Notes

on

Pharmaceutical
Quality Control
Prepared by: Bassam Abduh Ali

2022
Content:

Title Page
Introduction into quality control
Quality control of raw materials (preformulation studies)
Impurities in pharmaceutical substances
Quality control of partially completed products (intermediates)
Quality control of finished products
Quality control of liquid dosage forms (syrups, elixirs, suspension)
Quality control of semisolid dosage forms
Quality control of solid dosage forms (tablets and capsules)
Quality control of sterile dosage forms (parenterals)
Quality control of aerosols
Introduction into quality control

Definition:

In general: Quality control (QC) includes the activities from the suppliers, through
production, and to the customers.

 Incoming materials are examined to make sure they meet the appropriate
specifications.
 The quality of partially completed products (intermediates) are analyzed to
determine if production processes are functioning properly.
 Finished goods and services are studied to determine if they meet customer
expectations.

In pharmaceutical terms: The term quality control refers to the sum of all procedures
undertaken to ensure the identity and purity of a particular pharmaceutical product.

The quality of a product may deviate from the standard required.

So carrying out analysis is important in order to determine the quality. Testing a

pharmaceutical product involves chemical, physical, and some time microbiological
evaluation or test.
Objectives of quality control:

 To ensure the specifications of incoming materials and output products.

 To protect the consumer from defective products.
 To protect the company from damage to its reputation ‫ سمعة‬due to inferior
manufacturing processes.
 To avoid the production of counterfeit medicines.

Counterfeit medicines: ‫االدوية المزورة‬

The WHO defines a counterfeit drug as a product that is with intent and illegally
mislabeled with respect to its identity and/or source.

Counterfeiting of medicinal products, active pharmaceutical ingredients or product

labels are criminal offences ‫جرائم جنائية‬, which may endanger patient health.

Counterfeit medicines may:

 contain no active ingredient

 contain the wrong active ingredient (e.g. a cheap antibiotic instead of an
expensive antibiotic)
 contain an incorrect (usually low) quantity of the active ingredient
 be in low–quality packaging
 be manufactured using low–quality active ingredient or excipient
 be manufactured under poor standards of good manufacturing practice (GMP)
compliance.
Pharmaceutical Quality Control is a branch of pharmaceutical analytical chemistry
dealing with drugs analysis from starting as a raw material to the finished product
stage.

Quality Assurance (QA)

 Sum of all activities and responsibilities required to ensure that each medicine
reaching a patient is safe, effective, and of acceptable quality.
 QA includes: A quality system (organizational structure, procedures &
processes), personal, training, facilities, laboratory environment, quality control
procedures documentation, measurement, preventive maintenance, …….

Good Manufacturing Practices (GMPs)

 GMP is a part of quality assurance.

 GMP is the performance standards that WHO and many national governments
established for pharmaceutical manufacturers, for example personal, facilities,
packaging and quality control.

Quality Control (QC)

 QC is a part of GMP which is concerned with sampling, specifications,

inspection, testing, documentation, analytical methodologies and good
laboratory practice required to ensure that product is not released for use until
their quality has been evaluated.
QA and QC

QA QC
All systematic actions necessary for Operational laboratory techniques
quality necessary for quality
company system laboratory system
The system The tools
Prevention of defects in the products Detection of defects in the products

Processes of the pharmaceuticals quality

1. Raw materials tests.

2. In-process quality control (IPQC) tests.

3. Finished product quality control (FPQC) tests.

• QC is also including: Active ingredient, Packaging martial, Excipient…

Determinants of drug quality

 Identity: to confirm the actual presence of compound (active ingredients).

 Purity: to estimate the impurities and contamination in the drug.
 Potency: to estimate the concentration of an active ingredient in drug.
 Uniformity: consistency of color, shape, size.
 Bioavailability
 Stability

Steps of pharmaceutical analysis

 Define the problem

 Select the method
 Point out the conditions affecting on the measurement method (analyte
concentration, solvent, temperature, pH, reaction time,. .)
 Sample preparation
 Standard preparation
 Perform the measurement
 Calculations and report

WHO Good Practices of Pharmaceutical Quality Control Laboratories

Part one: Management and infrastructure

1. Organization and Management

2. Quality management system

3. Documentation

4. Records

6. Personnel

7. Facilities

Part two: Material, equipment, instruments and other devices

Part three: Working procedures

1. Incoming samples

2. Analytical worksheet

3. Validation of analytical procedures

4. Certificate of analysis

Part four: Safety

Classification of dosage forms physically:

1. Liquid dosage forms:

a. Monophasic liquid dosage forms (solutions)

 Aqueous solutions as syrups, glycerites, enemas, mouthwashes, gargles, …

 Nongaseous solutions as elixirs, oleovitamins, …

b. Polyphasic liquid dosage forms

 Suspensions
 Emulsions
 Colloids

2. Semisolid dosage forms:

 Ointments
 Creams
 Pastes
 Gels
 Suppositories and pessaries

3. Solid dosage forms:

 Powders
 Granules
 Tablets
 Capsules
 Sustained release systems

4. Gaseous dosage forms: aerosols

5. Sterile dosage forms:

 Parenterals
 Ophthalmics
 Irrigations
 Implants
Pharmaceutical preformulation
Before the formulation of dosage forms there are three considerations should be noted
that are:

a. Preformulation consideration: drug factors as physical and chemical properties of

drug substances.
b. Biopharmaceutical considerations including factors affecting the absorption of the
drug from different administration routes.
c. Therapeutic considerations including clinical indications and patients factors and
effect on:
 Duration of action
 Dose frequency
Preformulation Studies (drug factors or physic-chemical factors):

Preformulation is defined as phase of research and development in which

preformulation scientist characterize physical & chemical properties of new drug
molecule in order to develop safe, effective, and stable dosage form.

Goal of preformulation are:

1. Designing an optimum drug delivery system.

2. Formulation of an elegant, safe, efficacious dosage form with good
bioavailability.
3. Formulation of new dosage form of already existing drug.
4. Determination of all the properties of drug and the best suitable dosage form
for the drug molecule.
The main steps in preformulation pharmaceutical research are:
I. Physical characteristics:
1. Organoleptic properties
2. Assay development: UV, TLC and HPLC.
3. Bulk characterization:

 Crystallinity and polymorphism.

 Hygroscopicity.
 Fine particle characterization.
 Powder flow properties.
 Purity.

4. Solubility analysis:

 Solubility determination.
 Partition coefficient.
 Dissolution studies.

5. Membrane permeability
6. Stability analysis:

 Solution stability
 Solid state stability.
 Compatibility studies: stability in the presence of excipients

II. Chemical characteristics:

5. Polymerization. 1. Oxidation.
6. Isomerization. 2. Hydrolysis.
7. Decarboxylation. 3. Photolysis.
8. Enzyme Decomposition. 4. Racemization.
1. Organoleptic properties
This table suggests terminology to describe organoleptic properties of pharmaceutical
powders:

Color Odor Taste

- Off-white - Pungent - Acidic

- Cream yellow - Sulfurous - Bitter
- Tan - Fruity - Bland
- Shiny - Aromatic - Intense
- Odorless - Sweet
- Tasteless

2. Assay development
The first step in preformulation is to develop an analytical method for the quantitation
of the drug in different media:

a. UV spectroscopy:

 It is used for drugs that absorb energy at the ultraviolet region.

 The drug must be in a solution form.
 The type of the chosen solvent depends on drug solubility and functional groups
it has.
Steps: Look the video
1. Establish the UV spectrum of the drug.
2. Choose a suitable wavelength for drug quantitation (Usually λmax).
3. Apply Beer-Lambert law:
Absorbance (A) = log I°/I = εCL
I° is the intensity of the incident light at a given wavelength, I is the transmitted
intensity, L the path length through the sample, and C the concentration of the
absorbing species. For each species and wavelength, ε is a constant known as the
molar absorptivity or extinction coefficient. This constant is a fundamental molecular
property in a given solvent, at a particular temperature and pressure.

- So, the amount of light absorbed is directly proportional with concentration and
path length of the solution.

Uses of UV spectroscopy:
1. Quantitative determination of drugs that absorb in UV region.
2. Quantitative determination of drug degradation products when it absorbs at different
wavelength.
3. Determination of pka of drugs.
b. Thin layer chromatography (TLC):

Steps: Look the video

1. Prepare the extracted sample that contains different components.
2. Prepare the mobile phase (eluting solution) with the suitable composition.
3. Choose the appropriate stationary phase (plate packing material).
4. Spot the sample mixture at the base of the plate and place it horizontally in the
elution tank saturated with the mobile phase vapors.
5. After sample development, determine the Rf value for qualitative analysis.
6. Scratch each spot after separation and extract its components for quantitative
analysis by either UV or HPLC.
Uses of TLC:
1. Qualitative determination of mixtures of components.
2. Estimating their concentration using reference standard.
c. High performance liquid chromatography (HPLC):

- It is column chromatography with elution under high pressure.

- Characteristics (compared to column chromatography):

1. Much smaller column.

2. Shorter retention times.
3. Higher sensitivity (less than 1 ng/ml).
4. Smaller sample volume (1-200 μl).
5. Higher separation selectivity especially for complex mixtures.

- HPLC modes according to type of stationary phase:

1. Normal phase HPLC.

2. Reversed phase HPLC.
Normal phase HPLC
1. The stationary phase is silica (hydrophilic) with a non-polar mobile phase.
2. Mobile phase is usually hexane with the addition of chloroform, isopropyl alcohol,
or methanol (the order of increasing the polarity).
3. Separation occur by a process of partitioning of the solute between the stationary
and mobile phases (Adsorption and desorption).
4. Polar solutes will be retained and eluted faster as the polarity of the mobile phase
increases and vice versa.
Reversed phase HPLC
1. The stationary phase is made lipophilic by coating the silica (derivatization).
Examples: Octadecylsilane “ODS” (C18) and octylsilane (C8).
2. The mobile phase is hydrophilic such as methanol, acetonitrile, THF or mixtures to
modify the polarity.
3. Polar solutes will be eluted quickly with a short retention time. Non polar solutes
will be retained and eluted faster as the polarity of the mobile phase decreased and
vice versa.

Steps: Look the video

Crystallinity:

 Crystal habit (i.e outer appearance of the crystal) and the internal structure (i.e
molecular arrangement within the solid) can affect physicochemical property of the
drug such as; bulk density, particle size, flowability and stability.

Internal structure
Crystalline Amorphous
Molecules are arranged in 3D Molecules are randomly arranged
Prepared by slow precipitation Prepared by rapid precipitation
Low thermodynamic energy so Higher thermodynamic energy so
low solubility rate higher solubility rate

Polymorphism:

 It is defined as the ability of a compound to crystallize in more than one crystalline

form.
 Chemical stability and solubility changes due to polymorphism. For e.g
chloramphenicol palmitate exists in three (A,B,C) polymorphic form, from which
B is more soluble and melting point, density and hardness will also change.

Hygroscopicity:

 Some drugs have the tendency to adsorb atmospheric moisture

 Now the amount of adsorb moisture depends upon the atmospheric humidity,
temperature, surface area and the mechanism for the moisture uptake

 The change in moisture level greatly influences chemical stability, flowability, and
compactability.
Particle size and surface area:

 It affects on the bulk flow, formulation homogenicity of the drug particles.

 Each drug particle is tested for the smallest particle size as it facilitates preparation
of homogenous mixture.

 Instruments used for checking the size and shape are:

a. Light microscope.

b. Hemacytometer slide.

c. Coulter counter.

Flow property and bulk density:

 Bulk density is of greatest important in the size of high dose of capsule product and
in a low dose formulation in which there is a large difference in drug and excipients
density.

Purity:
- Testing purity is another control parameter for comparison with subsequent
batches.
- Impurity can affect:
a. Stability: e.g., metal contamination in ppm
b. Appearance.
c. Toxic: aromatic amine → carcinogenic
- Techniques used for characterizing purity are:
a. Thin Layer Chromatography (TLC)
b. High-Pressure Liquid Chromatography (HPLC)
 c. Gas Chromatography (GC)
d. Melting Point Depression
e. Thermal analysis

Solubility determination:

- One important goal of the preformulation effort is to devise a method for making
solutions of the drug.
- The solubility of drug is an important physicochemical property because it affects
the bioavailability of the drug, the rate of drug release into the dissolution medium,
and consequently, the therapeutic efficacy of the pharmaceutical product.
- A drug must possess some aqueous solubility for therapeutic efficacy. In order for
a drug to enter the systemic circulation to exert a therapeutic effect, it must first be
in solution. Relatively insoluble compounds often exhibit incomplete absorption.
- The solubility of a molecule in various solvents is determined as a first
- step. This information is valuable in developing a formulation. Solubility is usually
determined in a variety of commonly used solvents and some oils if the molecule is
lipophilic.
- Common solvents used for solubility determination are:
a. Water.
b. Propylene Glycol.
c. Glycerin.
d. Sorbitol.
e. Ethyl Alcohol.
f. Methanol.
g. Isopropyl Alcohol.
h. Castor Oil.
i. Peanut Oil.
j. Sesame Oil.
k. Buffers at various pHs
- The solubility of a material is usually determined by the equilibrium solubility
method, which employs a saturated solution of the material, obtained by stirring an
excess of material in the solvent for a prolonged period until equilibrium is
achieved.

Partition coefficient:

 When a solute is added to two immisible liquid it will distribute itself between two
phase in a fixed ratio, which is referred to as partition or distribution coefficient.

 Various organic solvents used in determination of partition coefficient include

chloroform, ether, amyl acetate, etc.

 In formulation development, the n-octanol/water partition coefficient is commonly

used

o p= (Concentration of drug in octanol)

(Concentration of drug in water) ------ For unionizable drug

o p= (Concentration of drug in octanol)

(1-alpha) (Conc of drug in water) ----- For ionizable drug
 p>1 – lipophillic drug

 P<1 – Hydrophillic drug

- Methods to determine P: Shake flask method

- Applications of P:
a. Measure of lipophillic character of molecule

b. Extraction of dosage from biological fluid

c. Absorption of drug from dosage form

d. Study of distribution of flavoring oil between oil & water in emulsion

Dissolution studies:
- The speed or rate at which drug substance dissolves in a medium is called
dissolution rate.
- Dissolution rate data when considered along with data on a drugs solubility,
dissociation constant and partition coefficient can provide an indication of the
drugs absorption potential following administration.
- If the rate of dissolution for a drug particle is slow as may be due to the
physicochemical characteristics of the drug substance or the dosage form, the
dissolution process itself would be a rate-limiting step in the absorption process.
- Poorly soluble drugs or poorly formulated drug products may result in a drugs
incomplete absorption and its passage, unchanged, out of the system via the feces.
- Measurement of dissolution rate:
The dissolution rates of chemical compounds are generally determined by two
methods: the constant surface method which provides the intrinsic dissolution rate of
the agent, and particulate dissolution method in which a suspension of the agent is
added to a fixed amount of solvent without exact control of surface area.
Constant surface method
- Compress the powdered drug into solid compacts. Dissolution study should made
using apparatus I (basket) or apparatus II (paddle) USP dissolution apparatus.
- The amount of the drug released should be monitored with time. The dissolution
rate is obtained by dividing the slope of the plot by the exposed surface area.
- This method eliminates surface area and surface electrical charges as dissolution
variables.
- The dissolution rate obtained by this method is termed the intrinsic dissolution rate
and is characteristic of each solid compound and a given solvent under the fixed
experimental conditions.
- The value is generally expressed as milligrams dissolved per centimeter squared
per minute (mg/cm2/min).
 5. Membrane permeability:
- Modern preformulation studies include an early assessment of passage of drug
molecules across biological membranes.
- Data obtained from the basic physical-chemical studies, specifically, pKa, solubility,
and dissolution rate provide an indication of absorption expectations.
- To enhance these data, a technique utilizing the "everted intestinal sac" may be used in
evaluating absorption characteristics of drug substances.
- In this method, a piece of intestine is removed from an intact animal, everted filled
with a solution of the drug substance, and the degree and rate of passage of the drug
through the membrane sac is determined.
- Through this method, both passive and active transport can be evaluated.
- In the latter stages of preformulation testing or early formulation studies, animals and
man must be studied to assess the absorption efficiency, pharmacokinetic parameters
and to establish possible in vitro/in vivo correlation for dissolution and bioavailability.
6. Stability analysis
- Commercial pharmaceutical products should have a shelf life of about 2-5 years
during which the drug content should not go below 90% and the product should
look and perform as it did when first manufactured.
- Factors affecting degradation rates:
1. Temperature
 2. Light
3. pH and Hydrolysis
4. Oxidation
- Preformulation stability studies are usually the first quantitative assessment of
chemical stability of a new drug. These studies include:
1. Solid-State Stability
2. Solution-Phase Stability
3. Compatibility Studies: Stability in the Presence of Excipients

1. Solid-State Stability
- In general, solid state reactions are much slower and more difficult to interpret than
solution state reactions, and it is customary to use stress conditions in the
investigation of stability.
- The data obtained under stress conditions are then extrapolated to make a
prediction of stability under appropriate storage conditions.
- Stress conditions utilized by the scientists are:
a. Elevated temperature Studies
b. Stability under High-Humidity Conditions
c. Photolytic Stability
d. Oxidative Stability

2. Solution-Phase Stability
 Reactions in solutions proceed considerably more rapidly than the corresponding
solid-state reactions. Due to the reduced molecular contacts between the drug and
excipients, solid state reactions are slower than solution stability.
 The primary objective of this phase of preformulation research is identification of
conditions necessary to form a stable solution.
 These studies should include the effects of pH, ionic strength, cosolvent, light,
temperature and oxygen. Thus, the stability of drug in buffers ranging from pH 1 to
8 should be investigated.
 Degradation in solution offers a rapid method for the generation of degradation
products. The latter are often needed for the purpose of identification (to study their
toxicity) and the development of analytical methods.
 This initial experiment should be done by the generation of a complete pH-rate
profile to identify the pH of maximum stability. Aqueous buffers are used to
produce solutions over a wide range of pH values with constant levels of drug,
cosolvent and ionic strength.
3. Compatibility Studies: Stability in the presence of excipients

 In the tablet dosage form the drug is in intimate contact with one or more
excipients; the latter could affect the stability of the drug.
 Knowledge of drug- excipient interactions is therefore very useful to the formulator
in selecting appropriate excipients.
 For, example, a typical tablet contains binders, disintegrants, lubricants, and fillers.
Compatibility screening for a new drug must consider two or more excipients from
each class. This is helpful for the proper selection of the dosage form components.
 The three techniques commonly employed in drug-excipient compatibility
screening are:
a. Chromatography (HPLC, GC, TLC,..)
b. Differential thermal analysis.
c. FT-IR.
Impurities in Pharmaceutical Substances
Impurities
• Presence undesirable foreign matter.
• The level of purity of the pharmaceutical substances depends on
- the cost-effectiveness of the process used,
- methods of purification, and
- stability of the final product.
Sources of impurities
1. Raw materials employed in the manufacturing of the pharmaceutical products
2. Reagents employed in the manufacturing process
3. Solvents: different types of water containing different types and amount of
impurities:
(i) Tap water:
Containing impurities of Ca2+, Mg2+ ,Na+, Cl-, CO3-2 and SO4-2 in trace amounts,
which remain in the product even after washing.
(ii) Softened water:
Free from divalent cations (Ca2+, Mg2+) but contains (Na+ and Cl-) as impurities.
(iii) Demineralized water:
Free from Na+, Ca2+, Mg2+, Cl-, SO4-2 and CO3-2 etc.
It may have pyrogens, bacteria and organic impurities.
(iv) Distilled water:
Free from all organic and inorganic impurities, therefore the best as a solvent
but it is expensive.
4. Intermediate substances:
5. Reaction vessels:
6. Atmospheric contamination:
7. Contamination by microbes:
8. Manufacturing hazards: can lead to:
(i) Contamination from the unwanted particulate matter:
 From the dirt or glass, porcelain, plastic or metallic fragments from sieves,
granulating, tabletting and filling machines or by the container or equipment.
e.g. metal particles found in eye ointments packed in metal tubes made up of tin
and aluminum. dust
(ii) Cross-contamination of the product:
• particularly in the preparation of solid dosage forms.
• Cross-contamination of product can occur by air-born dust arising out of
handling of powders, granules and tablets in bulk.
• Its dangerous particularly in steroidal and other synthetic hormones.
(iii) Errors in the manufacturing process:
• In a liquid preparation, there is incomplete solution of the solute.
• In a solid preparation, the efficiency of mixing, filling, tabletting → mixing
and filling errors, particularly in the preparation of low dosage forms (≥5mg)
such as tablets and capsules containing highly potent medicaments.
(iv) Errors in the packaging:
• Similar looking products, such as tablets of the same size, shape and colour,
packed in similar containers can result in mislabeling or substituting.
9. Instability of the product:
(A) Chemical instability:
• Impurities can also arise during storage because of chemical decomposition
which is catalyzed by light, traces of acid or alkali, traces of metallic impurities,
air oxidation, carbon dioxide and water vapours.
(B) Changes in physical properties:
• There can be changes in crystal size or sedimentation of the suspended
particles → significant changes in the physical appearance, pharmaceutical and
therapeutic effects of the product.
• Particle size and surface area is a critical factor in determining the
bioavailability of the low solubility drug such as griseofulvin.
(C) Reaction with container material:
 • Preparations susceptible to reaction with metal surfaces e.g. salicylic acid
ointment must not be packed in metal tubes.
• Solutions of substances which are alkali-sensitive e.g. atropine sulphate
injection must be packed in glass ampoules and must not be packed in
containers made from soda glass.
• Plastic containers and closures are tended to give undesirable additives, such
as plasticizers, particularly in the presence of non-aqueous solvents.
• Rubber closures are more susceptible to absorb medicaments, antioxidants and
bactericides from solution.

Control of Impurities
Pharmacopoeial methods:
• Pharmacopeias are standard references for quality control of drugs.
• Official monographs for pharmaceutical substances provide description and
information including:
1. Title:
The official name, the common names or synonyms of the substance.
2. Chemical formulae
The molecular formulae and the molecular weight.
3. Chemical names:
The IUPAC name of the substance.
4. Category:
The main pharmacological actions.
5. Dose:
6. Description:
It gives information of the general physical and organoleptic properties of the
substance.
7. Solubility:
Usually in water, organic solvents, acid and alkaline…etc
8. Storage:
• It contains information of the storage conditions (effect of atmosphere, moisture,
heat and light) that can be used against possible contamination or decomposition.
• The following terms are used in the IP for defining the conditions of temperature.
(a) Cold:
Any temperature not exceeding 8o C and usually between 2o C and 8o C.
A refrigerator is a cold place in which the temperature between 2 o C – 8o C.
(b) Cool:
Any temperature between 8o C and 25o C.
(c) Room temperature:
The temperature in the working area.
(d) Warm:
Any temperature between 30o C and 40o C.
(e) Excessive heat: Any temperature above 40o C.
(f) Protection from freezing:
• The label of container bears this instruction.
• Freezing results in a loss of strength or potency or changes of the properties.
(g) Storage under non-specific conditions:
When no specific storage conditions are indicated in the monograph, the storage
conditions include protection from moisture, freezing and excessive heat.
9. Standards as determined by the assay:
• It specifies the quantitative purity of the official compound.
• If a compound doesn't comply with all the stated requirements its not of
pharmacopoeial quality.
10. Identification test:
It includes various chemical tests to verify the identity of the substance.
11. Test for purity:
Test for purity including limits tests, melting point, boiling point…etc
12. Assay:
It describes the official method for the quantitative determination of the active
ingredient of the pharmaceutical substance and its preparation.
Test for purity
• Purity tests are the tests for the presence of impurities in the substance and fix the
limits of tolerance for these undesirable impurities.
• Some of the purity tests are:
(1) Melting Point
• It is an important parameter to know the purity of a substance.
• It has a few limitations.
• The accuracy of melting point is dependent on a number of factors such as
 Capillary size,
 Sample size,
 Initial temperature of heating-block and
 The rate of rise of temperature per unit time (minutes).
(2) Boiling Point
It is also an important parameter that establishes the purity of a substance.
(3) Loss on ignition:
• It is the loss of weight in % w/w resulting from a volatile part of material
under specified conditions.
• It is applied to thermostable substances which contain thermolabile impurities
that decompose and lose a volatile product e.g., zinc carbonate decomposes
losing CO2.
• The substance is heated, cooled and weighed repetitively until a constant
weight is attained.
• The loss on ignition in this case should not be more than 2% w/w.
(4) Moisture content:
Its a good measure of the purity of the substance especially in case of crude
drugs.
5. Limit Tests
• Limit tests are quantitative or semi-quantitative tests designed to identify and control
small amount of impurities present in the pharmaceutical compounds.
• They involve simple comparisons of opalescence, turbidity or colour produced in test
with that of fixed standards.
Chemicals are classified as:
1- Industrial, technical or commercial chemicals
• They contain great amounts of impurities and
• They have labels bearing the word "technical" or "Industrial".
• They are the cheapest class of chemical.
2-Pure chemicals
• These are chemicals that have been purified from impurities.
• They carry labels indicating type, quality, and quantity of impurities found,
which are presnt in very small amounts.
E.g. pure sulphoric acid may contain 2 ppm Cl—, 0.5 ppm As and 10 ppm lead.
• They are expensive.
3- Analytical reagents
• These are special chemicals of very high purity.
• They are the purest chemicals and the highest cost.
• They are used for the preparation of primary standard solution for
microanalysis, chromatographic analytical research … etc.
4- Pharmaceutical chemicals
• Chemicals should confirm with the pharmacopical requirments.
• They have labels bearing abbreviation of the pharmacopeia to which it
confirms, e.g. E.P, U.S.P, B.P….etc.
• These are a subdivision of pure chemicals and contain impurities but harmless
and do not cause undesirable results on dispending.
• The pure chemicals can be used as Pharmaceutical chemicals after
standardization and passing from limit tests specified in the pharmacopeia.
Quality Control Tests for Tablets
The quality control tests for tablets can be classified by two way:
1. Official and unofficial tests:
A. Official Tests: from which the batch can be reject.
Weight variation, disintegration, dissolution, drug content and Assay.
B. Non-Official Tests: from which the batch cannot rejected.
General Appearance, Hardness, friability
2. Physical and Chemical Tests
A. Physical Tests:
General Appearance, Tablet Thickness and Diameter, Hardness, Disintegration,
Weight Variation, Friability Tests.
B. Chemical Tests
Content Uniformity, Assay, Dissolution Test
Physical Tests
1. General Appearance:
• Important for:
a- Consumer acceptance
b- Facilitate packaging
c- Decide tablet-compressing machine to use.
• The control of general appearance involves the assessment of size, shape,
thickness, color, odor, taste etc.
• Color distribution must be uniform.
• For visual comparison between the color of sample against standard color.
2. Hardness (crushing strength) test:
It is the load required to crush the tablet when placed on its edge.
Why do we measure hardness?
• To determine the need for pressure adjustments on the tableting machine.
• Hardness can affect the disintegration.
 So if the tablet is too hard, it may not disintegrate in the required time period,
and if the tablet is too soft, it will not withstand the handling during subsequent
processing such as coating or packaging.
 In general, if the tablet hardness is too high, we first check its disintegration
before rejecting the batch, and if the disintegration is within limit, we accept the
batch.
Factors Affecting the Hardness:
• Compressive force.
• Amount of binder. (More binder a more hardness)
• Method of granulation in preparing the tablet (wet method gives more hardness
than direct method).
Limits:
• 5 kilograms minimum and 8 kilograms maximum.
• Make hardness test on 5 tablets and then take the average hardness.

3. Friability test:
 • It is the tendency of tablets to powder or fragment.
• Its used to evaluate the ability of the tablet to withstand abrasion in packaging,
handling, and shipping and this can affect
 The elegance appearance,
 Consumer acceptance, and
 Weight variation or content uniformity of tablets.
• Friability is a property that is related to the hardness of the tablet.
Procedure:
1. Weigh 20 tab altogether = W0
2. Put these tablets in the friabilator and adjust the instrument at 100 rpm (i.e. =
25 rpm for 4 min)
3. Weigh the 20 tablets (only the intact ones) = Wf
4. Friability (% loss) =
 %Friability = 100 (W0 - Wf )
W0
• It must be ≤ 1% but if more we do not reject the tablets.
• Perform this test using 20 tablets that were used first in the weight variation
test.

4. Thickness test

• Thickness of the tablet is inversely proportional to hardness i.e. increase in the

thickness decrease hardness & vice versa.
• Very thick tablet affects packaging either in blister or plastic container.
• The thickness for majority of tablets may vary from 2 mm to 4 mm.
• Thickness of tablet is measured by screw gauge/Vernier caliper for 10 tablets.
5. Disintegration test:
 • The disintegration test is a measure only of the time required to disintegrate
into particles under a given set of conditions for a group of tablets.
• All USP tablets must pass the official test for disintegration.
• Disintegration test is not performed for controlled & sustained release tablets.
Liquids used in disintegration
1. Water
2. Simulated gastric fluid (pH = 1.2)
- Sodium chloride 2 gm
- Pepsin 3.2 gm
- Hydrochloric acid 7 ml
- Water (q.s to make) 1000 ml
3. Simulated intestinal fluid (pH = 7.5)
- Potassium phosphate 6.8 gm
- Pancreatic enzyme 10 gm
- Sodium hydroxide 190 ml
- Water (q.s to make) 1000 ml

a. U.S.P. method for uncoated tablets:

• Place 1 tablet in each of the 6 tubes of the basket, add a disk to each tube.
• Use water as immersion fluid maintained at 37°C.
• If one or two tablets from the 6 tablets fail disintegrate completely within 30
min repeat the test on another 12 tablet. (i.e. the whole test will consume 18
tablets).
• Not less than 16 tablets disintegrate completely within the time.
 • If more than two tablets (from 18) fail to disintegrate, the batch must be
rejected.
Limits: For Uncoated tablets:

Temperatur
Medium Time limit
e

Not exceed 30
According to U.S.P. Water 37oC
min

Simulated gastric Not exceed 15

According to B.P. 37oC
fluid min

b. U.S.P. method for Coated tablets:

• To remove or dissolve the coat, immerse the tablet in distilled water for 5min.
• Put the tablet in the apparatus in simulated gastric fluid at 37°C for 30 min.
• If not disintegrated, put in intestinal fluid.
• If one or two tablets fail to disintegrate, repeat on 12 tablets.
• So 16 tablets from the 18 must completely disintegrate within the time.
• If two or more not disintegrated the batch is rejected.
c. U.S.P. method for Enteric coated tablets
• Place 1 tablet in each of the 6 tubes of the basket, add a disk to each tube
• Put in distilled water for five minutes at room temperature to dissolve the coat.
• Then operate the apparatus without the disks using simulated gastric fluid as
immersion fluid maintained at for one hour.
• After one hour, lift the basket and observe the tablets, the tablets show no
evidence of disintegration, cracking or softening
• Then add disk to each tube and operate the apparatus using simulated intestinal
fluid maintained at 37°C for two hours.
• If one or two tablets fail to disintegrate, repeat this test on another 12 tablets.
• So 16 tablets from 18 should completely disintegrate.
• If more than two fail to disintegrate the batch must be rejected.
d. Test method for Buccal tablets
• Place 1 tablet in each of the 6 tubes of the basket
• Use water as immersion fluid maintained at 37°C
• Operate the apparatus for 4 hours.
• If one or two tablets fail to disintegrate, repeat this test on another 12 tablets.
• So 16 tablets from 18 should completely disintegrate.
• If more than two fail to disintegrate the batch must be rejected.

f. Test method for Sublingual tablets

• Place 1 tablet in each of the 6 tubes of the basket.
• Use water as immersion fluid maintained at 37°C.
• Operate the apparatus for 3 minutes if one or two tablets fail to disintegrate,
repeat this test on another 12 tablets.
• So 16 tablets from 18 should completely disintegrate.
• If more than two fail to disintegrate the batch must be rejected.
6. Weight Variation ((uniformity of weight))
• The actual weight of a tablet is determined by
 the diameter of the die and
 the weight adjustment on the tablet machine
• This test is perform to ensure uniform distribution of ingredients throughout
batch.
Causes of Weight Variation
1. Poor flow of granules
2. Variation in size of granules due to improper sieving
3. Presence of very fine granules
4. Improper adjustment of machine
Method
 • Weigh 20 tablet selected at random, each one individually . X1, X2, X3… Xz
• Determine the average weight. X= (X1+X2 +X3+…+ Xz)/20
• Weight variation tolerances for uncoated tablets in U.S.P XVII
Average wt. of Max. % difference
No
tablet(mg) allowed

1 130 or Less 10%

2 130-324 7.5%

3 More than 324 5%

Limit:
• Not more than two of the tablets differ from the average weight by more than the %
error listed, and no tablet differs by more than double that percentage.
Chemical Tests
1-Content Uniformity
• Its used to ensure that every tablet contains the amount of drug substance
intended with little variation among tablets within a batch.
Method
• Randomly select 30 tablets.
• 10 of these assayed individually.
• The tablet pass the test if 9 of the 10 tablets must contain limit of 85% - 115%
of the labeled drug content and the 10th tablet may not contain 75% -125 %.
• If these conditions are not met, remaining 20 tablet assayed individually and
not more than one tablet should have 75-125%.

2-Assay
Assay is performed in finished form to know the amount or concentration of active
ingredients present in tablets. It include HPLC, spectroscopy, chemical tests etc
Method
Stage-1
• Weigh about 20 tablets and crush them
• To aliquot add 30ml (0.5N) NAOH
• Titrate the mixture with 0.5N HCl
• Use phenol red as indicator
• The point at which red color turns to yellow indicates the end point and
the amount of HCl used is noted.
Stage -2
• Repeat the titration with blank solution of 30ml (0.5N) NaOH
• Calculate the difference of HCl consumed in both titrations
NOTE: Each ml of 0.5N NaOH is equivalent to 0.04502gm or 45mg of
active ingredient.
3. Dissolution Test

• Dissolution is performed to check the percentage release from the tablet.

• Tablet breaks down into small particles which offers a greater surface area to the
dissolving media.
 • Disintegration test does not give assurance that particles will release drug in solution
at an appropriate rate, that’s why dissolution tests & its specifications developed for
all tablet products.
1. USP Dissolution apparatus I ( Basket method)
• A single tablet is placed in a small wire mesh basket attached to the bottom of
the shaft connected to a variable speed motor.
• The basket is immersed in a dissolution medium (as specified in monograph)
contained in a 1000 ml flask.
• The flask is maintained at 37 ± 0.50C by a constant temperature bath.
• The motor is adjusted to turn at the specified speed and sample of the fluid are
withdrawn at intervals to determine the amount of drug in solutions.
2. USP Dissolution apparatus II (Paddle method)
• It is same as apparatus-1, except the basket is replaced by a paddle.
• The dosage form is allowed to sink to the bottom of the flask before stirring.
• For dissolution test, U.S.P. specifies the test medium and volume, rpm of the
shaft, time limit of the test and assay procedure.
• The test tolerance is expressed as % of the labeled amount of drug dissolved in
the time limit.

No. of Acceptance criteria

Quantity
No. tablets
Stage/level
tested

1 S1 6 Each unit (tablet) < limit * by 5 %**, if S1 fail → S2

Average of 12 units (S1 +S2) is ≥ limit , and no unit is

2 S2 6
less than limit - 15 %** , if S2 fail → S3

Average of 24 units (S1+S2+S3) is ≥ limit and not

3 S3 12 more than 2 units are less than limit -15 %** and no
unit is less than
 limit -25 %**

* Limit is the amount of dissolved active ingredient specified in the individual

monograph (usually 80%), expressed as a percentage of the labelled content.
** Percentages of the labelled content.

• Acceptable in S1: if all of the tablets are not less than the monograph tolerance limit
(80%) by 5%.
• Acceptable in S2: if average of 12 tablets ≥ limit and no tablet is less than limit-15%.
• Acceptable in S3: not tablet less than limit and not more than 2 tablets = limit-15%
• USP limit for dissolution: not less than 75% of tablet dissolve in 45 min.

QC of Capsules

1) RAW MATERIALS :
The gelatin of the capsule shells should be assayed for:
 Various physical properties like bloom strength, viscosity , etc
 Chemical tests like purity, microbial properties, and limits for heavy metals like
arsenic, ash content should be determined.
The colorants should also be checked for purity, limits for heavy metals, color
properties, dye content.

2) MOISTURE PERMEATION TEST :

The degree & rate of moisture penetration is determined by:
1. Packaging the dosage unit with a color revealing desiccant pellet.
2. Expose the packaged unit to known relative humidity over a specified time.
3. Observe the desiccant pellet for color change.
4. Any change in color indicates absorption of moisture.
5. By measuring pretest weight & protest weight of pellet, amount can be calculated.

3) CONTENT UNIFORMITY:
1. 10 capsules are taken and subjected to assay.
2. 9 of 10 capsules should be in the range of ±15%( 85 - 115%) and 10 th capsule
in the range of 75 - 125%.
3. If 2 Capsules are beyond ± 15% range.
4. Then, 20 Capsules are assayed. All capsules should be in the range of ±
25%(75%-125%.)

4. WEIGHT VARIATION:
a. WEIGHT VARIATION: FOR HARD CAPSULES:
Weigh 20 capsules individually, and determine the average weight.
The individual weights should be within the limits of 90%and 110%of the average
weight.
If not all of the capsules fall within the limits, weigh the 20 capsules individually
remove the contents of each capsule with the aid of a small brush.
Weigh the emptied shells individually.
Net weight of contents (individual) = gross weight - the weight of shell
Determine the average net content from the sum of the individual net weights.
Then determine the difference between each individual net content and the average net
content Limits:
Not more than 2 of the differences are greater than 10%of the average net content
No case is the difference greater than 25% wt range.
Average Weight of Capsule Percentage Deviation

Less than 300 mg 10

300 mg or more 7.5

B. FOR SOFT CAPSULES:

Proceed as directed under Hard Capsules, but determine the net weight of the contents
of individual capsules as follows:
Weigh the capsules individually.
Then cut & open the capsules remove the contents by washing with a suitable solvent.
Allow the solvent to evaporate from the shells at room temperature.
Weigh the individual shells calculate the net contents.

6. DISSOLUTION TEST FOR CAPSULES

The dissolution test for capsules uses the same apparatus, dissolution medium, and test
as that for uncoated and coated tablets.
However, if the capsule shells interfere with the analysis, the contents of a specified
number of capsules can be removed and the empty capsule shells dissolved in the
dissolution medium before proceeding with the sampling and chemical analysis.

7. Disintegration of capsules:
Introduce one capsule into each tube and suspend the apparatus in a beaker containing
600 ml water at 37oC.
If hard capsules float on the surface of the water, the discs may be added.
Operate the apparatus for 30 minutes; remove the assembly from the liquid.
The capsules pass the test if:
1. No residue remains on the screen of the apparatus or,
2. If a residue remains, it consists of fragments of shell or,
3. Is a soft mass with no palpable core.
 4. If the disc is used, any residue remaining on its lower surface should only
consist of fragments of shell
Quality control tests of semisolid preparations:
A-In process control
Processing of semisolids involves mixing, milling, heating and cooling of bulk
products. Therefore, it is essential to develop in process control.
1. Complete solubilization (if applicable).
2. pH value.
3. Viscosity measurement.
4. Uniformity of distribution of active ingredients.
5. Physical stability.
6. Measurement of density or specific gravity.
B- Finished product specifications
1. Microbial test.
2. Physical tests.
a. Viscosity measurement.
b. Texture analysis: Texture analyzer is used to detect ointment flow
characteristic and consistency.
3. Chemical tests.
a. Chemical potency test.
b. Content uniformity test.
4. In-vitro release profile test.
Other special tests:
Evaluation of ointments
1. Penetration:
A weighed quantity of ointment is rubbed over skin for a given period of time and
unabsorbed ointment is collected and weighed. The differences in weights
represent the amount absorbed.
2. Rate of release of medicament:
 To assess rate of release of medicament, small amount of the ointment can be
placed on the surface of nutrient agar contained in a Petri dish or alternately in a
small cup cut in the agar surface. If the medicament is bactericidal the agar plate is
previously seeded with a suitable organism like S.aureus. After a suitable period of
incubation, the zone of inhibition is measured and correlated with the rate of
release.
3. Absorption of medicament into blood stream:
The ointment should be evaluated for the rate of absorption of drug into the blood
stream. This test can be run in-vivo only. Definite amount of ointments should be
rubbed through the skin. Under standard conditions and medicaments are estimated
in the blood plasma or urine.
4. Irritant Effect:
The irritant effect can be judged to a certain extent by injecting the ointment into
thigh muscles and under the abdominal skin of rats. Reaction are noted at intervals
of 24, 48, 72 and 96 hours. Presence of patches on the skin within 2 weeks indicate
irritancy to pressing skin. Lesions on cornea, iris, conjunctiva are used for judging
the irritancy to the eyes.
Evaluation of creams
1. Rheology
Rheology is very important as these creams are marketed in tubes or containers.
The rheology or viscosity should remain constant. As these products are normally
non-Newtonian in nature, the viscosity can be measured using viscometers used for
such liquids.
2. Sensitivity
As various types of ingredients are used with occasional use of antiseptics,
hormones etc. There is a possibility of sensitization or photosensitization of the
skin. This should be tested before hand. This test is normally done by patch test on
and can be either open or occlusive. The test sample is applied along with a
 standard market product at different places and effect is compared after a period of
time.
Evaluation of pastes
1. Abrasiveness- measure of amount of solid medicament present per unit of paste.
2. Particle size- This can be determined by microscopic study of the particles or other
means.
3. Rheology -Rheology is very important as these are marketed in tubes or containers.
The rheology or viscosity should remain constant. As these products are normally
non-Newtonian in nature, the viscosity can be measured using viscometers used for
such liquids.
4. pH of product- pH of the dispersion of 10% of the product in water is determined
by pH meter.
5. Foaming character- This test is specially required for foam-forming tooth pastes
or tooth pastes or tooth powers. Especially amount of product can be mixed with
specific amount of and water to be shaken. The foam thus formed is studies for its
nature, stability, washability.
Evaluation of gels
1. Drug content: 1gm of gel was accurately weighed in a 50ml of volumetric flask to
which 20ml purified water was added with continuous shaking. Volume was
adjusted with a mixture of 10% methanol in water. Absorbance of the solution with
the blank was measured at 360nm using UV-spectrophotometer.
2. Homogeneity of drug content: For homogeneity of drug contents, six tubes were
taken randomly and assayed for the drug content as stated above.
3. Measurement of pH: The pH of gels were determined by digital pH meter. One
gram of gel was dissolved in 100ml of distilled water and stored at 4°C for two
hours.
4. Viscosity: Brookfield viscometer is used for determination of viscosity. Gels were
filled in jar and spindle was lowered perpendicularly taking care that spindle do not
 touch bottom of the jar. The spindle was rotated in the gel at increasing shear rates
0.5, 1, 2.5 and 5rpm. At each speed, the corresponding dial reading was noted.
5. Spreadability: A modified apparatus consisting of two glass slides containing gel
in between with the lower slide fixed to a wooden plate and the upper one attached
to a balance by a hook was used to determine spreadability.
6. Extrudability: A simple method was adopted for determination of extrudability in
terms of weight in grams required to extrude a 0.5cm ribbon of gel in 10 seconds
from the collapsible tube.
Quality Control tests for Syrups

“Syrups are concentrated aqueous preparations of a sugar or sugar substance with or

without flavoring agents and medicinal substances.”

Components of Syrup:

1. Sugar (sucrose) or its substituents.

2. Water.
3. Flavors.
4. Colors.
 5. Preservatives.
6. Other additives.

Types of syrups:

1. Simple syrup: Syrups are the products of choice especially for children, because
of their acceptable taste; odor and they are devoid of ethanol. Syrups posses
remarkable masking properties for bitter and saline drugs.
2. Flavored syrup: It is syrup which contains aromatic or pleasantly flavored
substances, but it not medicated syrup.
3. Medicated syrup: It is syrup containing some added or medicinal substances

Quality Control Tests for syrups

1) Clean and purified vehicle (water)

 The water is filtered and purified to destroy any micro-organisms and to remove
particles from the water.
 Quality control technicians test the water frequently to ensure that it is clean and
pure before the syrup is made.
 The syrup is also thoroughly filtered before filling in bottles.
2) Light Transmittance Meter (Syrup color)

 A light transmittance meter is a newer tool that is used to check syrup color.
 In a light transmittance meter, a syrup sample is checked for color by passing
light through the sample. The percent of light transmission is compared to light
transmission rates set for different grades.
 When using one, you need to be sure there are no fingerprints on the syrup test
bottle, and that the syrup sample has no bubbles or cloudiness.
 Any of these conditions may diminish the light that is transmitted through the
sample and therefore lowers the grade of the sample.

3) Visual Inspection

 With visual inspection, the ingredients and the final products are carefully
examined for purity and for appearance.
 Physical appearance of products for patient adherence and compliance is critical
so it should be:
a. Good looking
b. Elegance in appearance

4) pH Measurement
  The measurement and maintenance pH is also very important step in the Quality
control testing.
 Generally there are 2 different types of methods used in the measurement of pH.
a. The simplest and cheapest is to dip a piece of pH paper into the sample. The
paper is impregnated with chemicals that change colour and the colour may be
compared to a chart supplied with the paper to give the pH of the sample.
b. If greater accuracy is required a pH meter should be used. A typical pH meter
consists of a special measuring glass electrode connected to an electronic meter
that measures and displays the pH reading

5) Physical stability in syrups

The syrups must be stable physically e.g.

 Appearance (no crystallization and microbial growth)

 Color must be completely soluble with other ingredients.
  Odor and taste (palatable)
 Solid material is completely miscible in liquid.

6) Sucrose concentration

 The determination of sucrose concentrations is also very important in Quality

control testing of syrups.
 if the concentration Sucrose in the syrup is very high it may crystallize the syrup
and less sucrose concentrations give favor for the microbial growth.
 There is no specific method for the determination sucrose in syrup, we use Hplc
and uv-spectroscopy for this purpose.

1. By using HPLC:

 HPLC technique is used for both qualitative and quantitative analysis of

sucrose.
 For qualitative analysis or to confirm the presence of sucrose we compare the
obtaining peaks after running hplc with standard and specific peaks of sucrose.
 And for quantitative analysis we measure area under the curve. That will tells us
about the concentration of sucrose present in the given sample.

2. By using UV-spectrometer

 Ultraviolet spectroscopy can be used for quantitative analysis, by using the

Beer-Lambert Law. The concentration of a single absorbing substance in a
solution can be readily determined from the equation.
 The absorptivities of many substances at specified wavelength are available in
the literature. However, if any absorptivity value in not available, it can be
 determined by measuring the absorbance of a solution of known concentration
of the substance concerned, using the Beer-Lambert Law equation.
 The recommended procedure therefore is to make a number of absorption
measurements at various concentrations of the solution, plot a graph of the
absorbance's against concentrations .

Quality Control tests of elixirs

Definition: they are clear, sweetened hydroalcoholic solutions intended for oral use
and are usually flavored to enhance their palatability.

1) Determination of alcohol concentration.

 Elixir usually contains 5 to 40% alcohol.
 The determination of alcohol unless otherwise specified in the individual
monograph.
 It is suitable for examining most fluid extracts and tinctures and elixirs
provided.
 The capacity of the distilling flask is sufficient (commonly two to four times the
volume of the liquid to be heated) and the rate of distillation is such that clear
distillates are produced.
 Cloudy distillates may be clarified by agitation with talc, or with calcium
carbonate. And filtration is done.
 After which the temperature of the filtrate is adjusted and the alcohol content
determined from the specific gravity.
 During all manipulations, take precautions to minimize the loss of alcohol by
evaporation.
2) Viscosity Measurement
 Viscosity is a property of liquids that is directly related to the resistance to flow.
 Viscosity measurement is very important quality control test in case of syrups
an elixirs.
 Viscosity and consistency directly relates with stability of solutions.
 Increasing viscosity leads to increase in chance of stability.
 Types of viscosity
a. Absolute viscosity: Measure when all the specifications and parameters are
defined.
b. Relative viscosity: Measure when we take any standard and make comparison.
 But no decisions are made after taking relative viscosity.
 Methods of viscosity measurement:
a. Method 1 (U tube viscometer):

b. Method II (Capillary viscometer method)

 c. Method III (Rotating viscometer method):

QC of Suspensions

Suspension is a coarse dispersions in which insoluble solids (with size10-1000 µm) is

suspended uniformly throughout a liquid medium.

1. Appearance
- It is checked in a graduated glass cylinder or transparent glass container.
- It is checked for:
o Uniformity of colour and appearance
o Any breaks or air pockets in the sediment
o Any material adhering to the inside wall of the container.
- Changes in appearance can indicates chemical instability, poor distribution
and/or differences in particle size.

2. Clarity test
Its carried out to check the particulate matter in the sample.

3. pH value
 - pH value contribute to stability of formulation.
- So pH of the different vehicles, phases of suspension before and after mixing
are monitored to ensure optimum pH environment.
- The measurement of pH by
 Dip a piece of pH paper into the sample.
 pH meter

4. Content uniformity test

Samples are withdrawn from the dispersed phase after micronization and after mixing
with dispersion medium, assayed to find out degree of homogeneity.

5. Viscosity
- Viscosity contribute to flow, dispersion properties and sedimentation rate of
dispersed phase which contribute to stability of a suspension.
- The optimum viscosity of the dispersion medium →↓ terminal settling rate of the
dispersed phase → remain dispersed for longer time →↑ stability.
- Too high viscosity is not desirable as:
 It causes difficulty in pouring and administration.
 It may affect drug absorption since they adsorb on the surface of particle and
suppress the dissolution rate.
- So this test is carried out to ensure optimum viscosity of the medium so a stable,
redispersible suspension can be formed.
- The viscosity of the dispersion medium is measured before mixing with dispersed
phase and after mixing.
- The calculated values are compared with standard values.
- Viscosity measurement by Cup and bob viscometer.
Method
- The sample is placed in the cup, and the bob is placed in the cup upto an
appropriate height.
 - Either the cup or bob is made to rotate and the torque resulting from the viscous
drag is measured by a spring or sensor in the drive of the bob.
- The number of revolutions and the torque represent the rate of shear (v) and
shearing stress(w)respectively.
ή=kw/v
ή=apparent viscosity
w=shearing stress
v=rpm(shear rate)
k=instrument constant

5. Pourability
Its carried out on the phases of suspension after mixing to ensure that the final
preparation is pourable and will not cause any problem during filling and during
handling by patient.

6. Particle size of dispersed phase

- Particle size within the limited range plays a role in stability of final suspension.
- Too large particles will:
 settle faster at the bottom of the container
 particles > 5 μm impart a gritty texture to the product and also cause irritation if
injected or instilled to the eye
 particles > 25 μm may block the needle
- Too fine particles will easily form hard cake at the bottom of the container.
- Particle size measurement by

a. Optical microscopy
- Particle size in the range of 0.2 to 100µm can be measured by optical
microscopy.

- The microscope can be used to estimate and detect changes in particle size
distribution and crystal shape.

Method:
- Eye piece of the microscope is fitted with a micrometer.
- The eye-piece micrometer is calibrated using a standard stage micrometer.
- The sample of suspension is mounted on a slide or a ruled cell and placed it
on the mechanical stage.
- The size of the particle is estimated with the help of the eye-piece
micrometer.
- Around 625 particles must be counted in order to estimate the true mean.
- The size frequency distribution curve is plotted by taking particle size in µm
on x-axis and frequency on y-axis.

b. Sedimentation method
- used over a size range of 1 to 200µm.
- Sedimentation of particles are evaluated by Andreasen pipette method
Andreasen pipette method
 - Andreasen apparatus consists of a 550 ml cylindrical vessel containing a 10 ml
pipette sealed to a ground glass stopper.
- When the pipette is placed in the cylinder its lower tip is 20 cm below the
surface of the suspension.
- Transfer the suspension into the Andreasen vessel and place the two-way
pipette and securely suspend the vessel in a constant temperature water bath.
- At different time intervals 10 ml of samples are withdrawn using two-way
stopcock and collected in watch-glass, evaporated and weighed.
- Particle diameter is calculated from stokes law.

x/t is the rate of sedimentation or distance of fall x in time t (in seconds).

d is the diameter of the particle (cm)
p, po = density of the dispersed phase and dispersion medium (g/ml)
ή = viscosity of the dispersion medium (poise)
g = acceleration due to gravity (980.7cm/sec)

7. Sedimentation rate
- Stokes law is useful in fixing factors to prevent sedimentation.
- The rate of sedimentation of particles is expressed by Stokes law.

8. Sedimentation volume
- The suspension formulation(50mL)was poured separately into100mL measuring
cylinders and sedimentation volume was read after 1,2,3 and 7days,and there after
at weekly intervals for 12 weeks.
- Triplicate results were obtained for each formulation.
- The ratio between ultimate volume of sediment to initial volume of the suspension.
F = Vu / V0 = ultimate volume of the sediment
initial volume of the suspension
- The F value is between the limits 0 to 1.
- The higher the sedimentation volume → the better physical stability.
QC of Parenteral preparations

 Parenteral preparations are sterile preparations containing one or more active

ingredients and they are directly administered in the systemic circulation of the
body by injection, infusion or implantation.
 They are very much susceptible to microbial attack → should be carried out in
clean areas with an appropriate standard of cleanliness and sterility.

1. Content Uniformity Test (BP)

 Single-dose suspensions for injection with a content of active substance < 2 mg
or < 2 % of the total mass, or with a unit mass ≤ 40 mg comply with the
following test.
 Using a suitable analytical method, determine the individual contents of active
substance (s) of 10 dosage units taken at random.
a. If each individual content is between 85%- 115% of the average content →
accepted.
 b. If more than one individual content is outside these limits or if one individual
content is outside the limits of 75 %- 125 % of the average content → rejected
c. If one individual content is outside the limits of 85%- 115% but within the
limits of 75 %- 125 %, determine the individual contents of another 20 dosage
units taken at random.
d. The preparation complies with the test if not more than one of the individual
contents of the 30 units is outside 85%- 115% of the average content and none
is outside the limits of 75 %- 125 % of the average content.

2. Mass Uniformity Test (BP)

Single-dose powders for injections comply with this test.
 Remove any labels from a container and wash and dry the outside.
 Open the container and weigh the container with its contents.
 Completely empty the container with purified water and then with ethanol
(96%) and dry at 100-105 °C for 1 h, or, based on the nature of the container,
dry at a lower temperature to constant mass.
 Allow to cool in a desiccator and weigh.
 The mass of the contents is the difference between the weightings (weight of
active substance with container – weight of empty container).
 Repeat the procedure with another 19 containers.
 Determine the average mass.
Dosage Form Average Mass Percentage Deviation
Powder for parenteral
administration (single More than 40 mg 10
dose)
Note: When the average mass is equal to or below 40 mg, the preparation
is not submitted to the test for uniformity of mass but to the test for
uniformity of content of single dose preparations.
 • Not more than 2 of the individual masses deviate from the average mass by more
than the percentage deviation and none deviates by more than twice that percentage
(20%).

3. Clarity test
 Its carried out to check the particulate matter in the sample.
 Since erythrocytes have a diameter of approximately 4.5 m, particles of more than
5 m should be the basis for evaluation.
 The unaided eye can see particles approximately 40-50 m.
 10 m particles can be seen by the light scattered from them.

a. Visual inspection by naked eye

 For visible particulate matter from particles that are 40-50 μm and larger.
 100% batch inspection is recommended by GMP.
Done:
 by human inspector for all the units
 under a good light, and
 against a black and white background.

b. Light obscuration particle count test (LOPC)

 For sub-visible particles.
 Use a suitable apparatus based on the principle of light blockage which
allows an automatic determination of the size of particles and the number of
particles according to size.
 Mix the contents of the sample by slowly inverting the container 20 times.
 Clean the outer surfaces of the container.
 For large-volume parenterals, single units are tested.
  For small-volume parenterals less than 25 ml are combined in a cleaned
container to obtain a volume of not less than 25 ml, or diluting to 25 ml with
particle-free water or with an appropriate particle-free solvent.
 Powders for parenteral use are reconstituted with particle-free water or with
an appropriate particle-free solvent.
Nominal Volume ≥ 10 μm ≥ 25 μm
More than 100 mL 25 particles/mL 3 particles/mL
100 mL or less than 100 mL 6000 particles/container 600 particles/container

c. Microscopic particle count test (MPC)

 In case of preparations having reduced clarity or increased viscosity e.g.
emulsions, colloids, and liposomal preparations.
 The sample is filtered through a membrane filter under ultra-clean conditions
 Placed under a suitable binocular microscope.
 Count the number of particles that are equal to or greater than 10 μm and the
number of particles that are equal to or greater than 25 μm.
Nominal Volume ≥ 10 μm ≥ 25 μm
More than 100 mL 12 particles/mL 2 particles/mL
100 mL or less than 100 mL 3000 particles/container 300 particles/container

4. Leakage test
It is used to test package integrity by
a. Bubble test
- The package is submerged in water or other suitable clear, colorless solvent
- A vacuum is exerted on the test system
 - The package is examined visually for evidence of gaseous leakage.
b. Dye test
- Containers are immersed in a dye solution (1% methylene blue solution)
- Subjected to pressure or vacuum variances.
c. Microbial test
- Containers are immersed in a microbial suspension (pressure differential) or
- Containers are subjected to a microbial aerosol. Then incubated.
d. Particulate Transmission
- The package is placed in a chamber and subjected to a charged aerosolized
dust. The units are removed from the chamber and examined for dust entry.

5. Sterility Test (BP and USP)

- Sterilization: destruction or removal of viable microorganisms by
 Heat
 Filtration (heat sensitive)
 Gas (ethylene oxide active against all microbes)
 Radiation (syringes, catheters, etc.
- The sterility test may be carried out using

a. Media sterility testing:

- The samples are removed aseptically from their container and cultured in
a. Thioglycollate medium which used to assure anaerobic growth
b. Soybean medium is used to aerobic microbial growth .
c. The sabaraud medium is used to mould or fungi growth.
- The incubation time is 7 days.

b. Direct transfer sterility testing

- Method of choice for medical devices
 - The sample is completely immersed in the test media.
- Complete immersion recommended: 2500 ml max. volume
- After transferring, the samples are incubated for 14 days.

6. Pyrogen test
- Pyrogens are bacterial products such as endotoxin.
- Can cause fever, alter carbohydrate lipid metabolism, produce shock and death.
- Pyrogen Test by

a. USP Rabbit Pyrogen Test

Rabbits show a physiological response to pyrogen similar to humans.
Method:
 Three healthy rabbits are chosen.
 Accurate thermometers are inserted into the rectum of the rabbits to
record their body temperature (control temp).
 Test solutions (10 mg/kg) are warmed to 37O C prior to injection and then
injected into ear vein.
 Rabbit temperatures are recorded at 30 min intervals between 1 and 3 h.
Results:
 If ↓Temperature → zero rise→ pyrogen -free.
 If no rabbit show, a rise in tempe of 0.5OC or more the product is pyrogen
-free.
 If any rabbit show a rise in tempe of 0.5OC or more, continue the test
using 5 other rabbits.
 If not more than 3 rabbits of 8 rabbits show individual rise in tempe of
0.5OC or more or if the sum of the 8 rabbits individual maximum tem.
rises dosen't exceed 3.3oC → the product is pyrogen -free.

b. Human Cell-Based Pyrogen Test

 - Pyrogen induce human monocytes to release pro-inflammatory cytokines
such as Interleukins.
- Incubate of a test sample with monocytes in whole blood or in cultured cell
lines and analysis of a specific cytokine after a suitable time.

c. Bacterial Endotoxins Test (LAL)

- A Limulus amebocyte lysate (LAL) reagent is the basis for an in vitro
pyrogen test method that is specific for bacterial endotoxin pyrogen.
- Equal volumes of test solution and LAL reagent are mixed in glass test
tubes.
- After incubation at 37O C for 1 h, the tubes are observed for clot formation.
- Formation of a solid gel clot that withstands inversion of the tube constitutes
a positive test.

7. pH value measurement
 Different types of methods used in the measurement of pH.
a. Dip a piece of pH paper into the sample.
b. pH meter

8. Conductivity measurement

 Measured by using conductometer.

 It is also necessary measure the conductivity of the vehicle used in sterile
preparations.
 The conductivity of the pure water is 0.055 µS/cm.