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QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 1
QUALITY CONTROL OF
SOLID DOSAGE FORMS
Dosage Forms:
Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included.
They are designed to:
 Resist action by gastric fluids.
 Prevent Vomiting and Nausea
 Reduce or alleviate the undesirable taste and smell associated with oral administration.
 Achieve a high concentration of drug at target site.
 Produce a delayed or long-acting drug effect.
Solid Dosage Forms:
Solid dosage forms include  Tablets  Capsules  Granules  Powders
Tablets:
Tablets are solid dosage forms containing one or more active ingredients. They are unit dosage form.
They are obtained by single or multiple compression and may be coated or uncoated. They are usually
intended for oral applications but sometime they also have some alternative applications such as implants,
tablets for injection, irrigation or external use, vaginal tablets etc.
Capsules:
Capsules are solid dosage forms with hard or soft gelatin shells. They are of various shapes and sizes;
contain a single dose of one or more ingredients. They are intended for oral administration.
Powders:
A powder is intimate mixture of dry, finely divided drugs and/or chemicals that may be intended for
internal or external use.
Granules:
Granule is generic term used for small particle or grain, A granule is formed when small particles
gathered into longer, permanent aggregate in which the original particles can still be identified.
QUALITY CONTROL OF TABLETS
INTRODUCTION
• Tablets are solid preparation intended for oral administration containing unit dose of one or more
medicaments.
• Tablets are prepared by compressing uniform volume of particles through:
- Direct Compression - Wet Granulation
- Dry Granulation (Slugging and double compression)
• They are swallowed whole or dissolved/dispersed in water before administration.
QUALITY CONTROL TESTS FOR TABLETS
Quality control tests for tablets includes:
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 2
PHYSICAL TESTS CHEMICAL TESTS Official Tests Non-Official Tests
• Tablet Hardness
• Thickness and diameter
• Friability
• Disintegration test
• Weight variation
• Content uniformity
• Assay of active
ingredients
• Dissolution test
• Weight variation
• Disintegration
• Dissolution
• Drug content
• Hardness
• Friability
UNOFFICIAL TESTS
1. HARDNESS (“Crushing Strength Test”)
Definition: Tablet hardness has been defined as the force required to break a tablet in a diametric
compression test
 Significance of Hardness : Tablets require a certain amount of strength, or hardness to withstand
mechanical shocks of handling in manufacturing, packaging and shipping
 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.
Why do we measure hardness?
 To determine the need for pressure adjustments on the tableting machine.
 To determine the disintegration time.  To determine elasticity.
Factors Affecting the Hardness
1. Compression of the tablet and compressive force.
2. Amount of binder. (More binder à more hardness)
3. Method of granulation in preparing the tablet (wet method gives more hardness than direct
method, Slugging method gives the best hardness).
Equipment used in this test:
- Strong-cobb - Monsanto tester - Erweka - Pfizer units
- Schleuniger Hardness tester
- Monsanto hardness tester:
 Here, tablet is put between moving jaw and fixed jaw
 Moving jaw is moved and pressure is applied on tablet by
means of screw knob
 The point where tablet get break down, it is recorded by
means of scale
 The hardness is measured in Kg/cm2.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 3
Pfizer hardness tester:
 The Pfizer tester compresses tablet between a holding anvil and a piston connected to a force-
reading gauge when its plier-like handles are gripped
 The point where tablet gets break down, it is noted by reading gauze
Strong-Cobb:
 The tablet is placed between two jaws that crush the tablet
 The machine measures the force applied to the tablet and detects when it fractures
Strong-Cobb Erweka hardness tester Schleuniger Hardness tester
MECHANICAL TESTER
• Hardness is normally tested by mechanical tester now a days with automatic operation. Mechanical
tester measures resistance to crushing of tablets.
• Principle: Force is applied by a beam. One end of beam is attached to pivot controlled mechanically by
a motor. The other end rests on tablets. Motor moves the beam which applies force on tablets
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 4
. When the tablet breaks a micro switch stops the motor. Mechanical strength
is shown in the digital indicator.
HARDNESS SPECIFICATIONS
Sometimes the scale is in Newton (1 Newton = 9.8 kg)
 4-8 kg/cm2 for standard compressed tablet except Effervescent tablet,
Dispersible tablet, Oro dispersible tablet, Chewable tablet, etc.
 More than 8-12 kg/cm2 for sustain released tablet and controlled
release tablet.
 2.25-2.5kg/cm2---- Dispersible/ Chewable tablets.
2. THICKNESS AND DIAMETER
• It is determined by the amount of tablet material and the position of the punches in relation to each
other, during compression. The shorter the distance between the punches thickness, the greater the
pressure applied during compression and sometimes the harder the tablet
• Checking of thickness and diameter is usually an in-process quality control check during production.
Dimensional specifications of tablets are very important because of many reasons:
- Packaging requirements - Patient compliance
• Thickness is often related to tablet’s hardness.
• Thickness is set according to tablet weight.
FACTORS AFFECTING THICKNESS
 Size and size distribution
 Compression force
APPARATUS
• The apparatus used for this purpose are:
- Micrometer screw gauge - Vernier caliper
• Now a days digital micrometers are available.
Micrometer:
 Here, put the tablet between two anvils and read it’s thickness by scale.
 It is measured in micrometer(mm).
Vernier caliper:
 Here, tablet is put between two jaws of vernier caliper and measure thickness of tablet by reading
scale.
 It is measured in centimeter(cm).
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 5
Procedure:
1) Find zero error, zero correction and least count of Vernier calipers.
2) Place sliding jaw against upper step of object (tablet).
3) Open caliper jaws.
4) Turn lock screw.
5) Read measured value.
6) Draw the table of observations and conclude
THICKNESS SPECIFICATION
• Thickness of tablet varies from 2 – 4 mm depending upon diameter of tablet.
• A deviation of ± 5% from stated diameter is allowed except that for exceeding 12.5 mm.
• For 12.5 mm or above deviation is ± 3%
DIAMETER SPECIFICATION
• Thickness of tablet varies from 4– 14 mm depending upon diameter of tablet. (Non-official)
• A deviation of ± 5% from stated diameter is allowed except that for exceeding 12.5 mm.
• For 12.5 mm or above deviation is ± 3%
3. FRIABILITY
• Definition: 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.
• Friction and shock during tableting can cause tablet to chip, cap and break. Loss of weight due to
abrasion of friction is the measure of tablet’s friability.
PURPOSE:
 To evaluate the ability of the tablets to withstand the breakage during the transportation and
handling.
 Friability testing is a method, which is employed to determine physical strength of uncoated
tablets upon exposure to mechanical shock and attrition.
• The apparatus used for the purpose is: - Roche Friabilator
ROCHE FRIABILATOR
• It consists of hard plastic cylinder of 6-inch radius. Motor which rotates cylinder at constant speed.
• A drum of transparent synthetic polymer with polished internal surfaces. One side of the drum is
removable. The tablets are tumbled at each turn of the drum by a curved projection that extends from the
middle of the drum to the outer wall.
• Internal diameter 283-291mm, Depth 36-40mm, A curved projection with an inside radius b/w 75.5-
85.5mm that extent from middle of the drum to outer wall from where tablets are tumbled., Drum is
rotated at 25± 1rpm., Thus at turn, tablets rolls or slide, and fall onto the drum wall or onto each other.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 6
• If tablet size or shape causes irregular tumbling, adjust the drum base so that the base forms an angle of
about 10° with the horizontal and the tablets no longer bind together when lying next to each other, which
prevents them from falling freely.
• Effervescent tablets and chewable tablets may have different specifications as far as friability is
concerned. In the case of hygroscopic tablets, a humidity-controlled environment is required for testing.
• For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding
as near as possible to 6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole
tablets. The tablets are 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.
• Generally, the test is run once. If obviously cracked, cleaved, or broken tablets are present in the tablet
sample after tumbling, the sample fails the test. If the results are difficult to interpret or if the weight loss
is greater than the targeted value, the test is repeated twice and the mean of the 3 tests determined. A
maximum loss of mass (obtained from a single test or from the mean of 3 tests) not greater than 1.0 per
cent is considered acceptable for most products.
Procedure for friability testing
1. Select 20 tablets randomly, dedust and weigh them.
2. Cumulative weight is recorded.
3. Tablets are rotated in Friabilator for 4 minutes 100 revolutions at constant speed. (25rpm)
4. At the end of procedure ,remove tablets from the apparatus , de-dust an weigh again.(Any tablet
that breaks up should be rejected before weighing )
5. Tablets are weighed and compare to original weight.
6. Value of friability (or weight loss) expressed as percent w/w.
% Friability can be calculated by following formula-
% Friability = W1 – W2/W1 × 100
Where, W1 = weight of tablets before testing
W2 = weight of tablets after testing
SPECIFICATIONS OF FRIABILITY
• The USP states that the friability should be 0.8 – 1%.
• For effervescent, chewable, or dispersible tablets % friability should be greater than 1.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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4. WEIGHT VARIATION TEST
• Compression weight, actual weight of tablet is determined by the diameter of the die and weight
adjustment came on tablet compression machine.
• The weight of the tablets being made should be routinely measured to help ensure that the tablet
contains the proper amount of the drug. Within the composite samples which has an acceptable average
weight, there could be tablets excessively overweight or underweight
• Weight control on tablet is continuously checked and adjusted during compression of whole batch. It is
normally done on uncoated tablets.
APPARATUS
• Digital weighing balances are used for the purpose.
PROCEDURE FOR WEIGHT VARIATION
• Take 20 tablets at random from the given batch.
• Weigh the 20 tablets individually.
• Determine average weight of the tablets.
• Note down the deviation in weight for each tablet (may be + or -).
• Determine %age deviation for the individual tablet by using the formula:
%Deviation = Deviation in weight/ Average weight × 100
• Compare the percentage deviation with the specification given in official table (B.P. or U.S.P.)
CAUSES OF WEIGHT VARIATION
1. The size & distribution of the granules being compressed (presence of too large or too fine
granules).
2. Poor flow and high-speed turret speed (incomplete filling of die),
3. Poor mixing. (Sometimes the lubricants & glidants have not been well distributed).
4. When lower punches are of unequal lengths, the fill of each die varies because the fill is
volumetric
5. Demixing or segregation of powder constituents of different crystallinity, size and densities; in
direct compression
WEIGHT VARIATION SPECIFICATIONS
• Not more than two of individual weights should deviate by more than given percentage.
• And none should deviate by more than twice that percentage.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 8
 If we are using 20 tablets, then according to U.S.P., not more than 2 tablets show % weight variation
and no tablet differs by more than double that percentage
 If we are taking 10 tablets, then according to U.S.P., not more than 1 tablet show % weight variation.
OFFICIAL TESTS
1. DISINTEGRATION TEST
• It is the time required for the tablet to break into particles, the disintegration test is a measure only to the
time required under a given set of conditions for a group of tablets to disintegrate into particles.
• Complete disintegration is defined as that state in which any residue of the tablet, except fragments of
insoluble coating remaining on the screen of the test apparatus. Soft mass having no firm core
remains.
• It is done because of following reasons:
- To ensure product uniformity
- Attempts are made to simulate in-vivo conditions. Actually, test does not correlate with physiological
conditions.
- It is done as a process control.
DISINTEGRATION APPARATUS
• Basket rack assembly
• Discs
• Thermostat
• Suitable vessel of immersion fluid
• Immersion fluid
• A motoring device for raising and lowering the basket
assembly in fluid
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 9
BASKET RACK ASSEMBLY
• It consists of six open ended glass tubes each 7.5 ± 0.25 cm long and inside diameter approx. 21.5 mm
and wall thickness are approx. 2mm.
• Tubes are held vertically with the help of two plastic plates each about 9 cm in diameter and 6 mm in
thickness. Plastic plates consist of 6 holes each about 24 mm diameter, equidistant from the center of
plate and equidistant from each other.
• 10 mesh (sieve opening 2 mm) and gauge woven stainless steel wire cloth is attached with screws to the
under surface of lower plate. Glass tubes and upper plastic plates are screwed in position by means of
stainless-steel plate of diameter 9 cm and 1 mm thick. Central shaft 8 cm in length upper end of which
terminates in an eye through which a string or wire may be inserted. Plates are assembled rigidly with
bolts through two plastic plates.
• Design of plastic assembly may vary between manufacturers but must comply with specifications.
DISCS
• The decision to include plastic discs is based on the specific gravity of the tablets to take care of floating
tablets. Slotted and perforated discs of 9.5 ± 0.15 min thickness and 20.7 ± 0.15 mm in diameter.
• They are made up of transparent material, specific gravity between 1.18 and 1.20. Equally distant 4 V
shaped notches in parallel to cylindrical axis. All surfaces of the discs of smooth. Five 2 mm holes are
drilled perpendicular to the cylindrical axis. One-hole pass through cylindrical axis other 4 are parallel to
it with distance 2 mm apart.
THERMOSTAT
• For heating the fluid between 35℃ to 39℃.
DEVICE FOR LOWERING AND RAISING BASKET RACK ASSEMBLY
• Up and down cycles performed at rate between 28 and 32 cycles per minute through a distance of not
less than 5 cm and not more than 6 cm.
• Volume of fluid in vessel is adjusted as such that the highest point of upward stoke the wire mesh
remains 2.5 cm from the bottom of vessel. One of downward stoke do not descend to not less than cm
from the bottom of vessel.
• Time required for upward stoke should be equal to time require for downward stoke. The change in
stoke direction should be smooth.
IMMERSION FLUID
• Water: use distilled water
• Hydrochloric acid: use ACS reagent code
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 10
• Sodium chloride: use ACS reagent code
• Pepsin
• Potassium phosphate, monobasic: use ACS reagent code
• Pancreatin: a USP grade
• Hydrochloride solution (0.1M): dilute 8.5 ml of HCl to 1000 ml with water or dilute a commercial
volumetric solution with water to obtain a final concentration of 0.1M.
• Sodium hydroxide (0.2M): use ACS reagent grade. Dissolve 8g of sodium hydroxide in and dilute to
1000 ml with carbon dioxide free water or dilute a commercial volumetric solution with carbon dioxide
free water to give a final concentration of 0.2M.
• Simulated gastric fluid: dissolve 2.0g of sodium chloride and 3.2 g of pepsin in 500 ml of water and
7.0 ml of HCl and dilute to 1000 ml with water. The pH is about 1.2
• Simulated intestinal fluid: dissolve 68g of potassium phosphate monobasic in 250 ml in water. Add
10.0g of pancreatin mix and adjust the pH of the resulting solution to 7.5 ± 0.1 with NaOH (0.2M) dilute
with water to 1000 ml.
UNCOATED AND PLAIN COATED TABLETS
BP METHOD FOR UNCOATED AND PLAIN COATED TABLETS
• Assemble the apparatus when the devise for arising a lowering the basket rack assembly in at rest and its
cylinder in the extreme down position.
• With 2.5 L or appropriate amount of water in the cylindrical jar, adjust the apparatus until the level of
fluid in the jar coincides approximately with the mid-line of the upper plastic plate.
• Maintain the temperature of the fluid at 37 ± 2℃ by suitable means.
• Remove the basket rack assembly form the water and disassemble.
Procedure:
1. Select at random six tablets from the sample and place one in each of the tubes of the basket rack
assembly.
2. Place a plastic disk on each tablet according to the specific gravity of tablet.
3. Reinsert the assembly in the water and set the machine in motion.
4. The plastic discs should travel and up and down freely exerting a gentle rubbing action on each
tablet. After 15 minutes remove the basket rack assembly from the water.
5. Uncoated tablets pass the test if each of the six uncoated tablets disintegrates in not more than 15
minutes.
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the total of 18 tablets tested disintegrate completely.
• Plain coated tablets pass the test if each of the six plain coated tablets disintegrate is not more than 60
minutes. If any of the tablets has not disintegrated at the end of 60 minutes, repeat the test of further six
plain coated tablets replacing the water in the cylindrical jar with HCl (0.1M). The tablets pass the test if
each of the six tablets disintegrates within 60 minutes in the acid medium.
USP METHOD FOR UNCOATED TABLETS
• Start the disintegration test on 6 tablets.
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the totals of 18 tablets tested disintegrate completely.
• If more than 2 tablets (from 18) fail to disintegrate the batch must be failed.
USP METHOD FOR COATED TABLETS
• To remove or dissolve the coat immerse the tablet in distilled water for 5 minutes. Put the tablet in the
apparatus is water or HCl for 30 minutes at 37℃. If not disintegrated put in intestinal fluid.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 11
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the total of 18 tablets tested disintegrate completely.
• If more than 2 tablets (from 18) fail to disintegrate the batch must be failed.
ENTERIC COATED TABLETS
BP METHOD FOR ENTERIC COATED TABLETS
• Assemble the apparatus as described using 2.5 L of simulated gastric fluid in place of water. Remove
the basket rack assembly from the simulated fluid and disassemble.
• Select at random six tablets from the sample and place one in each of the tubes of the basket rack
assembly. Place a plunger in each tube as specified (omitting the plastic disc). Insert the assembly in the
simulated gastric fluid and set the machine in motion.
• At the end of 30 minutes of operation, remove the basket rack assembly from the fluid and gently rinse
with water. Enteric coated tablets fail the test if any of tablet show distant evidence of disintegration.
• Replace the simulated gastric fluid in the jar with 2.5 L of simulated intestinal fluid. Remove the
plungers, place a plastic disc on each tablet, and re-insert the plunger. Continue the test by setting the
machine in motion.
• After 30 minutes remove the basket rack assembly from the fluid. Enteric coated tablets pass the test
each of the six tablets disintegrates in not more than 30 minutes in the simulated intestinal fluid.
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the total of 18 tablets tested disintegrate completely.
USP METHOD FOR ENTERIC COATED TABLETS
• Put in distilled water for 5 minutes to dissolve the coat. Then put it in simulated gastric fluid (0.1M HCl)
for 1 hour. Then put it in simulated intestinal fluid for 2 hours.
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the total of 18 tablets tested disintegrate completely.
• If more than 2 tablets (from 18) fail to disintegrate the batch must be failed.
BUCCAL TABLETS
• Apply the test for uncoated tablets, but omit the use of disc. After 4 hours, lift the basket from fluid and
observe the tablets all of the tablets should be disintegrated.
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the total of 18 tablets tested disintegrate completely.
SUBLINGUAL TABLETS
• Apply the test for uncoated tablets but omit the use of disc. Observe the tablets within the time limit
specified in individual monograph; all the tablets have disintegrated.
• If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16
of the total of 18 tablets tested disintegrate completely.
EFFERVESCENT TABLETS
•Place 1 tablet in a beaker containing 200 ml of water at (15-25°C; the tablet should evolve bubbles and
when the evolution of gas around the tablet stops, the tablet has disintegrated.
•The same procedures are performed for other 5 tablets.
•The tablets comply with the test if each of the six tablets used disintegrated within 3 min or as justified.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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2. DISSOLUTION TEST
• It is a process by which solid enters into solution. It is one of the most important QC tests. Dissolution
test represents in-vivo drug dissolution however far from being understood properly. Therapeutic
deficiency cannot rely on dissolution test alone.
In considering drug absorption one must consider:
- Total dose required
- Water and/or oil solubility
- pKa of drug
• Dissolution is directly related to solubility. Drugs that
have solubility greater than 1% (1 w/v) are generally no
problem. It is applied primarily to those drugs which
have low solubility. There is rapid increase in
dissolution testing of different dosage form in official
pharmacopoeias.
• Since drug absorption and physiological availability
are largely dependent upon having the drug in dissolve
state suitable dissolution characteristic are an important
property of QC. Usually, method of dissolution and
specifications are given in individual monographs
DOSAGE FORMS TO BE TESTED
• Immediate release dosage forms
• Controlled release dosage forms
• Transdermal systems
• Implants
OFFICIAL DISSOLUTION MONOGRAPHS
• United States Pharmacopoeia USP XXX (30)
• European pharmacopoeia
• Ph. Eur. 5th edition supplement 5.3
• British Pharmacopoeia BP 2007
• Japanese Pharmacopoeia JP XIV (14)
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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OFFICIAL DISSOLUTION
APPARATUSES
According to USP 7 types of apparatus are
used which are as follow:
1. Rotating basket
2. Paddle
3. Reciprocating cylinder
4. Flow through cell
5. Paddle over disk
6. Rotating cylinder
7. Reciprocating holder
SELECTION OF APPARATUS
• The choice of the apparatus is based on
one’s knowledge regarding the formulation
design, dosage form and performance. Besides the selection of an adequate dissolution apparatus
adequate test conditions are crucial for all purposes.
• It depends upon one’s intention
DISSOLUTION MEDIUM
Test is begun with aqueous media of pH 1.2-6.8. Simple water is usually not recommended due to the
ionic strength and pH can be vary. Different type of dissolution medium are as follow:
i. Water or medium pH less than 6.8 with addition of purified pepsin (protease activity)
ii. Medium with pH 6.8 or greater or pancreatic medium can be added (Intestinal environment)
iii. 0.1N HCl with pH 1.2
iv. Acetate buffer with pH 4.5
v. Phosphate buffer with pH 6.8-7.5
vi. Delayed release dosage form pH 6.8
QUALITY CONTROL
• Examining batch homogeneity
• Examining batch to batch conformity
• Examining stability
RESEARCH AND DEVELOPMENT
• Examining drug release behavior in preformulations
• In-vitro stimulation of the GIT passage
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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APPARATUS 1 – BASKET
• First official dissolution apparatus by USP in 1970.
• It is useful for capsules, bead, delayed release/ enteric coated dosage forms, floating dosage forms,
surfactants in media. The standard volume is 900/ 1000 ml. 1, 2- and 4-liter vessels.
• It consists of following parts:
- 1000 ml vessel
- A variable speed vessel
- Cylindrical stainless
-steel basket
- Water bath (whole assembly is immersed in it for keeping temperature constant at 37 ± 0.5℃
throughout the test).
- Vessel: it is made up of glass or any other inert transparent material. It is 1000 ml in volume capacity. It
has slightly concave bottom with 16cm height (internal height) and 10cm inside diameter. The slides are
flanged near top end to accept a fitted cover. Cover has four ports one of which is cantered for motor
shaft. One of the other ports is for thermometer. Other two ports are for sample removal for analysis and
one for addition/ replacement of dissolution medium.
- Variable speed motor: the shaft of the motor is placed in central port to facilitate the rotation of basket
assembly smoothly. Shaft is 6 mm in diameter and 30 cm in length. Motor speed is varied between 25
rpm – 200 rpm and to be maintained as described in individual monograph with ± 5%. Motor is
suspended in such a way that it may be raised or lowered to position the basket.
- Basket: assembly basket assembly consist of two parts:
▪ Part 1: it is attached to the shaft. It is solid metal except for 2 mm vent. It is fitted with three spring
clips that allows removal of lower parts or basket proper to admit test sample.
▪ Parts 2: it is detachable part consist of fabricated welded seam. It has 40 mesh stainless steel cloth
formed into cylinder shaped. Its height is 3.66 cm and diameter is 2.5cm.
▪ Basket also contain metal rim sheet at top. A gold-plated basket coating 0.0001 inch (2.5µm) thick is
recommended for tests carried out in dilute acid medium.
ADVANTAGES DISADVANTAGES
• It has a breadth of experience (more than 200
monographs)
• Full pH change during the tests
• It can be easily automated which is important
for routine investigations.
• Disintegration – dissolution interaction
• Hydrodermic dead zone under the basket
degassing is particularly important.
• Limited volume sink conditions for poorly
soluble drugs.
• Formulation can clog the mesh 40
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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APPARATUS 2 – PADDLE
• It is useful for tablets, capsules, beads, delayed release dosage forms, enteric coated dosage forms. Its
standard volume is 900/ 1000ml. it is normally the method of first choice. The coated material is inert.
The paddle is attached vertically to a variable speed motor that rotates at a controlled speed. The tablet is
placed into a round-bottom dissolution flask and the apparatus is housed in a constant temperature water
bath maintained at 37°C.Most common operating speeds are 50rpm for solid oral dosage forms and 25
rpm for suspensions.
ADVANTAGES DISADVANTAGES
• It is easy to use
• It is robust
• It is easily adapted to apparatus
• T has breadth of experience
• pH alteration is possible
• It can be easily automated which is important
for routine investigations
• pH/ media change is often difficult
• Limited volume, sink conditions for poorly
soluble drugs
• Hydrodynamics are complex, they vary with
site of the dosage form in the vessel (sticking,
floating) and therefore may significantly affect
drug dissolution.
• Sinkers for floating dosage form.
APPARATUS 3 – RECIPROCATING CYLINDER
 It is useful for tablets, beads, and controlled release dosage forms. Its standard volume is 200 –
250 ml per station. Place the stated volume (200-250 ml) of dissolution medium in each vessel
of the apparatus, assemble the apparatus, equilibrate the dissolution medium to 37±0.5 and
remove the thermometer Place one dosage form unit in inner cylinder taking care to exclude the
air bubbles from the surface of each dosage unit and immediately operate the apparatus as
specified in the monograph
 During the upward and downward stroke, the reciprocating cylinder moves through a total
distance of 9.9 to 10. 1cm.Within the time interval specified raise the cylinders and withdraw a
portion of the solution under test from a zone midway between the surface of the dissolution
medium and bottom of each vessel.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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ADVANTAGES DISADVANTAGES
• It is easy to change pH
• Huge pH profiles
• Hydrodynamics can be directly influenced by
varying the dip rate.
• Used during product development.
• It has small volume
• It has little experience and it provides limited
data
Apparatus 4- Flow through cell:
 The assembly consist of a reservoir and a pump for the dissolution medium; a flow through cell; a
water bath.
 The pump has delivery range between 240 and 960 ml per hour, with standard flow rates of 4,8
and 16 ml/minutes.
 The reservoir is immersed in a water bath and the temperature is maintained at 37°C ± 0.5 °C.
The flow through cell is transparent & inert mounted vertically with filters. Standard cell
diameters are 12 & 22.6 mm. The bottom cone usually filled with glass beads of 1 mm diameter
 Tablet holder used for positioning special dosage form.
PROCEDURE
1. Place the glass beads into the cell as specified in the monograph
2. Place one dosage unit on top of the beads or on a wire carrier.
3. Assemble the filter head and fix the parts together by means of a suitable clamping device
4. Introduce by the pump of the dissolution medium warmed to 37±0.5 through the bottom of the
cell to obtain the flow rate specified
5. Collect the elute by fractions at each of the times stated
6. Perform the analysis as directed in the individual monographs
ADVANTAGES DISADVANTAGES
• It is easy to change pH and media.
• pH profile is possible.
• No sink conditions.
• It has different modes; open and closed system.
• Deaeration is necessary
• High volume of media is required
• It is labor intensive process
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Apparatus 5; Paddle over Disk:
 The method is useful for the transdermal patches. The standard volume is 900 ml. This method is
used for testing the release of drugs from transdermal products.
 The apparatus consists of a sample holder or disc assembly that holds the product.
 The entire preparation is placed in a dissolution flask filled with specified medium maintained at
32ºC. The paddle is placed directly over the disc assembly.
 The disk assembly holds the system flat and is positioned such that release surface is placed
parallel with the bottom of the paddle blade.
 Vessel is covered to minimize evaporation during test.
 Samples are drawn midway between the surface of dissolution medium and the top of the paddle
blade at specified times.
ADVANTAGE DISADVANTAGE
• Standard apparatus (paddle) can be used, only
add a stainless-steel disk assembly
• Disk assembly restricts patch size.
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APPARATUS-6 (ROTATING CYLINDER):
 Use the assembly from apparatus 1 except to replace the basket
and shaft with a stainless-steel cylinder stirring element.
 The temperature is maintained at 32±0.5°C
 The dosage unit is placed on the cylinder with side out.
 Place the cylinder in the apparatus and immediately rotate at the
rate specified in the individual monograph.
 Samples are drawn midway between the surface of the
dissolution medium and the top of the rotating cylinder for
analysis.
 The distance between inside bottom of the vessel and the
cylinder is maintained at 25±2 mm during the test
Apparatus 7 (Reciprocating disk):
 The assembly consists of a set of volumetrically calibrated solution
containers made of glass or suitable inert material, a motor, a drive
assembly used to reciprocate the system vertically.
 The samples are placed on the disk-shaped holders.
 The test is carried out at 32°C.The reciprocating frequency is
30cycles/min.
Dissolution testing and interpretation standard USP:
Q* is amount of dissolved active ingredient specified in individual monograph, expressed as a percentage
of the labeled content. **Percent of labeled content
DISSOLUTION TESTING FOR VARIOUS DOSAGE FORMS
• Solid dosage forms include:
- Immediate release dosage forms (tablets and capsules)
- Delayed release
- Dosage forms for oral cavity:
▪ Buccal/ sublingual tablets
▪ Medicated chewing gums
• Suppositories
Sr.
No.
Quantity
stage /level
Number
of tablets
tested
Acceptance criteria
1 S1 6 Each unit not less than Q*+5 percent**
2 S2 6 Average of 12 units (S1+S2) is equal to greater than
(>) Q and no unit is less than Q-15 percent**
3 S3 12 Average of 24 units (S1+S2+S3) is equal to greater
than (>) Q, not more than 2 units less than Q-15
percent** and no unit is less than Q-25 percent**
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• Semisolid dosage forms
• Soft gelatin capsules
DISSOLUTION TESTING FOR IMMEDIATE RELEASE (IR) DOSAGE FORM
• Immediate release dosage form is designed to deliver the drug rapidly into the systemic circulation.
Therefore, the dissolution may be the rate limiting step for the absorption. Generally, dissolution of IR
dosage forms is being conducted using apparatuses of basket, paddle, reciprocating cylinder and flow
through cell. The apparatus 1 and 2 are most commonly used.
• USP uses basket, paddle, EP uses paddle basket and flow through cell apparatuses for solid dosage
forms of tablets, capsules. The dissolution test is carried out at 37℃ ± 0.5℃. In general, when basket
apparatus is used rotation speed is 100 rpm with 40 mesh screen of the basket is used.
• Paddle apparatus is used for tablets. Operating speed of 50 is used in general.
PROCEDURE
Method I
• Unless otherwise directed in the individual monograph, place 900ml fluid in the dissolution vessel.
Vessel should previously be immersed in water bath and allow dissolution temperature to come at 37℃ ±
0.5℃.
• Place one tablet or one capsule in the basket so that there is distance of 2.0 ± 0.2 cm between basket and
bottom of vessel. Rotate the basket at a rate specified in the monograph. Withdraw sample at the time
indicated and analyze them by procedure described in the individual monograph. The dissolution testing
is done in three stages of S1, S2, and S3.
Specifications
• In stage 1, 6 units are taken and the amount of drug from each unit should not be less than Q + 5%
where Q is the maximum amount of drug dissolved active ingredient specified in individual monograph.
Failure of first stage (if one or two tablets fail to comply) compensates to conductance of second stage S2
where additional 6 units are tested.
• The avg. of 12 units in two stages should be equal to or greater than Q and no unit should be less than Q
– 15%. Failure of stage 2 leads to conductance of stage S3 where additional 12 units are tested and the
avg. of total units of three stages S1, S2 and S3 should be greater than or equal to Q and no two units
should be less than Q – 15% and none should be less than Q – 25%.
METHOD II
• Use apparatus described under tablet disintegration with some changes. Replace 10 mesh stainless steel
cloth in basket rack assembly with 40 mesh also, to the top of the assembly to provide for immersion in
the dissolution medium.
• Adjust the apparatus so that it descends to 1 ± 0.1cm from bottom of the vessel on download stoke. Use
dissolution as specified in individual monograph.
• Apply the test firstly on 6 unit, if one or two tablets fails the specification then perform test on 6
additional tablets. 10 out of 12 should pass the specification.
DISSOLUTION TEST FOR DOSAGE FORMS OF THE ORAL CAVITY
• Development of dissolution method for these dosage forms possess several challenges due to short
residence time of dosage form in the mouth and limited volume of dissolution medium for dissolving the
dosage form.
DISSOLUTION TEST FOR CHEWABLE TABLETS
• USP insisted the use of apparatus 2 for dissolution excepting ampicillin where apparatus 1 is
recommended and carbamazepine where apparatus 2 and 3 are used.
• The design of apparatus should consist of a mechanical breakage of tablet prior to dissolution.
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DISSOLUTION TEST FOR BUCCAL/ SUBLINGUAL TABLETS
• Initially USP stated the use of disintegration apparatus for the ergotamine category sublingual products.
Later modified USP 3 apparatus with 20 strokes/ min was used for hydrocortisone mucoadhesive tablets
to mimic the low dissolution volume of in-vivo.
• Later another system continuous flow through filtration cell with dip tube for filtration. 10 ml of fluid is
pumped to give a short residence time of 8 minutes.
DISSOLUTION TEST FOR CHEWING GUMS
• USP has not recommended any apparatus for dissolution testing of chewing gums, but EP has
emphasized on the use of 3 piston apparatus that chews the gum at a rate of 60 cycles/ min in dissolution
medium of pH 6.0 at 37℃.
• Still controversies regarding this issue are existing and urges for development of an appropriate
apparatus.
3. CONTENT UNIFORMITY
• The content uniformity test is done to ensure that each dosage form contains the exact stated amount of
drug within a batch.
Mainly it is used for testing the consistency of:
o Bulk powders before or after compression
o Liquid orals before filling
o During filling of powders into capsules or liquids into vials and ampules
o Amount of API within individual unit of tablet and capsule
• Only when the ingredient of the tablet granulation is homogenous, tablet weight test as described earlier
can be considered as measure of drug content.
• Routinely the assay of the drug content in tablets involve the grinding of tablet of large sample of tablets
followed by the analysis of an aliquot. Normally testing is confirmed by performing specific assay to
determine the content of drug material contained in particular dosage form. Results obtained are
expressed as percentage of active ingredient in the tablet or on individual tablet basis. Different
pharmacopoeias describe the procedure of content uniformity test and giver their specifications.
CONTENT UNIFORMITY TEST USP
STAGE 1
• Take 10 units randomly and perform the assay. It passes the test if relative standard deviation is less
than 6% and no value is outside 85 – 115%. Fails the tests if one or more values are out of 75 – 125%.
STAGE 2
• Take 20 more units and perform the assay. Pass the test if RSD of all 30 tablets is less than 7.8%, not
more than one value is outside 85 – 115 % and no value is outside 75 – 125% or else, the batch fails the
test.
CONTENT UNIFORMITY TEST BP
TEST A
• The test is applicable for tablets, powders and parenteral use and suspensions for injection.
• Selects 10 units at random and perform the assay. Passes the test each individual unit is between 85 –
115% of the average content.
• Fails the test if more than one individual unit is outside these limits or if even one unit is outsides the
limit of 75 – 125% of the avg. content. But if one unit is outside the limit of 85 – 115 % and within 75 –
125 % then take another 10 units at random and perform the assay.
• The lot passes the test if not more than 1 unit of 30 units is outside 85 – 115% and not even one unit is
outside the limit of 75 – 125% of the avg. content.
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TEST B
• The test is used for capsules, powders, other than parenteral use, granules, suppositories and pessaries.
• Selects 10 units at random and perform the assay. Passes the test if not more than 1 individual unit is
outside the limits of 85 – 115% and none is outside the limits of 75 – 125%of the labelled content.
• The batch fails the test if more than 3 units are outside the limit of 85 – 115% or if one or more units are
outside the limits of 75 – 125% of the labelled content.
• If 2 or 3 units are outside the limits of 85 – 115% but within the limits of 75 – 125% then select another
20 units at random.
• The batch complies the test when not more than 3 units are out of these 30 units are outside the limits of
85 – 115% and not even one unit is outside the limits of 75 – 125% of the labelled content
TEST C
• The test is applicable to only transdermal patches.
• The preparation passes test only if the avg. content of 10 units is between 90 – 110% and if the content
of each unit is between 75 – 125% of the avg. content.
4. CHEMICAL ASSAY OF TABLETS
• Routinely the assay of the drug content in tablets involve the grinding of tablet of large sample of
tablets followed by the analysis of an aliquot. Representing the certain amount of drug normally in a
single unit.
• Analysis is performed by the methods prescribed in the individual monographs. Results obtained are
expressed in percentage of the active ingredient in the tablet or unit dose compared with limits in the
monograph of the drug.
• Common assay procedure involves:
- Titrimetric analysis
- Spectrophotometric methods
- UV spectroscopy
- HPLC
- Biological assay
- Microbial assay
TESTS FOR COATED TABLETS
• Water vapor permeability
• Film tensile strength
• Coated tablets evaluations
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QUALITY CONTROL
OF CAPSULES
DEFINITION:
Capsules are solid dosage forms in which one or more medicinal and inert ingredients are enclosed in
a Small Shell or container usually made of gelatin.
ADVANTAGES
▸ Capsules mask the taste and odour of unpleasant drugs and can be easily administered.
▸ They are slippery when moist and hence easy to swallow with a draught of water.
▸ As compared to tablets less adjuncts are required.
▸ The shells are physiologically inert and easily and quickly digested in the gastrointestinal tract.
They are economical.
▸ They are easy to handle and carry
▸ The shells can be opacified (with titanium dioxide) or coloured , to give protection from light
TYPES OF CAPSULE:
• Quality control tests for capsules includes:
- Weight variation
- Content uniformity
- Disintegration
- Dissolution
- Chemical or biological assay
DISSOLUTION TEST FOR CAPSULES
• Special type of basket rack assembly is used.
The apparatus consisting of:
- A glass tube 80 – 100 mm long with internal diameter of about 28mm and external diameter of 30-31
mm. At the bottom of the tube rust proof wire gauze (sieve # 1.7mm or 10 mesh) is attached to form a
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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basket. Wire gauze is fitted to the tube in such a manner that the overall diameter of the basket in not
materially increased.
- A glass cylinder with a flat base and an internal diameter of about 45mm used for disintegration media.
Cylinder contains water media not less than 15 cm deep maintained at the temperature 37±2℃ by suitable
means.
- Basket is raised and lowered repeatedly in a uniform manner so that at highest position the gauze breaks
the surface of water and at lowest position the upper rim of basket cylinder just remains clear of water.
Guiding disk made up of suitable material, lowering and raising device.
BP METHOD
• Place five capsules in the basket. Raise and lower the basket in such a manner that complete up and
down movement is repeated thirty times per minute.
• Capsules are disintegrated when no particle of any solid content remains above the gauze which would
not readily pass through it.
• Time required for capsules to disintegrate not more than 15 minutes unless otherwise stated in
individual monograph. If capsules fail the disintegration test because of aggregation, further five capsules
may be tested individually.
• The longest time taken by one of the five capsules is the disintegration time.
USP METHOD
• According to USP disintegration test is usually not require for capsules unless have been treated to resist
solution in gastric fluid (enteric coated). In this case they must meet the requirements of disintegration
test of enteric coated tablet i.e.
• Assemble the apparatus as described using 2.5 L of simulated gastric fluid in place of water. Remove
the basket rack assembly from the simulated fluid and disassemble.
• Select at random six capsule from the sample and place one in each of the tubes of the basket rack
assembly. Place a guided disc. Insert the assembly in the simulated gastric fluid and set the machine in
motion.
• At the end of 60 minutes of operation, remove the basket rack assembly from the fluid and gently rinse
with water. Enteric coated capsule fail the test if any of tablet show distant evidence of disintegration.
Replace the simulated gastric fluid in the jar with 2.5 L of simulated intestinal fluid.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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• Reinsert the guided disc. Continue the test by setting the machine in motion for 60 minutes. After 60
minutes remove the basket rack assembly from the fluid. Enteric coated tablets pass the test each of the
six tablets disintegrates in not more than 30 minutes in the simulated intestinal fluid.
2. WEIGHT VARIATION TEST FOR CAPSULES
• There are two methods for testing uniformity of weight of capsules:
METHOD A
• Method A is for capsules with dry content. Weigh a capsule, open it without loss of shell material,
remove the contents and weigh all parts of shell.
• The difference between the weights represents the weight of contents of capsule. Repeat the operation
with further 19 capsules (total 20).
• Capsules pass the test if not more than 2 capsules deviate from the mean weight by more than
percentage given in table.
• For one or two capsules (which are outside above given range) the weight of the content should not be
more than percentage given in the table below.
METHOD B
• The method B is for capsules containing liquid or base. Weigh a capsule, open it without loss of shell
material express as much of the contents is possible. Wash the shell with solvent ether, reject the washing.
Allow the shell to stand until all the odor of ether is no longer perceptible and weigh.
• The difference between the whole weight and shell weight represents in weigh of contents. Repeat the
operation with further 9 capsules (total 10) and calculate the average weight content of 10 capsules. The
weight of each capsule does not differ from the average weight by more than 7.5%. Except the one
capsule the weight of content may differ by not more than 15%.
• Regardless of the weight of content of this type of capsules the percentage deviation range should be
between ±7.5 – ±15%.
3. DISSOLUTION TEST
Definition It is a process by which solid enters into solution. Dissolution test represents in-vivo drug
dissolution
• The dissolution may be the rate limiting step in capsules absorption. Generally, the dissolution test of
capsules is conducted in paddle or basket assembly. USP uses basket, paddle, EP uses paddle, basket, and
flow through cell apparatuses for solid dosage forms of tablets and capsules. The choice of apparatus is
based on the knowledge regarding the size and type of capsules and selected according to individual
monograph.
• The dissolution test is carried out at 37℃ ± 0.5℃. In general, when basket apparatus is used rotation
speed is 100 rpm with 40 mesh screen of the basket is used. Other mesh sizes may also be used if
supported by necessary date documentation. It is generally used for capsules and floating type dosage
forms or to those which tend to disintegrate slowly. For floating type of dosage forms sinker may be used
to prevent the floating of capsules.
• Samples are withdrawn according to specifications with tolerance of ± 5%. The test is conducted on the
equipment which was pre-calibrated with USP salicylic acid and prednisone calibrator tablets (according
to USP).
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• The dissolution medium used should be deaerated and may be water, buffered aq. Solution of pH 4 – 8
and dilute acid of 0.001N to 0.1N HCl are used. The test time is 30 – 60 minutes and with a single point
specification or as specified in individual monographs.
PROCEDURE
• Unless otherwise directed in the individual monograph, place 900ml fluid in the dissolution vessel.
Vessel should previously be immersed in water bath and allow dissolution temperature to come at 37℃ ±
0.5℃.
• Place one tablet or one capsule in the basket so that there is distance of 2.0 ± 0.2 cm between basket and
bottom of vessel. Rotate the basket at a rate specified in the monograph. Withdraw sample at the time
indicated and analyze them by procedure described in the individual monograph.
• The dissolution testing is done in three stages of S1, S2, and S3. In stage 1, 6 units are taken and the
amount of drug from each unit should not be less than Q + 5% where Q is the maximum amount of drug
dissolved active ingredient specified in individual monograph.
• Failure of first stage (if one or two tablets fail to comply) compensates to conductance of second stage
S2 where additional 6 units are tested. The avg. of 12 units in two stages should be equal to or greater
than Q and no unit should be less than Q – 15%.
• Failure of stage 2 leads to conductance of stage S3 where additional 12 units are tested and the avg. of
total units of three stages S1, S2 and S3 should be greater than or equal to Q and no two units should be
less than Q – 15% and none should be less than Q – 25%
DISSOLUTION TESTING OF SOFT GELATIN CAPSULES
• USP has recommended the use of apparatus 1 and 2, but since there had been serious disadvantages
related, attempts had been made in literature to develop new methods for lipid filled soft gelatin capsules.
4. ASSAY OF ACTIVE INGREDIENTS IN CAPSULES
• Determine the amount of active ingredient by the method described in the assay.
• Calculate the amount of API in the mixed contents of the capsules taken and divide by the number of
capsules taken. The result should lie within the range specified in individual monograph.
• Sometime biological assay is described in the mono graph e.g., drugs of natural origin (vitamins,
antibiotics, insulin etc.).
4. MOISTURE PERMEATION TEST OF CAPSULES
• The USP requires determination of moisture-permeation characteristics of single-unit and unit dose
containers to assure their suitability for packaging capsules.
• The degree and rate of moisture penetration is determined by packaging the dosage unit together with a
colour revealing desiccant pellet
Desiccant
pellets
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
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Expose the packed unit to known relative humidity over a specified time
Observe the desiccant pellet for colour change
Any change in colour indicates absorption of moisture
By measuring pre-test weight and post-test weight of pellet, amount can be calculated.
QUALITY CONTROL
OF POWDERS
INTRODUCTION
▸ Powders are intimate mixture of dry finally divided drugs or chemicals that may be intended for
internal or external purposes
▸ Powder are solid dosage form of medicaments which are meant for internal and external uses
▸ They are available in amorphous or crystalline form
Drugs are prepared in different forms and shapes but many of them are prepared by using powder in one
way or the other.
POWDER FLOW
• The widespread use of powder in the pharmaceutical industries has generalized a variety of methods for
characterizing powder flow. Several references appear in the pharmaceutical literature attempting to
correlate the various measure of powder flow to manufacturing properties. The development of such a
variety of test methods was inevitable; powder behavior is multifaceted and thus complicates the efforts
to characterize the flow properties of the pharmaceutical powders.
• In addition, no single or simple method can adequately characterize the flow properties of
pharmaceutical powders.
• Four common reported methods for testing powder flow rate are:
1. Particle size analysis
2. Angle of repose
3. Compressibility index or Hausner ratio
4. Flow rate through an orifice
5. Shear cell
1. PARTICLE SIZE ANALYSIS
(ACCORDING TO USP) Powders may be course to very fine powders. Size analysis is done by sieving
method in specified time.
COARSE POWDER:
Particles pass through No. 20 sieve and not more than 60% through No. 40 sieve.
MODERATELY COARSE POWDER:
Particles pass through No. 40 sieve and not more than 60% through No. 60 sieve.
FINE POWDER:
Particles pass through No. 80 sieve. No limit as to greater fitness.
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VERY FINE POWDER:
Particles pass through No. 120 sieve. No limit as to greater fitness.
METHODS FOR DETERMINATION OF PARTICLE SIZE
I.SIEVING
A stack of different size sieves (Sieve No. 40, 60, 80, 100 and 120)
are placed tightly one over the other in such a manner that each
lower sieve has a small aperture size than that of the sieve above it.
Below the lowest sieve is placed a collecting tray. This assembly is
placed on mechanical shaker. Sample of 50gm of the drug is
placed in the upper most sieves and the top is then closed with a
lid. Then the shaker is operated for 5 minutes. In this way the
powders with different particle sizes is collected on each sieve and
stored separately
II. MICROSCOPY
In this method, small sample size is mounted on the stage of microscope and the particle size is measured
using the micrometer joined to it. Microscopy size range: 0.2 – 100 Micrometer.
III. SEDIMENTATION
Determined by measuring setting velocity of particles through liquid medium in gravitational or
centrifugal environment. It can be calculated by Stokes law using Andreasen pipette.
IV. LIGHT ENERGY DIFFRACTION
• Disperse particles in liquid/gas, sensing zone determines light reduction.
V. LASER HOLOGRAPHY
Pulsed laser is fired through an aerosolized particle spray and photographed in 3 dimensions with
holographic camera.
2. ANGLE OF REPOSE
• The angle of repose has been used in several branches of solid-state science to characterize the flow
properties of solid. Angle of repose is a characteristic related to inter particulate resistance or friction to
movement between particles.
Qualitative assessment of cohesive and frictional forces under levels of external loading, applied in
powder mixing, in tablet dye or capsule shell filling.
• “Maximum angle obtained between a freely standing
surface of powder heap and horizontal surface or
plane”
Angle of repose is determined by Funnel and Cone
method.
The funnel is fixed in place, 4 cm above the Petri dish
surface. Powder sample (5gm) is poured through funnel
and a cone is built. The height of cone (h) and the radius
(R) is measured. The angle of repose (θ) is calculated as
follows:
Angle of Repose (θ) = tan-¹ h/R
- Static angle of repose
- Drained angle of repose
- Dynamic angle of repose
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Static angle of repose
Static angle of repose is calculated by the use of funnel. The most common method of determining the
static angle of repose can be classified on the bases of following two important experimental variables;
1. The height of the funnel through which the powder passes may be fixed relative to the base or the
height may be varied as the pile forms.
2. The base upon which the pile forms may be of fixed diameter or the diameter of the powder cone may
be followed to vary as the pile forms.
Drained angle of repose
Drained angle of repose is determined by allowing an excess quantity of material positioned above a fixed
container base to drain from the container.
Formulation of a cone of a powder on a fixed diameter base allows determination of the drained angle of
repose.
Dynamic angle of repose
Dynamic angle of repose is calculated by filling a cylinder (with a clear flat cover at the end) and rotating
at a specific speed. The dynamic angle of a repose is an angle (relative to the horizontal) formed by the
flowing powder. The internal angle of kinetic friction is defined by the plane separating those particles
sliding down the top layer of the powder and those particles that are rotating with the drum (with
roughened surface).
Specifications
Although these is some variation in the qualitative description of powder flow using the angle of repose
much of the pharmaceutical literature appears to be consistent with the classification by Carr, shown in
the table.
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PROCEDURE FOR ANGLE OF REPOSE
• The base should be free from vibration. Vary the height of the funnel to carefully build up a symmetrical
cone of powder. Care should be taken to prevent vibration as the funnel moved.
• The funnel height should be maintained approximately 2 – 4 cm from the top of powder pile as it being
formed in order to minimize the impact of falling powder on the tip of the cone.
• If a symmetrical cone of powder cannot be successfully or reproducibly prepared, this method is not
appropriate. Determine the angle of repose by measuring the height of the cone of powder and calculating
the angle of repose from the following equation:
tanθ = height 0.5 / base OR θ = tan−1 h / R
FACTORS AFFECTING ANGLE OF REPOSE
• Angle of repose is affected by different coefficients of friction between different substances.
• The size of the particles is a factor. Other factors being equal, fine grained material will form a
shallower pile with a smaller angle of repose than coarse grains.
• Moisture affects the angle of repose.
• The method by which the angle of repose is measured can also affect the measurement.
3. COMPRESSIBILITY INDEX & HAUSNER RATIO
• It is simple, fast and popular method of determining powder flow characteristics. The compressibility
index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture
content, and cohesiveness of materials because all of these can influence the observed compressibility
index.
• The compressibility index and the Hausner ratio are determined by measuring both the bulk volume and
the tapped volume of powder.
• Although there are some variations in the method of determining the compressibility index and Hausner
ratio, the basic procedure is to measure:
- The unsettled apparent volume V0
- The final tapped volume V1 of the powder then tapping the material until no further volume changes
occur.
• The compressibility and Hausner ratio are calculated as follows:
Compressibility index = 100 × ( 𝑉0 − 𝑉1 / 𝑉0)
Hausner ratio = 𝑉1 / 𝑉0
Alternatively, the compressibility index and Hausner ratio may be calculated using measured values for
bulk density and tapped density as follows
Compressibility index = 100 × (ρbulk − ρtap /ρbulk)
Hausner ratio = ρtap / ρbulk
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• For compressibility and Hausner ratio the generally accepted scale of flow ability is given in the table:
• Compressibility index and Hausner ratio are not intrinsic properties of the powder. They are very much
dependent upon the methodology used.
• Recommended procedure for Compressibility index and Hausner ratio:
- Use a 250 ml volumetric flask with a test sample weight of 100g.
- Smaller weights and volume may be used but variations in the method should be described with the
results. An average of three determinations are recommended.
4. FLOW THROUGH AN ORIFICE
• The flow rate of a substance depends upon many factors some of which are particle related and some
related to the process.
• Monitoring the rate of flow of material through an orifice has been proposed as a better measure of
powder flowability. Of particular significance is the utility of monitoring flow continuously because
pulsating flow patterns have been observed even for free floating materials. Changes in the flow rate as
the container empties can also be observed.
RECOMMENDED PROCEDURE FOR FLOW THROUGH AN ORIFICE
• Flow through an orifice is generally measured as the mass per time flowing from any of a number of
types of containers (cylinders, funnels, hoppers). It can be used only for those materials having some
capacity to flow, it is not useful for cohesive materials.
• Provided that the height of the powdered bed is much greater than the diameter of the orifice, the flow
rate is virtually independent of the powder head.
- Use the cylinder as a container because the cylinder material should have little effect on flow.
- The configuration results in flow rate being determined by the movement of powder over powder rather
than powder along the wall of the container.
- Powder flow rate often increases when the height of the powder column is less than two times of the
diameter of the column.
- The orifice should be circular and the cylinder should be free of vibration.
• General guidelines for dimensions of the cylinder are as follows:
- Diameter of opening > 6 times of the diameter of the particles
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 31
- Diameter of the cylinder > 2 times the diameter of the opening
• For the opening in the cylinder use a flat faced bottom plate with an option to vary orifice diameter to
provide maximum flexibility and to better ensure the powder over powder flow pattern.
• Rate measurement can either be discrete or continuous. Continuous measurement using an electronic
balance can more effectively detect momentary flow rate variations.
GENERAL SCALE FOR FLOWABILITY FOR FLOW THROUGH AND ORIFICE • No
general scale is available because flow rate is critically dependent on the method used to measure it.
Comparison between the published results is difficult.
5. SHEAR CELL METHODS
• In an effort to put powder flow studies and hopper design on a more fundamental basis, a verity of
powder shear testers and methods that permit more thorough and precisely, defined assessment of powder
flow properties have been developed.
• Shear cell methodology has been used extensively in the study of pharmaceutical materials.
• From these methods a wide verity of parameters can be obtained including the yield loci representing
the shear stress and shear stain relationship. The angle of internal friction, the unconfirmed yield strength,
the tensile strength and the verity of divided parameters such as the flow factor and other flowability
indices.
• Because of the ability to move precisely control experimental parameters flow properties can also be
determined as a function of consolidation load, time and other environmental conditions.
BASIC METHODS FOR SHEAR CELL
• One type of the cell is the cylindrical shear cell that is split horizontally forming a shear place between
the lower stationary base and the upper movable portion of the shear cell ring. After powder bed
consolidation in the shear cell (using a well-defined procedure) the force necessary shear the powder bed
by moving the upper ring is determined.
• Annular shear cell designs offer some advantages over the cylindrical shear cell design including the
need for less material. A disadvantage, however, is that because of its design the powder bed is not
sheared as uniformly i.e., material on the outside of the annulus is sheared more than material in the inner
region.
QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2
PREPARED BY :HASNAT TARIQ (GDIP) 32
• A third type of shear cell, plate shear cell consists of a thin sandwich powder between a lower
stationary rough surface and an upper rough surface that is moveable.
• All of the shear cells have their merits and demerits. As with the other methods of characterizing powder
flow many variations are described in the literature.
• A significant advantage of shear cell methodology in general is a greater degree of experimental control.
6. MOISTURE CONTENT
• The amount of moisture present in the granule is called moisture content.
• Generally the granules contain 2 % of the moisture. It is required for the binding of the powders or
granules during compression.
• Determined by IR balance
Procedure
1. Sample placed in the balance and initial weight is determined
2. IR bulb is initiated and the moisture is removed via heating
3. Note the reading or final weight%
Formulae:
Moisture content= {(initial wt -final wt) /final wt}*100
% loss on drying = {(initial wt-final wt) /initial wt}*100

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QUALITY CONTROL OF SOLID DOSAGE FORMS (TABLETS , CAPSULES & POWDERS)

  • 1. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 1 QUALITY CONTROL OF SOLID DOSAGE FORMS Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to:  Resist action by gastric fluids.  Prevent Vomiting and Nausea  Reduce or alleviate the undesirable taste and smell associated with oral administration.  Achieve a high concentration of drug at target site.  Produce a delayed or long-acting drug effect. Solid Dosage Forms: Solid dosage forms include  Tablets  Capsules  Granules  Powders Tablets: Tablets are solid dosage forms containing one or more active ingredients. They are unit dosage form. They are obtained by single or multiple compression and may be coated or uncoated. They are usually intended for oral applications but sometime they also have some alternative applications such as implants, tablets for injection, irrigation or external use, vaginal tablets etc. Capsules: Capsules are solid dosage forms with hard or soft gelatin shells. They are of various shapes and sizes; contain a single dose of one or more ingredients. They are intended for oral administration. Powders: A powder is intimate mixture of dry, finely divided drugs and/or chemicals that may be intended for internal or external use. Granules: Granule is generic term used for small particle or grain, A granule is formed when small particles gathered into longer, permanent aggregate in which the original particles can still be identified. QUALITY CONTROL OF TABLETS INTRODUCTION • Tablets are solid preparation intended for oral administration containing unit dose of one or more medicaments. • Tablets are prepared by compressing uniform volume of particles through: - Direct Compression - Wet Granulation - Dry Granulation (Slugging and double compression) • They are swallowed whole or dissolved/dispersed in water before administration. QUALITY CONTROL TESTS FOR TABLETS Quality control tests for tablets includes:
  • 2. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 2 PHYSICAL TESTS CHEMICAL TESTS Official Tests Non-Official Tests • Tablet Hardness • Thickness and diameter • Friability • Disintegration test • Weight variation • Content uniformity • Assay of active ingredients • Dissolution test • Weight variation • Disintegration • Dissolution • Drug content • Hardness • Friability UNOFFICIAL TESTS 1. HARDNESS (“Crushing Strength Test”) Definition: Tablet hardness has been defined as the force required to break a tablet in a diametric compression test  Significance of Hardness : Tablets require a certain amount of strength, or hardness to withstand mechanical shocks of handling in manufacturing, packaging and shipping  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. Why do we measure hardness?  To determine the need for pressure adjustments on the tableting machine.  To determine the disintegration time.  To determine elasticity. Factors Affecting the Hardness 1. Compression of the tablet and compressive force. 2. Amount of binder. (More binder à more hardness) 3. Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness). Equipment used in this test: - Strong-cobb - Monsanto tester - Erweka - Pfizer units - Schleuniger Hardness tester - Monsanto hardness tester:  Here, tablet is put between moving jaw and fixed jaw  Moving jaw is moved and pressure is applied on tablet by means of screw knob  The point where tablet get break down, it is recorded by means of scale  The hardness is measured in Kg/cm2.
  • 3. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 3 Pfizer hardness tester:  The Pfizer tester compresses tablet between a holding anvil and a piston connected to a force- reading gauge when its plier-like handles are gripped  The point where tablet gets break down, it is noted by reading gauze Strong-Cobb:  The tablet is placed between two jaws that crush the tablet  The machine measures the force applied to the tablet and detects when it fractures Strong-Cobb Erweka hardness tester Schleuniger Hardness tester MECHANICAL TESTER • Hardness is normally tested by mechanical tester now a days with automatic operation. Mechanical tester measures resistance to crushing of tablets. • Principle: Force is applied by a beam. One end of beam is attached to pivot controlled mechanically by a motor. The other end rests on tablets. Motor moves the beam which applies force on tablets
  • 4. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 4 . When the tablet breaks a micro switch stops the motor. Mechanical strength is shown in the digital indicator. HARDNESS SPECIFICATIONS Sometimes the scale is in Newton (1 Newton = 9.8 kg)  4-8 kg/cm2 for standard compressed tablet except Effervescent tablet, Dispersible tablet, Oro dispersible tablet, Chewable tablet, etc.  More than 8-12 kg/cm2 for sustain released tablet and controlled release tablet.  2.25-2.5kg/cm2---- Dispersible/ Chewable tablets. 2. THICKNESS AND DIAMETER • It is determined by the amount of tablet material and the position of the punches in relation to each other, during compression. The shorter the distance between the punches thickness, the greater the pressure applied during compression and sometimes the harder the tablet • Checking of thickness and diameter is usually an in-process quality control check during production. Dimensional specifications of tablets are very important because of many reasons: - Packaging requirements - Patient compliance • Thickness is often related to tablet’s hardness. • Thickness is set according to tablet weight. FACTORS AFFECTING THICKNESS  Size and size distribution  Compression force APPARATUS • The apparatus used for this purpose are: - Micrometer screw gauge - Vernier caliper • Now a days digital micrometers are available. Micrometer:  Here, put the tablet between two anvils and read it’s thickness by scale.  It is measured in micrometer(mm). Vernier caliper:  Here, tablet is put between two jaws of vernier caliper and measure thickness of tablet by reading scale.  It is measured in centimeter(cm).
  • 5. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 5 Procedure: 1) Find zero error, zero correction and least count of Vernier calipers. 2) Place sliding jaw against upper step of object (tablet). 3) Open caliper jaws. 4) Turn lock screw. 5) Read measured value. 6) Draw the table of observations and conclude THICKNESS SPECIFICATION • Thickness of tablet varies from 2 – 4 mm depending upon diameter of tablet. • A deviation of ± 5% from stated diameter is allowed except that for exceeding 12.5 mm. • For 12.5 mm or above deviation is ± 3% DIAMETER SPECIFICATION • Thickness of tablet varies from 4– 14 mm depending upon diameter of tablet. (Non-official) • A deviation of ± 5% from stated diameter is allowed except that for exceeding 12.5 mm. • For 12.5 mm or above deviation is ± 3% 3. FRIABILITY • Definition: 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. • Friction and shock during tableting can cause tablet to chip, cap and break. Loss of weight due to abrasion of friction is the measure of tablet’s friability. PURPOSE:  To evaluate the ability of the tablets to withstand the breakage during the transportation and handling.  Friability testing is a method, which is employed to determine physical strength of uncoated tablets upon exposure to mechanical shock and attrition. • The apparatus used for the purpose is: - Roche Friabilator ROCHE FRIABILATOR • It consists of hard plastic cylinder of 6-inch radius. Motor which rotates cylinder at constant speed. • A drum of transparent synthetic polymer with polished internal surfaces. One side of the drum is removable. The tablets are tumbled at each turn of the drum by a curved projection that extends from the middle of the drum to the outer wall. • Internal diameter 283-291mm, Depth 36-40mm, A curved projection with an inside radius b/w 75.5- 85.5mm that extent from middle of the drum to outer wall from where tablets are tumbled., Drum is rotated at 25± 1rpm., Thus at turn, tablets rolls or slide, and fall onto the drum wall or onto each other.
  • 6. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 6 • If tablet size or shape causes irregular tumbling, adjust the drum base so that the base forms an angle of about 10° with the horizontal and the tablets no longer bind together when lying next to each other, which prevents them from falling freely. • Effervescent tablets and chewable tablets may have different specifications as far as friability is concerned. In the case of hygroscopic tablets, a humidity-controlled environment is required for testing. • For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding as near as possible to 6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets. The tablets are 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. • Generally, the test is run once. If obviously cracked, cleaved, or broken tablets are present in the tablet sample after tumbling, the sample fails the test. If the results are difficult to interpret or if the weight loss is greater than the targeted value, the test is repeated twice and the mean of the 3 tests determined. A maximum loss of mass (obtained from a single test or from the mean of 3 tests) not greater than 1.0 per cent is considered acceptable for most products. Procedure for friability testing 1. Select 20 tablets randomly, dedust and weigh them. 2. Cumulative weight is recorded. 3. Tablets are rotated in Friabilator for 4 minutes 100 revolutions at constant speed. (25rpm) 4. At the end of procedure ,remove tablets from the apparatus , de-dust an weigh again.(Any tablet that breaks up should be rejected before weighing ) 5. Tablets are weighed and compare to original weight. 6. Value of friability (or weight loss) expressed as percent w/w. % Friability can be calculated by following formula- % Friability = W1 – W2/W1 × 100 Where, W1 = weight of tablets before testing W2 = weight of tablets after testing SPECIFICATIONS OF FRIABILITY • The USP states that the friability should be 0.8 – 1%. • For effervescent, chewable, or dispersible tablets % friability should be greater than 1.
  • 7. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 7 4. WEIGHT VARIATION TEST • Compression weight, actual weight of tablet is determined by the diameter of the die and weight adjustment came on tablet compression machine. • The weight of the tablets being made should be routinely measured to help ensure that the tablet contains the proper amount of the drug. Within the composite samples which has an acceptable average weight, there could be tablets excessively overweight or underweight • Weight control on tablet is continuously checked and adjusted during compression of whole batch. It is normally done on uncoated tablets. APPARATUS • Digital weighing balances are used for the purpose. PROCEDURE FOR WEIGHT VARIATION • Take 20 tablets at random from the given batch. • Weigh the 20 tablets individually. • Determine average weight of the tablets. • Note down the deviation in weight for each tablet (may be + or -). • Determine %age deviation for the individual tablet by using the formula: %Deviation = Deviation in weight/ Average weight × 100 • Compare the percentage deviation with the specification given in official table (B.P. or U.S.P.) CAUSES OF WEIGHT VARIATION 1. The size & distribution of the granules being compressed (presence of too large or too fine granules). 2. Poor flow and high-speed turret speed (incomplete filling of die), 3. Poor mixing. (Sometimes the lubricants & glidants have not been well distributed). 4. When lower punches are of unequal lengths, the fill of each die varies because the fill is volumetric 5. Demixing or segregation of powder constituents of different crystallinity, size and densities; in direct compression WEIGHT VARIATION SPECIFICATIONS • Not more than two of individual weights should deviate by more than given percentage. • And none should deviate by more than twice that percentage.
  • 8. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 8  If we are using 20 tablets, then according to U.S.P., not more than 2 tablets show % weight variation and no tablet differs by more than double that percentage  If we are taking 10 tablets, then according to U.S.P., not more than 1 tablet show % weight variation. OFFICIAL TESTS 1. DISINTEGRATION TEST • It is the time required for the tablet to break into particles, the disintegration test is a measure only to the time required under a given set of conditions for a group of tablets to disintegrate into particles. • Complete disintegration is defined as that state in which any residue of the tablet, except fragments of insoluble coating remaining on the screen of the test apparatus. Soft mass having no firm core remains. • It is done because of following reasons: - To ensure product uniformity - Attempts are made to simulate in-vivo conditions. Actually, test does not correlate with physiological conditions. - It is done as a process control. DISINTEGRATION APPARATUS • Basket rack assembly • Discs • Thermostat • Suitable vessel of immersion fluid • Immersion fluid • A motoring device for raising and lowering the basket assembly in fluid
  • 9. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 9 BASKET RACK ASSEMBLY • It consists of six open ended glass tubes each 7.5 ± 0.25 cm long and inside diameter approx. 21.5 mm and wall thickness are approx. 2mm. • Tubes are held vertically with the help of two plastic plates each about 9 cm in diameter and 6 mm in thickness. Plastic plates consist of 6 holes each about 24 mm diameter, equidistant from the center of plate and equidistant from each other. • 10 mesh (sieve opening 2 mm) and gauge woven stainless steel wire cloth is attached with screws to the under surface of lower plate. Glass tubes and upper plastic plates are screwed in position by means of stainless-steel plate of diameter 9 cm and 1 mm thick. Central shaft 8 cm in length upper end of which terminates in an eye through which a string or wire may be inserted. Plates are assembled rigidly with bolts through two plastic plates. • Design of plastic assembly may vary between manufacturers but must comply with specifications. DISCS • The decision to include plastic discs is based on the specific gravity of the tablets to take care of floating tablets. Slotted and perforated discs of 9.5 ± 0.15 min thickness and 20.7 ± 0.15 mm in diameter. • They are made up of transparent material, specific gravity between 1.18 and 1.20. Equally distant 4 V shaped notches in parallel to cylindrical axis. All surfaces of the discs of smooth. Five 2 mm holes are drilled perpendicular to the cylindrical axis. One-hole pass through cylindrical axis other 4 are parallel to it with distance 2 mm apart. THERMOSTAT • For heating the fluid between 35℃ to 39℃. DEVICE FOR LOWERING AND RAISING BASKET RACK ASSEMBLY • Up and down cycles performed at rate between 28 and 32 cycles per minute through a distance of not less than 5 cm and not more than 6 cm. • Volume of fluid in vessel is adjusted as such that the highest point of upward stoke the wire mesh remains 2.5 cm from the bottom of vessel. One of downward stoke do not descend to not less than cm from the bottom of vessel. • Time required for upward stoke should be equal to time require for downward stoke. The change in stoke direction should be smooth. IMMERSION FLUID • Water: use distilled water • Hydrochloric acid: use ACS reagent code
  • 10. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 10 • Sodium chloride: use ACS reagent code • Pepsin • Potassium phosphate, monobasic: use ACS reagent code • Pancreatin: a USP grade • Hydrochloride solution (0.1M): dilute 8.5 ml of HCl to 1000 ml with water or dilute a commercial volumetric solution with water to obtain a final concentration of 0.1M. • Sodium hydroxide (0.2M): use ACS reagent grade. Dissolve 8g of sodium hydroxide in and dilute to 1000 ml with carbon dioxide free water or dilute a commercial volumetric solution with carbon dioxide free water to give a final concentration of 0.2M. • Simulated gastric fluid: dissolve 2.0g of sodium chloride and 3.2 g of pepsin in 500 ml of water and 7.0 ml of HCl and dilute to 1000 ml with water. The pH is about 1.2 • Simulated intestinal fluid: dissolve 68g of potassium phosphate monobasic in 250 ml in water. Add 10.0g of pancreatin mix and adjust the pH of the resulting solution to 7.5 ± 0.1 with NaOH (0.2M) dilute with water to 1000 ml. UNCOATED AND PLAIN COATED TABLETS BP METHOD FOR UNCOATED AND PLAIN COATED TABLETS • Assemble the apparatus when the devise for arising a lowering the basket rack assembly in at rest and its cylinder in the extreme down position. • With 2.5 L or appropriate amount of water in the cylindrical jar, adjust the apparatus until the level of fluid in the jar coincides approximately with the mid-line of the upper plastic plate. • Maintain the temperature of the fluid at 37 ± 2℃ by suitable means. • Remove the basket rack assembly form the water and disassemble. Procedure: 1. Select at random six tablets from the sample and place one in each of the tubes of the basket rack assembly. 2. Place a plastic disk on each tablet according to the specific gravity of tablet. 3. Reinsert the assembly in the water and set the machine in motion. 4. The plastic discs should travel and up and down freely exerting a gentle rubbing action on each tablet. After 15 minutes remove the basket rack assembly from the water. 5. Uncoated tablets pass the test if each of the six uncoated tablets disintegrates in not more than 15 minutes. • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate completely. • Plain coated tablets pass the test if each of the six plain coated tablets disintegrate is not more than 60 minutes. If any of the tablets has not disintegrated at the end of 60 minutes, repeat the test of further six plain coated tablets replacing the water in the cylindrical jar with HCl (0.1M). The tablets pass the test if each of the six tablets disintegrates within 60 minutes in the acid medium. USP METHOD FOR UNCOATED TABLETS • Start the disintegration test on 6 tablets. • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the totals of 18 tablets tested disintegrate completely. • If more than 2 tablets (from 18) fail to disintegrate the batch must be failed. USP METHOD FOR COATED TABLETS • To remove or dissolve the coat immerse the tablet in distilled water for 5 minutes. Put the tablet in the apparatus is water or HCl for 30 minutes at 37℃. If not disintegrated put in intestinal fluid.
  • 11. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 11 • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate completely. • If more than 2 tablets (from 18) fail to disintegrate the batch must be failed. ENTERIC COATED TABLETS BP METHOD FOR ENTERIC COATED TABLETS • Assemble the apparatus as described using 2.5 L of simulated gastric fluid in place of water. Remove the basket rack assembly from the simulated fluid and disassemble. • Select at random six tablets from the sample and place one in each of the tubes of the basket rack assembly. Place a plunger in each tube as specified (omitting the plastic disc). Insert the assembly in the simulated gastric fluid and set the machine in motion. • At the end of 30 minutes of operation, remove the basket rack assembly from the fluid and gently rinse with water. Enteric coated tablets fail the test if any of tablet show distant evidence of disintegration. • Replace the simulated gastric fluid in the jar with 2.5 L of simulated intestinal fluid. Remove the plungers, place a plastic disc on each tablet, and re-insert the plunger. Continue the test by setting the machine in motion. • After 30 minutes remove the basket rack assembly from the fluid. Enteric coated tablets pass the test each of the six tablets disintegrates in not more than 30 minutes in the simulated intestinal fluid. • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate completely. USP METHOD FOR ENTERIC COATED TABLETS • Put in distilled water for 5 minutes to dissolve the coat. Then put it in simulated gastric fluid (0.1M HCl) for 1 hour. Then put it in simulated intestinal fluid for 2 hours. • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate completely. • If more than 2 tablets (from 18) fail to disintegrate the batch must be failed. BUCCAL TABLETS • Apply the test for uncoated tablets, but omit the use of disc. After 4 hours, lift the basket from fluid and observe the tablets all of the tablets should be disintegrated. • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate completely. SUBLINGUAL TABLETS • Apply the test for uncoated tablets but omit the use of disc. Observe the tablets within the time limit specified in individual monograph; all the tablets have disintegrated. • If 1 and 2 tablets fail to disintegrate completely repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate completely. EFFERVESCENT TABLETS •Place 1 tablet in a beaker containing 200 ml of water at (15-25°C; the tablet should evolve bubbles and when the evolution of gas around the tablet stops, the tablet has disintegrated. •The same procedures are performed for other 5 tablets. •The tablets comply with the test if each of the six tablets used disintegrated within 3 min or as justified.
  • 12. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 12 2. DISSOLUTION TEST • It is a process by which solid enters into solution. It is one of the most important QC tests. Dissolution test represents in-vivo drug dissolution however far from being understood properly. Therapeutic deficiency cannot rely on dissolution test alone. In considering drug absorption one must consider: - Total dose required - Water and/or oil solubility - pKa of drug • Dissolution is directly related to solubility. Drugs that have solubility greater than 1% (1 w/v) are generally no problem. It is applied primarily to those drugs which have low solubility. There is rapid increase in dissolution testing of different dosage form in official pharmacopoeias. • Since drug absorption and physiological availability are largely dependent upon having the drug in dissolve state suitable dissolution characteristic are an important property of QC. Usually, method of dissolution and specifications are given in individual monographs DOSAGE FORMS TO BE TESTED • Immediate release dosage forms • Controlled release dosage forms • Transdermal systems • Implants OFFICIAL DISSOLUTION MONOGRAPHS • United States Pharmacopoeia USP XXX (30) • European pharmacopoeia • Ph. Eur. 5th edition supplement 5.3 • British Pharmacopoeia BP 2007 • Japanese Pharmacopoeia JP XIV (14)
  • 13. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 13 OFFICIAL DISSOLUTION APPARATUSES According to USP 7 types of apparatus are used which are as follow: 1. Rotating basket 2. Paddle 3. Reciprocating cylinder 4. Flow through cell 5. Paddle over disk 6. Rotating cylinder 7. Reciprocating holder SELECTION OF APPARATUS • The choice of the apparatus is based on one’s knowledge regarding the formulation design, dosage form and performance. Besides the selection of an adequate dissolution apparatus adequate test conditions are crucial for all purposes. • It depends upon one’s intention DISSOLUTION MEDIUM Test is begun with aqueous media of pH 1.2-6.8. Simple water is usually not recommended due to the ionic strength and pH can be vary. Different type of dissolution medium are as follow: i. Water or medium pH less than 6.8 with addition of purified pepsin (protease activity) ii. Medium with pH 6.8 or greater or pancreatic medium can be added (Intestinal environment) iii. 0.1N HCl with pH 1.2 iv. Acetate buffer with pH 4.5 v. Phosphate buffer with pH 6.8-7.5 vi. Delayed release dosage form pH 6.8 QUALITY CONTROL • Examining batch homogeneity • Examining batch to batch conformity • Examining stability RESEARCH AND DEVELOPMENT • Examining drug release behavior in preformulations • In-vitro stimulation of the GIT passage
  • 14. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 14 APPARATUS 1 – BASKET • First official dissolution apparatus by USP in 1970. • It is useful for capsules, bead, delayed release/ enteric coated dosage forms, floating dosage forms, surfactants in media. The standard volume is 900/ 1000 ml. 1, 2- and 4-liter vessels. • It consists of following parts: - 1000 ml vessel - A variable speed vessel - Cylindrical stainless -steel basket - Water bath (whole assembly is immersed in it for keeping temperature constant at 37 ± 0.5℃ throughout the test). - Vessel: it is made up of glass or any other inert transparent material. It is 1000 ml in volume capacity. It has slightly concave bottom with 16cm height (internal height) and 10cm inside diameter. The slides are flanged near top end to accept a fitted cover. Cover has four ports one of which is cantered for motor shaft. One of the other ports is for thermometer. Other two ports are for sample removal for analysis and one for addition/ replacement of dissolution medium. - Variable speed motor: the shaft of the motor is placed in central port to facilitate the rotation of basket assembly smoothly. Shaft is 6 mm in diameter and 30 cm in length. Motor speed is varied between 25 rpm – 200 rpm and to be maintained as described in individual monograph with ± 5%. Motor is suspended in such a way that it may be raised or lowered to position the basket. - Basket: assembly basket assembly consist of two parts: ▪ Part 1: it is attached to the shaft. It is solid metal except for 2 mm vent. It is fitted with three spring clips that allows removal of lower parts or basket proper to admit test sample. ▪ Parts 2: it is detachable part consist of fabricated welded seam. It has 40 mesh stainless steel cloth formed into cylinder shaped. Its height is 3.66 cm and diameter is 2.5cm. ▪ Basket also contain metal rim sheet at top. A gold-plated basket coating 0.0001 inch (2.5µm) thick is recommended for tests carried out in dilute acid medium. ADVANTAGES DISADVANTAGES • It has a breadth of experience (more than 200 monographs) • Full pH change during the tests • It can be easily automated which is important for routine investigations. • Disintegration – dissolution interaction • Hydrodermic dead zone under the basket degassing is particularly important. • Limited volume sink conditions for poorly soluble drugs. • Formulation can clog the mesh 40
  • 15. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 15 APPARATUS 2 – PADDLE • It is useful for tablets, capsules, beads, delayed release dosage forms, enteric coated dosage forms. Its standard volume is 900/ 1000ml. it is normally the method of first choice. The coated material is inert. The paddle is attached vertically to a variable speed motor that rotates at a controlled speed. The tablet is placed into a round-bottom dissolution flask and the apparatus is housed in a constant temperature water bath maintained at 37°C.Most common operating speeds are 50rpm for solid oral dosage forms and 25 rpm for suspensions. ADVANTAGES DISADVANTAGES • It is easy to use • It is robust • It is easily adapted to apparatus • T has breadth of experience • pH alteration is possible • It can be easily automated which is important for routine investigations • pH/ media change is often difficult • Limited volume, sink conditions for poorly soluble drugs • Hydrodynamics are complex, they vary with site of the dosage form in the vessel (sticking, floating) and therefore may significantly affect drug dissolution. • Sinkers for floating dosage form. APPARATUS 3 – RECIPROCATING CYLINDER  It is useful for tablets, beads, and controlled release dosage forms. Its standard volume is 200 – 250 ml per station. Place the stated volume (200-250 ml) of dissolution medium in each vessel of the apparatus, assemble the apparatus, equilibrate the dissolution medium to 37±0.5 and remove the thermometer Place one dosage form unit in inner cylinder taking care to exclude the air bubbles from the surface of each dosage unit and immediately operate the apparatus as specified in the monograph  During the upward and downward stroke, the reciprocating cylinder moves through a total distance of 9.9 to 10. 1cm.Within the time interval specified raise the cylinders and withdraw a portion of the solution under test from a zone midway between the surface of the dissolution medium and bottom of each vessel.
  • 16. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 16 ADVANTAGES DISADVANTAGES • It is easy to change pH • Huge pH profiles • Hydrodynamics can be directly influenced by varying the dip rate. • Used during product development. • It has small volume • It has little experience and it provides limited data Apparatus 4- Flow through cell:  The assembly consist of a reservoir and a pump for the dissolution medium; a flow through cell; a water bath.  The pump has delivery range between 240 and 960 ml per hour, with standard flow rates of 4,8 and 16 ml/minutes.  The reservoir is immersed in a water bath and the temperature is maintained at 37°C ± 0.5 °C. The flow through cell is transparent & inert mounted vertically with filters. Standard cell diameters are 12 & 22.6 mm. The bottom cone usually filled with glass beads of 1 mm diameter  Tablet holder used for positioning special dosage form. PROCEDURE 1. Place the glass beads into the cell as specified in the monograph 2. Place one dosage unit on top of the beads or on a wire carrier. 3. Assemble the filter head and fix the parts together by means of a suitable clamping device 4. Introduce by the pump of the dissolution medium warmed to 37±0.5 through the bottom of the cell to obtain the flow rate specified 5. Collect the elute by fractions at each of the times stated 6. Perform the analysis as directed in the individual monographs ADVANTAGES DISADVANTAGES • It is easy to change pH and media. • pH profile is possible. • No sink conditions. • It has different modes; open and closed system. • Deaeration is necessary • High volume of media is required • It is labor intensive process
  • 17. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 17 Apparatus 5; Paddle over Disk:  The method is useful for the transdermal patches. The standard volume is 900 ml. This method is used for testing the release of drugs from transdermal products.  The apparatus consists of a sample holder or disc assembly that holds the product.  The entire preparation is placed in a dissolution flask filled with specified medium maintained at 32ºC. The paddle is placed directly over the disc assembly.  The disk assembly holds the system flat and is positioned such that release surface is placed parallel with the bottom of the paddle blade.  Vessel is covered to minimize evaporation during test.  Samples are drawn midway between the surface of dissolution medium and the top of the paddle blade at specified times. ADVANTAGE DISADVANTAGE • Standard apparatus (paddle) can be used, only add a stainless-steel disk assembly • Disk assembly restricts patch size.
  • 18. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 18 APPARATUS-6 (ROTATING CYLINDER):  Use the assembly from apparatus 1 except to replace the basket and shaft with a stainless-steel cylinder stirring element.  The temperature is maintained at 32±0.5°C  The dosage unit is placed on the cylinder with side out.  Place the cylinder in the apparatus and immediately rotate at the rate specified in the individual monograph.  Samples are drawn midway between the surface of the dissolution medium and the top of the rotating cylinder for analysis.  The distance between inside bottom of the vessel and the cylinder is maintained at 25±2 mm during the test Apparatus 7 (Reciprocating disk):  The assembly consists of a set of volumetrically calibrated solution containers made of glass or suitable inert material, a motor, a drive assembly used to reciprocate the system vertically.  The samples are placed on the disk-shaped holders.  The test is carried out at 32°C.The reciprocating frequency is 30cycles/min. Dissolution testing and interpretation standard USP: Q* is amount of dissolved active ingredient specified in individual monograph, expressed as a percentage of the labeled content. **Percent of labeled content DISSOLUTION TESTING FOR VARIOUS DOSAGE FORMS • Solid dosage forms include: - Immediate release dosage forms (tablets and capsules) - Delayed release - Dosage forms for oral cavity: ▪ Buccal/ sublingual tablets ▪ Medicated chewing gums • Suppositories Sr. No. Quantity stage /level Number of tablets tested Acceptance criteria 1 S1 6 Each unit not less than Q*+5 percent** 2 S2 6 Average of 12 units (S1+S2) is equal to greater than (>) Q and no unit is less than Q-15 percent** 3 S3 12 Average of 24 units (S1+S2+S3) is equal to greater than (>) Q, not more than 2 units less than Q-15 percent** and no unit is less than Q-25 percent**
  • 19. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 19 • Semisolid dosage forms • Soft gelatin capsules DISSOLUTION TESTING FOR IMMEDIATE RELEASE (IR) DOSAGE FORM • Immediate release dosage form is designed to deliver the drug rapidly into the systemic circulation. Therefore, the dissolution may be the rate limiting step for the absorption. Generally, dissolution of IR dosage forms is being conducted using apparatuses of basket, paddle, reciprocating cylinder and flow through cell. The apparatus 1 and 2 are most commonly used. • USP uses basket, paddle, EP uses paddle basket and flow through cell apparatuses for solid dosage forms of tablets, capsules. The dissolution test is carried out at 37℃ ± 0.5℃. In general, when basket apparatus is used rotation speed is 100 rpm with 40 mesh screen of the basket is used. • Paddle apparatus is used for tablets. Operating speed of 50 is used in general. PROCEDURE Method I • Unless otherwise directed in the individual monograph, place 900ml fluid in the dissolution vessel. Vessel should previously be immersed in water bath and allow dissolution temperature to come at 37℃ ± 0.5℃. • Place one tablet or one capsule in the basket so that there is distance of 2.0 ± 0.2 cm between basket and bottom of vessel. Rotate the basket at a rate specified in the monograph. Withdraw sample at the time indicated and analyze them by procedure described in the individual monograph. The dissolution testing is done in three stages of S1, S2, and S3. Specifications • In stage 1, 6 units are taken and the amount of drug from each unit should not be less than Q + 5% where Q is the maximum amount of drug dissolved active ingredient specified in individual monograph. Failure of first stage (if one or two tablets fail to comply) compensates to conductance of second stage S2 where additional 6 units are tested. • The avg. of 12 units in two stages should be equal to or greater than Q and no unit should be less than Q – 15%. Failure of stage 2 leads to conductance of stage S3 where additional 12 units are tested and the avg. of total units of three stages S1, S2 and S3 should be greater than or equal to Q and no two units should be less than Q – 15% and none should be less than Q – 25%. METHOD II • Use apparatus described under tablet disintegration with some changes. Replace 10 mesh stainless steel cloth in basket rack assembly with 40 mesh also, to the top of the assembly to provide for immersion in the dissolution medium. • Adjust the apparatus so that it descends to 1 ± 0.1cm from bottom of the vessel on download stoke. Use dissolution as specified in individual monograph. • Apply the test firstly on 6 unit, if one or two tablets fails the specification then perform test on 6 additional tablets. 10 out of 12 should pass the specification. DISSOLUTION TEST FOR DOSAGE FORMS OF THE ORAL CAVITY • Development of dissolution method for these dosage forms possess several challenges due to short residence time of dosage form in the mouth and limited volume of dissolution medium for dissolving the dosage form. DISSOLUTION TEST FOR CHEWABLE TABLETS • USP insisted the use of apparatus 2 for dissolution excepting ampicillin where apparatus 1 is recommended and carbamazepine where apparatus 2 and 3 are used. • The design of apparatus should consist of a mechanical breakage of tablet prior to dissolution.
  • 20. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 20 DISSOLUTION TEST FOR BUCCAL/ SUBLINGUAL TABLETS • Initially USP stated the use of disintegration apparatus for the ergotamine category sublingual products. Later modified USP 3 apparatus with 20 strokes/ min was used for hydrocortisone mucoadhesive tablets to mimic the low dissolution volume of in-vivo. • Later another system continuous flow through filtration cell with dip tube for filtration. 10 ml of fluid is pumped to give a short residence time of 8 minutes. DISSOLUTION TEST FOR CHEWING GUMS • USP has not recommended any apparatus for dissolution testing of chewing gums, but EP has emphasized on the use of 3 piston apparatus that chews the gum at a rate of 60 cycles/ min in dissolution medium of pH 6.0 at 37℃. • Still controversies regarding this issue are existing and urges for development of an appropriate apparatus. 3. CONTENT UNIFORMITY • The content uniformity test is done to ensure that each dosage form contains the exact stated amount of drug within a batch. Mainly it is used for testing the consistency of: o Bulk powders before or after compression o Liquid orals before filling o During filling of powders into capsules or liquids into vials and ampules o Amount of API within individual unit of tablet and capsule • Only when the ingredient of the tablet granulation is homogenous, tablet weight test as described earlier can be considered as measure of drug content. • Routinely the assay of the drug content in tablets involve the grinding of tablet of large sample of tablets followed by the analysis of an aliquot. Normally testing is confirmed by performing specific assay to determine the content of drug material contained in particular dosage form. Results obtained are expressed as percentage of active ingredient in the tablet or on individual tablet basis. Different pharmacopoeias describe the procedure of content uniformity test and giver their specifications. CONTENT UNIFORMITY TEST USP STAGE 1 • Take 10 units randomly and perform the assay. It passes the test if relative standard deviation is less than 6% and no value is outside 85 – 115%. Fails the tests if one or more values are out of 75 – 125%. STAGE 2 • Take 20 more units and perform the assay. Pass the test if RSD of all 30 tablets is less than 7.8%, not more than one value is outside 85 – 115 % and no value is outside 75 – 125% or else, the batch fails the test. CONTENT UNIFORMITY TEST BP TEST A • The test is applicable for tablets, powders and parenteral use and suspensions for injection. • Selects 10 units at random and perform the assay. Passes the test each individual unit is between 85 – 115% of the average content. • Fails the test if more than one individual unit is outside these limits or if even one unit is outsides the limit of 75 – 125% of the avg. content. But if one unit is outside the limit of 85 – 115 % and within 75 – 125 % then take another 10 units at random and perform the assay. • The lot passes the test if not more than 1 unit of 30 units is outside 85 – 115% and not even one unit is outside the limit of 75 – 125% of the avg. content.
  • 21. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 21 TEST B • The test is used for capsules, powders, other than parenteral use, granules, suppositories and pessaries. • Selects 10 units at random and perform the assay. Passes the test if not more than 1 individual unit is outside the limits of 85 – 115% and none is outside the limits of 75 – 125%of the labelled content. • The batch fails the test if more than 3 units are outside the limit of 85 – 115% or if one or more units are outside the limits of 75 – 125% of the labelled content. • If 2 or 3 units are outside the limits of 85 – 115% but within the limits of 75 – 125% then select another 20 units at random. • The batch complies the test when not more than 3 units are out of these 30 units are outside the limits of 85 – 115% and not even one unit is outside the limits of 75 – 125% of the labelled content TEST C • The test is applicable to only transdermal patches. • The preparation passes test only if the avg. content of 10 units is between 90 – 110% and if the content of each unit is between 75 – 125% of the avg. content. 4. CHEMICAL ASSAY OF TABLETS • Routinely the assay of the drug content in tablets involve the grinding of tablet of large sample of tablets followed by the analysis of an aliquot. Representing the certain amount of drug normally in a single unit. • Analysis is performed by the methods prescribed in the individual monographs. Results obtained are expressed in percentage of the active ingredient in the tablet or unit dose compared with limits in the monograph of the drug. • Common assay procedure involves: - Titrimetric analysis - Spectrophotometric methods - UV spectroscopy - HPLC - Biological assay - Microbial assay TESTS FOR COATED TABLETS • Water vapor permeability • Film tensile strength • Coated tablets evaluations
  • 22. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 22 QUALITY CONTROL OF CAPSULES DEFINITION: Capsules are solid dosage forms in which one or more medicinal and inert ingredients are enclosed in a Small Shell or container usually made of gelatin. ADVANTAGES ▸ Capsules mask the taste and odour of unpleasant drugs and can be easily administered. ▸ They are slippery when moist and hence easy to swallow with a draught of water. ▸ As compared to tablets less adjuncts are required. ▸ The shells are physiologically inert and easily and quickly digested in the gastrointestinal tract. They are economical. ▸ They are easy to handle and carry ▸ The shells can be opacified (with titanium dioxide) or coloured , to give protection from light TYPES OF CAPSULE: • Quality control tests for capsules includes: - Weight variation - Content uniformity - Disintegration - Dissolution - Chemical or biological assay DISSOLUTION TEST FOR CAPSULES • Special type of basket rack assembly is used. The apparatus consisting of: - A glass tube 80 – 100 mm long with internal diameter of about 28mm and external diameter of 30-31 mm. At the bottom of the tube rust proof wire gauze (sieve # 1.7mm or 10 mesh) is attached to form a
  • 23. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 23 basket. Wire gauze is fitted to the tube in such a manner that the overall diameter of the basket in not materially increased. - A glass cylinder with a flat base and an internal diameter of about 45mm used for disintegration media. Cylinder contains water media not less than 15 cm deep maintained at the temperature 37±2℃ by suitable means. - Basket is raised and lowered repeatedly in a uniform manner so that at highest position the gauze breaks the surface of water and at lowest position the upper rim of basket cylinder just remains clear of water. Guiding disk made up of suitable material, lowering and raising device. BP METHOD • Place five capsules in the basket. Raise and lower the basket in such a manner that complete up and down movement is repeated thirty times per minute. • Capsules are disintegrated when no particle of any solid content remains above the gauze which would not readily pass through it. • Time required for capsules to disintegrate not more than 15 minutes unless otherwise stated in individual monograph. If capsules fail the disintegration test because of aggregation, further five capsules may be tested individually. • The longest time taken by one of the five capsules is the disintegration time. USP METHOD • According to USP disintegration test is usually not require for capsules unless have been treated to resist solution in gastric fluid (enteric coated). In this case they must meet the requirements of disintegration test of enteric coated tablet i.e. • Assemble the apparatus as described using 2.5 L of simulated gastric fluid in place of water. Remove the basket rack assembly from the simulated fluid and disassemble. • Select at random six capsule from the sample and place one in each of the tubes of the basket rack assembly. Place a guided disc. Insert the assembly in the simulated gastric fluid and set the machine in motion. • At the end of 60 minutes of operation, remove the basket rack assembly from the fluid and gently rinse with water. Enteric coated capsule fail the test if any of tablet show distant evidence of disintegration. Replace the simulated gastric fluid in the jar with 2.5 L of simulated intestinal fluid.
  • 24. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 24 • Reinsert the guided disc. Continue the test by setting the machine in motion for 60 minutes. After 60 minutes remove the basket rack assembly from the fluid. Enteric coated tablets pass the test each of the six tablets disintegrates in not more than 30 minutes in the simulated intestinal fluid. 2. WEIGHT VARIATION TEST FOR CAPSULES • There are two methods for testing uniformity of weight of capsules: METHOD A • Method A is for capsules with dry content. Weigh a capsule, open it without loss of shell material, remove the contents and weigh all parts of shell. • The difference between the weights represents the weight of contents of capsule. Repeat the operation with further 19 capsules (total 20). • Capsules pass the test if not more than 2 capsules deviate from the mean weight by more than percentage given in table. • For one or two capsules (which are outside above given range) the weight of the content should not be more than percentage given in the table below. METHOD B • The method B is for capsules containing liquid or base. Weigh a capsule, open it without loss of shell material express as much of the contents is possible. Wash the shell with solvent ether, reject the washing. Allow the shell to stand until all the odor of ether is no longer perceptible and weigh. • The difference between the whole weight and shell weight represents in weigh of contents. Repeat the operation with further 9 capsules (total 10) and calculate the average weight content of 10 capsules. The weight of each capsule does not differ from the average weight by more than 7.5%. Except the one capsule the weight of content may differ by not more than 15%. • Regardless of the weight of content of this type of capsules the percentage deviation range should be between ±7.5 – ±15%. 3. DISSOLUTION TEST Definition It is a process by which solid enters into solution. Dissolution test represents in-vivo drug dissolution • The dissolution may be the rate limiting step in capsules absorption. Generally, the dissolution test of capsules is conducted in paddle or basket assembly. USP uses basket, paddle, EP uses paddle, basket, and flow through cell apparatuses for solid dosage forms of tablets and capsules. The choice of apparatus is based on the knowledge regarding the size and type of capsules and selected according to individual monograph. • The dissolution test is carried out at 37℃ ± 0.5℃. In general, when basket apparatus is used rotation speed is 100 rpm with 40 mesh screen of the basket is used. Other mesh sizes may also be used if supported by necessary date documentation. It is generally used for capsules and floating type dosage forms or to those which tend to disintegrate slowly. For floating type of dosage forms sinker may be used to prevent the floating of capsules. • Samples are withdrawn according to specifications with tolerance of ± 5%. The test is conducted on the equipment which was pre-calibrated with USP salicylic acid and prednisone calibrator tablets (according to USP).
  • 25. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 25 • The dissolution medium used should be deaerated and may be water, buffered aq. Solution of pH 4 – 8 and dilute acid of 0.001N to 0.1N HCl are used. The test time is 30 – 60 minutes and with a single point specification or as specified in individual monographs. PROCEDURE • Unless otherwise directed in the individual monograph, place 900ml fluid in the dissolution vessel. Vessel should previously be immersed in water bath and allow dissolution temperature to come at 37℃ ± 0.5℃. • Place one tablet or one capsule in the basket so that there is distance of 2.0 ± 0.2 cm between basket and bottom of vessel. Rotate the basket at a rate specified in the monograph. Withdraw sample at the time indicated and analyze them by procedure described in the individual monograph. • The dissolution testing is done in three stages of S1, S2, and S3. In stage 1, 6 units are taken and the amount of drug from each unit should not be less than Q + 5% where Q is the maximum amount of drug dissolved active ingredient specified in individual monograph. • Failure of first stage (if one or two tablets fail to comply) compensates to conductance of second stage S2 where additional 6 units are tested. The avg. of 12 units in two stages should be equal to or greater than Q and no unit should be less than Q – 15%. • Failure of stage 2 leads to conductance of stage S3 where additional 12 units are tested and the avg. of total units of three stages S1, S2 and S3 should be greater than or equal to Q and no two units should be less than Q – 15% and none should be less than Q – 25% DISSOLUTION TESTING OF SOFT GELATIN CAPSULES • USP has recommended the use of apparatus 1 and 2, but since there had been serious disadvantages related, attempts had been made in literature to develop new methods for lipid filled soft gelatin capsules. 4. ASSAY OF ACTIVE INGREDIENTS IN CAPSULES • Determine the amount of active ingredient by the method described in the assay. • Calculate the amount of API in the mixed contents of the capsules taken and divide by the number of capsules taken. The result should lie within the range specified in individual monograph. • Sometime biological assay is described in the mono graph e.g., drugs of natural origin (vitamins, antibiotics, insulin etc.). 4. MOISTURE PERMEATION TEST OF CAPSULES • The USP requires determination of moisture-permeation characteristics of single-unit and unit dose containers to assure their suitability for packaging capsules. • The degree and rate of moisture penetration is determined by packaging the dosage unit together with a colour revealing desiccant pellet Desiccant pellets
  • 26. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 26 Expose the packed unit to known relative humidity over a specified time Observe the desiccant pellet for colour change Any change in colour indicates absorption of moisture By measuring pre-test weight and post-test weight of pellet, amount can be calculated. QUALITY CONTROL OF POWDERS INTRODUCTION ▸ Powders are intimate mixture of dry finally divided drugs or chemicals that may be intended for internal or external purposes ▸ Powder are solid dosage form of medicaments which are meant for internal and external uses ▸ They are available in amorphous or crystalline form Drugs are prepared in different forms and shapes but many of them are prepared by using powder in one way or the other. POWDER FLOW • The widespread use of powder in the pharmaceutical industries has generalized a variety of methods for characterizing powder flow. Several references appear in the pharmaceutical literature attempting to correlate the various measure of powder flow to manufacturing properties. The development of such a variety of test methods was inevitable; powder behavior is multifaceted and thus complicates the efforts to characterize the flow properties of the pharmaceutical powders. • In addition, no single or simple method can adequately characterize the flow properties of pharmaceutical powders. • Four common reported methods for testing powder flow rate are: 1. Particle size analysis 2. Angle of repose 3. Compressibility index or Hausner ratio 4. Flow rate through an orifice 5. Shear cell 1. PARTICLE SIZE ANALYSIS (ACCORDING TO USP) Powders may be course to very fine powders. Size analysis is done by sieving method in specified time. COARSE POWDER: Particles pass through No. 20 sieve and not more than 60% through No. 40 sieve. MODERATELY COARSE POWDER: Particles pass through No. 40 sieve and not more than 60% through No. 60 sieve. FINE POWDER: Particles pass through No. 80 sieve. No limit as to greater fitness.
  • 27. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 27 VERY FINE POWDER: Particles pass through No. 120 sieve. No limit as to greater fitness. METHODS FOR DETERMINATION OF PARTICLE SIZE I.SIEVING A stack of different size sieves (Sieve No. 40, 60, 80, 100 and 120) are placed tightly one over the other in such a manner that each lower sieve has a small aperture size than that of the sieve above it. Below the lowest sieve is placed a collecting tray. This assembly is placed on mechanical shaker. Sample of 50gm of the drug is placed in the upper most sieves and the top is then closed with a lid. Then the shaker is operated for 5 minutes. In this way the powders with different particle sizes is collected on each sieve and stored separately II. MICROSCOPY In this method, small sample size is mounted on the stage of microscope and the particle size is measured using the micrometer joined to it. Microscopy size range: 0.2 – 100 Micrometer. III. SEDIMENTATION Determined by measuring setting velocity of particles through liquid medium in gravitational or centrifugal environment. It can be calculated by Stokes law using Andreasen pipette. IV. LIGHT ENERGY DIFFRACTION • Disperse particles in liquid/gas, sensing zone determines light reduction. V. LASER HOLOGRAPHY Pulsed laser is fired through an aerosolized particle spray and photographed in 3 dimensions with holographic camera. 2. ANGLE OF REPOSE • The angle of repose has been used in several branches of solid-state science to characterize the flow properties of solid. Angle of repose is a characteristic related to inter particulate resistance or friction to movement between particles. Qualitative assessment of cohesive and frictional forces under levels of external loading, applied in powder mixing, in tablet dye or capsule shell filling. • “Maximum angle obtained between a freely standing surface of powder heap and horizontal surface or plane” Angle of repose is determined by Funnel and Cone method. The funnel is fixed in place, 4 cm above the Petri dish surface. Powder sample (5gm) is poured through funnel and a cone is built. The height of cone (h) and the radius (R) is measured. The angle of repose (θ) is calculated as follows: Angle of Repose (θ) = tan-¹ h/R - Static angle of repose - Drained angle of repose - Dynamic angle of repose
  • 28. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 28 Static angle of repose Static angle of repose is calculated by the use of funnel. The most common method of determining the static angle of repose can be classified on the bases of following two important experimental variables; 1. The height of the funnel through which the powder passes may be fixed relative to the base or the height may be varied as the pile forms. 2. The base upon which the pile forms may be of fixed diameter or the diameter of the powder cone may be followed to vary as the pile forms. Drained angle of repose Drained angle of repose is determined by allowing an excess quantity of material positioned above a fixed container base to drain from the container. Formulation of a cone of a powder on a fixed diameter base allows determination of the drained angle of repose. Dynamic angle of repose Dynamic angle of repose is calculated by filling a cylinder (with a clear flat cover at the end) and rotating at a specific speed. The dynamic angle of a repose is an angle (relative to the horizontal) formed by the flowing powder. The internal angle of kinetic friction is defined by the plane separating those particles sliding down the top layer of the powder and those particles that are rotating with the drum (with roughened surface). Specifications Although these is some variation in the qualitative description of powder flow using the angle of repose much of the pharmaceutical literature appears to be consistent with the classification by Carr, shown in the table.
  • 29. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 29 PROCEDURE FOR ANGLE OF REPOSE • The base should be free from vibration. Vary the height of the funnel to carefully build up a symmetrical cone of powder. Care should be taken to prevent vibration as the funnel moved. • The funnel height should be maintained approximately 2 – 4 cm from the top of powder pile as it being formed in order to minimize the impact of falling powder on the tip of the cone. • If a symmetrical cone of powder cannot be successfully or reproducibly prepared, this method is not appropriate. Determine the angle of repose by measuring the height of the cone of powder and calculating the angle of repose from the following equation: tanθ = height 0.5 / base OR θ = tan−1 h / R FACTORS AFFECTING ANGLE OF REPOSE • Angle of repose is affected by different coefficients of friction between different substances. • The size of the particles is a factor. Other factors being equal, fine grained material will form a shallower pile with a smaller angle of repose than coarse grains. • Moisture affects the angle of repose. • The method by which the angle of repose is measured can also affect the measurement. 3. COMPRESSIBILITY INDEX & HAUSNER RATIO • It is simple, fast and popular method of determining powder flow characteristics. The compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content, and cohesiveness of materials because all of these can influence the observed compressibility index. • The compressibility index and the Hausner ratio are determined by measuring both the bulk volume and the tapped volume of powder. • Although there are some variations in the method of determining the compressibility index and Hausner ratio, the basic procedure is to measure: - The unsettled apparent volume V0 - The final tapped volume V1 of the powder then tapping the material until no further volume changes occur. • The compressibility and Hausner ratio are calculated as follows: Compressibility index = 100 × ( 𝑉0 − 𝑉1 / 𝑉0) Hausner ratio = 𝑉1 / 𝑉0 Alternatively, the compressibility index and Hausner ratio may be calculated using measured values for bulk density and tapped density as follows Compressibility index = 100 × (ρbulk − ρtap /ρbulk) Hausner ratio = ρtap / ρbulk
  • 30. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 30 • For compressibility and Hausner ratio the generally accepted scale of flow ability is given in the table: • Compressibility index and Hausner ratio are not intrinsic properties of the powder. They are very much dependent upon the methodology used. • Recommended procedure for Compressibility index and Hausner ratio: - Use a 250 ml volumetric flask with a test sample weight of 100g. - Smaller weights and volume may be used but variations in the method should be described with the results. An average of three determinations are recommended. 4. FLOW THROUGH AN ORIFICE • The flow rate of a substance depends upon many factors some of which are particle related and some related to the process. • Monitoring the rate of flow of material through an orifice has been proposed as a better measure of powder flowability. Of particular significance is the utility of monitoring flow continuously because pulsating flow patterns have been observed even for free floating materials. Changes in the flow rate as the container empties can also be observed. RECOMMENDED PROCEDURE FOR FLOW THROUGH AN ORIFICE • Flow through an orifice is generally measured as the mass per time flowing from any of a number of types of containers (cylinders, funnels, hoppers). It can be used only for those materials having some capacity to flow, it is not useful for cohesive materials. • Provided that the height of the powdered bed is much greater than the diameter of the orifice, the flow rate is virtually independent of the powder head. - Use the cylinder as a container because the cylinder material should have little effect on flow. - The configuration results in flow rate being determined by the movement of powder over powder rather than powder along the wall of the container. - Powder flow rate often increases when the height of the powder column is less than two times of the diameter of the column. - The orifice should be circular and the cylinder should be free of vibration. • General guidelines for dimensions of the cylinder are as follows: - Diameter of opening > 6 times of the diameter of the particles
  • 31. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 31 - Diameter of the cylinder > 2 times the diameter of the opening • For the opening in the cylinder use a flat faced bottom plate with an option to vary orifice diameter to provide maximum flexibility and to better ensure the powder over powder flow pattern. • Rate measurement can either be discrete or continuous. Continuous measurement using an electronic balance can more effectively detect momentary flow rate variations. GENERAL SCALE FOR FLOWABILITY FOR FLOW THROUGH AND ORIFICE • No general scale is available because flow rate is critically dependent on the method used to measure it. Comparison between the published results is difficult. 5. SHEAR CELL METHODS • In an effort to put powder flow studies and hopper design on a more fundamental basis, a verity of powder shear testers and methods that permit more thorough and precisely, defined assessment of powder flow properties have been developed. • Shear cell methodology has been used extensively in the study of pharmaceutical materials. • From these methods a wide verity of parameters can be obtained including the yield loci representing the shear stress and shear stain relationship. The angle of internal friction, the unconfirmed yield strength, the tensile strength and the verity of divided parameters such as the flow factor and other flowability indices. • Because of the ability to move precisely control experimental parameters flow properties can also be determined as a function of consolidation load, time and other environmental conditions. BASIC METHODS FOR SHEAR CELL • One type of the cell is the cylindrical shear cell that is split horizontally forming a shear place between the lower stationary base and the upper movable portion of the shear cell ring. After powder bed consolidation in the shear cell (using a well-defined procedure) the force necessary shear the powder bed by moving the upper ring is determined. • Annular shear cell designs offer some advantages over the cylindrical shear cell design including the need for less material. A disadvantage, however, is that because of its design the powder bed is not sheared as uniformly i.e., material on the outside of the annulus is sheared more than material in the inner region.
  • 32. QUALITY CONTROL OF SOLID DOSAGE FORMS CHAPTER NO 2 PREPARED BY :HASNAT TARIQ (GDIP) 32 • A third type of shear cell, plate shear cell consists of a thin sandwich powder between a lower stationary rough surface and an upper rough surface that is moveable. • All of the shear cells have their merits and demerits. As with the other methods of characterizing powder flow many variations are described in the literature. • A significant advantage of shear cell methodology in general is a greater degree of experimental control. 6. MOISTURE CONTENT • The amount of moisture present in the granule is called moisture content. • Generally the granules contain 2 % of the moisture. It is required for the binding of the powders or granules during compression. • Determined by IR balance Procedure 1. Sample placed in the balance and initial weight is determined 2. IR bulb is initiated and the moisture is removed via heating 3. Note the reading or final weight% Formulae: Moisture content= {(initial wt -final wt) /final wt}*100 % loss on drying = {(initial wt-final wt) /initial wt}*100