Quality control complete notes

QUALITY CONTROL
4th
PROFESSIONAL
GHULAM MURTAZA HAMAD
4TH
PROFF. EVENING
PUNJAB UNIVERSITY COLLEGE OF PHARMACY, LAHORE

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TABLE OF CONTENTS
Contents
1. Introduction
2. Quality Control of Solid Dosage Form
3. Quality Control of Syrups, Elixirs and Disperse System
4. Quality Control of Suppositories
5. Quality Control of Sterile Products
6. Biological Assays
7. Alcohol Determinations
8. Alkaloidal Drug Assay
9. Quality Assurance of Vaccines
10. Miscellaneous Determinations and Tests
11. Standardization of Pharmaceuticals
12. Statistical Quality Control Charts

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INTRODUCTION
QUALITY MANAGEMENT SYSTEM (QMS)
• Quality Management System a set of interacting elements based on
procedures, policies, resources, and objectives that are established
collectively to guide an organization.
• Quality Management System takes into account all applicable guidelines
and regulations that are designed to maintain its robustness.
QUALITY
• Quality is the name of attributes. They are highly specific characters and
vary from dosage form to dosage form. They are pre-defined before the
preparation of dosage form. In-short we set standards (specifications).
These specifications are mentioned in official books like; BP, USP and
NF.
QA, GMP & QC INTER-RELATIONSHIP
QUALITY ASSURANCE (QA)
• It is the sum total of the organized arrangements with the
objective of ensuring that products will be of the quality
required for their intended use.
GOOD MANUFACTURING PRACTICE (GMP)
• Part of QA system aimed at ensuring that products are consistently
manufactured to a quality appropriate to their intended use.
QUALITY CONTROL
• QC Is that part of GMP concerned with sampling, specification and
testing, documentation and release procedures which ensure that the
necessary and relevant tests are performed and the product is released
for use only after ascertaining its quality.
• Quality is always a comparative study with the standard. Standards are
of high purity. The standards are mentioned in official books,
Pharmacopoeia.
Difference between Quality Control (QC) and Quality Assurance (QA)
QC QA
QA
GMP
QC
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QC is that part of GMP which is
concerned with Sampling,
Specifications testing and within the
organization, documentation and
release procedures which ensure that
the necessary and relevant tests are
carried out.
QA is the sum total of organized
arrangements made with the object
of ensuring that product will be of
the quality required for their
intended use.
Operational laboratory techniques
and activities used to fulfill the
requirement of quality.
All those planned or systematic
actions necessary to provide
adequate confidence that a product
will satisfy the requirements for
quality.
QC is lab based. QA is company based.
CURRENT GOOD MANUFACTURING PRACTICES (cGMP)
• cGMP refers to the Current Good Manufacturing Practice regulations
enforced by the US Food and Drug Administration (FDA).
• cGMP provide for systems that assure proper design, monitoring and
control of manufacturing processes and facilities.
GOOD LABORATORY PRACTICES (GLP)
• GLP embodies a set of principles that provides a frame-work within
which laboratory studies are planned, performed, monitored and
archived and reported.
• GLP is an FDA regulation.
PURPOSE OF GLP
• GLP is to certify that every step of the analysis is valid or not.
• Assure the quality and integrity of data submitted to FDA in support of
the safety of regulated products.
• GLPs have heavy emphasis on data recording, record and specimen
retention.
GOOD LABORATORY PRACTICES PRINCIPLES
1. Test facility management.
2. Quality assurance program (QAP).
3. Facilities.
4. Apparatus, material and reagents.
5. Test systems.
6. Test and reference substances.
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7. Standard operating procedures (SOP).
8. Performance of the study.
9. Reporting of study results.
10.Storage and retention of records and materials.
VALIDATION
• Validation is the assessment of a process or instrument to assure that
the process and instrument is suitable for its intended use (FDA, 1987).
• Validation enables an efficient and productive use of the process and
instrumental variables.
• A new assay method, change in operator, laboratory and equipment
than the one in previous method requires validation.
STEPS IN VALIDATION
• Specificity
• Linearity
• Range
• Accuracy
• Precision
• Sensitivity
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QUALITY CONTROL OF SOLID DOSAGE
FORM
• QC is strictly observed in order to ensure that the product is not only
meeting the requisite specifications but also a reproducible in term of
quality, hence therapeutically effective.
• Solid dosage forms are:
- Tablets
- Capsules
- Powders
- Granules
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. Also known as:
▪ 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:
PHYSICAL TESTS
• Tablet Hardness
• Thickness and diameter
• Friability
• Disintegration test
• Weight variation
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CHEMICAL TESTS
• Content uniformity
• Assay of active ingredients
• Dissolution test
UNOFFICIAL TESTS
1. HARDNESS
• Hardness is related to solubility, proper hardness for tablets ensures that
tablet withstand the shock of handling, packing and shipping.
• Common hardness tester:
- Strong-cobb
- Monsanto tester
- Eureka
- Pfizer units
MECHANICAL TESTER
• Hardness is normally tested by mechanical tester now a days with
automatic operation. Mechanical tester measures resistance to
crushing of tablets.
• 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.
When the tablet breaks a micro switch stops the motor.
Mechanical strength is shown in the digital indicator.
HARDNESS SPECIFICATIONS
• Acceptable hardness range is 5 – 10 Kg/cm-2
. Sometimes the scale is in
Newton (1 Newton = 9.8 kg)
2. THICKNESS AND DIAMETER
• 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.
APPARATUS
• The apparatus used for this purpose are:
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- Micrometer screw gauge
- Vernier caliper
• Now a days digital micrometers are available.
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%
3. FRIABILITY
• 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.
• The apparatus used for the purpose is:
- Roche Friabilator
ROCHE FRIABILATOR
• It consist 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.
• The drum is attached to the horizontal axis of a device that rotates at 25
± 1 r/min. Thus, at each turn the tablets roll or slide and fall onto the
drum wall or onto each other.
• 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
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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.
SPECIFICATIONS OF FRIABILITY
• The USP states that the friability should be 0.8 – 1%.
4. WEIGHT VARIATION TEST
• Compression weight, actual weight of tablet is determined by the
diameter of the die and weight adjustment cam on tablet compression
machine.
• 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.)
WEIGHT VARIATION SPECIFICATIONS
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• Not more than two of individual weights should deviate by more than
given percentage.
• And none should deviate by more than twice that percentage.
OFFICIAL TABLE
Avg. weight of
tablet (USP)
%age Deviation
Avg. weight of
tablet (BP)
%age Deviation
130 mg or less ± 10.0 % 80 mg or less ± 10.0 %
For 130 mg to
324 mg
± 7.5 %
> 80 mg to < 250
mg
± 7.5 %
More than 324
mg
± 5.0 % 250 mg or more ± 5.0 %
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 mess 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
BASKET RACK ASSEMBLY
• It consist of six open ended glass tubes each 7.5 ± 0.25 cm long and
inside diameter approx. 21.5 mm and wall thickness is approx. 2mm.
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• 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 perforated 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 in 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.
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IMMERSION FLUID
• Water: use distilled water
• Hydrochloric acid: use ACS reagent code
• 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.
• Select at random six tablets from the sample and place one in each of
the tubes of the basket rack assembly.
• Place a plastic disk on each tablet according to the specific gravity of
tablet.
• Reinsert the assembly in the water and set the machine in motion.
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• 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.
• 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 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.
failed.
ENTERIC COATED TABLETS
BP METHOD FOR ENTERIC COATED TABLETS
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• 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.
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.
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.
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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.
2. DISSOLUTION TEST
• It is a process by which solid enters into solution. It is one of the most
important QC test. 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)
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OFFICIAL DISSOLUTION APPARATUSES
• Rotating basket
• Paddle
• Reciprocating cylinder
• Flow through cell
• Paddle over disk
• Rotating cylinder
• 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
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
APPARATUS 1 – BASKET
• 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 consist 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
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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 port 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
in 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
• 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.
DISADVANTAGES
• Disintegration – dissolution interaction
• Hydrodermic dead zone under the basket degassing is particularly
important.
• Limited volume sink conditions for poorly soluble drugs.
APPARATUS 2 – PADDLE
• It is useful for tablets, capsules, beads, delayed release dosage forms,
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enteric coated dosage forms. Its standard volume is 900/
1000ml. it is normally the method of first choice.
ADVANTAGES
• It is easy to use
• It is robust
• It is easily adapted to apparatus 5
• T has breadth of experience
• pH alteration is possible
• It can be easily automated which is important for routine investigations.
DISADVANTAGES
• 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.
ADVANTAGES
• It is easy to change pH
• Huge pH profiles
• Hydrodynamics can be directly influenced by varying the dip rate.
DISADVANTAGES
• It has small volume
• It has little experience and It provides limited data.
APPARATUS 4 – FLOW THROUGH CELL
• It is used for low solubility drugs, microparticulates, implants,
suppositories, and controlled release formulations. It has
variations; open or closed system.
ADVANTAGES
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• It is easy to change pH and media.
• pH profile is possible.
• No sink conditions.
• It has different modes; open and closed system.
DISADVANTAGES
• Deaeration is necessary
• High volume of media is required
• It is labor intensive process
APPARATUS 5 – PADDLE OVER DISK
• The method is useful for the transdermal patches. The
standard volume is 900 ml.
ADVANTAGES
• Standard apparatus (paddle) can be used, only add a stainless-
steel disk assembly.
DISADVANTAGES
• Disk assembly restricts patch size.
APPARATUS 6 – ROTATING CYLINDER
• Most probably will be removed from USP.
APPARATUS 7 – RECIPROCATING HOLDER
• Most probably will be removed from USP.
DISSOLUTION TESTING FOR VARIOUS DOSAGE FORMS
• Solid dosage forms includes:
- Immediate release dosage forms (tablets and capsules)
- Delayed release
- Dosage forms for oral cavity:
▪ Buccal/ sublingual tablets
▪ Medicated chewing gums
• Suppositories
• Semisolid dosage forms
• Soft gelatin capsules
DISSOLUTION TESTING FOR IMMEDIATE RELEASE (IR) DOSAGE FORMS
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• 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 are 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.
• 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%.
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Stage Number tested Acceptance criteria
S1 6
Amount of drug release from each unit not less
than Q + 5%.
S2 6
Avg. of S1+S2 (12 units) should be equal to or
greater than Q and no unit be less than Q -15%.
S3 12
Avg. of S1+S2+S3 (24 units) should be equal to or
greater than Q and not more than one unit 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 descend 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 resistance 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.
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
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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:
- Bulk powders before or after compression
- Liquid orals before filling
- During filling of powders into capsules or liquids into vials and
ampules
- Amount of API within individual unit of tablet and capsule
• Only when the ingredient of the tablet granulation are 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
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• 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.
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.
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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
• Coted tablets evaluations
ADHESION TEST WITH TENSILE STRENGTH TESTER
• It measure the force required to peel the film of from the tablet
surface.
DIAMETRAL CRUSHING STRENGTH OF COATED TABLETS
• Tablets hardness testers are used. This test gives information
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on the relative increase in crushing strength provided by the
film and the contribution made by changes in the film
composition.
• Temperature and humidity may cause film defects, hence
studies are to be carried out.
• Quantification of film roughness, hardness and color
uniformity.
• Visual inspection or instruments are used. Resistance of coated
tablets on a white sheet of paper. Resilient films remain intact
and no color is transferred to the paper, very softy coating are
readily “erased” from the tablet surface to the paper.
QUALITY CONTROL OF CAPSULES
• Quality control tests for capsules includes:
- Weight variation
- Content uniformity
- Disintegration
- Dissolution
- Chemical or biological
assay
1. 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 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
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GM Hamad
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.
• 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:
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GM Hamad
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.
Average weight
Percentage deviation
A B
0.120g or less ± 10% (18 out of 20) ± 20% (2 out of 20)
More than 0.120g ± 7.5% (18 out of 20) ± 15%(2 out of 20)
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%.
DISSOLUTION TEST
• 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
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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).
• 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
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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%.
Stage Number tested Acceptance criteria
S1 6
Amount of drug release from each unit not less
than Q + 5%.
S2 6
Avg. of S1+S2 (12 units) should be equal to or
greater than Q and no unit be less than Q -15%.
S3 12
Avg. of S1+S2+S3 (24 units) should be equal to or
greater than Q and not more than one unit 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.
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.).
QUALITY CONTROL OF POWDERS
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.
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• 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:
- Angle of repose
- Compressibility index or Hausner ratio
- Flow rate through an orifice
- Shear cell
1. ANGLE OF REPOSE
• The angle of repose have been used in several branches of solid-state
science to characterize the flow properties of solid. Angle of repose is a
characteristic related to interparticulate resistance or friction to
movement between particles.
• Angle of repose test result are reported to be very dependent upon the
method used. Experimental difficulties arise as a result of segregation of
material and consolidation or aeration of the powder as the cone is
formed.
• It is the constant three-dimensional angle (relative to horizontal base)
assumed by a cone like pile of material formed by any of several
different methods. Basic methods of angle of repose are as follows:
- Static angle of repose
- Drained angle of repose
- Dynamic angle of repose
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:
- 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.
- 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
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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 there 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 shown in the table.
Flow property Angle of repose (degrees)
Excellent 25 – 30
Good 31 -35
Fair – aid not needed 36 – 40
Passable – may hang up 41 – 45
Poor – must agitate, vibrate 46 – 55
Very poor 56 – 65
Very, very poor > 66
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:
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GM Hamad
tanθ =
height
0.5 base
OR
θ = tan−1
h
R
2. 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:
Compressibilty index = 100 × (
𝑉0 − 𝑉1
𝑉0
)
Hausner ratio =
𝑉1
𝑉0
• Alternatively, the compressibility index and Hausner ratio may be
calculated using measured values for bilk density and tapped density as
fallows
Compressibility index = 100 × (
ρbulk − ρtap
ρbulk
)
Hausner ratio =
ρtap
ρbulk
• For compressibility and Hausner ratio the generally accepted scale of
flow ability is given in the table:
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Compressibility index % Flow character Hausner ratio
< 10 Excellent 1.35 – 1.45
11 – 15 Good 1.46 – 1.59
16 – 20 Fair > 1.60
21 – 25 Passable 1.00 – 1.11
26 -31 Poor 1.12 – 1.18
32 – 37 Very poor 1.19 – 1.25
> 38 Very very poor 1.26 – 1.34
• 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.
3. 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 that 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.
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- 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
- 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.
4. 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
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• 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.
• A third type of shear cell, plate shear cell consist 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.
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QUALITY CONTROL OF SYRUPS AND ELIXIRS
SYRUPS
• “Syrups are concentrated, viscous aqueous solutions of sugar or sugar
substitutes with or without flavor and medical substances.”
• When purified water alone is used in making the solution of sucrose, the
preparation is known as syrup, or simple syrup if the sucrose
concentration is 85%.
PROPERTIES
• Syrups are aqueous preparations characterized by a sweet taste and
viscous consistency.
• They may contain sucrose at a concentration of at least 45% w/w.
• The sweet taste can also be obtained by using other polyols or
sweetening agents.
• Syrups usually contain aromatic or other flavoring agents.
ELIXIRS
• “Elixirs are clear, pleasantly flavored, sweetened hydroalcoholic liquids
intended for oral use.” The main ingredients in elixirs is ethanol and
water but glycine, sorbitol, PEG, flavoring agent, preservative and syrups
often are used in the preparation of final product.
PROPERTIES
• The solvents are often used to increase the solubility of the drug
substance in the dosage form.
• Elixirs are more fluid then syrups, due to use of less viscous ingredients
such as alcohol and the minimal use of viscosity improving agents such
as sucrose.
• They are used as flavors and vehicles such as aromatic elixir USP for drug
substances, with drug substances they are called medicated elixirs. For
example: Dexamethasone elixir.
QUALITY CONTROL TESTS
• The quality control tests for syrups and elixirs are as follows:
1. Viscosity 2. Weight per ml
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GM Hamad
3. Content uniformity 4. Drug assay
VISCOSITY
INTRODUCTION
• Viscosity is the property of liquid that is closely related to resistance to
flow. It is defined as, “the force required to move one plane surface
continuously past another under specified steady state conditions when
the space between is filled by the liquid in question.
• It is defined as the shear stress divided by rate of shear strain.
• There are two types of viscosity:
- Dynamic viscosity
- Kinematic viscosity
DYNAMIC VISCOSITY
• The dynamic viscosity or the viscosity coefficient ‘h’ is the tangential
force per unit surface, known as shearing stress ‘t’ and expressed in
Pascal, necessary to move parallel to the sliding plane a layer of liquid of
1 square meter at a rate ‘v’ of 1ms-1
relative to parallel layer at a
distance ‘x’ of 1 meter.
• The ratio dv/dx is speed gradient giving the rate of shear D expressed in
reciprocal seconds that:
h =
t
D
• The unit of dynamic viscosity is the Pascal second (Pa.s). The most
commonly used submultiple is the milliPascal second (mPa.s)
KINEMATIC VISCOSITY
• The kinematic viscosity ‘V’ is expressed in square meter per second is
obtained by diving the dynamic viscosity ‘h’ by the density ‘d’ expressed
in kilograms per cubic meter of the liquid measured at same
temperature:
V =
h
d
• The kinematic viscosity is expressed in square millimeters per second.
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GM Hamad
UNITS OF VISCOSITY
• The basic unit is the poise (according to USP). However, viscosities
commonly encountered represent fractions of the poise, so that the
centipoise proves to be an easier unit.
• When the absolute scale viscosity is measured in poises or centipoises
for convenience the kinematic scale in which the units are strokes and
centi-strokes is commonly used.
• To obtain the kinematic viscosity from absolute viscosity the latter is
divided by the density of the liquid at the same temperature:
𝐾𝑖𝑛𝑒𝑚𝑎𝑡𝑖𝑐 𝑣𝑖𝑠𝑐𝑜𝑠𝑖𝑡𝑦 = 𝑎𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑣𝑖𝑠𝑐𝑜𝑠𝑖𝑡𝑦 / 𝑑𝑒𝑛𝑠𝑖𝑡𝑦
MEASUREMENT OF VISCOSITY
• A capillary viscometer is used for the determination of viscosity of
Newtonian liquid and a rotating viscometer is used for the
determination of viscosity of both Newtonian and Non – Newtonian
liquids. Other viscometers may be used provided that the accuracy and
precision is not less than that obtained with the viscometers described
above.
• The absolute viscosity can be measured directly if accurate dimensions
of the measuring instrument are known, but it is more common practice
to calibrate the instrument with a liquid of known viscosity and to
determine the viscosity of the unknown fluid by comparison with that of
the known.
CAPILLARY VISCOMETER
• The usual method for the measurement of viscosity involves the
determination of the liquid required for a given volume of the liquid to
flow through a capillary.
EXAMPLE
• Many capillary tube viscometers have been devised, Ostwald and
Ubbelohde viscometers are among the most frequently used.
ROTATIONAL VISCOMETER
• A particularly easier and rapid type of instrument is a Rotational
viscometer, which utilizes the bob or a spindle immersed in the test
specimen and measures the resistance to movement of the rotating
part.
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GM Hamad
• Different spindles are available for given viscosity ranges and several
rotational speeds are generally available. Other rotational instruments
may have a stationary bob or rotating cup.
EXAMPLE
• Brookfield, Rotouisco, and Stormer viscometers are the examples of
rotating viscometers. MacMichael is an example of rotating cup
instrument.
TEMPERATURE SPECIFICATION
• Specifying the temperature is important because viscosity changes with
the temperature. In general viscosity decreases as the temperature is
raised.
• For the measurement of viscosity or apparent viscosity the temperature
of the substances must be accurately controlled, since small changes in
temperature may lead to marked changes in the viscosity. For usual
pharmaceutical purposes, temperature should be held to within ± 0.1.
COMMON METHODS FOR THE DETERMINATION OF VISCOSITY
METHOD I (U-TUBE VISCOMETER)
• The monograph states the size of the viscometer to be used.
APPARATUS
• The apparatus consist of a glass U – tube viscometer made up of clear
borosilicate and constructed in accordance with the dimensions given in
official books.
PROCEDURE
• Fill the viscometer with the liquid being in question through tube
L to slightly above the mark G using a long pipette to minimize
wetting the tube above the mark.
• Place the tube vertically in the water bath when it has attained
the specific temperature adjust the volume of the liquid so that
the bottom of the meniscus settles at the mark G.
• Adjust the liquid to a point about 5 mm above the mark E.
• After releasing the pressure or suction measure the time taken
for the bottom of the meniscus to fall from the top edge of mark
E to top edge of mark F.
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GM Hamad
• Calculate as either the kinematic viscosity ‘V’ in sq. millimeters per
second (mm2
s-1
) from the expression:
𝑉 = 𝐾 𝑡
• Or the dynamic viscosity in milli Pascal seconds from the expression:
ɳ = k ρ t
• Where, t = time in seconds for the meniscus to fall from E to F, 𝜌 = mass/
volume (gcm-3
) obtained by multiplying the relative density (Appendix V)
the G is being examined by 0.9982, K = the constant of the instrument is
determined by using the appropriate European pharmacopoeia
reference liquid for viscometers.
METHOD II (CAPILLARY VISCOMETERS METHOD)
• The determination of viscosity by using a suitable capillary viscometer is
carried out a temperature of 20 ± 0.1℃ unless otherwise prescribed. The
time required for the level of the liquid to drop form one mark to the
other is measured with a stopwatch to the nearest one-fifth of a second.
• The result is valid only if two consecutive readings do not differ by more
than 1%. The average of not fewer than 3 readings gives the flow time of
the liquid to be examined.
• The determination may be carried out with an apparatus having the
specifications described in official books. The minimum flow time should
be 350s for size no. 1 and 200s for all other sizes.
PROCEDURE
•
• Fill the viscometer through tube L with sufficient quantity of
the liquid in question, previously brought to 20℃ unless
otherwise prescribed to fill blub A but ensuring that the level of
liquid in bulb B is below the exit to ventilation tube M.
• Immerse the viscometer in the water bath of water at 20 ±
0.1℃ unless otherwise prescribed, maintain it in upright
position and allow to stand not less than 30 minutes to allow
the temperature to reach equilibrium.
• Close the tube M and raise the level of the liquid in tube N up
to a level about 8 mm above mark E.
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• Keep the liquid at this level by closing tube N and opening tube M. Open
the tube N and measure with a stopwatch to the nearest 1/5th
of a
second, the time required for the level of the liquid to drop from mark E
to mark F.
• Calculate kinematic viscosity ‘V’ in sq. millimeters per second (mm2
s-1
)
from the expression:
𝑉 = 𝑘 𝑡
• Calculate the dynamic viscosity in milli Pascal seconds from the
expression:
ɳ = k ρ t
METHOD III (ROTATING VISCOMETER METHOD)
• The principle of this method is to measure the force acting on a rotor
(torque) when it rotates at a constant angular velocity (rotational speed)
in the liquid.
• A rotating viscometer is used for the determination of viscosity of both
Non – Newtonian liquids (shear dependent viscosity or apparent
viscosity) and Newtonian (shear independent viscosity).
• The rotating viscometer can be divided into two groups:
- Absolute viscometers
- Relative viscometers
• In the relative viscometers the flow in the measuring geometry is not
defined. The measurements result in relative viscosity values, which
cannot be compared with absolute values or other relative values if not
determined by the same relative viscometer method.
• In absolute viscometers the flow in the measuring geometry is well
defined. The measurements result in absolute viscosity values, which
can be compared with any other absolute values.
• Different measuring systems are available for given viscosity ranges as
well as several rotational speed.
APPARATUS
• Following viscometers are used:
- Concentric cylinder viscometers
- Cone plate viscometers
- Spindle viscometers
I. CONCENTRIC CYLINDER VISCOMETERS (ABSOLUTE VISCOMETER)
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• In this type of viscometer (coaxial double cylinder viscometer or simply
coaxial cylinder viscometer) the viscosity is measured by placing the
liquid in the gap between the inner cylinder and the outer cylinder.
• Viscosity measurement can be performed by rotating the inner cylinder
(Searle type viscometer) or the outer cylinder (Couette viscometer).
• For laminar flow, the viscosity ‘h’ expressed in Pascal seconds is given by
the following:
ɳ =
1
ω
(
M
4πh
) (
1
Ri
−
1
Ro
) = k
M
ω
• For Non – Newtonian liquids it is indispensable to specify the shear
stress T or the shear rate γ at which the viscosity is measured. Under
narrow gap conditions (conditions satisfied in absolute viscometers)
there is a proportional relationship between M and t and also between
𝜔 and γ:
t = A M γ = Bω
- Where, A and B are the constants for the instruments and are
calculated by following expressions:
• For concentric surfaces:
A =
1Ri
2
+ Ro
2
4πh Ri
2
Ro
2
𝐵 =
𝑅𝑖
2
+ 𝑅 𝑜
2
𝑅 𝑜
2 − 𝑅𝑖
2
• Where, M = torque in newton meters acting on cylinder surface, 𝜔 =
angular velocity in radians per second, h = height of immersion in meters
of the inner cylinder in the liquid medium, Ri = radius in meter of inner
cylinder, Ro = radius in meter of outer cylinder, R = radius in meters of
the cone.
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II. CONE PLATE VISCOMETERS (ABSOLUTE VISCOMETERS)
• In the cone plate viscometer, the liquid is introduced into the gap
between the flat disc and a cone forming a define angle. Viscosity
measurement can be performed by rotating the cone or the flat disc. For
laminar flow, the viscosity ‘h’ expressed in Pascal seconds is given by the
following:
ɳ = (
M
ω
) (
3α
2πR3
) = k
M
ω
• For Non – Newtonian liquids it is indispensable to specify the shear
stress T or the shear rate γ at which the viscosity is measured. Under
narrow gap conditions (conditions satisfied in absolute viscometers)
there is a proportional relationship between M and t and also between
𝜔 and γ
t = A M γ = Bω
• Where, A and B are the constants for the instruments and are calculated
by following expressions; For cone plates:
A =
3
2πR3
B =
1
α
angular velocity in radians per second, h = height of immersion in meters
of the inner cylinder in the liquid medium, R = radius in meters of the
cone, α = angle in radians between the flat disc and the cone, K =
constant of the apparatus expressed in radians per cubic meter
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III. SPINDLE VISCOMETERS (RELATIVE VISCOMETERS)
• In the spindle viscometers the viscosity is determined by rotating a
spindle (cylinder or disc shaped) immersed in the liquid. Relative values
of viscosity can be directly calculated using conversion factors from the
scale reading at a given rotational speed.
• In general way, the constant K of the apparatus may be determined at
various speeds of rotation using a certified viscometer calibration liquid.
The viscosity then corresponds to the expression:
η = K
M
ω
angular velocity in radians per second, K = constant of the apparatus
expressed in radians per cubic meter.
PROCEDURE
• Measuring the viscosity according to the instructions for the operation
of the rotating viscometer.
• The temperature of measuring the viscosity is indicated in the
monograph.
• For non – Newtonian systems the monograph indicates the type of
viscometer to be used and if absolute viscometers are used the angular
velocity or the shear rate at which the
measurement is made.
• If it is impossible to obtain the indicated shear rate use a shear rate
slightly higher and a shear rate slightly lower and interpolate.
• With relative viscometers the shear rate is not the same throughout the
sample and therefore it cannot be defined.
• Under these conditions the viscosity of non – Newtonian liquids
determined from the previous formula has a relative character, which
depends upon the type of the spindle and the angular velocity as well as
the dimensions of the sample container and the depth of the immersion
of the spindle.
• The values obtained are comparable only if the method is carried out
under experimental conditions that are rigorously the same.
IV. METHOD IV (FALLING BALL VISCOMETER METHOD)
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• The determination of dynamic viscosity of Newtonian liquids using a
suitable falling ball viscometer is performed at 20 ± 0.1℃ unless
otherwise prescribed, in the monograph.
• The time required for the test ball to fall in the liquid to be examined
from one ring mark to the other is determined. If no striker limit is not
defined for the equipment used the results is valid only if two
consecutive measurements do not differ by more than 1.5%.
APPARATUS
• The falling ball viscometer consist of a glass tube enclosed in a mantle
that allows direct control of temperature. Six balls made of glass, nickel,
iron or steel with different densities and diameters. The tube is fixed in
such a way that the axis is inclined by 10 ± 0.1o
with regard to the
vertical. The tube has two ring marks which defines the distance the ball
has to roll.
• Commercially available apparatus is supplied with table giving the
constants, the density of the balls and the suitability of the different
balls for the expected range of viscosity.
PROCEDURE
• Fill the clean dry tube of the viscometer previously brought to 20 ± 0.1o
C
with the liquid to be examined avoiding bubbles.
• Add the ball suitable for the range of viscosity of the liquid so as to
obtain a falling time not less than 30s.
• Close the tube and maintain the solution at 20 ± 0.1o
C for at least 15
• minutes. Let the ball run through the liquid between the 2 ring marks
once without measurement.
• Let it run again and measure with a stopwatch to the nearest 1/5th
of a
second the time required for the ball to roll from the upper to the lower
ring mark.
• Repeat the test run at least 3 times.
• Calculate the dynamic viscosity in the milli Pascal using the formula:
ɳ = k(ρ1 − ρ2) × t
• Where, K = constant expressed in millimeter sq. per second square, t =
falling time of the ball in seconds, 𝜌1 = density of the ball used,
expressed in grams per cubic centimeter, 𝜌2 = density of the liquid to be
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examined, g=expressed in gcm-3
obtained by multiplying its relative
density by 0.9982
WEIGHT PER MILLILITER
• It is defined as, “The weight per ml of a liquid in the weight in gram of 1
ml of a liquid when weighed in the air at 20℃ unless otherwise specified
in the monograph.”
DETERMINATION
• The weight per ml is determined by dividing the weight in air expressed
in grams of the quantity of the liquid that falls on pycnometer at the
specified temperature by the capacity expressed in ml of the
pycnometer at the same temperature.
• The capacity of the pycnometer is ascertained from the weight in air
expressed in grams of the quantity of the water required to fill the
pycnometer at same temperature.
• The weight of a liter of water at specified temperatures when weighed
against brass weights in air of density 0.0012 g per ml is given in the
following table:
Temperature (o
C) Weight of water (g)
20 997.91
25 997.07
30 995.67
DENSITY
• The density can be defined as, “the density of a substance is the ratio of
its mass to its volume at 20o
C. It is expressed in Kgm-3
.
DETERMINATION
• The density is determined by dividing the weight in air of the quantity of
liquid being examined that fills a pycnometer at 20o
C by the weight of air
of water required to fill the pycnometer after making allowance for the
thrust of the air.
• The density is calculated from the expression:
ρ20 =
998.2 (𝑀1 + A)
(𝑀2 + A)
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• Where, M1 = weight in air, in the grams of the substance being
examined, M2 = wright in air in grams of water, A = the correction factor
for the thrust of the air 0.0012 M2, 998.2 = the density of water at 20o
C
in Kgm-3
. In most cases the correction for the thrust of the air may be
disregarded.
RELATIVE DENSITY
• The relative density can be defined as, “the relative density is the ratio
of the mass of a certain volume of a substance at a temperature t1 to the
mass of an equal volume of water at temperature t2 unless otherwise
indicated the relative density is used. Relative density is also commonly
expressed as 𝑑4
20
• Density, defined as the mass of a unit volume of the substance at 20o
C
may also be used, expressed in kg/m3
or g/cm3
.
• The quantities are related by the following equations, where the density
is expressed in g/cm3
.
ρ20 = 0.998203 × d20
20
𝑜𝑟 d20
20
= 1.00180 × ρ20
ρ20 = 0.999972 × d4
20
or d4
20
= 1.00003 × ρ20
d4
20
= 0.998203 × d20
20
• Relative density are measured with the precision to the number of
decimals prescribed in the monograph using a density bottle (solid or
liquids), a hydrostatic balance (solids), a hydrometer (liquids) or a digital
density meter with an oscillating transducer (liquids or gases).
• When the determination is made by weighing the buoyancy of air is
disregarded which may introduce an error of 1 unit in the third decimal
place. When using a density meter, the buoyancy of air has no influence.
OSCILLATING TRANSDUCER DENSITY METER
• The apparatus consist of:
- A U – shaped tube made up of borosilicate glass which contains
the liquid to be examined.
- A magneto electrical or piezo-electrical excitation system that
causes the tube to oscillate as a cantilever oscillator at a
characteristic frequency depending upon the density of the liquid
to be examined.
- A means of measuring the oscillation period T, which may be
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converted by the apparatus to give a direct reading of density or
used to calculate density using the constants A and B.
• The resonant frequency ‘f’ is a function of the spring constant ‘c’ and the
mass ‘m’ of the system.
𝑓2
=
1
𝑇2
=
𝑐
𝑚
×
1
4𝜋2
• Hence,
𝑇2
= (
𝑀
𝐶
+
𝜌 × 𝑉
𝐶
) × 4𝜋2
• Where, M = mass of the tube, V = inner volume of the tube
• Introduction of 2 constants 𝐴 = 𝑐/ (4𝜋2 × 𝑉) and 𝐵 = M/𝑉 leads to the
classical equation for the oscillating transducer.
ρ = A × T2
− B
• The constants A and B are determined by operating the instrument by
the U- Tube filled with two different samples of known density. For
example; degassed water R and air. Control measurements are made
daily using degassed water R.
• The results displayed for the control measurement using degassed water
R shall not deviate from the reference value (𝜌20 = 0.998203 gcm-3
=
1.000000) by more than its specified error.
FACTORS AFFECTING ACCURACY
• Temperature uniformity throughout the tube
• Non – linearity over a range of density
• Parasitic resonant effect
• Viscosity, whereby solutions with a higher viscosity the calibrant have
density that is apparently higher than the true value.
APPARENT DENSITY
• The term apparent density is used in monographs for dilute Ethanol,
Industrial methylated spirit and industrial methylate spirit (ketone free).
• It is defined as, “weight in air per unit volume.” It is expressed in kgm-3
.
It named density in the laboratory alcohol table for laboratory use.
• The apparent density is calculated by the following expression:
𝐴𝑝𝑝𝑎𝑟𝑒𝑛𝑡 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 = 997.0 × 𝑑20
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• Where, 𝑑20 = Relative density of the substance being examined, 997.2 =
Weight in air in kg of 1 cubic meter of water.
CHEMICAL ASSAY OF SYRUP AND ELIXIR
• Routinely the assay of content in syrup and elixirs is done by the amount
of liquid representing the certain amount of drug normally in a single
unit. It is then diluted according to the procedure and instrument use.
• Analysis is performed by the method prescribed in the individual
monographs.
• Results obtained are expressed as percentage of the active ingredient in
the table or unit dose and compared with limits in the monograph of
drug.
• Common assay procedure involves:
- Titrimetric method
- Spectroscopic method
- UV spectroscopy
- HPLC
- Biological assay
- Microbial assay
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QUALITY CONTROL OF SUPPOSITORIES
SUPPOSITORIES
• Suppositories are medicated solid bodies of various sizes and shapes
suitable for introduction into body cavities for their local and systemic
effect.
• The medicament is incorporated into the base such as coca butter that
melts at body temperature or into one such as glycerol gelatin or PEG
which slowly dissolve into the mucous secretions.
• Suppositories are suited particularly for producing local action but may
also be used to produce a systemic effect or exert a mechanical effect to
facilitate emptying the lower bowel.
CLASSIFICATION OF SUPPOSITORIES
• Rectal suppositories for adults weigh 2 gm and are torpedo shape.
Children's suppositories weigh about 1 gm.
• Vaginal suppositories or Pessaries weigh about 3-5gm and are molded
in globular or oviform shape or compressed on a tablet press into conical
shapes.
• Urethral suppositories called bogies are pencil shape. Those intended
for males weigh 4 gm each and are 100-150 mm long while those for
females are 2 gm each and 60-75 mm in length.
QUALITY CONTROL TESTS FOR SUPPOSITORIES
1. VISUAL EXAMINATION
• This includes shape, color, surface condition and odor.
I. SHAPE
• It is advisable to check the shape of the suppository to see if it is
consistent.
II. COLOR
• The intensity, nature and homogeneity of the color should be verified.
The use of color chart is advisable.
III. SURFACE CONDITION
• The surface conditions can be checked for brilliance, dullness, mottling,
cracks, dark regions, axial cavities, bursts, air bubbles, holes, etc.
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IV. ODOR
• A change in the odor may also be indicative of a degradation process.
2. DISSOLUTION TEST
• Dissolution testing is often required for suppositories to test for
hardening and polymorphic transitions of active ingredients and
suppository bases.
• Dissolution testing methods include the paddle method, basket method,
membrane diffusion method/dialysis method, and the continuous
flow/bead method.
• The melting suppositories with the paddle method showed fat floating
rapidly to the surface of the fluid instead of staying below the water
surface. With the basket method, the surfactant produced small droplets
of the fat that were dispersed into the medium almost immediately.
3. WEIGHT UNIFORMITY
• Weigh 20 suppositories individually. w1, w2, w3….w20
• Weigh all the suppositories together = W.
• Calculate the average weight = W/20.
LIMIT
• No suppository should deviate more than 5% from the average weight
except that two may deviate by not more than 7.5% of the average
weight of suppository.
NOTE
• If the weight is found to be too small, it is advisable to check whether
the mold is being well filled and whether there are axial cavities or air
bubbles caused by badly adjusted mechanical stirring or the presence of
an undesirable surfactant.
• If the weight is found to be too high, check that scraping has been
carried out correctly, and also that the mixture is homogeneous.
4. ASSAY OF ACTIVE INGREDIENTS
• Determine the amount of active ingredients in suppositories by the
method described in the Assay.
• It should be according to the specification given in individual
monograph.
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5. LIQUEFACTION TIME OR SOFTENING TIME TEST
• In this test a U tube is partially immersed in a constant temperature bath
and is maintained at a temperature between 35°C to 37°C. There is a
constriction in the tube in which the suppository is kept and above the
suppository, a glass rod is kept. The time taken for the glass rod to go
through the suppository and reach the constriction is known as the
liquefaction time or softening time.
• Another apparatus is there for finding “softening time” which mimics in
vivo conditions. It uses a cellophane tube, and the temperature is
maintained by water circulation at 37°C. Time taken for the suppository
to melt is noted. Time is 5-25 mins.
6. BREAKING TEST (HARDNESS)
• The breaking test is designed as a method for measuring the fragility or
brittleness of suppository.
• The suppository is placed in the instrument. Add 600 g weight and leave
it for one min. If not broken, add 200 g weight every one minute until
the suppository is broken.
CALCULATIONS
• The hardness of the suppository is calculated by adding the weights
together. But if the suppository is broken before the end of the last min,
the last weight is canceled.
7. MELTING RANGE (MELTING POINT, MELTING ZONE)
• Many suppository bases and medicated suppositories are mixtures, and
so do not have a precise melting point. Melting range or melting zone is
the term often preferred.
• The release rate of the suppository is related to its melting point; it is
therefore critical that this test be evaluated using a non-destructive
method. A number of different techniques are used to study melting
behavior, including the open capillary tube, the U-tube, and the drop
point methods.
• The methods used are similar in principle but include different steps and
techniques. In general, they include the set-up of the equipment,
placement of the suppository dosage unit in the apparatus, followed by
the application of heat and observation for a change in the system, such
as melting or movement. In general, the melting point should be equal
to or less than 37℃. A non-destructive method must be used because if
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the suppository is melted before a measurement is made, the
suppository constituents may be transformed into a metastable state.
• The melting test consists of placing a suppository on the surface of water
thermostatically controlled at 37℃ and verifying the complete melting
of the suppository in a few minutes. This is not so much a measurement
as an evaluation.
MELTING RANGE TEST
• Determines the time taken by an entire suppository to melt when it is
immersed in a constant temperature bath at 37°C.
• The experiment done by using the USP Tablet Disintegration Apparatus.
PROCEDURE
• The suppository is completely immersed in the constant temperature
water bath, and the time for the entire suppository to melt or disperse
in the surrounding water is measured.
• The suppository is considered disintegrated when:
- It is completely dissolved or
- Dispersed into its component part.
- Become soft “change in shape” with formation of core which is
not resistant to pressure with glass rod.
TYPES
• Melting Range tests are of two types:
- Macro-Melting Range Test
▪ Macro-melting range test is applied for entire suppository
and measure the time it takes for complete melting.
- Micro-Melting range test
▪ The test is performed for suppository bases only.
8. DISINTEGRATION TEST
APPARATUS
• Cylinder of glass or other transparent material, 60 mm high, 50 mm
internal diameter and thickness of walls is 8 mm.
• The cylinder is fitted with two horizontal parallel perforated stainless-
steel plates. These plates are 30 mm apart.
• A device to maintain the temperature at 37℃ i. e. water bath.
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• A device which will hold the cylinder 90 mm below the water i. e. surface
of the water and after every 10 mins. the cylinder can be inverted
without emerging from water.
METHOD
• Place a suppository to the lower perforated plate insert the cylinder for
30 mins. Unless otherwise specified in individual monograph.
• The suppository is disintegrated when:
- It has completely dissolved except for any insoluble material.
- The disintegration product has fallen through the perforated tube
or risen to the surface of water.
- Any solid material remaining between the plates melted
completely and no longer has a solid core.
• Repeat the test for two more suppositories. All three should disintegrate
within 30 mins. unless otherwise specified in individual monographs.
9. STABILITY TESTING
• Cocoa butter suppositories on storage, “bloom”; i.e., they form a white
powdery deposit on the surface. This can be avoided by storing the
suppositories at uniform cool temperatures and by wrapping them in
foils.
• Fat based suppositories harden on storage, i.e. there is an upward shift
in melting range due to slow crystallization to the more stable
polymorphic forms of the base.
• The softening time test and differential scanning calorimetry can be used
as stability indicating test methods.
• If we store the suppositories at an elevated temperature, just below its
melting range, immediately after manufacture, the aging process is
speeded up.
TESTS FOR SUPPOSITORY BASES
1. MELTING RANGE
• Since fats do not have sharp melting point, their melting characteristics
are expressed as a range indicating the temperature at which the fat
start to melt and the temperature at which it is completely melted.
2. SOLIDIFICATION POINT
• This value indicates the time required for the base solidification when it
is chilled in the mold. If the interval between the melting range and
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solidification point is 10℃ or more, the time require for solidification
may have to be shortened for more efficient manufacturing procedure
by augmenting refrigeration.
3. SAPONIFICATION VALUE
• The number of milligrams of potassium hydroxide require to neutralize
the free acids and to saponify the esters contained in 1 g of fat is an
indication of the type of glyceride (mono or tri) as well as the amount of
glyceride present.
4. IODINE VALUE
• The value expresses the number of grams of iodine that react with 100 g
of fat or other unsaturated material.
• The possibility of the decomposition by moisture, acid, or oxygen (leads
to rancidity in fats) increases with high iodine values.
5. WATER NUMBER
• The amount of water in grams which can be incorporated in 100 gram of
fat is expressed by this value.
• The water number can be increased by addition of surface-active agents
(surfactants).
6. ACID VALUE
• The number of milligrams of potassium hydroxide required to neutralize
the free acid in 1 gram of substance is expressed by this value.
• Low acid values or complete absence of acid are important for good
suppository base. Free acids complicate formulation work, because they
react with other ingredients and can also cause irritation when in
contact with mucous membranes.
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QUALITY CONTROL OF PARENTERAL
DEDINITION
• Parenteral dosage form is used through injection and must be free of
any viable micro-organism, pyrogens and also meeting the other official
criteria of the dosage form including Isotonicity.
QUALITY CONTROL TESTS FOR PARENTERALS
• Three general areas of quality control tests for sterile products are:
- Incoming stock
- Manufacturing
- Finished product
INCOMING STOCK
• For sterile products, incoming stock control encompasses routine
conformation of color, odor, crystalline state, solubility, identification,
melting point, loss on drying, residue on ignition, heavy metal and
specific gravity on all ingredient.
• It also includes special evaluation such as pyrogen test for water for
injection, glass test on containers and identity test on rubber closures.
IN PROCESS QUALITY CONTROL
• In process control, manufacturing of sterile products involves many
tests, readings and observations are made throughout the
manufacturing process of products.
• In-process quality control of sterile product includes:
- Conductivity measurement during the distillation of water for
injection.
- Confirmation of volume of fill in product containers.
- Recording of cycle time and temperature for thermal sterilization
of the product.
- Confirming the count and identity of labels for the product.
FINISHED PRODUCT
• The finished product control tests includes the final assay and tests to
which a product is subjected.
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• In addition to usual chemical and biological tests, sterile product should
be subjected to:
- Sterility test
- Pyrogen test
- Leaker test
- Clarity test
- Final assay of drug
product
1. STERILITY TEST
• It is used for Parenteral, ophthalmic preparations, syringes and implants.
STERILITY TESTING FOR PARENTERAL
BASIC CONCEPTS
NON-STERILE PRODUCTS
• Means that presence of any viable micro-organisms (Bacteria, Fungi,
Yeast etc.) is there.
STERILE PRODUCTS
• Absence of any viable micro-organism in preparation.
ASSUMPTION
• It is assumed that organisms will grow in the given culture medium
although some limitations are there.
LIMITATIONS
• Different organisms have different nutritional need.
• Different temperature for different organisms is required.
• Some micro-organisms especially spores need longer period to grow
than recommended one.
SELECTION OF CULTURE MEDIA
• Various culture media with methods of preparation are given in B.P. and
U.S.P. which should be chosen.
• Any other medium should give equal or more growth of micro-organisms
like Aerobic, Anaerobic or Fungi.
TESTS FOR MEDIA
I. STERILITY
• Prior to testing it is checked the media prepared is sterilized or not.
PROCEDURE
• Incubate the portions of the media for 14 days.
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• Incubation of media for Bacteria at 30℃– 35℃
• Incubation of media for Fungi at 20℃ – 25℃
• Observe the microbial growth.
RESULT
• If there is no growth of microbes, media is sterilized and ready for
testing.
II. GROWTH PROMOTION TEST OF AEROBES, ANAEROBES AND FUNGI
• The growth promotion test is performed to check whether the media
prepared is good for the microbial growth or not. Test each batch of
ready-prepared medium and each batch of medium prepared either
from dehydrated medium or from the ingredients.
PROCEDURE
• Inoculation of the medium with 100 viable micro-organisms of each of
the following micro-organisms.
- An aerobe ------ (Staphylococcus aureus)
- Spore forming aerobe --- (Bacillus subtilis)
- An anaerobe ----- (Clostridium sporogenes)
- A Fungus ----- (Candida albicans)
• Incubation Temperature:
- For Bacteria: 30℃ to 35℃
- For Fungus: 20℃ to 25℃
• Incubation Period.
- Incubation period should not be less than 07 days.
RESULT
• If early and copious growth occurs, the medium contains required
nutritive properties and is suitable.
EFFECTIVENESS OF MEDIA IN THE PRESENCE AND ABSENCE OF THE
PREPARATION BEING EXAMINED
• Two containers of media are prepared for each of aerobe, anaerobe,
fungus or a spore forming aerobe.
• To each container, add preparation. Inoculate each container with 100
viable micro-organisms. Prepare similar sets without preparation.
• Incubate all containers at an appropriate temperature i.e. 30℃ to 35℃
for bacteria and 20℃ to 25℃ for fungus not more than 07 days.
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RESULT
• Equal growth in all the containers indicate that preparation has no
antimicrobial activity.
• Less growth, delayed growth or no growth in containers having
preparation shows antimicrobial activity.
ELIMINATION OF ANTIMICROBIAL ACTIVITY OF PREPARATION
• Antimicrobial activity of preparation is eliminated by:
- Dilution
- Neutralization of activity
- Filtration
• After treatment (removal of activity), it is again checked for
antimicrobial activity as above.
METHODS FOR STERILITY TESTING
• Two methods/techniques of sterility testing are:
- Membrane Filtration
- Direct Inoculation
I. MEMBRANE FILTRATION
• The method is preferably used for:
- Filterable aqueous preparations
- Alcoholic or oily preparations
- Preparations miscible with or soluble in aqueous or oily solvents
that do not have antimicrobial activity.
• Membrane filters of esters or mixture of cellulose are recommended for
alcoholic or oily preparations.
• Pore size should not be greater than 0.450 micrometer or 450 nm.
Diameter of the filter is 50 mm, if more than 50 mm then adjusted as per
procedure given in the official procedure.
• The apparatus is designed so that the solution to be examined can be
introduced and filtered under aseptic conditions; it permits the aseptic
removal of the membrane for transfer to the medium or it is suitable for
carrying out the incubation after adding the medium to the apparatus
itself.
DIFFERENT DOSAGE FORMS/PREPARATIONS ARE TREATED BEFORE
MEMBRANE FILTRATION
A. AQUEOUS SOLUTION
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• Membrane is moistened with sterile diluent like 0.1% w/v neutral
solution of meat or casein peptone.
• Volume of the preparation should be according to the specifications.
Dilute the volume of the preparation to about 100 ml with diluent
and filter immediately.
• If preparation has antimicrobial activity, washing is done by three
portions of diluents each of 100 ml.
• Transfer the whole membrane to the culture medium or cut it
aseptically into two equal parts and transfer one half to each of two
suitable media. Incubate the media for not less than 14 days.
• Alternatively, transfer the medium onto the membrane in the
apparatus. Incubate the media for not less than 14 days.
B. SOLUBLE SOLIDS
• Specified quantity dissolved in 0.1% w/v neutral solution of meat or
casein peptone (sterile).
• After filtration, perform the test as for aqueous solution.
C. OILS AND OILY SOLUTION
• Low viscosity oils/oily preparations filtered through dry membrane
directly.
• Viscous preparations are diluted with isopropyl myristate having no
antimicrobial activity.
• After penetration, the oil into membrane, filtrations is facilitated by
pressure or suction. Washing with diluents (sterile neutral meat
solution, 0.1% w/v or casein peptone) containing 0.1 % w/v (4-
tertoctylphenoxy) polyethoxy ethanol or 0.1 % w/v polysorbate 80.
• Complete test as in the case of aqueous solutions.
D. OINTMENTS AND CREAMS
• Ointments in fatty bases or W/O emulsion diluted by heating (40℃ or
up to 45℃) and add diluent (Isopropyl myristate). Filter rapidly.
• Test as for oily preparations.
II. DIRECT INOCULATION
• Dilution of the dosage forms. Liquids are to be diluted 10 folds. Solids
are to be diluted 100 folds. To eliminate antimicrobial activity of the
preparation, larger volume is required for dilution. Either concentrated
medium is to be added to the preparation or preparations are added to
the medium.
OILY LIQUIDS
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GM Hamad
• Use media to which have been added a suitable emulsifying agent at a
concentration shown to be appropriate in the method suitability of the
test, for example, polysorbate 80 at a concentration of 10 g/l.
OINTMENTS AND CREAMS
• Prepare by diluting to about 1 in 10 by emulsifying with the chosen
emulsifying agent in a suitable sterile diluent such as peptone (1 g/l) TS1.
Transfer the diluted product to a medium not containing an emulsifying
agent.
• Incubate the inoculated media for not less than 14 days. Observe the
cultures several times during the incubation period. Shake cultures
containing oily products gently each day.
• For anaerobic micro-organisms, for example Clostridium sporogenes,
mercapto acetate or similar medium is used. Minimum shaking is done
to maintain anaerobic condition.
OBSERVATION AND INTERPRETATION OF RESULTS
• At intervals during the incubation period and at its conclusion examine
the media for macroscopic evidence of microbial growth.
- If no evidence of microbial growth is found, the product to be
examined complies with the test for sterility.
- If evidence of microbial growth is found, the product, in this case
preserve the culture and repeat the whole procedure, if again a
culture is formed, compare it with the first growth. If it matches
then the product to be examined does not comply with the test
for sterility.
• Conventional microbiological methods are generally satisfactory for
identification of microorganisms recovered from a sterility test. While,
routine microbiological method can demonstrate that 2 isolates are not
identical these methods may not be sufficiently sensitive or reliable
enough to provide unequivocal evidence that two isolates are from the
same source.
• More sensitive tests, for example; Molecular typing with RNA/ DNA
homology, may be necessary to determine that microorganism are
clonally related and have a common origin.
OPHTHALMIC PREPARATIONS
• Ophthalmic preparations include:
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GM Hamad
- Eye solutions
- Eye ointments
- Eye creams
• These preparations are sterile and tested for sterility along with other
tests. Tests are:
- Sterility (as given in official Books).
- Clarity.
- Heavy metal particles.
- Active contents determination.
- pH.
- Retention time.
2. PYROGEN TEST
• Pyrogens are products of the growth of micro-organisms especially
molds, bacteria (in particular gram negative), viruses and fungi.
• Debris left after killing micro-organisms. Chemically, pyrogenic materials
are lipid in nature.
SYMPTOMS CAUSED BY PYROGENS
• Febrile reaction in human being.
• Other symptoms include:
- Chills, pains in the back and legs and malaise.
ELIMINATION OF PYROGENS
• Heating equipment and material at:
- 180℃ for 04 hours.
- 200℃ for 01 hour.
- 250℃ for 30 to 45 minutes.
- 650℃ requires only 01 minute to destroy pyrogens.
• Distillation
• Filtration (Reverse osmosis)
• Adsorption (low molecular weight drugs e.g. glucose etc. can only be
used).
METHODS
• Two Methods are used officially
- LAL (limulus amebocyte lysate) test. Also, known as the in vitro
testing.
- Biological Test. Also, known as the in vivo testing.
I. LAL TEST
60

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