 3 trials)
– For new formulation: NMT 0.8%
– No capping and chipping (considered failed)
FRIABILITY ADDITIONAL
TESTS:
Rough handling tests usually include:
1. Vibration test Simulated or
demonstrated
2. Drop test using a Roche
3. Incline plane test Friabilator
4. Shipped bottled products across the country and back
again to estimate the strength of the new tablet product in
shipment.

These tests can be performed to give indication of how well

a tablet will hold up in its specified package and shipping
container during shipment.
OFFICIAL TESTS
A.Drug content and release.
To evaluate a tablet’s potential for efficacy:
1. The amount of drug per tablet needs to be
monitored from tablet to tablet and batch to
batch.
2. Measure the tablet’s ability to release the drug
needs to be ascertained.
B. UNIFORMITY OF DOSAGE UNITS
A tablet designed to contain a specific amount of drug in a
specific amount of tablet formula

Weight of tablet is measured to ensure that a tablet

contains the proper amount of drug.

Test: samples of tablets (usually 10) are weighted throughout

the compression process. The composite weight divided by 10.
Problem in the test: Within the sample that has an acceptable average
weight, there could be tablets excessively overweight or underweight.
 Uniformity of Dosage Units
1. Weight Variation – Tablets > 50 mg
Steps:
• Weigh
• Average
• Upper and lower limits
• Compare
Unofficial method
10 tablets weighed individually, take average weight.
Criteria
NMT 2 tablets differ by more than % variation.
NO tab differ by more than double % variation
2. Content Uniformity – Tablets <50 mg
official test for potency
 USP quality control test for tablets containing 20mg of drug to ensure that each include the
correct dose
Note: (USP)/(NF) provides limits for the permissible Table: Weight Variation
variations in the weights of individual tablets Tolerances for Uncoated
(expressed as a percentage of the average weight of Tablets
sample).
Average Weight Maximum
of Tablets (mg) Percentag
The USP variation test e
Difference
Weight 20 tablets individually, calculating the allowed

average weight, and comparing the individual 130 or less 10

tablet weights to the average. 130-324 7.5

(The tablets meet the USP test if no more than More than 324 5
2 tablets are outside the percentage limit and
no tablet differs by more than 2 times the
percentage limit).
 Weight Tolerance
(Weight Variation Test)
Sample Size: 10 Tablets
Upper limit (at % deviation)=

Lower limit (at % deviation)=

Upper limit (at double %) =

Lower limit (at double %) =

 Weight Tolerance
(Weight Variation Test)
Sample Size: 10 Tablets

AVERAGE WEIGHT % WEIGHT VARIATION % WEIGHT VARIATION

(1st Tolerance Limit) (2nd Tolerance Limit)
< 130 mg 10% 20%
130 -324 mg 7.5% 15%
>325 mg 5% 10%
The weight variation test method determinedrug
content uniformity of tablets if:
i. All Tablets (90 to 95%) active ingredient.
ii. Uniformity of the drug distribution in the granulation or
powder in tablets made were perfect.

Ex: Aspirin tablets (90% or more active ingredient)

±5% weight variation is close to define true potency and

content uniformity (95 to 105% of the label strength)
(if the average tablet weight is close to the theoretic
average weight).
Content Uniformity
Important note:
1. The weight variation test is clearly not sufficient to assure uniform
potency of tablets of moderate- or low-dose drug (excipients make up
the bulk of the tablet weight).
2. The potency of tablets is expressed in terms of grams, mg, or
micrograms (for some potent drugs) of drug per tablet and is given as
the label strength of the product.

Official compendia or other standards provide an

acceptable potency range around the label potency.
i. For highly potent, low-dose drugs such as digitoxin (not less than
90% and not more than 110%).
ii. For most of larger-dose drugs in tablet form (not less
than 95% and not more than 105%).
Three factors can directly contribute to content uniformity problems in
tablets:

1. Nonuniform distribution of the drug substance throughout the

powder mixture or granulation
2. Segregation of powder mixture or granulation during the various
manufacturing processes
3. Tablet weight variation.

Note:
i. The weight cannot be used as a potency indicator (except when the active
ingredient is 90 to 95% of the total tablet weight).
ii. In tablets with smaller dosages, good weight variation does not ensure good
content uniformity, (large weight variation does not indicates good content
uniformity).
C. DISINTEGRATION.
For most tablets, the first important step toward solution is breakdown of the tablet
into smaller particles or granules, a process known as disintegration.

The time that it takes a tablet to disintegrate is measured in a device described in

the USP/NF.

Question: Research has established that one should not automatically expect a
correlation between disintegration and dissolution?
Since the dissolution of a drug from the fragmented tablet control the appearance of
the drug in the blood

Disintegration is a (guide for an optimum tablet formula) and (as an

in-process control test to ensure lot-to-lot uniformity).
 Disintegration
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.

Complete Disintegration – residue is only a soft mass with no palpable firm

core.

Apparatus: Basket Rack

Assembly: 1000 mL Beaker at 37 ± 2 degrees
• Basket rack
assembly
composed of 6
cylindrical tubes
with 10-mesh
wire cloth at
botom portion
and disks
Liquids used in disintegration
oWater,
osimulated gastric fluid (PH = 1.2 HCl),
oSimulated intestinal fluid (PH = 7.5, KH2PO4
(phosphate buffer) + pancreatin enzyme +NaOH)
• Limits:
For Uncoated tablets:
Medium Temperatur Time limit
e
According to U.S.P. Simulated 37 Not exceed
gastric fluid 30min

According to B.P. water 37 ± 2 ֯C Not exceed

15min
U.S.P. method for uncoated tablets:
oStart the disintegration test on 6 tablets.
oIf 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).

Acceptance Criteria:
oNot less then 16 tablets disintegrate completely within the
time
oif more than two tablets (from the 18) fail to disintegrate,
the batch must be rejected.
For Coated tablets:
oTo remove or dissolve the coat, immerse the tablet in distilled
water for 5min.
oPut the tablet in the apparatus in water or HCl for 30min at 37 oC
(according to the U.S.P). If not disintegrated, put in intestinal
fluid.
oIf one or two tablets fail to disintegrate, repeat on 12 tablets.

Acceptance Criteria:
o 16 tablets from the 18 must completely disintegrate within the
time
o if more than two tablets (from the 18) fail to disintegrate, the
batch must be rejected.
U.S.P. Method for Enteric coated tablets:

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

o Then put in simulated gastric fluid (0.1M HCl) for one hour.
o Then put in simulated intestinal fluid for two hours.
o If one or two tablets fail to disintegrate, repeat this test on
another 12 tablets.

Acceptance Criteria:
o 16 tablets from the 18 must completely disintegrate within the
time
o if more than two tablets (from the 18) fail to disintegrate, the
batch must be rejected.
 Important note:
To be in compliance with the USP standards, the tablets must disintegrate, and all
particles must pass through the 10-mesh screen in time specified.
If any residue remains, it must have a soft mass with no palpably firm core.

Disintegration times is running for (uncoated tab., plain- coated tab., enteric
coated tab., buccal tab., and sublingual tab.).
i. Uncoated USP tablets (disintegration time 5 min (aspirin tablets)), but majority
of the tablets have a maximum disintegration time of 30 min.
ii. Enteric coated tablets are not to disintegrate after 1 hr in simulated gastric
fluid. The same tablets are then tested in simulated intestinal fluid and are to
disintegrate in 2 hrs plus the time specified in the monograph.
D.
DISSOLUTION.
Since disintegration test offers
no assurance that the resultant
particle will release the drug in
solution at an appropriate rate

Dissolution tests and test

specifications have now
developed for nearly all tablet
products.
 Dissolution
Is a physicochemical process by which a solid substance enters the solvent phase
to yield a solution.

Temperature: 37 ± 0.5 degrees

o Apparatus 1 – Basket (37oC)
o Apparatus 2 - Paddle (37oC)
o Apparatus 3 – Reciprocating Cylinder (37oC)
o Apparatus 4 – Flow through Cell (37oC)
o Apparatus 5 – Paddle over Disk (32oC)
o Apparatus 6 – Rotating Cylinder (32oC)
o Apparatus 7 – Reciprocating Holder
 PURPOSE OF
DISSOLUTION
• To show that the release of drug from the tablet is close to
100%.
• To show that the rate of drug release is uniform batch to
batch.
• And to show that release is equivalent to those batches
proven to be bioavailable and clinically effective.
HISTORY OF DISSOLUTION
•Started in 1897 with the first
reference to dissolution:
•Noyes and Whitney published a paper
on "The Rate of Solution of Solid
Substances in Their Own Solution."
They suggested that the dissolution
rate was controlled by a layer of
saturated solution that forms
instantly around a solid particle.
HISTORY OF DISSOLUTION
• 1904 - Nernst and Brunner modified the
Noyes-Whitney equation by applying
Fick's law of diffusion.

• 1930 - Experiments begin with in vivo-In

vitro correlations
HISTORY OF DISSOLUTION

• 1934 - Switzerland's Pharmacopoeia

Helvetica was the first regulatory
body to introduce a disintegration test
for tablets.
HISTORY OF DISSOLUTION
• 1950 - Disintegration became an official USP
Method, USP 14.
- Emphasis moved from studying the effects
of physiochemical properties of drugs on
dissolution to correlation of dissolution to
bioavailability of dosage forms.
HISTORY OF DISSOLUTION
• 1960 - Levy and Hayes, utilizing a beaker and a
three blade stirrer at 30-60 RPM, found significant
differences in the in vitro dissolution rates of
different brands of aspirin tablets and linked them
to the incidence of gastrointestinal irritation
caused by various brands due to their slow
dissolution rates.
HISTORY OF DISSOLUTION

• 1970 - USP 18 incorporated the first

official dissolution test for solid
dosage forms. Twelve Monographs
published in USP-NF with the official
dissolution test - a rotating basket.
HISTORY OF DISSOLUTION

• 1990 - Paddle over disk, Rotating

Cylinder and Reciprocating Disk.

• 1995-Reciprocating Cylinder and Flow

through cell
 COMMON CONDITION
o _________________ and _________________ at 37 ± 0.5
degrees Celcius
o Fixed speed agitator.
o Screen for separation of disintegrated particles from the
bulk.
 COMMON CONDITION
Plain, coated tablet and capsules Water: 30 minutes

Water: 5 minutes soaking (if it contains soluble coatings)

Simulated Gastric juice: 1 hour in, and
Enteric coated tablet Simulated Intestinal Juice: as specified in monograph (usually
1 hour)

Buccal tablet Water: 4 hours

Sublingual tablets Water: 3 minutes (or as specified in monograph)

 Dissolution
Tolerance (Q): Amount of dissolved active ingredient

STAGE SAMPLES ACCEPTANCE CRITERIA

S1 6 Each unit is not less than the Q.
Average of 12 units is equal to or greater
S2 +6 than the Q and no unit is less than the Q-
15%
Average of 24 units is equal to or greater
S3 +12 than Q and no more than 2 units are less
than Q-15% and no unit is less than Q-25%.
 CLASSIFICATION OF
DISSOLUTION APPARATUS
• Apparatus 1 – Basket (37oC)
• Apparatus 2 - Paddle (37 C)
o

• Apparatus 3 – Reciprocating Cylinder (37oC)

• Apparatus 4 – Flow through Cell (37oC)
 CLASSIFICATION OF
DISSOLUTION APPARATUS
• Apparatus 5 – Paddle over Disk (32oC)
Transdermal Delivery System, use paddle and
vessel from Apparatus 2 with a stainless steel
disk assembly to hold the transdermal on the
bottom of vessel
 CLASSIFICATION OF
DISSOLUTION APPARATUS
• Apparatus 6 – Rotating Cylinder (32oC)
Transdermal Delivery System, use Apparatus 1
except replace the basket with shaft with a
stainless steel cylinder element.
 CLASSIFICATION OF
DISSOLUTION APPARATUS
• Apparatus 7 – Reciprocating Holder
For Transdermal Delivery System and also a
variety of dosage forms.
 APPARATU
S1
• The assembly consist of the following:
 A covered vessel with cylindrical or hemispherical
bottom.
 A motor
 A metallic drive shaft
 A cylindrical basket
 The water bath
DRUG PRODUCTS:
1. Solid (Mostly floating)
2. Monodisperse (tablets)
3. Polydisperse (encapsulated
beads/capsules)

DISADVANTAGE:
Formulation may clog up to 40 mesh screen.
 APPARATU
S2
• In the Apparatus 2, the basket
is replaced with a stirrer.
• A small, loose wire helix may
be attached to the dosage
form that would otherwise
float.
• Standard Volume: 1 Litre

• Advantage: Easy to use and robust

• Disadvantage: Floating dosage forms

requires a sinker.
SINKERS
 APPARATU
S 3of the following:
• The assembly consist

 A set of cylindrical, flat-bottomed glass vessels.

 A set of glass reciprocating cylinder.

USEFUL FOR:
1. Tablets
2. Beads
3. Controlled Release Dosage Form

STANDARD VOLUME:
200 – 250 mL/installation
ADVANTAGE:
1. Can change speed
2. Easy to change the pH profiles
3. Hydrodynamics can be directly influence by
varying the dip rate

DISADVANTAGE:
Small Volume – 250mL
 APPARATU
 Reservior
S 4of the following:
• The assembly consist
 Pump for the dissolution medium
 Flow through cell
 A clamp
 An O-ring
 A water bath
USEFUL FOR:
1. Low solubility drugs
2. Micro-particulates
3. Implants
4. Suppository
ADVANTAGES:
1. Easy to change media pH because of
pump.

DISADVANTAGES:
Labor intensive
 APPARATU
S
• The paddle and vessel5assembly from
apparatus 2 with the addition of stainless
steel disk assembly.

• The temperature is maintained at 32 ±0.5oC

Apparatus 5 is not applicable to oral dosage forms but applicable to transdermal patch.
• Standard Volume : 900 mL

• Disadvantage :
- Disk assembly restricts the
patch size.
 APPARATU
• The vessel assemblySfrom
6 apparatus 1 except
to replace the basket and shaft with a
stainless steel cylinder stirring element and
to maintain the temperature at 32 ±0.5oC
• The dosage unit is placed on the cylinder at
the beginning of each test.

• The distance between the inside bottom of

the vessel and the cylinder is maintained at
25 +/- 2mm during the test.
 APPARATU
S7
• The assembly consist of the following:
 A set of volumetrically calibrated or tared solution
containers
 A motor and drive assembly to reciprocate the
system vertically
 A set of suitable sample holders.
As the other side goes up,
the other goes down.
 CONCLUSI
Dissolution test isON
done to verify the release
of drug in the solution from the dosage form
because certain excipient may affect the
release of drug.