PHARMACEUTICS

SHRI HARI CHAURASIYA

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Sl. TOPICS PAGE NUMBER

No.
1. History of pharmacy
2. Pharmacy as a Career
3. Pharmacopoeia
4. Indian Pharmacopoeia (I.P.)
5. British pharmacopoeia (B.P.)
6. United State Pharmacopoeia (U.S.P)
7. Extra Pharmacopoeia [Martindale]
CHAPTER - 2
1. Packaging materials
2. Glass as packaging material
3. Plastic as packaging material
4. Metal as a packaging material
5. Rubber as a packaging material
CHAPTER – 3 (Pharmaceutical Aids)
1. Pharmaceutical Aids
2. Colours/Colouring Agents
3. Flavouring agents
4. Sweeteners/Sweetening Agents
5. Preservatives
CHAPTER – 4 (Unit Operation)
SIZE REDUCTION
Hammer Mill
Ball Mill
Size Separation
Sieves
Cyclone Separator
Mixing
Double Cone Blender
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Turbine Mixer
Silverson Mixer Homogeniser
Triple Roller Mill
Filtration
Sintered filters
Membrane Filters
Drying
Fluidised Bed Dryer
Freeze Dryer
Extraction
Maceration
Digestion
CHAPTER-5 (Pharmaceutical Dosage Forms)
Tablets
Capsules
Liquid Oral Preparations
Topical Preparations
Powders and Granules
Sterile Formulations
Immunological Products
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Chapter-1

History of Pharmacy Profession and

Pharmacopoeia

 Pharmacy refers to the health care profession that deals with both fields of health
science as well as chemistry.
 It is defined as the profession of the art, science, and economics of discovery and
preparation from natural and synthesis sources, drugs and non-drug material needed
for the prevention management and treatment of diseases in man and animals.
 The word Pharmacy was constituted from Greek word.
Pharmakon meaning medicine or drug

History of pharmacy
1. History of pharmacy with respect to Pharmacy education.
2. History of pharmacy with respect to Pharmaceutics Industries.

Education Regulation by
1. PCI: Pharmacy council of India.
2. AICTE: All India council of Technical Education.

History of pharmacy with respect to Pharmacy education

1. 1860: 1st Pharmacy course started in Madras medical college.
2. 1937: 1st Degree level course in pharmacy started at Banaras Hindu University
(BHU) (3-year degree course)
3. 1940: 1-year Master course (M Pharma) started at Banaras Hindu University (BHU)
4. 1990: B.V. Patel PERD Centre (Pharmaceutics Education & Research Development
Centre) established at Ahmedabad & The director was H.L Bhalla.
5. 1991: National Institute of pharmaceutical Education and Research (NIPER) was
established at Mohali With Dr. C.L. Kaul as the first Director.

Courses
1. D. Pharm (Diploma in pharmacy).
2. B. Pharm (Bachelor of Pharmacy).
3. M. Pharm (Master of Pharmacy).
4. MS Pharm (Master of Science in Pharmacy).
5. M. Tech (Master of Technology in Pharmacy).
6. Pharm D. (Doctor of Pharmacy).
7. PhD (Doctor of Philosophy in Pharmacy).

History of pharmacy with respect to Pharmaceutics Industries

1. 19th Century Britishers used to import Allopathic Medicines from Germany & U.K.
2. 1901 Establish BCPW (Bengal Chemical and Pharmaceutical Works) in Calcutta by
 4

Acharya P.C Roy.

3. 1904 – 07 Establish four Research institutes
a. Huffkins Institute
b. King Institute
c. Central research Institute
d. Pester Institute

4. 1930 First time BCPW started Producing Tetanus Antitoxin.

5. 1939 - 13% Medical requirement met by India rest by imports.
6. During Independence (1947) Production of Galenical’s Simple Formulation & Few
vaccines
7. Post-Independence (1948) Govt. of India launched a five-year plan.
8. 1954 Establish “Hindustan Antibiotic LTD “

Act in Pharmacy
1. Patent Act
2. DPCO Act (Drug price control act)
3. FERA Act (Foreign establish Regulation act)

Amendments in Patent Act

1. 1995 1st Amendments in Patent Act.
2. 1999 2nd Amendments in Patent Act.
3. 2004 3rd Amendments in Patent Act.
4. 2015 4th Amendments in Patent Act.

Amendments in DPCO (Drug Price Control Act)

1. 1955 1st Amendments in DPCO Act.
2. 2013 2nd Amendments in DPCO Act.

Amendments in FERA Act (Foreign Establish Regulation ACT)

1. 1993 1st Amendments in FERA Act.
2. 1999 Abolish / Closed.
3. 2004 FEMA (Foreign Established Management Act) is Established)

Pharmacy as a Career
1. Pharmacist
a. Hospital Pharmacist
b. Community Pharmacist
c. Clinical Pharmacist
2. Industries Production
a. Quality Control
b. Quality Assurance
c. Research & Development
d. Marketing Representative (MR)
3. Hospital
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a. Medical Writer
b. Medical Coder
c. Medical Adviser
d. Medical Claim Association
4. Academic Lectures
a. Assent Professor
b. Associated Professor
c. Professor
5. Other
a. Bioinformatics
b. Clinical research coordinator
c. Pharmacovigilance

Pharmacopoeia
The term pharmacopoeia comes from Greek Word
Pharmakon means Drug
Poiein means Make
It can be defined as any recipe or formula that standard required for making or preparing a
drug.
It is also known as Compendia.

Indian Pharmacopoeia (I.P.)

 Indian Pharmacopoeia is an official document meant for overall quality control and
assurance of pharmaceutical product marketed in India by way of contributing to their
safety & affordability.
 The Indian Pharmacopoeia is published by the Indian Pharmacopoeia Commission
(IPC) on the behalf of the Ministry of Health and Family Welfare, Government of
India.
 The Indian Pharmacopoeia is being produced to fulfil the requirement in the Drug &
Cosmetics Rules, 1945 of standard of drugs produced in India.

Editions of Indian Pharmacopoeia

Sl. Sl. No. OF EDITION EDITIONS OF YEAR OF ADDENDUM
No PUBLICATION RELEASED
.
1. First Edition 1955 1960
2. Second Edition 1966 1975
3. Third Edition 1985 1989, 1991
4. Fourth Edition 1996 2000, 2002, 2005
5. Fifth Edition 2007 2008
6. Six Edition 2010 2012
7. Seventh Edition 2014 2015
8. Eight Edition 2018 2018

Sailent Features of I.P. 6th Edition

 6

1. It contains 3 volumes which are hard bound.

2. It contains a total of 1918 monographs out of which 287 were newly added.
3. Categorisation, dosage, and available strength of dose for the drug were also added.
4. Traditional tests were replaced with more specific tests, such as IR and UV
spectrophotometry.
5. Application of chromatography is done extensively.
6. Monographs related to herbal drugs are also added.
7. It also contains many monographs which are not press globally.
8. It also contains a certificate to prove its authenticity.
9. The format is quite simple and easy to understand.

Sailent Features of I.P. 7th Edition

1. A total of 2548 monographs were added.
2. This edition also contains 577 new monographs.
3. 19 monographs and one general chapter were added related to radiopharmaceuticals.
4. The edition comprises of 4 volumes which are in hard bound, along with a DVD.
5. Monographs related to veterinary are considered to be vital portion of this edition.
6. Use of chromatographic methods is extensively mentioned.
7. Traditional tests were replaced with more specific tests, such as IR and UV
spectrophotometry.
8. Monographs which were irrelevant were eliminated.
9. Many monographs related to herbs were added.
10. It also contains a certificate to prove its authenticity.
11. The format is quite easy and simple to understand.

Sailent Features of I.P. 8th Edition

1. IP-2018, comprises of 4 Volumes, having 220 new monographs that are as follows.
2. 170 chemical monographs.
3. 15 herbal monographs.
4. 10 blood and blood related products.
5. 02 vaccines and immunosera for human monographs use.
6. 03 radiopharmaceutical monographs.
7. 06 biotechnology derived therapeutic products.
8. 14 veterinary monographs.
9. It also contains 366 revised monographs and 7 omissions.

British pharmacopoeia (B.P.)

The British pharmacopoeia is published annually & comprises of the standard required for
maintaining the quality of medical substance of United Kingdom (U.K).
In 1864, the 1st Edition of B.P. was Punished.

Sl. EDITION YEAR Sl. EDITION YEAR

No No.
.
1. 1st 1864 12. 12th 1993
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2. 2nd 1874 13. 13th 2007

3. 3rd 1885 14. 14th 2008
4. 4th 1898 15. 15th 2010
5. 5th 1914 16. 16th 2013
6. 6th 1932 17. 17th 2014
7. 7th 1948 18. 18th 2016
8. 8th 1953 19. 19th 2018
9. 9th 1958 20. 20th 2020
10. 10th 1963 21. 21th 2021
11. 11th 1980

United State Pharmacopoeia (U.S.P)

The united states pharmacopoeia is a pharmacopoeia for the united states published annually
by the United States Pharmacopoeial Convention.
EDITION YEAR
1st 1820
9th 1905
22nd 1990
USP 37, NF 32 2013-2014
USP 39, NF 34 2016
USP 43, NF 38 2020

Extra Pharmacopoeia [Martindale]

1. A Pharmacist, William Martindale in 1883 edited, compiled, and published the extra
pharmacopoeia to provide updated information regarding drugs as well as Galenical’s
to pharmacist & physicians.
2. Pharmacopoeia [I.P., B.P., etc] does not contain & explanatory notes but only large
amount of information.
3. One should be aware of journal notices & appendices Maintain in pharmacopoeia.
4. The extra Pharmacopoeia was included in B.P & four edition of Martindale published
in 3 years it has been 37 times & contain almost all the updated information about
drugs & medicines.
EDITION YEAR
st
1 1933
rd
23 1955
th
24 1958
th
25 1967
th
26 1972
th
40 2011
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Chapter 2
Packaging Materials

PACKAGING MATERIALS
It is the art of science of packing of different dosage form to provide storage, safe
Transportation, Stability of the product.

Factors of Packing
1. Route of Administrations
2. Sensitivity of Product
3. Physical state of product

Components Required for Packaging

Container: It encloses the drug, thereby remains in direct contact with the drug. Such a
container which is always in direct contact with the drug is an immediate container.

Types of Container
1. Well Closed Container
2. Tight closed Container
3. Hermetically Sealed Container
4. Child Resistant Container
5. Light resistant Container
6. Single dose Container
7. Multi dose Container

Closure: It seals the container to eliminate oxygen, carbon dioxide, moisture, and
microorganisms. A closure prevents the loss of volatile substances, and also the loss of
medicament during transport and handling. It is a component of container system, and has no
direct contact with the drug.
Carton: It is made up of cardboard, moulded wood pulp, or expanded polystyrene, and
provides secondary protection. It is an outer covering and protects against mechanical and
other environmental hazards.
Box: It is made up of thick cardboard, wood, or any other suitable material, and carries
multiples of a product. It provides primary protection against external hazards while
transportation and handling.

Objectives of Packaging
Physical Protection: The package provides protection to the product against mechanical
shock, vibration, electrostatic discharge, compression, temperature, etc.
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Barrier Protection: A barrier is required to protect the product from oxygen, water vapour,
dust, etc.
Information Transmission: Packages and labels provide information about the usage,
transport, recycling, or disposing of the package or product. Pharmaceuticals, food, medical
and chemical products need special information stated by the governments.
Marketing: Marketers use the packaging and labels of a particular product for convincing
the buyers to purchase.
Security: The security, risks of shipment are minimised by packaging.

Ideal Properties of a Packaging Material

1. It should be strong enough to endure handling while emptying, filling, closing,
sterilising, labelling, transporting, storing, and using by the consumers.
2. It should not cause product loss due to any leakage or permeation.
3. Its material should be non-reactive to the product components and the closure.
4. It should not absorb the product components.
Example: Cardboard boxes absorb the water and oily substances present in ointment
and creams.
5. It should not impart any colour, taste, and odour to the product.
6. Its size should be according to the product volume.
7. Its closure should be easily removable and replaceable.
8. Amber coloured glass containers provide protection to light-sensitive products.
9. The container surface should be clear to facilitate easy labelling.
10. It should ease product identification.

GLASS AS PACKAGING MATERIAL

1. A Glass is economical, chemically inert, impermeable, strong, rigid, has FDA
clearance, and possesses superior protectivve qualities thus, is used for packaging
pharmaceuticals.
2. Glass containers are available in various size and shapes.
3. Glass does not get depreciated with time.
4. If a proper closure system is provided, glass serves as an efficient barrier against
every element however, only amber-coloured glass can provide protection against
light.
5. The fragile nature and weight of glass are its major limitations when used for
packaging.

Selection Criteria
1. Limit of alkalinity and hydrolytic resistance of the glass container.
2. Thermal expansion properties of the glass container(freeze-drying).
3. Sensitivity of the glass container to barium or calcium ions.

Types of Glasses
1. Borosilicate Glasses
2. Soda Lime Glasses
3. Sulphur Treated Glasses
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4. Silica Treated Glasses

5. Neutral Glasses
6. Light Resistance Glasses / Coloured Glasses

Advantage
1. It does not deteriorate with age.
2. It is heat resistant, thus can undergo heat sterilisation.
3. It can be easily cleaned.
4. It is impermeable.
5. It is economical.
6. It enables identification of products.

Disadvantage
1. It is of fragile and brittle nature.
2. It is heavy in weight and occupies more volume.
3. Once broken, it cannot be joined back.

PLASTIC AS PACKAGING MATERIAL

Plastic containers are used because of their light weight, non-breakable nature, low toxicity
and low reactivity with the products (provided they contain fewer amounts of additives).

Selection Criteria
1. Stability
2. Compatibility with the contents
3. Strength of container and the degree of protection required.
4. Moisture-proof ness.
5. Resistance to corrosion by Acids or Alkalis
6. Protection against salt
7. Resistance to microorganisms
8. Resistance to insects

Types
1. Polyethylene
2. Nylon (Polyamide)
3. Polycarbonate

Advantages
1. It has low thermal and electrical resistance.
2. It is resistant to weak mineral acids.
3. It remains unaffected by inorganic salts.
4. It is resistant to slight pH changes.
5. It is not very heavy.

Disadvantages
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1. It has low mechanical strength.

2. Its expansion rate is high.
3. It is not completely impermeable to moisture, gases etc.

METAL AS A PACKAGING MATERIAL

A Metal packaging plays an important role in the process of food preservation that can be
described by using the term “canning”. Canned food has become an essential part of human
diet in the developed countries.

Metals used for packaging

1. Aluminium
2. Steel
3. Tin

Types
1. Cans
2. Drums and Pails
3. Aerosols
4. Tubes
5. Closures
Advantages
1. They are durable.
2. They do not allow light, moisture and gases to pass through.
3. They can be made into rigid resilient containers by impact extrusion.
4. They are lighter in weight than the glass container.
Disadvantages
1. They are costly.
2. They may cause adulteration of pharmaceutical products by shedding metal particles
into them.

RUBBER AS A PACKAGING MATERIAL

Rubber is either used as such or as lining materials for plant construction.
Rubbers are categorised into:
Natural Rubber:
This naturally occurring polymer is obtained from rubber trees in the form of latex.
It is a common example of an elastomer, which is a substance that can be easily stretched and
on releasing quickly move to its original form

Natural Rubber are two types

1. Soft Rubber
2. Hard Rubber
Synthetic Rubber:
This rubber is resistant to oxidation, solvents, oils, and other chemicals.
Due to these superior properties, synthetic rubber is more important than Natural.
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Examples: Neoprene (Polychloroprene), Nitrile Rubber, Butyl Rubber, Polyisoprene, etc.

Advantage • Soft rubber provides resistance against dilute mineral acids, dilute alkalis, and
salts.
Disadvantage • Soft rubber can be attacked by oxidising media, oils, and organic solvents.

Chapter 3
Pharmaceutical Aids

The elements having little or no therapeutic value, but are basically used in production or
compounding of various pharmaceuticals, are known as pharmaceutical aids or
pharmaceutical necessities.
The functions of pharmaceutical aids in pharmaceutical dosage form are
1. They also modify the API's solubility and bioavailability.
2. They also help the API's to maintain their polymorphic forms or conformations.
3. They help the liquid dosage forms in maintaining their pH or osmolarity.
4. They prevent aggregation or dissociation (e.g., of protein and polysaccharide actives).
5. They modulate the APIs immunogenic responses (e.g., adjuvants).
6. They make up the bulk of a potent drug formulation to obtain an accurate dosage
form.
7. They improve the patient compliance.
8. They modify the formulation's safety and effectiveness during its use and storage
period.

Ideal Properties
1. Non-reactive and inert,
2. Chemically stable,
3. Non-toxic,
4. Requires less equipment and process-sensitive,
5. Acceptable organoleptically,
6. Economical.

Classification
On the basis of their origin, dosage forms, and functions,
Based on their Origin
1. Animal Source: Lactose, Gelatine, Stearic acid, Bees wax, Honey, Musk, Lanolin,
etc.
2. Vegetable Source: Starch, Peppermint, Turmeric, Guar gum, Arginate, Acacia, etc.
3. Mineral Source: Calcium phosphate, Silica, Talc, Calamine, Asbestos, Kaolin,
Paraffin etc.
4. Synthetic Source: Boric acid, Saccharin, Lactic acid, Polyethylene glycols,
Polysorbates, Povidone, etc.

Based on Dosage Forms

1. Solid dosage forms (tablets, capsules, etc.)
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2. liquid dosage forms (solutions, syrups, etc.),

3. Semi-solid dosage forms (ointments, pastes, etc.)

Pharmaceutical Aids Used in Solid Dosage Forms

The pharmaceutical aids commonly used in solid dosage form

Sl. CATEGORY EXAMPLE

No
.
1. Diluents Lactose, Dextrose
2. Binders and Adhesives Acacia, Gelatine
3. Lubricants Talc, Starch paste
4. Glidants Corn Starch, Carbosil
5. Desenitigentrants & Super- Starch, Clay & Cross povidone, Sodium starch
Desenitigentrants glycolate
6. Colouring Agent D and C dyes
7. Flavours Spray dried and other flavour
8. Sweeteners Mannitol
9. Sorbents Silica gel, clay
10. Coating Materials Hydroxypropyl methylcellulose (HPMC)

Pharmaceutical Aids Used in Liquid Dosage Form

Sl. CATEGORY EXAMPLE

No
.
1. Solvent Water, Alcohol
2. Co-Solvent Ethanol, Sorbitol
3. Buffers Phosphate Buffer
4. Antimicrobial Preservative Benzyl Alcohol
5. Antioxidants Ascorbic Acid
6. Antifoaming Agents Paraffin Oil, Alcohols,
7. Chelating Agent Citric acid and Tartaric acid
8. Emulsifying Agent Sorbitol esters
9. Flocculating Agent Starch, Carbomer

Pharmaceutical Aids Used in Semi-Solid Dosage Form

Sl. CATEGORY EXAMPLE

No
.
1. Preservative Benzyl Alcohol
2. Solubilizers Lanolin, Cholesterol
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3. Gelling Agent Pemulen, Cellulose

4. Suppository Base Glycerine, Coconut Oil

Colours/Colouring Agents
In pharmacy, the colourants or colouring agents obtained from plants, animals and mineral
sources are particularly used for the purpose of providing colour so as to impart pleasing
appearance to the drugs and cosmetics.
They are also used as colouring agents in the foods and for other psychological effects.

Some of the colouring agents or colourants are given below:

1. Mineral Colours: These are used to colour cosmetics, lotions, and other preparations
for external use, e.g., red and yellow ferric oxides, titanium dioxide, Prussian blue,
etc. Mineral colours are generally called pigments.
2. Plant Colours: These colours are generally obtained by extraction from plants, e.g.,
chlorophyll, B-carotene, alizarin, indigo, anthocyanin and flavones.
3. Animal Colours: Carminic acid, a bright red colouring agent is present in cochineal
which is obtained from the insect Coccus cacti. These are also used as synthetic
colorants.
4. Synthetic Colours: In the early days, aniline was used for the preparation of synthetic
colours. Since, all the synthetic colours are not fit for human consumption; therefore,
governments of different countries have approved only some specific colours to be
used in the preparations.

The Drugs and Cosmetics Act 1940 and Rules 1945, in India have permitted the use of
the following colours in drugs:
1. Coal Tar Colours: Amaranth, green S, orange G, patent blue and tartrazine.
2. Lakes: Lakes are the aluminium or calcium salts of any water-soluble food dye.

Classification

Colouring Agent

Natural Colour Natural Colour

Animals Plants Minerals Example:

Coal Tar colour:
Amaranth, Green.
Lakes: Aluminium or
Example Example Example Calcium Salt
Coccuscacti: Alizarin, Ferric Oxide,
Carminicacid Indigo Titanium
Dioxide
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Selection Criteria
1. The certification status and the aesthetics of a dye.
2. The physicochemical properties of the dye.
3. pH and pH stability of the liquid preparations.
4. The dye must be photo stabilised.
5. Personal preference of the consumer population.
Advantages
1. They provide grace and better eye-appealing character to the product.
2. For the effective treatment of poisoning in the early stage, colours play an important
role in the fast recognition of the medicine.
3. Different colours of the medicines can also help the doctor in identifying the drugs
given to the patient during previous treatment.
4. Doctors become familiar with the colour of the products and this helps in the sale of
the medicine.
Disadvantages
1. The colouring property was not much elegant.
2. They do not show their lasting effect in solutions.
3. Sometimes the effect of sunlight fades the colour of coal tar.
4. Many colours behave as feeble indicators and alteration in pH may be accompanied
by the changes in colour and tinctorial power.
Uses
1. For Identification.
2. To Increase their Acceptability to Patients.
3. To Give Warning.
4. To product Standard Preparation.

Flavouring agents
1. Flavouring agents play a vital role in masking the Flavours/Flavouring Agents
disagreeable taste of liquid dosage forms used for oral purposes.
2. In order to increase the patient compliance, certain antibiotics masticated in the mouth
and chewable tablets of antacids are generally sweetened and added with flavouring
agent.
Suitable Masking Flavours for Various Product Tastes
Sl. Taste of Product Suitable Masking Flavour
No
.
1. Salty Apricot, Butterscotch, Vanilla
2. Bitter Chocolate, Wild cherry
3. Sweet Vanilla, Fruits, Berries
4. Sour Citrus Fruit, Raspberry

Classification
Flavours/Flavouring Agents

Sweetening Agent Flavours Syrup Aromatic Oils Synthesis Flavours

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Selection Criteria
1. The qualities of the taste of flavour.
2. Suitability of the combination of flavour, colour and sweetener.
3. Type of the preparation, whether for internal or external use.
4. Patient's age.
5. General liking and disliking of the intended users.
6. Best flavour for a particular product is usually selected by forming a panel and by the
consent of majority.
Advantages
1. The unpleasant taste of the medicament is masked by the flavouring agents.
2. These agents help in increasing patient compliance for tablets that are chewable.
Disadvantages
1. There are certain intolerable flavours that cannot be masked, e.g., in case of male fern
extract, which is initially sweet, then astringent and finally bitter in taste.
2. The formulations meant for patients on reducing diets or diabetics do not contain the
sweetening agents that increase calories or blood sugar levels.
Uses
1. Flavouring agents aids in masking the disagreeable odour or taste of the medications
so as to increase the patient's acceptance towards the drug.
2. They induce an acceptable flavour in the medicament.
Sweeteners/Sweetening Agents
1. Sweetening agents are the constituents that are added to a drug preparation to mask its
bitter taste. The most widely used natural sweetening agent is sugar.
2. It gives viscosity to drug and also acts as preservative for liquid dosage form. There
are two varieties of substitutes which are used as sweeteners:
a. Natural sweeteners
b. Artificial sweeteners
Classification
On the basis of Nutritive value

Sweetening Agents

Nutritive Sweetener Non - Nutritive Sweetener

It is Less Sweet and Have It is Strong Sweeter and Have

 17

Selection Criteria
1. Sweeteners provide a substitute to sugar without the related energy (kilojoules), for
those who mainly have sweet tooth.
2. There are various ways by which sweeteners can be added into the diet and the
sweetener is selected on the basis of requirement.
3. An artificial or table top sweetener can be used in case an individual is resisting
sweetness in a cup of tea or coffee.
4. In case of stability of the sweeteners, a natural intense sweetener is preferred over
other sweeteners as they are more heat stable.

Advantages
1. Weight Control: An artificial sweetening agent should be used, in case; someone
wants to reduce their weight as it contains zero calories. Whereas, one gram of sugar
contains 4 calories and one teaspoon of sugar contains about 4 grams of sugar, 16
calories per teaspoon.
2. Diabetes: It also assists in monitoring diabetes as it does not increase the blood sugar
levels due to absence of carbohydrates in it.

Disadvantages
1. They can cause dental cavities, raised blood sugar, calories.
2. They increase the risk of cancer and may destroy blood sugar and intestinal health.
3. They may result in weight gain and poor nutrition.

Uses
1. Saccharine can be utilised to sweeten candies, drinks, and toothpaste.
2. Lactose is an additive and filler found in various products to maintain structure and
consistency.
3. Sorbitol is mainly used as a laxative to relieve constipation.

Preservatives
Preservatives
1. A preservative is a natural or synthetic substance that is added in the products like
foods, pharmaceuticals, paints, biological samples, wood, etc., to avoid decomposition
by microbial growth or by unwanted chemical changes.
2. These are chemicals that are commonly added to many foods and pharmaceutical
products in order to extend their shelf life.
 18

3. Preservatives are added especially, to the products having greater water content to
prevent them from alteration and degradation by microorganisms while storing.
4. Preservatives are added in foods to prevent growth of bacteria, yeasts, or moulds that
may cause a disease.

Ideal Properties of Preservatives

1. It should be non-irritant.
2. It should be non-toxic.
3. It should have physical and chemical stability.
4. It should be compatible with other ingredients added in formulation.
5. I should be a good antimicrobial agent and should exert wide range of activities.

Classification
On the Basis of Mechanism of Action

Preservatives

Antioxidants Antimicrobial Agents Chelating Agents

Example Example Example

Vitamin E, Vitamin C, Benzoates, Sorbates Citric Acid, Polyphosphates
Butylated hydroxyanisole
(BHA)

Based on Source

Preservatives

Natural Preservative Artificial Preservative

Example Example
Neem oil, Lemon, Benzoates, Nitrites,
Honey, etc Propionates, etc
 19

Selection Criteria
1. It should be stable and highly effective even in small concentrations.
2. It should not react with other ingredients of the product to form any harmful
substance.
3. It must be easily soluble in the desired vehicle.
4. It should be odourless, tasteless, and colourless.
5. The physicochemical properties of the preservative should not get affected by the pH.
6. It should not produce any sensitising effects. toxic, irritant and

Advantages
1. They help in maintaining the consistency with the texture and provide thickness.
2. They also increase the appearance of the product to make it look edible and safe to
consume for a respectable amount of time.

Disadvantages
1. A group of preservatives used in fruit drinks, tea and coffee are benzoates that cause
allergic reactions, asthma attacks, skin rashes, and is considered to cause brain
damage.

Uses
1. Preservatives are added to food to fight spoilage caused by bacteria, moulds, fungus,
and yeast.
2. Preservatives can keep food fresher for longer periods of time, extending its shelf life.
Food preservatives also are used to slow or prevent changes in colour, flavour or texture and
delay rancidity.
 20

CHAPTER 4
UNIT OPERATION

SIZE REDUCTION
 The process in which the particle size of a substance is the reduced from its smaller
size to a finer state of sub division (coarse or powdered state) is known as size
reduction.
 Milling is the process in which the particle size of solid substance is reduced into
coarse or powdered state by employing mechanical strength.
 In some cases, the process of size reduction is also known as comminution and
grinding.
 Depending on the type of material used (solid or liquid), the methods employed for
the reduction of particle size are broadly categorised into two classes:
1. Grinding and Cutting: These methods are employed for reducing the size of solid
substances.
2. Emulsification or Atomisation: These methods are used for the liquid phase.

Advantages of Size Reduction

1. It maintains content uniformity and uniform flow of materials.
2. It enables extraction and drying of drugs in an effective manner.
3. It improves the absorption and dissolution rates and physical stability of the product.
4. It enhances the viscosity and surface area of the drug.
5. It improves the drug bioavailability.
6. It aids in manufacturing of aerosols, inhalation and ophthalmic preparations, and
parenteral suspensions.

Disadvantages of Size Reduction

1. It may degrade the drug.
2. It leads to poor mixing.
3. It may lead to product contamination.
4. It may also lead to some instrumental problems like noisy environment.

Objectives
1. By reducing the size of particles, the surface area of the drug gets increased. Hence, in
case of any chemical substance, this increased surface area helps in quick formation
of the solution.
 21

2. By reducing the particle size of certain drugs, their therapeutic efficacy gets enhanced,
e.g. the therapeutic effectiveness of Griseofulvin is increased by reducing its dose to
half of the original of by requirement.
3. If the particle size of different solid ingredients is reduced to the same size, their
mixing becomes much easier and produces a uniform product.
4. In order to increase the stability of emulsions, the size of oil globules should be
reduced.
5. By reducing the particle size of ointments, pastes, and creams, their physical
appearance can be enhanced.
6. It facilitates drying of the wet masses by milling: as milling increases the surface area
and hence the rate of drying increases.
7. Size reduction reduces the bulkiness of drugs.

Factor Affecting Size Reduction

1. Toughness: Those crude drugs are usually tough in nature which have high water
content or are soft and fibrous. Problems are faced in the size reduction of soft but
tough substances as compared to hard and fragile substances.
2. Hardness: The size reduction of soft materials is comparatively easier than the hard
substances. Hence the process of size reduction is also affected by the hardness of
material.
3. Stickiness: Sticky substances are resinous or gummy in nature. Therefore, during the
process of size reduction, certain problems are faced as they stick to the grinding or
sieve surfaces of the mill, which makes it difficult to break them into small pieces.
4. Moisture Content: The process of particle size reduction is also affected by the
moisture present in the material which affects different physical properties of the
substance like stickiness, toughness, or hardness.
5. Softening Temperature: During the process of size reduction, the material with a
wax-like property (e.g. stearic acid or other drugs containing oils or fats) becomes soft
because the temperature of the mill rises to a large extent.

Methods of Size Reduction

1. Cutting: In this method, the material is cut with the help of blades having a fine
sharpness, e.g. cutter mill.
2. Compression: In this method, pressure is applied on the material so that it gets
crushed into smaller size particles, e.g., roller mill.
3. Impact: In this method, the material is kept stationary and an object moving with
high speed strikes the material in order to reduce its particle size. Impact also occurs
when the particles in motion strike the non-moving surface of the mill.
4. Attrition: In this method (similar to that compression in which pressure is applied on
the material), both the surfaces (machine and material) move with respect to each
other, and produces shear forces which reduces the size of particles, e.g., fluid energy
mill. The size up to which the above-mentioned methods reduce the particles are
given in the.

Table
Sl. METHOD/MECHANISM COMMON APROX. PARTICLE SIZE
No EQUIPMENT (MICRON)
.
1. Cutting Cutter Mill 100-80000
2. Compression Roller Mill 50-10000
 22

3. Impact Hammer Mil 50-8000

4. Attrition Colloid & Roller Mill 1-50
5. Impact and Attrition Ball Mill 1-2000

EQUIPMENT FOR SIZE REDUCTION

The common size reduction mills used in pharmaceutical industries are:
1. Hammer mill,
2. Ball mill,
3. Fluid energy mill,
8. Disintegrator
Hammer Mill
1. Hammer mill is a type of crusher used for grinding and pulverising various materials.
2. It is the device used for Crushing or milling agglomerates or large sized particles into
small-sized freely flowing particles (although the property of free flowing depends on
the speed of the mill.

Principle
1. Hammer mill works on the principle of impaction, in which a speedily moving object
is made to hit a stationary substance. Thus, the size of the particles is reduced by the
mechanism of pulverisation or grinding.

Construction
2. The hammer mill consists essentially of a high-speed rotor turning inside a cylindrical
casing. The rotor is mounted on a shaft which is usually horizontal. The swing
hammers are pinned to a rotor disk. The hammers are rectangular bars of metal with
plain or enlarged ends. In this mill, the particles are broken by the sets of swing
hammers. The product falls through a grate or screen which forms the lower portion
of the casing.
3. Several rotor disks each carrying four to eight swing hammers are often mounted on a
single shaft. The rotor disk diameter ranges from 150 mm to 250 mm. As the
hammers are hinged, the presence of any hard material does not cause damage to the
equipment. The hammers can be readily replaced when they work out.

Hammer Mill (a) Schematic & (b) Industrial Equipment

 23

Working
1. The material to be crushed is fed into the hopper connected to a drum.
2. The fast-rotating hammers powder the material into required size.
3. The resultant powder is coarse to moderately fine and is collected beneath the screen.
4. Hammer mill operates continuously because the hammers are not fixed, thus the
chance of getting choked is less.
5. The mill operates at a very high speed due to which heat is generated, which then
affects the thermolabile materials.
6. Also, the mill may get damaged for the same reason if the feed contains foreign
objects like stone or metal.

Applications
1. In pharmaceutical industries it is used in wet or dry granulations and to disperse
powder mixtures.
2. It is used to grind pharmaceutical raw materials, herbal medicines, and sugar.
3. It is used to make powder of barks, leaves, and roots having medicinal properties.
4. It is used for milling Active Pharmaceutical Ingredients (APIS), excipients, etc

Merits
1. Its reduction ratio and capacity are high for primary, secondary, or tertiary grinding.
2. It requires moderate energy.
3. It is used for milling variety of materials.
4. It is easy to install, dismantle, and clean.
5. It requires a small space for installation.

Demerits
1. It cannot be used for fine grinding of hard and abrasive materials due to excessive
wear.
2. It cannot be used for low-melting sticky or plastic-like materials due to heat
generation.
3. It may get choked and damaged in case of uncontrolled feed rate.
4. It may damage the heat-sensitive materials due to heat generated when operating at a
very high speed.

Ball Mill
Ball mill is one of the types of grinders employed in grinding the drug substances into
superfine powders. These powders are used in pyrotechnics, ceramics, and paints.

Construction
Ball mill consists of the following parts: Hollow Cylinder
1. The hollow cylinder is formed of metal and has a chromium lining.
2. The metallic frame attaches the hollow cylinder in such a way that it can rotate at its
longitudinal axis.
3. About 30-50% volume of the mill remains the mill remain as occupied by the steel
balls.
 24

Low Speed High Speed Correct

Cascade Operation in Ball Mill Speed

Working
Working of a ball mill can be summarised in the following steps:
1. The cylinder of the mill is filled with the drug substance to be grinded and is then
rotated.
2. In the whole process of size reduction, the speed of rotation plays a key role as.

At Low Speed (Sliding):

1. The balls will only tend to roll and slide over each other.
2. Very small quantity of material will be reduced to small particles.

At High Speed (Centrifugation):

 25

1. Due to the centrifugal force the balls are moved towards the walls, and thus do not
grind the material.
2. This is because the compression force applied by the balls against the wall is not
enough for size reduction of materials.

At Correct Speed (Cascading):

1. The centrifugal force causes the balls to move up to the roof of the mill and then fall
off.
2. Thus, attrition and impact between the balls cause maximum size reduction of the
particles.
3. Later, after a particular time period the material being grinded is withdrawn from the
container and passed via suitable sieve in order to obtain the powder desired size
particles.

Applications
1. It is the key equipment for regrinding.
2. It is widely used for cement, silicate product, new type building material, fire proof
material, chemical fertilisers, black and non-ferrous metals, glass, etc.
3. It can grind ores or other materials either by wet process or by dry process.

Merits
1. It can be easily cleaned and operated.
2. The grinding process can easily be seen.
3. During the grinding process, there is minimum loss of material.
4. Both dry and wet grinding can be processed.
5. It can produce very fine powder.

Demerits
1. It has a large size.
2. During the process of size reduction, strong vibrations and sounds are produced.
3. Ball milling is a slow process.
4. Due to frictional loss it consumes a large amount of Energy.
5. It has low efficiency.

Size Separation
1. A unit operation used to separate or categorise the particles on the basis of differences
between the physical properties of the particles like density, shape, and size is termed
as size separation (or screening or Sifting or Cassitying). Once the size of the material
is reduced, it is Subjected to size separation techniques in order to obtain the powder
of desired particle size range.
2. Particle size distribution is defined as the number of particles in each size range
present in a given powder of specified weight.

Objectives
1. The techniques of size separation particularly sieving is employed for the
determination of average particle size and particle size distribution which is
considered as the first step in the manufacturing of tablets and capsules.
2. There are certain drugs which are needed in extremely fine state with the particle size
of 10u so that they can get absorbed from the gastrointestinal tract rapidly and
effectively. e.g., griseofulvin (antifungal) and aspirin (analgesic, antipyretic).
 26

3. Size separation is also essential for evaluation of the efficiency of different

equipment’s used for the process of size reduction.

Applications
1. Release and Dissolution: Clinically, the particle size of a drug can affect its release
from dosage form administered orally, parentally, rectally, and topically.
2. Absorption and Drug Action: Drug absorption and its pharmacological response are
affected by the size of particles. Higher the dissolution rate, faster the absorption rate,
hence quicker and greater the drug action.
3. Physical Stability: The physical stability of some pharmaceutical preparations like
suspensions and emulsions are affected by the particle size. Depending upon the size
of particle, the physical stability of the also changes; smaller the size of particles, drug
greater will be the physical stability of the drug owing to the Brownian movement of
the particles in the dispersion.

Mechanism of Action
1. Agitation: This mode of motion involves vigorous shaking of sieves following ways.
2. Oscillatory Motion: In this type of motion, the movement of sieves takes place with
the help of rotating shaft. In this, the sieves placed on the frame are moved in to and
fro motion corresponding to the plane of sieve.
3. Vibrating Motion: In this type of motion, the material is placed on the sieve which is
then subjected to high speed vibration by employing either an electrical or a
mechanical device.
4. Gyratory Motion: In this type of motion, an eccentric flywheel is used for rotating the
sieve (placed on the rubber mounting) at a fixed axis in a circular motion.

Classification of Powders According to IP

1. Powders are generally termed as coarse and fine powders. But it is necessary that they
should be defined with some official specifications.
2. Pharmaceutical powders have been assigned some standards by the I.P., according to
which degree of coarseness or fineness is expressed with reference to the aperture size
of the sieve through which powder can pass.

a. Coarse Powder (10/44): All the particles of this powder pass through a sieve no. 10,
having the nominal mesh aperture of 1,700um but not more than 40% of the powder
by weight must pass through the sieve no. 44, having the nominal mesh aperture of
355um.
b. Moderately Coarse Powder (22/60): All the particles of this powder pass through a
sieve no. 22, having the nominal mesh aperture of 710um but not more than 40% of
the powder by weight must pass through sieve no. 60, having the nominal mesh
aperture of 250um.
c. Moderately Fine Powder (44/85): All the particles of this powder pass through a
sieve no. 44, having the nominal mesh aperture of 355um but not more than 40% of
the powder by weight must pass through sieve no. 85, having the nominal mesh
aperture of 180um.
d. Fine Powder (85/120): All the particles of this powder pass through a sieve no. 85,
having the nominal mesh aperture of 180um but not more than 40% of the powder by
weight must pass through sieve no. 120, having the nominal mesh aperture of 125um.
 27

e. Very Fine Powder (120/350): All the particles of this powder pass through a sieve
no. 120, having the nominal mesh aperture of 125umn but not more 40% of the
powder by weight must pass through sieve no. 350 with the nominal mesh aperture of
45um.)
f. Microfine Powder (350): The powder whose particles are not less than 90% by
weight must pass through sieve no. 350, having the nominal mesh aperture of 45um.
g. Superfine Powder: The powder in which the number of particles is not less than 90%
and is less than 10um in size.

Sieves

1. Normally, a sieve is used for separating the unwanted or useless material from that of
the desired one with the help of different tools such as net, mesh, or other distillation
and filtration techniques.
2. For the separation of liquids from the solids, a particular type of sieve is used, known
as strainer. Sieving is also used as an analytical technique for the measurement of size
and classifying the powders according to the size of the particles.

Types of Sieves
1. The size and shape of sieve aperture is the main concern while setting standards.
Square meshes are arranged as per the specifications. The following types of sieves
are used mostly for pharmaceutical purposes:
Woven Wire Sieves: These sieves are of the following types:
a. Plain weave,
b. Twilled weave

Standards of Sieves
Common standards used for sieves are as follows.
1. Tyler standard sieve series (in U.S.A.),
2. US standard sieve series (in U.S.A.),
3. British standard sieve series (in U.K.),
4. German DIN (Deutsche Industry-Norman) (in Germany and Europe).
5. I.P. standard sieve series (in India),
6. International test sieve series (ISO) (Worldwide)

The specifications given below should be matched by the sieves used for
Pharmacopoeial testing:
1. Sieve Number: This is the number of meshes present per linear length of 25.4mm.
2. Nominal Aperture Size: This is the distance between the two adjacent wires,
representing the side of a square aperture. The nominal mesh aperture size for most of
the sieves is given in the I.P. 1996 (either in mm or in um).
3. Nominal Wire Diameter: The wire used in wire mesh sieves has a specified diameter
which provides a suitable aperture size and sufficient strength so that sieve distortion
can be avoided.
4. Approximate Percentage Sieving Area: This is the mesh area expressed as a
percentage of the total sieve area. It depends on the wire size used for a sieve. The
sieving area is appropriately maintained within 35-40% to provide the required
strength to the sieve.
 28

5. Aperture Tolerance Average Size: Some variations which the aperture size
undergoes cannot be avoided, such variations are termed aperture tolerance average,
expressed as a percentage.

Cyclone Separator
1. The method used to remove particulate matter from air, gas, or water stream with the
help of vortex rather than filters, is known as cyclonic separation. Gravity and
rotational effects are helpful in the separation of solid mixtures from those of the
fluids.

Principle
2. Cyclone separator is a type of sedimentation technique which works on the principle
of centrifugal force rather than the gravitational force.
3. Thus, based on the fluid velocity, cyclone enables the separation of all the particles or
only the coarse particles can be removed, leaving behind the fine particles which are
then carried away by the fluid.

Construction
1. Cyclone separator consists of a cylindrical vessel having a conical base., The vessel is
divided into two parts.
2. The upper part consists of a tangential inlet and a fluid outlet at the centre of the top
portion and extending inwardly into the separator, and
3. The lower part or the base is fitted with the outlet for the solid particles

Cyclone Separator
 29

Working
1. The suspension is introduced into the cylindrical vessel through the tangential inlet at
high speed in order to provide the rotary movement inside the vessel.
2. The fluid outlet located at the top of the vessel helps in removing the fluid.
3. The solid particles are thrown out towards the cyclone walls due to the rotary
movement occurring inside the cyclone which causes the movement of particles by
the centrifugal force. The particles thrown out then fall down on the conical base
which is removed ultimately from the solid outlet at the bottom of the cylinder.

Applications
1. It is used for the separation of suspensions of solids in liquids with the preference for
suspension of a solid in a gas (air).
2. It is also used for separating the heavy or coarse fraction from fine dust.

Merits
1. It involves low capital costs.
2. It can operate at high temperatures.
3. It can be used for liquid mists or dry materials.
4. Its maintenance requirements are less.
5. It requires a small space for installation.

Demerits
1. Its operating cost is high due to pressure drop.
2. It shows low efficiency for small particles.
3. It cannot be used for sticky materials.

Mixing

1. Mixing is one of the most important processes of unit operation and is used in many
industries. It involves mixing of solids, liquids, or gases having two or more than two
components.
2. Mixing may be defined as the process in which two or more ingredients are treated so
that every particle of any one ingredient lies as near as possible to the particle of the
other ingredient.
3. There are several factors, which affect the process of mixing, like density of the
material, particle size, shape, and proportion of the constituents.
4. Mixing is thought to be an important process in the field of pharmacy because at
different steps it might affect the preparation's efficiency.

Objectives of Mixing
1. Chemical Reaction Enhancement: In chemical industries, it is uses mixing to
continue a reaction appropriately which require a close contact among reacting
substances.
2. Simple Physical Mixtures: It is a mixture of two or more miscible liquids,
homogeneously divided solids, etc.
 30

3. Physical Changes: They are carried out by mixing such as from supersaturated
solution crystals are formed.
4. Achieving Dispersion: It is also an objective of mixing in which two or more
immiscible liquids and one or more liquids with finely divided solids are mixed to
produce a quasi-homogenous substance.

In order to obtain the following types of product usually the process of mixing operation
1. True Solutions: These solutions are formed when two or more miscible liquids are
mixed with each other.
2. Emulsions: These are formed when two immiscible liquids are mixed together with
the addition of an emulsifying agent.
3. Solutions: These are formed when any solute (solid) is dissolved in a solvent
(vehicle).
4. Suspensions: These are formed when an insoluble solid (solute) is mixed with the
solvent or vehicle.
5. Ointments or Suppositories: These are formed when any liquid or a solid is mixed
with a semisolid base.
6. Capsules: These are formed when two or more solid materials are mixed with each
other to form a powder which is then filled into the gelatine capsule shells.
7. Tablets: These are formed when two or more solid substances are mixed with each
other to form a powder which is then compressed under heavy pressure to obtain
tablets.

Applications
1. During tablet and capsule manufacturing, wet mixing is done in the granulation stage.
2. For easy compression of tablets, various components are mixed by dry mixing.
3. In the manufacturing of capsules, compound powders, and dry syrups, dry blending of
powder is done.
4. For capsule manufacturing, pellets are formed.
5. In tablet manufacturing, powder mixing is an important step because many additives
are added to this process.

Factors Affecting Mixing

1. Surface Nature
2. Particle Density
3. Particle Size
4. Particle Shape
5. Particle Charge
6. Material Proportion

Equipment’s for Mixing

For mixing and homogenisation process such mixer should be used which facilitates random
mixing, and also prevents the conditions which may result in segregation. Thus, the
operational conditions should be critically optimised.

Mixing Equipment’s
1. Double cone mixer
2. Turbine mixer
3. Triple roller mill
4. Silverson mixer (homogenizer)
 31

Double Cone Blender

1. Double cone blender is a competent and versatile machine used for uniform blending
of granules and dry powders.
2. It is made up of stainless steel.
3. It is available in a wide range of working capacities ranging from 5-500 litres.

Principle
1. Double cone blender produces a homogeneous solid-solid mixture.
2. This equipment involves axial mixing as the powder moves in different sections.
3. This blender provides thorough mixing depending on its speed of rotation.

Construction

Double Cone Blender

1. The body of double cone blender consists of two cone shaped sections.
2. These are joined to a central cylindrical section at their bases.
3. The rotational axis is perpendicular to the cone axis and passes through the cylindrical
section.
4. The blender body is held by two lateral supports.
5. One of these supports is fitted with the driving motor.

Working
1. The autoclaved double cone blender's angle is adjusted with the help of a moving
wheel so that the material can be conveniently loaded.
2. After loading, the lid of the blender is closed, and the lid is secured by fitting the
safety pin within its groove.
3. Then the safety guard is put and the equipment is switched on.
 32

4. After the blending process is complete, the safety guard is put is removed (only after
switching the equipment off), the blender is adjusted to an angle (so that the material
can be conveniently unloaded), the safety pin is unlocked, and the lid is opened.

Applications
1. It is employed in different industries for the preparation of different products such as
pharmaceutical, food, chemical, cosmetic products, etc.
2. It is used for uniform mixing of granules or dry powders.
3. It is used for the preparation of pharmaceuticals, food, and chemical products.
4. It is suitable for homogeneous mixing of small amount of powders.
5. It is used for providing heating and cooling effect with the help of jacketed
construction.

Merits
1. Large quantity of material can be easily handled.
2. It requires minimum maintenance cost.
3. It can be easily cleaned and maintained.
4. It can be easily operated with easy charging and discharging of the material.

Demerits
1. It requires large headspace for installation.
2. Due to insufficient shearing force, it is not suitable for materials having large
differences in particle size distribution or for systems containing fine particles.

Turbine Mixer

1. Turbines are mechanical devices used for mixing different types of fluids with
different types of blades and impellers.
2. Turbines are used for mixing high viscosity liquids because of the greater shear forces
produced by them as compared to the propellers.
3. They are used especially for the preparation of emulsion. For preventing vortex
formation, baffles are often used.

Construction
Turbines consist of a circular disc having short blades attached to it Their diameter is 30-50%
of the vessel diameter. They rotate at 50-200rpm speed speed (lesser than the propellers).
Different turbines have blades of different shapes, like straight, curved, pitched, or vertical.

Working
1. Turbines operate similar to a centrifugal pump working in a vessel against negligible
back pressure.
2. Mixing is accomplished by the turbine blades which constrain and discharge the
liquid.
 33

Applications
1. Due to high shear forces, they are effective for high viscous solutions, e.g., syrups,
glycerine, etc.
2. They are suitable for liquids of large volume and high viscosity.

Merits
1. They provide greater shearing forces than propellers, So the pumping rate is less;
therefore, are suitable for emulsification.
2. They do not damage dispersed particles at economical speeds.

Demerits
1. Due to the absence of vertical flow, they are less suitable for suspension.
2. They are expensive to fabricate, and are restricted to a narrow range of speeds.
3. They are expensive.

Silverson Mixer Homogeniser

Silverson emulsifiers used for mixing or homogenising coarse particles in the emulsion and
suspension to the fine form of reduced particles. Its capacity ranges from 1ml to 12lt, and its
ability to mix in-line with flow rates is up to 20lt/min.

Principle
1. Silverson emulsifier works on the principle of shearing forces and turbulence
produced by the high-speed rotors.
2. The fluid passes through fine spaces formed by closely placed perforated metal sheets
under the influence of turbulence.
3. The material circulates through the head by the suction produced in the inlet at the
head bottom.
4. As the material circulates, the dispersed fluid rapidly breaks down into smaller
globules

Construction
1. Silverson emulsifier consists of long supporting columns connected to a motor
providing support to the head.
2. It has a centrally located shaft with one end connected to the motor and the other end
connected to the head.
3. Turbine blades are present in the head.
4. These blades are surrounded by a mesh enclosed by a cover having openings

Working
 34

1. The head of Silverson emulsifier is placed in the vessel (containing immiscible fluid
or coarse emulsion) in such a way that it gets completely immersed in the fluid.
2. On starting the motor, the central rotating shaft rotates the head at a very high speed,
which further rotat pressure difference.
3. As a result, fluid in the centre of the base is sucked into the head and subjected to
intense mixing action.
4. The contents of the head are forcefully expelled through the mesh a cover by the
centrifugal forces. A fine emulsion is obtained through the openings of the outer
cover.
5. This intake and expulsion of mixture set up (such a circulation pattern) rapidly breaks
the bigger globules into smaller ones

Silverson Mixer Homogeniser

Application
 It is used for mixing creams, ointments, sauces, flavouring emulsions, and
pharmaceutical suspensions of globule or droplet size ranging from 2-5u.

Merits
1. It is available in different sizes, thus making handling of liquids ranging from a few
millilitres to several thousand litres possible.
2. lts mixing action reduces the processing time and also reduces the mixing time by up
to 90%.
Demerit
 35

1. It may clog pores of mesh.

2. It consumes high operating power.
3. It requires high shear force

Triple Roller Mill

Triple roller mill is used for mixing semisolids while preparing ointments, creams, pill
masses and wet mass for making granules, etc.

Principle
1. The material experiences a high shear developed by the differential speed and the
narrow space between the rollers.
2. Under the influence of this shear, aggregates and particles get crushed, and also the
drug gets distributed uniformly throughout the semi-solid base.

Construction
1. A triple roller mill consists of three rollers of equal diameters and made up of hard
abrasion resistant material (stainless steel usually).
2. These rollers are arranged parallelly, and are horizontally fixed to a rigid frame.
3. The pressure and gap between the rollers can be adjusted.
4. A hopper is fixed between the first two rollers, and the last roller has a scrapper
attached to it.

Triple Roller Mill

Working
1. The last two rollers are adjusted such that the distance between them is less than the
distance between the first two rollers.
2. The first roller is the receiving -roller, which rotates at a speed slower than that of the
second roller, which itself rotates at a speed slower than that of the third roller, which
is the discharge roller.
3. The feed introduced is made to pass through the gap between the first and second
rollers.
 36

4. The aggregates and particles are crushed and abraded by the rubbing action of the
rollers; this action develops due to different rotation speed.
5. A film of the feed of desirable thickness is produced.
6. The feed introduced passes from the slow rotating roller to the fast rotating one.
7. The gap between the second and third roller is small, thus a thinner film of feed is
produced Speed of the third roller can be increased to compensate the reduction of
cross-sectional area.
8. Finally, the material removed by the scrapper from the last roller is collected in a
receiver or transported through a suitable conveyor.

Application
1. It is used for mixing solid powders with an ointment base.

Merits
2. It is used in pharmaceutical industries for preparing uniform dispersion of the
semisolid drugs and bases.
3. It is also used in continuous processes for preparing semisolid dosage forms.

Demerits
1. It is not suitable for liquid material whose viscosity is 5 Pa/Sec, such as glycerine,
castor oil, etc

Filtration

1. The process in which a heterogeneous mixture of a fluid and solid particles is

separated by a filter medium which permits the passage of fluid but retains the solid
particles, is termed filtration.
2. Oversize solids in the fluid are retained but the separation is not complete as filtrate
may be contaminated with solid particles smaller in size than pore size of filter media.
The suspension of solid or liquid to be filtered is known as slurry.
3. The porous medium used to retain the solids is known as filter medium.
4. The accumulated solids on the filter media are referred to as filter cake, while the
clear liquid passing through the filter is the filtrate.
5. Filtration is also used to separate particles and fluid in a suspension where the fluid
can be a liquid, a gas, or a supercritical fluid.
6. Depending on the application either one or both of the components may be isolated.

Objectives
1. It aims to clarify liquor purification.
2. It aims to separate the solids recovered.
3. It aims to separate both the liquids and solids recovered.
4. It aims to facilitate or improve other plant operations.

Applications
1. It is used for improving the appearance of various pharmaceutical preparations like
solutions, mouthwashes, etc.
2. It is used for removing potential irritants; for example, various irritants are removed
from eye drops or solutions used on mucous membrane.
 37

3. It is used for removing the turbid products obtained after various unit operations for
example, filtration is performed to separate the turbid product with a small quantity of
fine suspended colloidal matter obtained by the extraction of vegetable drugs with a
solvent.
4. It is used for detecting microorganisms present in liquids by using a filter which
retains the bacteria. The efficiency of preservatives can also be evaluated by this
method.

Theories
1. The liquid flowing through a filter follows the basic rules governing the flow of any
liquid through a medium which offers resistance.
2. The rate of flow 1s expressed as:
Rate = Driving force / Resistance
3. Theory of filtration can be explained by the following equations:
 Poiseuille's equation,
 Darcy's equation, and
 Kozeny-Carman equation

Poiseuille's Equation
 According to Poiseuille, filtration is similar to the streamline flow of a liquid under
pressure through capillaries, thus Poiseuille's equation is expressed as:

Where,
 V= Rate of flow, i.e., liquid volume flowing in unit time (m3/s)
 P= Pressure difference across the filter media (Pa)
 r= Radius of the capillary in filter bed (m)
 L= Thickness of the filter cake (m)
 = Viscosity of the filtrate (Pa S)

 If a bulky mass of particles forms a cake and the liquid flows in between he spaces
(correspond to a multiplicity of capillary tubes), the flow of liquids is expressed by
the Poiseuille's equation.

Darcy's Equation
 Poiseuille's equation considers that non-uniform and highly irregular capillaries are
present in the filter. So, if the capillary length is assumed to be the bed (filter medium)
thickness, a correction factor for radius is applied to approximate and simplify the rate
equation.
 Therefore, Darcy incorporated the factor influencing the filtration rate into an
equation which is expressed as:

Where,
 V= Volume of liquid flowing in unit time (m3 /s)
 K=Permeability coefficient of the cake (m2)
 A = Surface area of the porous bed (m2)
 38

 P = Pressure difference across the filter (Pa)

 = Viscosity of the filtrate (Pa. S)
 L=Thickness of the filter cake (capillary length) (m)
Kozeny-Carman Equation
 Poiseuille's equation is applicable to porous bed, based on a capillary type structure
and other parameters. Thus, Kozeny- Carman equation is expressed as:

Where,
 A = Area of filter medium
 S = Specific surface area of the particles comprising the cake (m2/m3)
 P = Pressure drop across the filter medium and the filter cake.
 K = Kozeny constant
o  =Porosity of the cake (bed) Since the flow rate and 3/(1-)3 are directly
proportional, 10% change in porosity can change V up to 3-folds.

Factors Affecting Filtration

1. Pressure
2. Viscosity
3. Surface area of Filter Media
4. Temperature
5. Particle Size
6. Thickness of Cake
7. Characteristics of slurry

Filtration Equipment
1. In the bulk drug industry, solid is the desired product.
2. Its Size, physical properties, and purity are important.
3. A filter is a device (usually a membrane or layer) that is designed to physically block
certain objects or substances while letting others to pass through.
4. Filters are often used to remove solid substances suspended in fluids

Sintered filters
 Sintered filters consist of a filtering medium made up of jean or Pyrex ground glass
particles fused in the form of a disc by heating to its sintering point.
 The liquids pass through the spaces existing between the fused particles.
Applications
1. These are used for coarse, fine, and bacterial filtration.
2. These are used for parenteral injection, ophthalmic solution, and solution of potent
drugs.

Merits
 39

1. They are easily cleanable.

2. No foreign body can enter the filtrate
3. A very small amount of medicament is absorbed
4. Negligible volume of filtrate is retained in the medium.

Demerits
1. They are expensive.
2. They cannot be used for large volume as it provides a small area of filtration.
3. They are fragile.

Membrane Filters
Membrane filter consists of microporous plastic films of specific pore sizes; therefore, it is
also known as screen, sieve, or microporous filter.
Membrane present in these filters retains particles or microorganisms (larger than the pore
size) by surface capture.

Principle
 Membrane filter functions like a sieve and traps the particles on its surface.

Construction
1. Membrane filter consists of membranes of cellulose acetate, cellulose nitrate on
mixed cellulose ester.
2. The pore size of filter is in the micron or submicron range. Many grades of membrane
filters are available with pore sizes ranging from 0.010  1.2u).

Working
1. The membrane filter functions like a sieve and thus removes particles.
2. The filter of 0.010-0. 10u pore sizes remove even viruses from water or air, and filter
of 0.30 0.65u pore sizes remove bacteria.
3. Filter with largest pore sizes (0.8, 1.2, 3.0-5u) is used in aerosol radioactivity and
particle sizing applications.

Applications
1. It is used for enhanced recovery of particular gram- positive organisms.
2. It is used for filtration of enzyme solution.
3. It is used for diagnostic cytology.
4. It is used for receptor binding studies.
5. It is used as a clarifying filter.

Merits
1. It does not allow bacterial growth.
2. It can be easily disposed of.
3. It does not allow any cross-contamination.
4. Since adsorption is negligible, it does not impart any fibres or alkali into the filtrate.
5. Its filtration rate is rapid.
 40

Demerits
1. It may get clogged.
2. If ordinary, it is less resistant to solvents like chloroform.

Drying

1. The process in which water and other solvents are removed from a substance by
applying heat is called drying.
2. Removal of liquid from the solids can be done either mechanically (by using filter
press or centrifuge) or thermally (by vaporisation).
3. The mechanical method is more favourable and Inexpensive compared to the thermal
process. Hence, before drying, the amount of liquid must be reduced to minimum.
Objective
1. It decreases food decomposition caused by the moisture present.
2. It prevents decomposition by the microbes so the product can be used for longer
duration.
3. It is used for reducing transportation and storage cost by reducing bulk and weight.
4. Manufacturers get more benefit because dried goods of superior quality will also have
more market value.
5. It aids in granule formation.
6. It is used in material processing, while preparing spray-dried lactose, dried aluminium
hydroxide, and also in scale preparation of ferric ammonium citrate.
7. It enables size reduction.
8. It prevents bacterial and mould growth, thus increases product stability.
9. In dry state, some substances like aspirin, penicillin, ascorbic acid, etc. are stable.

Application
1. Preparation of Bulk Drugs:
2. Preservation of Drug Products:
3. Improved Handling:
4. Reduction transportation cost:
5. Easy Handling and Storing:
6. Provides Properties:

Factors Affecting Drying

1. Particulate Diameter
2. Mechanism Involved in Drying Operation
3. Size Uniformity
4. Physical Properties of Wet and Dry Solid Particles
5. Product mass flow rate.

Equipment Drying
1. Dryers are classified on the basis of the material being dried, i.e., solids, pastes, and
solutions.
2. Some of the commonly used dryers discussed below are;
 Fluidized bed dry,
 Freeze dryer.
 41

Fluidised Bed Dryer

 When a solid material present in a holding vessel is placed under suitable conditions
for the solid/fluid mixture to act as a fluid, a fluidised bed is formed.
 This is possible by exposing the material to pressurised fluid.

Principle
1. In fluidised bed dryer hot air or gas (at high pressure) is introduced within a container
through its perforated bottom.
2. The container is filled with granules to be dried.
3. The gas introduced lifts up the granules from the bottom and suspends them in the air
stream, thus, resulting in a fluidised state.
4. This dryer is useful for uniform drying of the material as the hot gas surrounds all the
granules completely.

Construction
1. Vertical fluid bed dryer and horizontal fluid bed dryer are the two types of bed dryers.
2. A vertical fluidised bed dryer is made up of stainless steel or plastic.
3. At the bottom of the dryer, a detachable bowl used for charging and discharging is
present.
4. This bowl has a perforated bottom with a wire mesh which supports the materials to
be dried.
5. The upper part of the dryer is equipped with a fan for circulating hot air.
6. The air is heated up to the desired temperature with the help of fresh air inlet, pre-
filter, and heat exchanger connected in a series.
7. Temperature of the air at the inlet and outlet are monitored. Filter bags are placed
above the drying bowl to recover the fines.

Fluidised Bed Dryer

Working
 42

1. The wet granules to be dried are put in the detachable bowl, which is then placed into
the dryer.
2. The fresh air introduced is allowed to pass through a pre-filter, and then through a
heat exchanger after which it gets heated.
3. The hot air flows through the bottom of the bowl and the fan is allowed to rotate.
4. Velocity of the air is increased gradually and when it exceeds the settling velocity of
granules, the granules remain partially suspended in the gas stream.
5. At a point of pressure, the frictional drag on the particles equals the gravity force.
6. At this point, the granules rise in the container because of high velocity gas (1.5-
7.5m/min) and then fall back in a random boiling motion. This condition is the
fluidised state.
7. The hot air completely dries the material by surrounding each and every granule.
8. The air passes through the filter bags and exits the dryer.
9. The particles trapped in the filter bags remain adhered to their inside surface which
can be removed by shaking the bags at frequent intervals.
10. Intense mixing of granules and hot air give uniform conditions of temperature,
composition, and particle size distribution.
11. Drying is achieved at a constant rate and a short falling rate period.
12. The residence time for drying is 40 minutes.
13. The material reaches the ambient temperature when left for some time in the dryer.
14. Thereafter, the bowl is pulled out for discharging the free-flowing end product.

Applications
1. It is used for drying granules to be punched into tablets.
2. It is used for mixing, granulation, and drying.
3. It is used for coating granules.
4. It is used for mixing ingredients.

Merits
1. It is less time-consuming and is 15 times faster than the tray dryer (as it takes 20-40
minutes for drying in comparison to tray dryer which takes 24 hrs).
2. Its handling of material is simple and demands reduced labour as the drying
containers are mobile.
3. It is available in different sizes with 5-200kg/hrs drying capacity.
4. Its mixing efficiency is high.
5. Its temperatures for drying can be higher than that of the tray dryer and truck dryer.
6. It occupies a small floor space.

Demerits
1. Drying of organic powders results in electrostatic charges which can be avoided by
electrical earthening of the dryer.
2. Fine particles get entrapped, therefore, should be collected using filter bags.

Freeze Dryer

 The freeze drying involves freezing of the material and then warming in a vacuum so
that the ice sublimes.
 This method is used for drying food, blood plasma or tissues, and pharmaceuticals
without affecting their physical structure.
 43

Principle
1. The principle of freeze drying involves removal of water from the frozen material by
Sublimation.
2. The experimental conditions required for freeze drying can be decided by the solid-
liquid-vapour equilibrium phase diagram of water.
3. Exposing the material to temperature and pressures the below the triple point, results
in drying.
4. Under these Conditions, the heat transferred is used as latent heat and ice sublimes
(i.e., changes to vapour state directly).
5. The water Vapour is removed by condensation in a cold trap maintained at a
temperature lower than the frozen material.
6. Freeze drying is also known as lyophilisation Which means that for the removal of
solvent, the system is made solvent loving.
Construction
Freeze dryer consists of the following parts
1. Drying chamber for loading trays,
2. Radiation source or heating coils for supplying heat,
3. Vapour condensing or adsorption system, and
4. Vacuum pump, or steam ejector, or both.
 The vacuum chamber (suitable for batch operation. The batch operation) consists of
shelves for loading the material to be freeze dried.
 The distance between the subliming surface an and condenser should be less than the
molecules' mean path, thus, increasing the drying rate.
 The condenser has a large surface area, which is cooled by solid carbon dioxide
slurred with acetone or ethanol.
 The condenser temperature should be less than the evaporated surface of frozen
material.
 This condition can be maintained by frequent cleaning of the condenser surface.

Application
1. It is used for manufacturing injections, solutions, and suspensions.
2. It can be also be used for drying:
3. Blood plasma and its fractionated products.
4. Bacterial and viral cultures,
5. Human tissue (arteries and corneal tissue),
6. Antibiotics and plant extracts, and
7. Steroids, vitamins, and enzymes.
8. Food items like prawns, mushrooms, meat and poultry products, coffee and tea
concentrates, and citrus fruit juices can also be dried.

Merits
1. It is used for drying thermolabile materials.
2. The porous and uniform product obtained retains its bulk volume as reconstitution of
the material is easy.
3. Product denaturation does not occur.
4. Migration of salts and other solutes does not occur.
5. Less volatile material is lost.
 44

Demerits
1. Equipment and running costs are high.
2. Solutions containing non-aqueous solvents cannot be dried by this method
3. It is a time-consuming process (it takes around 10 hours) and the time cannot be
shortened.

Extraction
The process of separating medicinally active constituents of plant and animal tissues with the
help of selective solvents and standard procedures is termed extraction.

Methods of Extraction
Extraction of crude drugs can be carried out by various processes, and the selection of
process depends on the chemical properties of the drug's active constituents.

Various extraction methods employed are:

1. Maceration,
2. Digestion, and
3. Percolation

Maceration
The word maceration denotes softening. The maceration process (or Process M) is used for
producing tinctures, extracts, and concentrated infusions.  It is the simplest method of crude
drug extraction, which was official in I.P., 1966.

Classification
1. Simple Maceration: A method for preparing tinctures from organised drugs, e.g.,
roots, stems, leaves, etc.
2. Modified Maceration: A method for preparing tinctures from unorganised drugs, eg.,
oleo-resins and gum resins.
3. Multiple Maceration: A method for preparing concentrated extracts. This method
includes:
 Double maceration,
 Triple maceration.

Simple maceration
 Simple maceration involves extraction of organised drugs having specific cell
structures, e.g., roots, stems, leaves, flowers, etc.
 It is a very simple method and does not require trained operators.
 Tincture of myrrh and compound tincture of benzoin are examples of products
prepared by simple maceration.

Principle
1. In simple maceration, solid ingredients and the solvent are taken in a stoppered
container, and left undisturbed for at least 3-7 days with frequent agitation.
 45

2. When the soluble matter dissolves in the solvent, the resultant mixture is passed
through sieves or nets.
3. The marc retained in the sieves is pressed, the liquids are combined, and filtered or
decanted after standing.

Apparatus
 Simple maceration is performed using a wide mouthed bottle or any other container
which can be closed tightly to prevent evaporation of the menstruum.

Procedure
 In simple maceration, the crude drug to be extracted and the menstruum are placed in
close contact in a closed vessel for 7 days with frequent agitation. After 7 days, the
resultant mixture is strained through sieves, the marc retained is pressed, the liquids
are combined, and filtered. The drug should be properly commented.
 The menstruum penetrates the cellular structure of drug, and softens and ultimately
dissolves the soluble dissolves portions.
 A closed vessel is used for preventing menstruum loss by evaporation.
 Occasional shaking is recommended to maintain a rapid equilibrium between the
intra- and extra-cellular fluids.
 The degree of pressing the marc may vary, thus the final product is not adjusted to a
fixed volume.
 Simple maceration process may take around 14 days to complete.
 The ratio of drugs to menstruum should be 1:10.
 When the drug and menstruum are left undisturbed, sediment may form, which can be
avoided by standing the fluid product for a few days prior to use.
 Simple maceration method cannot be used for extracting all the drugs, thus other
maceration processes have to be employed.

Digestion
Digestion is a modified maceration process. It involves extraction at such a high temperature
which does not put adverse effects on the active ingredients. Higher temperature enhances the
solvent action of menstruum and constant mechanical agitation of the system speed up the
attainment of equilibrium. If at the used temperature the menstruum gets volatilised easily, a
reflux condenser should be attached to the vessel in which the digestion process is being
performed; this facilitates the condensation of menstruum, so that it can be recovered and
returned back to the container.
 46

Chapter 5
Pharmaceutical Dosage Forms

Tablets
Definition: Tablet may be defined as a solid unit dosage form, containing one or two drugs
with or without non-drug component called excipients or additives. Tablets are prepared
either by compression or moulding method. They may be either circular, flat or biconvex in
shape.

The ideal properties of a tablet

1. It should be attractive having its own identity and free from defects such as cracks,
chips, contamination, discolouration, etc.
2. It should have chemical and physical stability to maintain its physical integrity over
timey
3. It should prevent any alteration in chemical and physical properties of medicinal
agent.
4. It should withstand the rigours of mechanical shocks encountered during its
production, packaging, shipping, and dispensing.
5. It should release the medicament in the body in a predictable and reproducible
manner.

Advantages:
1. The tablets are easy to be administered.
2. They are easy to be dispensed.
3. These are more stable dosage forms.
4. They maintain the accuracy of dosage.
5. Bitter and nauseous substances can be given easily in tablet form after giving easily in
tablet form after giving a suitable coating to the tablets.
6. They are the lightest and the most compact of all dosage forms.
7. Tablets are easiest and the cheapest as regard packing and transport.
8. These are an economical dosage form.

Disadvantage:
1. Manufacturing of tablets needs labours and machines.
 47

2. The onset of action is slow compare to liquid dosage form.

3. Potent drugs are difficult to convert into tablets.
4. The bioavailability is less compared to liquids and parenterals.
5. The drugs which get decomposed by gastric juices and enzymes cannot be formulated
as tablets.
6. The drugs which are sensitive to light and moisture requires coating.

Production of Tablet
Tablets are manufactured by granulation technique which can be carried out by the following
three methods:
 Direct compression,
 Wet granulation, and
 Dry granulation.

Direct compression
Crystalline substances (e.g., sodium chloride, sodium bromide, and potassium chloride) are
directly Compressible.
Most of the medicinal agents cannot be easily formulated into tablets; however, compressing
single substance can form tablets which do not disintegrate.
The materials to be directly compressed should have the following properties:
1. Good flowability,
2. Compressibility
3. Inert,
4. Tasteless,
5. Able to disintegrate, and
6. Economical.
 48

Merits
1. This method results in increased output,
2. It is of low cost,
3. It requires less machinery,
4. It increases the stability of drug
5. It involves rapid drug dissolution
6. It experiences less wear and tear of punches, and
7. It involves simplified validation.

Demerits
1. In this method, segregation problems occur in weight variation and content uniformity
2. Since the directly compressible excipients are expensive, the tablet cost also rises.
3. The active material is 30-40% as the requirement of excipient, thus the tablet is
swallowed by the patients with much difficulty.
4. The method is not suitable for drugs with poor flowability or low bulk density.

Dry Granulation
 In dry granulation process, the powder mixture is compressed without the use of heat
and solvent.
 The two basic procedures are to form a compact of the material by compression and
to mill the compact to obtain granules.
Some of the dry granulation methods
1. Pressing
2. Extruding
3. Tumbling
4. Fluidising
5. Slugging Process
6. Roller Compaction.

Merits of Dry Granulation Technique

1. It uses less equipment and space.
2. It does not require binder solution and heavy mixing equipment.
3. The costly and time-consuming drying step required for wet granulation is also
avoided.
4. It is suitable for moisture- and heat-sensitive materials.
5. Tablets with improved disintegration are produced as powder particles are not bonded
together by a binder.
6. Solubility of the drug is also improved.

Demerits of Dry Granulation Technique

1. It requires a specialised heavy-duty tablet press to form the slug.
2. It does not permit uniform colour distribution.
3. It creates more dust than wet granulation thus increasing the potential contamination.
 49

Wet Granulation
 The most widely used process of agglomeration in pharmaceutical industry is wet
granulation.
 This process simply involves wet massing of the powder blend with a granulating
liquid followed by wet sizing and drying.

Important steps involved in the Wet granulation are:

1. Mixing the drug(s) and excipients,
2. Preparing the binder solution,
3. Mixing the binder solution with powder mixture to form a wet mass.
4. Coarse screening the wet mass using a suitable sieve (sieve no. 6-12).
5. Drying the moist granules,
6. Screening the dry granules through a suitable sieve (sieve no. 14-20).
7. Mixing the Screened granules with disintegrate, glidant, and lubricant, and
8. Compressing the mixture into tablet.

Special Wet granulation Processes are:

 High Shear Mixture Granulation
 Fluid Bed Granulation
 Extrusion and Splenisation
 Spray Drying Granulation.

Merits of Wet Granulation Technique

1. High dose drugs having a poor flow or compressibility properties can be prepared.
2. The soluble low dosage or potent drugs can attain uniform distribution and content.
3. Colour distribution also occurs evenly.
4. It prevents the segregation or separation of components of a homogenous powder
mix.
5. The dissolution rate of hydrophobic drugs is improved.

Demerits of Wet Granulation Technique

1. It is an expensive process because of the labour, time, equipment, energy, and space
requirements.
2. Loss of material occurs during various stages of processing.
3. Heat-sensitive drugs also cannot be processed as it involves drying steps.
4. Multiple processing steps add complexity and make validation and control difficult.

Coated Tablet
 Tablet coating is the process where coating material is applied to the surface of the
tablet to achieve the desired properties of dosage form over the uncoated variety.
 The advantages of coating are listed below.
1. Improving taste, odour, and colour of the drug.
2. Improving ease of swallowing by the patient.
3. Improving product stability.
4. To protect against the gastric environment.
5. To improve mechanical resistance of the dosage form.

Uncoated Tablet
 50

 Uncoated tablets are generally single-layer tablets prepared by a single compression

of granules or multi-layer tablets consisting of parallel layers prepared by
compression of granules of different compositions. No treatment is given to such
tablets after compression.

Difference
 Tablets can be either coated with a sugar or film coating, or uncoated. Uncoated
tablets are rougher, may be more difficult to swallow, and often leave a bad taste in
the mouth when swallowed. A coated tablet generally goes down easier and with less
aftertaste.

Various Modified Tablets

Sustained Release Tablets
 The drug delivery system that is intended to attain a prolonged therapeutic effect by
releasing the medication continuously over an extended period of time once a single
dose is administered, is termed as sustained release.
Manufacturing
1. Wet Granulation
2. Dry Granulation
3. Direct Compression

Advantages
a. Minimum drug is used.
b. The efficacy in the treatment gets improved
c. It avoids patient compliance problems
d. The local, systemic side effects are minimised.
e. Less fluctuation occurs in the concentration of drug

Disadvantages
a. Therapy cannot be terminated in case of any side effects.
b. Expensive
c. Dose dumping
d. Poor systemic availability.

Extended Release Tablets

 Extended-release medications are gradually released into the body over a period of
time (12 or 24 hours).
 Usually they are available in the form of an oral tablet or an oral capsule.
 These medications do not release the content immediately.
Extended-release medications offer several advantages which include, but are not
limited to, the following:
i. They are not taken frequently.
ii. They cause fewer side effects.
iii. They cause less fluctuation in blood levels.
iv. They are completely absorbed.

Fast Dissolving Tablets

 51

 After coming in contact with saliva, they disintegrate and dissolve to release the drug,
thus, eliminating the need of water during drug administration.
 Tablets dissolving completely within a few seconds are true fast-dissolving tablets.
 Fast-disintegrating tablets may take about a minute to disintegrate completely.

Manufacturing
1. Freeze-Drying or Lyophilisation
2. Tablet Moulding
3. Solvent Method
4. Heat Moulding

Advantages
i. They can be easily administered to patients who cannot swallow (elderly, stroke
victims and bedridden patients), who should not swallow (renal to swallow fa failure
patients), and who refuse (paediatric, geriatric, and psychiatric patients).
ii. They show patient compliance for disabled bedridden patients, for travellers, and busy
people who do not have ready access to water.
iii. They can be administered conveniently with accurate dosing in comparison to liquid
formulations.
iv. They provide advantages of liquid medication in the form of solid preparations.

Double Layered Tablets

 Bilayer tablets can be a primary option for avoiding tabletting chemical
incompatibilities between API by physical separation, and to allow the development
of different drug release profiles (immediate release with extended release).

Manufacturing 
1. OROS Push Pull Technology.
2. L-OROS tm Technology.
3. EN SO TROL Technology.

Advantages
1. They are unit dosage forms and deliver the utmost capabilities of all oral dosage
forms for the maximum dose accuracy and the minimum content variability.
2. Not expensive in comparison to all other oral dosage forms.
3. Lighter and compact.
4. Easiest and cheapest in packing and striping.
5. Can be swallowed easily with least tendency for hanging
6. Coating can be done to cover the objection able odour and bitter taste of the drug.

Disadvantages
1. Children and unconscious patients may face difficulties in swallowing.
2. Some drugs resist Compression into dense Compacts, due to amorphous nature and
low-density character.
3. It can be difficult to formulate drugs having poor wetting, slow dissolution properties,
optimum absorption and high in GIT as a tablet because they can deliver adequate or
full drug bioavailability.

Capsules
 52

 Capsules are solid dosage forms in which one or more medicinal and inert ingredients
are enclosed in a small shell usually made up of gelati.
 They are of various shapes and sizes, and contain a single dose of one or more active
pharmaceutical ingredients.
 Capsules are also defined as "gelatine or methylcellulose shell designed to hold solids
and liquids for oral administration'.
 There are two types of capsules, hard and soft.

HARD GELATIN CAPSULES

 Hard capsules have a rigid shell in two separate pieces fitted together, hence are also
called two-piece capsules.
 There was a time when two-piece capsules could be filled the time, only with dry
powders; but over the time, the manufacturers began filling capsules with pellets,
granules, pastes, and liquids.
 Since hard capsules can be with substances in a variety of f versatile than soft gels.

The material types which can be filled into hard gelatine capsules are:
 Dry Solids: Powders, pellets, granules, or tablets.
 Semi-Solids: Suspensions or pastes.
 Liquids: Non-aqueous liquids

The large-scale or Small-Scale preparation of filled hard gelatine capsules is divided

into the following general steps:
i. Formulation development and selection of capsule size,
ii. Manufacturing of hard gelatine capsule shells,
iii. Filling of hard gelatine capsule shell
iv. Sealing of hard gelatine capsules, and
v. Cleaning and polishing of filled.

Merits
i. They have a greater bioavailability in comparison to tablets.
ii. Their drug releasing rate is much faster because of high solubility of gelatine shell.
iii. They provide high degree of flexibility for formulations.
iv. Their manufacturing is simple.
v. They involve less production steps.
vi. They undergo less analytical tests.

Demerits
i. It is very difficult to ingest hard gelatine capsules containing very large doses of drug.
ii. Drugs prone to dissolve the capsule shell cannot be dispensed in these capsules.
iii. These capsules are also not suitable to dispense highly soluble salts (iodides,
bromides, and chlorides).
iv. These capsules involve rapid release of medicaments, thus, may result in gastric
irritation due to high drug concentration in localised areas.

SOFT GELATIN CAPSULES

 Soft capsules or liquid gel caps are formed from liquid gelatine which is later
hardened in a humid environment.
 Soft gel capsules are one continuous piece of gelatine.
 53

 Soft capsules have thicker shells than hard capsules, and contain antimicrobial
preservatives,
 The shells are available in various shapes and sizes.
 The contents of soft capsules are usually solutions or Suspensions of the API(s) in
non-aqueous liquid.

Merits
i. They can be used for dispensing solids, liquids suspension, emulsions, volatile oils,
semisolids, etc.
ii. Their disintegration is faster than that of hard gelatine capsules and tablets.
iii. They are available in various sizes and shapes.
iv. They can be easily swallowed as compared to hard gelatine capsules.

Demerits
i. They cannot be used for dispensing hygroscopic, effervescent, and deliquescent
drugs.
ii. They cannot be used for dispensing acidic drugs ketones, and aqueous products.
iii. They cannot be used for dispensing drugs that cause stomach irritation.

Liquid Oral Preparations

 Solutions, syrups, suspensions, elixirs, and concentrates are oral liquid dosage forms.
 These dosage forms offer exclusive advantages to numerous patients.
 For example, in patients facing problems in swallowing oral solid dosage forms,
liquids offer better compliance for the patients and also provide enhanced dosage
control against a fixed dose of tablet.

Advantages
i. It is easier to swallow liquids than solids, thus these dosage forms are more
satisfactory and suitable for paediatrics and geriatrics.
ii. Solutions get absorbed easily, thus, producing therapeutic response at a faster rate
than the solids (which first disintegrates and then getting absorbed from the
gastrointestinal fluid).
iii. In case a drug precipitates from the solution form under acidic conditions of the
stomach, it will become moist and will divide into fine particles, allowing rapid
absorption.
iv. The drug in solutions is uniformly distributed; where’s in suspensions or emulsions,
dose variation may Occur resulting from phase separation during storage.
v. If a drug is administered in a solution form, gastric irritation is reduced as it
immediately gets diluted by the contents present in the gastric area.

Disadvantages
i. The transportation and storage of liquids are problematic, as they are bulky.
ii. Growth of microorganisms is supported by liquid media; thus, the preparation needs a
preservative to be incorporated within it.
iii. Dose inaccuracy may occur if a patient takes a dose using household devices, like a
teaspoon, etc.
iv. These dosage forms also have flavouring and sweetening properties.
v. The dissolved substances in the liquids may result in incompatible interactions.

Classification
 54

Liquids

Monophas Biphasic
ic

Aqueous Non-Aqueous Emulsions Suspensio

Internal External ns
Syrups, Elixirs, Lotions, Mouthwash,
Drops Eye & Ear
MONOPHASIC LIQUID DOSAGE FORMS
 Monophasic Liquid Dosage Forms: These dosage forms comprise of a single
homogeneous phase, e.g., solutions, waters, tinctures, etc.
 Biphasic Liquid Dosage Forms: These dosage forms comprise of two discrete phases,
e.g., emulsions and suspensions.

Solution
 Solution can be defined as a homogeneous system made up or a phase containing two
or more components.

The two components of a solution are:

a. Solvent: It is the phase in which dispersion occur.
b. Solute: It is the phase which is dispersed in the form of molecules or small ions in the
solvent.

Characteristics
1. In any formulation both the phases should be uniformly distributed and clear in
composition.
2. The preparation should remain stable before the expiry period.
3. No irritant or toxic effect should be produced by it to the human body.
4. Suitable additives should be present in the product to provide a better patient
compliance.
5. During the storage of the solution for a specific period of time, it should not get
precipitated or show any type of discolouration.

Advantages
i. Drug absorption is rapid.
ii. Being a liquid dosage form they can be swallowed conveniently than the solid dosage
form.
iii. They are a homogeneous system as the drug in the solution remains uniformly
distributed throughout the formulation.
iv. They do not cause damage and irritation to GIT (often caused by tablets or capsules).

Disadvantages
i. Their transportation is not easy because the liquids are bulky in nature.
ii. Loss of complete preparation occurs if during transportation the container breaks.
iii. Their shelf-life is shorter than tablets or capsules.
iv. The stability of drugs in aqueous solution is less than those in solid dosage forms.
 55

v. Dose accuracy in liquid dosage forms is less than in solid dosage forms.

Syrups
A saturated solution of sucrose formed in purified water with the concentration of 66% w/w
sugar is known as simple syrup.

Classification
1. Simple Syrups: These syrups are made up of simple solutions or are admixture of
solutions. Examples of simple syrup include syrups (I.P.), ginger syrup, orange syrup,
and lemon syrup.
2. Preparation: Sucrose is added to the purified water and heated with occasional
stirring until the sucrose gets dissolved. The solution is then cooled and sufficient
purified water is added to make up the desired weight.
3. Medicated therapeutic agents: Examples of medicated syrups: These syrups include
are chlorpheniramine maleate syrup, ephedrine sulphate syrup, etc.
4. Flavoured Syrups: These syrups comprise of different flavoured or aromatic
substances which give a pleasant smell and taste. These are usually added to the
preparation for providing a flavour, as a preservative, or as a vehicle. It does not
contain any pharmacological activity.
Preparation
1. Hot Process
2. Percolation (cold process)

Elixirs
 Elixirs are defined as clear, sweetened, aromatic, hydroalcoholic liquids intended for
oral use.
 Elixirs are less sweet and less viscous than syrups and may contain less or no sucrose.
 Elixirs are clear preparation and drugs in liquid from to be administered orally.

Classification
1. Non-Medicated Elixirs: Such elixirs do not contain a medicament and are employed
as not flavouring vehicles, e.g., aromatic elixir U.S.P., iso alcoholic elixir NF,
compound benzaldehyde elixir as NF, etc.
2. Medicated Elixirs: These elixirs are employed for the therapeutic action of the
medicinal substances they contain, e.g., chlorpheniramine maleate elixir U.S.P,
diphenhydramine hydrochloride elixir U.S.P., piperazine citrate elixir, terpine hydrate
elixir, etc.

Preparation
The preparation method for elixirs is the simple dissolution method involving the following
the following steps:
1. In this method, either an admixture of two or more liquid components is used or the
components are dissolved by agitation.
2. The ingredients are dissolved in the respective Solvents, for example, water is used as
a solvent for the water-soluble ingredients, and alcohol is used as a solvent for the
alcohol soluble ingredients.
3. Always the aqueous solution is added to the alcoholic solution for maintaining the
ideal alcoholic Strength and preventing the separation of alcohol.
 56

4. The desired volume is adjusted during the vehicle or solvent specified in the
formulation.
5. At this point, reduction in alcoholic strength is noted which leads to the separation of
a few noted flavouring agents, thus, the product may not be found clear.
6. In such a case, the elixir preparation is kept aside for some time so that the hydro-
alcoholic solvent saturates resulting the cluster of globules.
7. Filtration facilitates the removal of these globules.
8. To absorb the excess oil and removing it from the elixir solution, up to 3% of talc is
used.
9. Filtration yields a bright and clear product.
BIPHASIC LIQUIDS
 Liquid preparations having two phases are termed as biphasic liquids.
 These preparations essentially require a dispersed phase and a dispersion medium in
order dissolve many insoluble solid and liquid medicaments that are either insoluble
in or immiscible with water (mostly used as a vehicle).

Following are the examples of biphasic liquid dosage forms:

1. Emulsions: These are biphasic liquid preparations of two immiscible liquids, with
one liquid dispersed in the other liquid (continuous phase) in the form of globules.
2. Suspensions: These are biphasic liquid preparations in which the finely divided drug
particles (with minimum solubility) are uniformly dispersed throughout the vehicle.

Suspensions
 Suspensions are biphasic liquid preparations containing finely divided 0.5-5 u solid
drug particles (discontinuous phase).
 Suspensions are intended for oral administration, external application, or parenteral
use.
 A coarse dispersion in which insoluble solids are suspended in a liquid medium is
termed as a pharmaceutical suspension.
 In suspensions, water or water-based vehicle are normally used as a liquid medium, in
which the insoluble solids (size ranging from 10-1000um) are suspended.

Advantages
i. Stability
ii. Choice of Solvent
iii. Taste Masking
iv. Prolonged Action Dosage Forms
v. Bioavailability

Disadvantages
i. An accurate dose can be attained only if the suspensions are packed in unit dosage
forms. Thus, the potent drugs are not administered as suspension.
ii. Problems related to physical stability, sedimentation, and compaction of sediment can
occur. These problems cannot be solved easily.
iii. Oxidation and hydrolysis may affect the chemical stability of suspension.
iv. Suspensions are liquid dosage forms, therefore, are need to be protected against
microbial attack.

Types of Suspensions
 57

On the basis of their general classes:

1. Oral Suspensions: These are meant for oral administration in which one or more
insoluble medicaments are dispersed in the liquid vehicle.
2. Externally Applied Suspensions: These are meant for topical application.
3. Parenteral Suspensions: These are heterogeneous systems in which the solid phase
dispersed within a liquid phase.

Pharmaceutical Applications
The applications of suspensions are as follows:
1. They are used either for avoiding drug damage or for improving drug stability, e.g.,
oxytetracycline suspensions.
2. They are required to conceal the obnoxious taste of certain drugs, e.g.,
chloramphenicol palmitate suspensions.
3. They can be modified to control the drug absorption rate for parenteral administration,
e.g., penicillin procaine suspensions.
4. Some of the vaccines containing immunising agents are prepared as suspensions, e.g.,
cholera vaccine.
5. They can be formulated with drugs intended for topical use, e.g., calamine lotion.

Emulsions
A biphasic liquid preparation containing two immiscible liquids, one of which is dispersed as
minute globules into the other, is termed as a pharmaceutical emulsion.
The liquid in the form of minute globules is the dispersed phase, while the liquid containing
the dispersed globules is the continuous phase.

Advantages
i. The inedible oils can easily be administered as edible emulsions.
ii. The obnoxious taste of oils can be concealed.
iii. The flavouring of aqueous phase of emulsion is possible.
iv. They are more rapidly absorbed than the solid dosage forms.
v. Two incompatible ingredients can incorporate, with one in each phase.

Disadvantages
i. The manufacturing process of stable emulsions requires technical experts and
calculations of primary emulsion formulae.
ii. A measuring device is employed for administering emulsions.
iii. In case they are not shaken well before use, dose accuracy decreases in comparison to
solutions.
iv. The dispersion system may get affected if the emulsions are improperly stored.

Types of Emulsions
Depending on dispersed phase, emulsions can be categorised into:
1. Water-in-Oil (w/o) Emulsions:
2. Oil-in-Water (o/w) Emulsions:

Pharmaceutical Applications
 58

i. The o/w type emulsions are known to enhance the drug absorption through GIT.
ii. The nutrient oils that are difficult to swallow can be injected intravenously as
emulsions.
iii. Certain o/w emulsions like per-fluorinated hydrocarbons are used for oxygen
replacement therapy.
iv. Many water-soluble antigens and certain drugs are prepared as w/o type emulsions to
be given as depot injection (sustain and release).
v. Certain emulsions comprising different radio opaque elements can be used for
diagnosis.

Dry Powder for Reconstitution

Powders for oral suspension are preparations that include solid, loose, dry particles of
different degrees of fine particle size.
They are prepared as powder mixtures of typical ingredients required for an aqueous
suspension.

Types of powder for Oral Suspension

i. Unit Dose / Single Dose Powders for Oral Suspension.
ii. Multidose Powders for Oral Suspension.

TOPICAL PREPARATIONS
Ointments
 Ointments are semisolid formulations carrying medicaments and are designed for
topical application.
 The ointment should be of such consistency that it can be easily rubbed on the skin.
 The ointment base contains the medicament in solution suspension, or emulsion form
the vehicles used act as skin protective and emollient

Advantages
i. They are easy to handle than the bulky liquid dosage.
ii. They are chemically more stable than the liquid dosage forms.
iii. They are directly applied to the target area avoiding the other body parts.
iv. Patients sensitive to parenteral and oral routes prefer ointments.
v. The contact time between the medicament and the applied area is enhanced by
ointments.
vi. Drugs undergoing first-pass metabolism on oral administration are given as
ointments.

Disadvantages
i. They are bulkier than the solid dosage forms.
ii. They are less stable than the solid dosage forms.

Types of Ointments
1. Hydrophobic / Lipophilic
2. Water-Emulsifying Ointments
3. Hydrophilic Ointments

Preparation of Ointments
i. Trituration
 59

ii. Fusion
iii. Chemical Reaction
iv. Emulsification.

Pastes
 Pastes are one of the types of semisolid preparations intended to be used externally on
the surface of the skin, in order to provide a protective covering.

Preparation of pastes
i. Trituration method
ii. Fusion Method
Suppositories and Pessaries
 Suppositories are defined as medicated solid or semisolid dosage forms meant for
insertion into the body cavities like rectum, vagina, or urethral tract.
 When inserted into the body these dosage forms melt, disintegrate, or dissolve at the
body temperature.
 Pessaries are solid medicated preparations designed for insertion into the vagina
where thy melt or dissolve.

They are of the following three types:

1. Moulded Pessaries: These are cone-shaped and prepared in a similar way to moulded
suppositories.
2. Compressed Pessaries: These are of various shapes and are prepared by compression
similar to oral tablets.
3. Vaginal Capsules: These are similar to soft gelation oral capsules differing only in
size and shape.

Merits
i. Improved Enzymatic Drug Stability
ii. Avoidance of Hepatic First Pass Metabolism
iii. Higher Drug Load
iv. Lymphatic Delivery
v. Constant and Static Environment
vi. Patients with Swallowing Difficulty

Demerits
i. Patient Acceptance and Compliance
ii. Potential for Non-Specific Drug Loss
iii. Limited Fluid in Rectum
iv. Formulation
v. Expensive

Types of Suppositories
i. Rectal Suppositories
ii. Vaginal Suppositories (Pessaries)
iii. Nasal Bougies
iv. Ear Cones (Aurinaries).

Preparation of Suppositories
Suppositories can be prepared by any of the three methods:
 60

i. Hand rolling and moulding,

ii. Compression moulding, and
iii. Fusion moulding (hot process).

Liniments
 Liniments are the liquid or semisolid dosage forms applied with friction over
unbroken skin.
 They can also be applied on lint or any other suitable material which is then placed
should be scratch-free, or else uneven surfaced on the affected area.
 Liniments are either soap solutions or emulsions.
 Use of oil or soap base in the formulation facilitates the ease of application and
massage.

Preparation
 The nature of individual ingredients present in the formulation determines the method
employed for preparing liniments.
 Therefore, the methods used to prepare solutions, suspensions, or emulsions, can be
employed for preparing liniments also.

Lotions
 Lotions are liquid preparations intended to be applied externally on broken skin
without friction.
 They possess low to medium viscosity.
 They, are formulated as oil-in-water or water-in-oil emulsions.
 Absorbent material like gauze or a cotton wool is Soaked in lotions and then directly
applied over the affected skin.
 Lotions provide local cooling, soothing. actions as they are incorporated with or
protective alcohol.
 Some lotions provide antiseptic action, e.g., calamine lotion.
 Lotions are either applied directly on the skin or are applied on a dressing which is
further covered with a waterproof dressing, thus, reducing evaporation.

Preparation
The following methods are used to prepare lotions:
 High-speed mixers or homogenisers are used to triturate the ingredients and form a
smooth paste to which the leftover liquid phase is carefully added.
 For example, in calamine lotion the finely divided insoluble solids are held in
somewhat permanent Suspension, in the presence of suspending agents or surface-
active agents.
 Through chemical interactions in the liquid. For example, freshly prepared white
lotion without any Suspending agent.

Gels or Jellies
 Jellies are semisolid gels, having suspensions containing either small inorganic
particles or large organic molecules interpenetrated by a liquid.
 Types of Jellies Jellies are transparent or translucent, non-greasy, and semisolid gels
meant for external application.

They are of the following types:

1. Medicated Jellies
 61

2. Lubricants
3. Miscellaneous Jellies

Cold Cream
 Cold creams are water-in-oil or oil-in-water type emulsions added with certain fats
(generally beeswax) and perfuming agents.
 These are applied on skin to provide smoothness and remove makeup.
 Cold creams are named so due to the cooling effect they impart on application.

An ideal cold cream should have the following properties:

i. It should have a low sensitisation index.
ii. It should be elegant in appearance.
iii. It should be non-dehydrating.
iv. It should provide a smooth texture.
v. It should be non-greasy and non-staining.
vi. It should not cause irritation to the skin.
vii. It should not alter the membrane or skin functioning.
viii. It should be miscible with skin secretion.

Vanishing Cream
 Vanishing creams are also known as day creams as they are applied in the day times.
 These creams provide emollient and protective action to the skin against
environmental conditions by forming a neither greasy nor oily semi-occlusive residual
film.
 Vanishing creams are oil-in-water type emulsions.

Properties
1. It should have a high melting point.
2. It should be pure white in colour.
3. It should possess a very slight odour.
4. It should have a less amount of iodine.

Preparation
The Methods of preparation of different formulations of vanishing creams are given below:

Formula %
Stearic acid 24.0%
Potassium Hydroxide 1.0%
Water 64.0%
Glycerine 10.5%
Perfume 0.5%
100%

Method:
i. Stearic acid is melted by heating on a water bath.
 62

ii. Potassium hydroxide is dissolved in water. glycerine is added, and the mixture is
heated at 75°C temperature.
iii. This heated mixture is slowly added to the melted stearic acid with constant stirring.
iv. The obtained mixture is maintained at 40°C temperature and added with a suitable
perfume.

Nasal Drops
 Nasal Drops are aqueous or Oily Solution Which are instilled into the nostrils using a
dropper. There solutions Contain antiseptics, local analgesics or Vasoconstrictors.

Preparation

Ingredients Examples
Vehicles Purified Water
For tonicity adjustment Sodium Chloride, Dextrose
Buffers Phosphate Buffer
Preservatives Chloro-butanol (0.5%), Benzalkonium Chloride (0.01-
0.05%) Aromatic Alcohols (0.5-0.9%)

 Since the nasal drops are almost similar to nasal secretion with respect to formulation.
 They are made isotonic and buffered in order to maintain their pH in the range of 5.5-
7.5.
 The viscosity of nasal drops is almost equivalent to that of the nasal secretions, thus,
thickening agents (e.g., methylcellulose and hydroxypropyl methylcellulose) are
added to adjust the viscosity.
 The nasal drops are prepared using aqueous vehicles (and not oily vehicles since the
oily nasal drops obstruct the ciliary movement of the nasal mucosa and also involve
the risk of lipoidal pneumonia (presence of oil drops in the lungs).

Examples
Some of the nasal drop preparations are discussed below: Ephedrine Hydrochloride Nasal
Drops B.P.C.

Ingredients Quantity uses

Ephedrine Hydrochloride 0.1g Nasal decongestant
Sodium Chloride 0.1g Tonicity adjustment
Chlorobutanol 0.5% Preservative
Purified Water 20ml Vehicle

Preparation:
i. All the ingredients are dissolved in purified water, filtered, and dispensed in a clear
bottle.
ii. The ephedrine hydrochloride nasal drops should be stored in a well-closed vial fitted
with a dropper.
 63

iii. In this preparation, ephedrine hydrochloride is used as an anti-asthmatic and a nasal

decongestant.
iv. Chlorobutanol is added as a preservative and antiseptic.
v. The tonicity of the preparation is adjusted by sodium chloride. Purified water is used
as vehicle.

Uses: Nasal decongestant.

Ear drops
 Ear drops are the solutions prepared in water, glycerine, or propylene glycol, and are
instilled into the ear using a dropper.
 They are used for cleaning the ear, softening wax, and treating mild infections.
 During the instillation of ear drops the patients either have to lie down or tit their head
at 45° angle, thus, causing inconvenience.

Preparation
i. Ear drops are clear solutions and do not contain any particles when observed under a
microscope under suitable conditions of visibility.
ii. Ear drops are also available as suspensions which form sediment that freely disperses
on shaking the container, and remain dispersed for a sufficient duration.

Example
Some of the ear drop preparations are discussed below:
Sodium bicarbonate Ear Drops B.P.

Ingredients Quantity
Sodium Bicarbonate 7.0g
Phenol 0.5g
Glycerine 50ml
Purified Water q.s. to 100ml

Preparation:
i. Sodium bicarbonate is dissolved in water and glycerine is added to this solution to
provide softening capacity to the solution.
ii. The emollient property of glycerine reduces itching.
iii. The remaining quantity of water is added to make up the desired volume.

Uses: To soften dry and hardened earwax.

POWDERS AND GRANULES

 Powder is defined as a uniform and dry mixture of one or more finely divided
particulate material.
 In the current scenario, powder is rarely used as a dosage form but it is being
employed as the starting material in the manufacture of many dosage forms.
 64

 The significance of particle size is well-known in powder dosage forms.

 Powder is one of the oldest dosage forms which are meant for internal as well as
external application.

Classification of Powders
Based on Usage: Depending on their use, powders are divided into 3 type.
1. Powder for Internal Use: The powders meant for internal application.
i. Simple powders,
ii. Compound powders, and
iii. Bulk powders, e.g., effervescent powders or granules, laxatives, and dietary
powders.
2. Powder for External Use:
i.Dusting powders
 Medicated Dusting powders
 Surgical Dusting Powders
 Cosmetic Dusting Powders
ii. Powders for Insufflation
iii. Douche Powders
iv. Powder Dentifrices
3. Special Powders
i. Eutectic Mixtures
ii. Effervescent Powders.

Advantages
Powdered dosage forms exhibit the following advantages,
i. These are the oldest dosage form, used both internally and externally.
ii. As compared to liquid dosage forms, they are more stable.
iii. Specific amount of drug can be prescribed by the physician depending on the patient's
need.
iv. They easily dissolve in body fluids due to greater surface area, thus, the blood
concentration of drug increases in a very short time span.
v. They are portable.
vi. By dissolving or mixing the powdered drugs in an appropriate liquid, large quantity of
the drug can be administered easily.

Disadvantages
i. Powdered drugs possessing bitter, nauseous, and unpleasant taste cannot be
dispensed.
ii. Powdered drugs which are deliquescent and hygroscopic in nature cannot be
dispensed.
iii. Drugs affected by atmospheric conditions are inappropriate for dispensing in
powdered dosage form.
iv. Preparation of powdered drugs is a time-consuming process.

Granules

 Granules are powder agglomerates.

 The normal size range of granules is 4-12 sieves. Different size of granules can be
formed according to the application.
 65

Following are the advantages of granules:

 They have good flowability than powders.
 They also remove or control the dust.
 They increase the compressibility.
 Their physical and chemical stability is much more than powders because they have a
smaller surface area.
 They give rise to particle size uniformity, which further leads to content uniformity.

STERILE FORMULATIONS

 According to I.P. Parenteral are injectable preparations and parenteral products are
formulated for administration by the method of injection, infusion or implantation
inside the body.
 Parenterals should be free of physical, chemical and biological contamination.
 Parenteral preparations should be sterile, pyrogen free liquids (solutions, emulsions,
or suspensions) or solid dosage forms packaged in either single-dose or multi dose
containers.
 These preparations can be administered through the skin or mucus membranes into
internal body compartments.
 These include any method of administration n which passage through the digestive
tract is not involved.
 Injectable solutions need to be free from visible particulate matter like reconstituted
sterile powders.

1. Injectables
 Parenteral preparations are defined as sterile and pyrogen free solutions, suspensions,
emulsions of drug in aqueous or oily vehicles for injection or infusion, powders for
injection or infusion, gels for injection and implants meant for introduction into the
body by means of an injection under or through one or more layers of the skin or
mucous membrane.

Classification of Injectables:
i. Liquid solution for injection: Liquid injectables is sterile preparations of drug
substances or solutions thereof. They may be made with aqueous or oily vehicles.
Examples: B Complex Injection, Prozinc Injection, Meloxicam Injection, etc.
Oily injectables are used for introduction into the body by means of an injection
under or through one or more layers of the skin or mucous membrane.
Examples: Dimercaprol injection, Oily Phenol Injection, Salvarsan Oily Injection,
etc.
ii. Powder for injection: It is a powder intended for injection following reconstitution
in suitable solvent to form a solution or suspension.
Example: Cefuroxime for Injection, Sodium Aescinate for Injection, etc.
iii. Colloidal solution for injection: A colloid is a high molecular weight substance that
mostly remains confined to the intravascular compartment and thus generates oncotic
pressure.
Examples: Natural colloids: Albumin, fresh frozen plasma, etc.
Artificial colloids: Gelatin, dextran, hydroxyethyl starch, iron, etc.
 66

iv. Injectable emulsion: These are liquid preparations of drug substances dissolved or
dispersed in a suitable emulsion medium.
Examples: Propofol Emulsion Injection, Vitamin A, D and E Emulsion Injections
etc.
v. Injectable suspension: These are liquid preparations of solids suspended in a
suitable liquid medium.
Example: Amoxicillin Suspension for Injection, Methylprednisolone Acetate
Suspension for Injection, Deoxycorticosterone Pivalate Suspension for Injection, etc.
vi. Infusion fluid: This is a liquid preparation containing medication, nutrient, or other
fluid given by parenteral route, usually over minutes or hours, either by gravity flow
or often by infusion pumping.
Examples: Normal (isotonic) Saline.


Parenteral preparations may also be categorized as following:
i. Based on types of packaging or dosing:
a) Single dose units: Ampoules, infusions and prefilled disposable syringes.
b) Multiple dose units: Multiple dose vials.
ii. Based on the production and control:
a) Small volume parenterals: Volume < 100 ml
Examples: Furosemide Injection, Heparin Injection, Cimetidine Injection, etc.
b) Large volume parenterals: Volume 100 mL
Examples: Infusion Fluids, Total Parenteral Nutrition Solutions, Dialysis Fluids.
iii. Based on clinical use:
a) Solutions for irrigation
b) Ophthalmic solution
c) Dialysis solution
d) Diagnostic agent
e) Allergenic extracts
f) Implants
iv. Based on physical state of product:
a) Sterile solutions
b) Sterile suspensions
c) Sterile emulsions
d) Sterile solids
v. Based on route of administration:
a) Intravenous injection: Drug is directly administered into the blood veins.
b) Intramuscular injection: Drug is directly administered into large skeletal
muscles.
c) Intra-peritoneal injection: Drug is administered into the peritoneal cavity.
d) Subcutaneous: Drug is injected just below the skin.
e) Intra-dermal injection: Drug is given into the skin so it forms a small bulge.
f) Intrathecal: Here drug is administered into the spinal cord.
g) Epidural: The drug is injected near the spinal cord to affect the local nerves.
h) Intraosseous: The injection is directly administered into the bone marrow.
 67

Advantages of Injectables:
i. Injectables are reliable and precise in dosage and show rapid onset of action.
ii. Injectables are best in emergency conditions, for example, in heart failure.
iii. They have ability to provide control over drug delivery to the administrator.
iv. Avoids first pass metabolism of drugs which are destroyed in liver.
v. Drugs can be administered at low drug concentration with minimum wastage.
vi. They have low toxicity as compared to solid dosage form.
vii. Suitable for drugs which are degraded or unreliably absorbed orally.
Limitations of Injectables:
i. Injectable drugs are expensive as compared to solid dosage form.
ii. Injectables are highly risky if any mistake happens during administration.
iii. Through injectables distribution cannot be stopped once administered.
iv. For injectables needs to be sterilized else can lead to microbial growth.
v. Injectables require trained personnel for its administration.
vi. Injectables have chances of pain and injury at site of injection.

Essential Requirements of Injectables:

1. All injectable products must be sterile.
2. All injectable products must be free from pyrogens (endotoxins).
3. Injectable solutions must be free from visible particulate matter.
4. Injectable products should be isotonic.
5. All injectable products must be chemically, physically and microbiologically stable.
6. Injectables must be compatible with IV diluents, delivery systems, and other drug
products co-administered.

Formulation of Injectables:
1. Small volume parenterals (SVP):
The volume of SVP is less than 100 ml. The large-scale production of SVP requires
appropriate adjustments in the processes and their control. A master formula is developed
and each batch formula is prepared from the master formula. All quantities of materials
are measured accurately and checked by qualified responsible person. Care needs to be
taken that equipment is not wet enough to dilute the product significantly or, in the case
of anhydrous products, to cause a physical incompatibility, the sequence of mixing of
excipients may affect the product significantly. Many of active ingredients are usually
extremely sensitive to temperature, mixing time and speed, order of addition of
excipients, pH adjustment and control, and contact time with various surfaces like filters
and tubing. The assurance of attaining product stability requires a high order of
pharmaceutical knowledge and responsibility.
Examples: Enoxaparin Sodium Injection I.P., Ascorbic Acid Injection I.P., Amikacin
Sulphate Injection, etc.
Ascorbic Acid Injection I.P.

Acerbic acid 25g

Sodium bicarbonate 14.58g
P-chloro M-cresol 0.1g
Water for injection I.P. 100ml
 68

Method of Preparation:
This injection is prepared in aseptic room under a laminar airflow hood in a clean
room using strict aseptic technique. Ascorbic acid solution is prepared by transferring 2/3 rd
of the total volume of water in a beaker. Ascorbic acid is weighed and suspended in water
with continuous stirring. Sodium bicarbonate is slowly added with vigorous stirring to
produce effervescence. After subsidizing the effervescence, remaining. sodium bicarbonate is
added. This process is continued till ascorbic acid completely dissolves. Then p-chloro m-
cresol is added and stirred to dissolve, the pH is adjusted to 5.7 and the solution is filtered
through G-4 filter. The 2 mL ascorbic acid solution is aseptically transferred to ampoules and
heat sealed.
Uses: Vitamin C deficiency.

2. Large volume parenterals (LVP):

LVPs are single-dose injections having a volume of 100 mL or greater that are
intended for I.V. use and are packaged in containers labelled as containing more than 100
ml. LVP products administered by I.V. routes are called as transfusion fluids or
intravenous infusions. They are sterile aqueous solutions or emulsions with water for
injections as the main component. They also incorporate other ingredients including
carbohydrates such as dextrose, sucrose, dextran, etc., amino acids and lipid emulsions
which contain vegetable or semisynthetic oils, electrolytes such as sodium chloride and
polyols such as glycerol, sorbitol and mannitol. Manufacturing of SVP involves
additional step of sequential mixing of ingredients to attain homogeneity which requires
considerable mixing time. The most common sizes of LVP are 100, 250, 500, and 1,000
ml. Generally, they are packaged in plastic bags due to its less weight, more compact
storage, and disposable. They may be packaged in glass bottle for drugs that interact with
plastic bags such as nitro-glycerine and amiodarone.
Examples: Sodium Chloride Solution, Dextrose Solution, Ringers Solution, etc.
Normal Saline Solution:
Sodium chloride I.P. 0.9 %

Sterile Water for Injection I.P. 200ml

Method of Preparation:
The Normal Saline Solution for injection is prepared in aseptic room under a laminar
airflow hood using strict aseptic technique. Accurately weighed sodium chloride is dissolved
in 95 ml- of Sterile Water for Injection. Once dissolved sufficient Sterile Water for Injection
is added to make the final volume and mixed well. The mixture is filtered through a sterile
0.22 pm filter into a sterile appropriate container, packaged and labelled.
Use: Nutritional supplement.

3. Lyophilized products:
Lyophilized (or freeze dried) products are solid dosage form prepared by freeze dying
(lyophilization) process in which water is removed from a product after it is frozen and
placed under a vacuum, allowing the ice to change directly from solid to vapor
(sublimation) without passing through a liquid phase. The process consists of three
separate, unique, and interdependent processes namely freezing, primary drying, and
secondary drying. The products obtained by freeze drying can also be called as dry
injectables. Dry injectable product is packaged as dry solids because therapeutic agent is
 69

unstable in the presence of liquid component; usually a water. These dry powders are
packaged in the final container to be reconstituted, generally to a solution or less
frequently a suspension. The common examples of drugs processed by lyophilization are
antibiotics, anticancer drugs, enzymes and biological components such as cells, tissues
and membranes. In addition, there are many new parenteral products, including anti-
infective, biotechnology derived products, and in-vitro diagnostics which are
manufactured as lyophilized products. These lyophilized products have problems
associated with the manufacture and control of potency, sterility and stability.
Examples: Doxorubicin Hydrochloride Lyophilized Powder for Injection I.P., Cephalothin
Lyophilized Powder for Injection, Dobutamine Lyophilized Powder for Injection, etc.

Doxorubicin Hydrochloride Injection I.P.

Doxorubicin hydrochloride 50 mg
Lactose monohydrate 250mg
Water for injection I.P. 2ml

Method of Preparation:
The formulation is prepared in aseptic room under a laminar airflow hood in a clean room
using strict aseptic technique. Accurately doxorubicin hydrochloride and lactose
monohydrate are weighed and dissolved in about 3.5 mL of Sterile Water for Injection.
Sufficient amount of Sterile Water for Injection is added to make up final volume and mixed
well, the solution is lyophilized in freeze dryer by refreezing, primary drying and secondary
drying and finally vacuum sealed.
Use: Anticancer
Storage of Injectables:
Proper environmental control must be maintained while storing injectables„ Usually
liquid injectables are stored between 25 oc to 30 oc. An emulsion injectable should be stored
at cool place in air tight container, protected from light and freezing. Injectable suspension
should be stored in a cool place but not be kept in a refrigerator. Freezing of suspension
injectables at a very low temperature should be avoided as it may lead to aggregation of the
suspended particles. Lyophilized injectables are stored at 4-8 oc, protected from heat and
light.

Quality Control Tests for Injectables:

1. Identity tests: These tests, for example, colour formation, precipitation etc., are
qualitative chemical methods used to confirm the actual presence of compound.
2. Quality tests: These tests, for example, absorbance, Refractive index, etc., are the
physical methods used to measure accurately the characteristic properties of drug.
3. Purity tests: Purity tests, for example, tests for clarity of solutions, acidity, alkalinity,
etc., are performed to estimate the level of all known and significant impurities and
contaminants in the drug substance under evaluation.
4. Potency tests: Potency tests are assays that estimate the quantity of an active
ingredient in the drug product.
5. Sterility test: Sterility test determines complete absence of ail forms of
microorganisms in injectables. The methods used to perform sterility testing are direct
transfer method and membrane filtration method.
 70

6. Test for pyrogen: Pyrogens are metabolic products of micro-organisms. Pyrogens

are produced by gram negative bacteria. These are heat stable, lipopolysaccharides
which are capable of passing through bacteria retentive filters. They produce a mark
response of fever with body ache and vasoconstriction when injected into the body
within an onset of 1 h. The presence of pyrogen is tested by Sham test and Rabbit test.
Sham test is a preliminary test used to detect presence of pyrogens in parenteral
products.
7. Bacterial endotoxin test: The Lysates of Amoebocytes of Limulus (LAL) test is used
to detect the presence and concentration of bacterial endotoxins in injectables. This
test utilizes gelling property of Lysates of Amoebocytes of Limulus Polyphemus
derived from horse shoe crab.
8. Leaker test: Leakage test is performed to test the package integrity such as capillary
pores or tiny cracks that are present on the vials or ampoules. This test is conducted
by placing ampoules in a vacuum chamber and completely submerging in 0.5 to 1%
methylene blue solution. A negative pressure is applied making the dye to penetrate
through any opening, if present, on the ampoule, the container is then inspected for
the presence of dye either visually or by means of UV spectroscopy.
9. Particulate matter test: The procedure employed in this test for LVP's involves
filtration followed by microscopical examination. For SVPs a light obscuration-based
sensor containing electronic liquid borne particle counter system is used.
10. Clarity Test: Clarity test involves the visual assessment of formulation in light on
suitable background. The transparent particles are observed against the black
background and the black or dark particles observed against a black and white
background.
11. Content uniformity and weight: This test determines the content of the active
ingredient in each of 10 containers selected at random. The preparation under
examination must comply with the test if the individual values obtained are all
between 85 and 115 % of the average value.
12. Extractable volume test: This test is used to determine total volume of contents
filled in a container. Each container of an injection is filled with sufficient excess of
the labelled volume. Individually contents of each container selected are withdrawn
into a dry hypodermic syringe. The contents of the syringe are discharged, into a dry
graduated cylinder. The volume (mL) is calculated as the weight (g) of injection taken
divided by its density.
13. Stability testing: Stability testing is performed to provide evidence on how the
quality of an active substance or pharmaceutical product varies with time under the
influence of a variety of environmental factors such as temperature, humidity, and
light. This helps to determine identity, strength, quality and purity throughout the
shelf life of products.
Other quality control tests used for injectable products pH, viscosity, isotonicity, osmolality,
conductivity, etc.

Eye Drops

 Eye Drops are sterile aqueous or oily solutions or suspensions of drug that are infused
into eye through dropper.
 The Eye Drops are usually comprised of drugs having antiseptic, anaesthetic, anti-
inflammatory, etc.
 71

Some of the essential characteristics of eye drops are as follows:

i. They should be sterile.
ii. They should be iso-Osmotic with lachrymal secretion
iii. They should be free from the foreign particles. fibres and filaments
iv. They should have almost neutral pH.
v. They should be preserved with suitable bacteriocidic.
vi. They should remain stable during their storage.

Classification of Eye Drops:

1. Eye drop solutions.
2. Eye drop microemulsions.
3. Eye drop suspensions.

Formulation
An eye drop formulation comprises of the following:
i. Active ingredient(s) to produce the desired therapeutic effect
ii. Vehicle (aqueous or oily).
iii. Inert antimicrobial preservatives to prevent microbial contamination and to maintain
sterility.
iv. Inert adjuvants for adjusting tonicity, viscosity or pH to increase the stability of active
ingredient(s).
v. Suitable container to maintain the preparation in a form and provide protection against
stable contamination during preparation, storage, and use.
vi. The most important requirement of eye drops is that they should be sterile.
vii. In history, some eye drops were found to be contaminated with Pseudomonas
aeruginosa, which is difficult to treat and can cause loss of vision.

Advantages
i. It can be used in replacing the natural moisture in patient's eye, and can be a life saver
for anyone with dry eyes.
ii. Medication in eye drops can help the eye to recover fast after an injury on the surface
of the eye.
iii. They are compact and easy to administer and much simpler to deal with overall in
comparison to injections or pills.

Disadvantages
i. Usually, eye drops are stored in a bottle that should be handled carefully to prevent
contamination.
ii. At times the eye drops do not work for some patients because of which patient has to
apply it repeatedly for several days and gets minimal results in return.
iii. In some cases, the use of eye drops can mask minor symptoms that can be tackled
from the source and treating the effect is not required as it won't recover the actual
cause.

Limitations of Eye Drops:

1. Solution eye drops undergo rapid precorneal elimination.
2. Solution eye drops need to be administered at frequent intervals.
3. Solution eye drops show non-sustained action.
 72

4. Drug properties in suspension eye drops decide performance loss of particles.

5. Suspension eye drop has irritation potential due to particle size of the drug.
6. Emulsion eye drops causes blurred vision.
7. Improper use may of eye drops may lead to complications.
Uses
i. Used for treating infection.
ii. Used for dilating or contracting pupil.
iii. Used for instilling medication before examination or Surgery to eyes.
iv. Used for relieving pain, itching, discomfort.
v. Used for lubricating the eyes.
vi. Used for staining the cornea for identifying abrasion and scars.

Storage
Eyed drops are kept out of the reach and sight of children. They are stored in a cool and dry
place,

Eye Ointments
 Ophthalmic ointment vehicle can be used to maintain the stability of the drug in
contact with the external ocular surface for the longer time duration.
 The ointment base is sterilised through heat and filtered properly in liquid phase for
removing the foreign particulate matter. (repeat).
 The ointment base selected for an ophthalmic ointment should be non-irritating to the
eye and must permit the diffusion of the active ingredient throughout the secretions
bathing the eye.
 Eye ointment base can be sterilised by heat and filtered in liquid phase for removing
the foreign particulate matter.
 Then it is placed in a sterile steam jacketed for maintaining the ointment in a molten
state and excipients are added.
 Thus, the entire ointment can be passed through a previously sterilised colloid mill.

Formulation
The following bases can be used for the preparation of eye ointments:
i. Yellow soft paraffin (80gm),
ii. Liquid paraffin (10gm), or
iii. Wool fat (10gm).

Preparation
i. Wool fat and yellow soft paraffin are melted on a heated water bath.
ii. Liquid paraffin is added to the melted mixture and filtered through a coarse filter
Paper (e.g., Whatman 54) placed in a heated funnel.
iii. The obtained mixture is sterilised at 160°C temperature for 2 hours
iv. The medicament is added with eye ointment base, and the final mixture is packed in a
sterile container.
Methods of Manufacturing:
Eye ointments are prepared aseptically by incorporating the sterile medicament(s) into
a sterile base. These ointments are primarily anhydrous and the base consists of mineral oil
and white petrolatum. The proportion of these bases can be varied to adjust consistency and
the melting point.
 73

There are two methods of incorporating the drugs in ointment bases while
maintaining aseptic conditions throughout the process.
1. Water soluble medicaments: Drug is dissolved in minimum volume of purified
water; the solution is then sterilized by autoclaving or filtration and gradually
incorporated in the previously melted sterile base which is stirred until cold.
Example: Atropine Eye Ointment, Hyoscine Eye Ointment, etc.
2. Insoluble medicaments: Drug is finely powdered and triturated with a small quantity
of the melted, previously sterilized base. The mixture is then incorporated with the
remainder of the melted base.
Example: Chloramphenicol Eye Ointment, Hydrocortisone Acetate Eye Ointment
Formulation of Eye Ointment:
The ointment base used in preparing ophthalmic ointments must be non-irritant and
should melt near to the body temperature, so as to permit the diffusion of the drug through
the lachrymal secretion of the eye. For preparation of Atropine eye ointment following sterile
ointment base is used:
Sterile Ointment Base:
Yellow soft paraffin 80g

Liquid paraffin 10g

Wool fat 10g

Atropine Eye Ointment

Atropine sulphate I.P. 1g
Sterile ointment base 100g
The atropine sulphate is incorporated in sterile ointment base, mixed well to obtain uniform
mass and packaged in the sterile container. The ointment is packaged in small, sterilized
tamper-evident collapsible aluminium or polyvinyl chloride tubes

Advantages:
i. Eye ointments offer longer contact time and greater total drug bioavailability.
ii. They have flexibility in drug choice.
iii. They show improved drug stability.
iv. Eye ointments show better bioavailability than eye drops.
v. Eye ointments have no tear dilution

Disadvantages
i. After using it eye lids starts sticking.
ii. Person may experience the blurred vision.
iii. It has poor patient compliance.
iv. They interfere with the attachment of new corneal epithelial cells to their normal base.
v. Matting of eyelids occur

Limitations:
1. Eye ointments may interfere with the vision and may stick eyes lids.
2. Eye ointment has poor patient compliance.
3. They have slower onset of action and takes longer time for peak absorption,
 74

Storage:
These products should be stored to maintain their integrity throughout their shelf-life at
the temperature indicated on the label. Some products are stored in refrigerator whereas some
at room temperature away from heat and light.

Quality Control Tests:

1. Assay: The strength of drug in sterile formulation is determined using suitable
method specified under monograph. The concentration of drug must lie within 95—
105% of the nominal concentration.
2. Concentration of preservative: Analysis of preservative concentration within sterile
preparations is determined using suitable analytical method as specified in
monograph and must comply with it.
3. Preservative efficacy test: The efficacy of the preservative(s) within the eye
ointment is tested using appropriate Pharmacopoeial method using test organisms
specified.
4. Sterility testing: The assessment of sterility of ophthalmic products is performed
using Pharmacopoeial methods using thioglycolate medium over period not shorter
than 14 days. Examination of sterility involves inspection of inoculated sample for
growth of aerobic and anaerobic bacteria, and aerobic bacteria and fungi.
5. Metal particles in eye ointments: The presence of metai particles in ophthalmic eye
ointment is determined by completely extruding the contents of 10 tubes. The sample
is transferred into separate, clear, flat-bottom, 60 mm Petri dishes and heated at 85 oc
for 2 h and then cooled to room temperature to solidify. Petri dish is inverted and on
the stage of a suitable microscope to examine for metal particles. The number of
metal particles of size 50 pm or larger are counted. The sample pass the test if the
total number of such particles in all 10 tubes does not exceed 50, and if not more than
1 tube is found to contain more than 8 such particle.
6. Eye irritancy test: Eye irritation by eye ointment is determined by Draize eye test.
For the test, eye ointment is applied directly on the cornea 3 to 6 albino rabbits. Left
eye ball is used as a control and right eye ball for test sample. After introducing an
ointment, the eyelids are kept closed for a few seconds. Eyeball condition is observed
before and after introducing the formulation. The evaluation is conducted at time
interval of 1 h, 24 h, 48 h, and 72 h from introducing samples. Ocular changes may be
assessed using a scoring system, in which every change in the area of eyelid,
conjunctiva, cornea, and iris is scored.
In addition to above tests, other quality control tests used include uniformity of weight,
viscosity, particle size, drug release, stability test, etc.

Immunological products

Immunity is classified into to natural immunity and acquired immunity.

1. Natural (Innate) immunity: It is the immunity in which antibodies generated due to
a normal. infection. It includes antibodies provided by mother through their
colostrum’s and the initial breast milk. This immunity only protects for short time,
but when infant is most vulnerable.
2. Acquired immunity: When natural immunity is insufficient to protect the body
against many microbial infections, an additional immunity is acquired either actively
or passively.
 75

i. Active immunity: Active immunity can be acquired by natural disease or by

vaccination. Vaccines stimulate production of antibodies and other components of the
immune mechanism.
ii. Passive immunity: It is the immunity with immediate protection against certain
infective organisms. It can be obtained by injecting preparations made from the
plasma of immune individuals with adequate levels of antibody to the disease under
consideration. The duration of this immunity depends upon the dose and the type of
immunoglobulin. Passive immunity may last only for few weeks; and when
necessary, passive immunisation can be repeated. Antibodies in human are termed as
immunoglobulins while those prepared in animals are called antiserum.
iii. Artificial immunity: Artificial immunity is induced by immunization by giving a
vaccine or immunoglobulin. Vaccination means administration of a vaccine to help
the immune system develop protection from a disease, the immune response may be
humoral or cell-mediated.
iv. Humoral immunity: Humoral immunity is based on serum antibodies that are
produced by plasma cells and bind to antigens in order to assist with their elimination.
v. Cell-mediated immunity: This immune depends on antigen recognition and
lymphocyte responses to destroy infected cells and prevent organisms replicating
within.

Definition:
Immunological products can be defined as the proprietary dilapidation-based methods and
systems for the production of treatments for viral or bacterial infections. These products are
the preparations used for the prevention of diseases (vaccines) or for the treatment of diseases
(antitoxin and antiserum) or for the diagnostic purposes (bacterial toxins). These are
biological products of protein us nature except poliomyelitis vaccine. Majority of
immunological preparations are administered by parenteral routes as they become inactive
when administered by oral route, The exception is poliomyelitis vaccine, which is
administered by oral route.

Features of Antisera
1. These are antibodies which are developed in animals (horses especially).
2. They are obtained from the serum of an animal (e.g., rabies antiserum), containing the
target antibody for which a specific antigen has been injected.
3. Antitoxins are prepared by injecting toxin or toxoid.

Vaccines
i. To memorialise the work of Edward Jenner (i.e., first successful immunisation against
small pox), Louis Pasteur invented the term vaccine derived from the term vaccinia
(means cow), because Jenner prevented smallpox infection using Vaccinia (cowpox
virus).
ii. A process in which an individual is intentionally exposed to antigen under such
conditions where disease should not occur is termed vaccination.
iii. Vaccine is a live attenuated (weakened) or killed microorganism or parts or products
of them containing antigens which induce a specific immune response consisting of
protective antibodies and T cell immunity.

1. Live Attenuated Vaccines

i. Live attenuated vaccines are prepared using a non- virulent microorganism that
retained its antigenicity.
 76

ii. These vaccines can provide permanent or lifetime immunity to an individual against a
disease.

Merits
i. Multiple booster doses are not always required; most of these vaccines provide
lifelong immunity with a single dose.
ii. Whole microorganisms stimulate immune response to antigens in their natural
conformation.
iii. Orally administered live vaccines induce mucosal immunity and IgA synthesis, which
provides more protection at the site of entry.
iv. Oral preparations of these vaccines are less expensive than the injections.
v. These vaccines can even help in eliminating the wild type virus from the community.

Demerits
i. The microorganisms in these vaccines may relapse to their virulent form and cause a
disease; however, this rarely happens.

2. Inactivated- Killed Vaccines

i. Inactivated-killed vaccines are prepared using either killed pathogens using with
altered or inactivated by applying heat or chemical.
ii. These vaccines are first administered as a primary dose and antigenicity.
iii. These microorganisms are killed or These then a single or multiple booster dos are
required.
iv. A killed form of the disease-causing microorganism is used for making inactivated
vaccines.
v. A single dose of inactivated vaccine does not provide immunity as strong as live
vaccines; thus, booster doses are required after specific time intervals in order to
achieve continuous immunity against diseases.

Merits
i. These vaccines can be safely used in immunocompromised individuals and pregnant
women.
ii. These vaccines are less expensive than live attenuated vaccines.
iii. These vaccines do not demand storage facilities as critical as live vaccines.

Demerits
i. The microorganisms in these vaccines cannot multiply, thus a large amount is needed
to be injected for stimulating immunity.
ii. Periodic booster shots are also required for achieving desired immunity.
iii. These vaccines can be only injected.
iv. Presence of some un-inactivated microorganisms can cause some vaccine- associated
diseases.

Toxoids
i. Toxoid vaccines are prepared from the toxins secreted by certain bacterial species.
ii. The preparative method of these vaccines is termed taxiing
iii. Bacterial Cell Component Vaccines
iv. Conjugate Vaccines
v. Viral Subunit Vaccines
vi. DNA Vaccine
 77

Production of Vaccines
 Vaccines are used for providing good health to large number of populations; thus,
they should be manufactured on a large-scale, which is a challenging task.

Vaccine production includes:

i. Generation of the Antigen: In the first step, the antigen that will evoke immune
response is generated by growing and harvesting the proteins or DNA of the pathogen
using the following mechanisms:
a. For preparing influenza vaccine, viruses are grown on primary cells (e.g., cells
from chicken embryos or fertilised eggs); and for preparing hepatitis A vaccines,
viruses are grown on repeatedly reproducing cell lines.
b. Bacteria are grown in bioreactors which utilise a particular growth medium to
optimise the antigen production.
c. Recombinant proteins derived from the pathogen are generated either in yeast,
bacteria, or cell cultures.
ii. Release and Isolation of the Antigen: In the second step, virus or bacteria are
released by separating the antigen from the cells and isolating from the proteins and
other parts of the growth medium are still present.
iii. Purification Process: In the third step, membrane separation (ultrafiltration) and
chromatographic separation (gel filtration and size exclusion) are used for separating
inactivated antigen in group separation mode. Separation of large viruses from the
fermentation broth is beneficial, e.g., human influenza viruses which are larger than
protein and peptide molecules can be separated. shows a basic purification process
after the sample has been prepared by centrifugation and depth filtration.
iv. Addition of Other Components: In the fourth step, vaccine is formulated by adding
an adjuvant which enhances the immune response the recipient produces against a
supplied antigen. stabilisers which modify the shelf-life and preservatives which
allow multi-dose vials to be used safely. Development of combination vaccines
challenging incompatibilities and interactions between antigens and other ingredients.
All the components constant vaccine is combined and uniformly mixed in a single
vial or syringe.
v. Packaging: In the final step, the vial or syringe (recipient vessel) containing the
vaccines are sealed with sterile stoppers. After packaging the vaccines are labelled a
throughout the world all the above given process should comply with the GMP
including the quality control methods and adequate infrastructure having separate
areas for different activities to avoid cross-contamination.
 78

CHAPTER-6
PHARMACEUTICAL INDUSTRY AND BASIC CONCEPTS

INTRODUCTION
The roots of the pharmaceutical industry, also known as pharmaceutical manufacturing
plant, lie back with the apothecaries and pharmacies that offered traditional remedies as far
back as the Middle Ages. Today, it has become an emerging industry worldwide. It is an
important element of healthcare systems throughout the world. It comprises of many public
and private organizations that discover, develop, manufacture and market pharmaceutical
products and devices for human and animal health. The pharmaceutical industry is based
primarily upon the scientific R&D of products and devices that prevent or treat diseases and
disorders. Many dynamic scientific, social and economic factors affect the pharmaceutical
industry. Some pharmaceutical companies operate in both national and multinational
markets. Therefore, their activities are subject to legislation, regulation and policies relating
to drug development and approval, manufacturing and quality control marketing and sales.

PHARMACEUTICAL MANUFACTURING PLANTS

i. Pharma industry is one of the fastest-growing industries in India.
ii. The pharmaceutical industry in the India continues to grow and pharmacists are
making an impact on the industry's landscape.
iii. Pharmaceutical manufacturing is the process that starts from industrial-scale synthesis
of pharmaceutical drugs to manufacturing of their products.
iv. The process of pharmaceutical manufacturing can be broken down into a series of unit
operations, such as milling, weighing, mixing, granulation, coating, tablet
compression, etc.
v. In addition to unit operations the process of manufacturing of medicines also includes
other aspects that include batch integrity testing, quality assurance, calibration,
validation and facility maintenance.
vi. The manufacturing plant offers a wide range of dosage forms.

Basic Structure
 A pharmaceutical manufacturing plant is an industry which manufactures and sells
pharmaceutical products such as medicines, cosmetics and drugs.
 The basic requirement of any manufacturing plant is personnel and their functions.
Within the working of a pharmaceutical company lies a whole hierarchy of job
positions, designations and roles.
 All the jobs and departments together are responsible for the success and profit of the
organization.
 The organization structure of a "Typical" Pharmaceutical plant is categorized as
functional structure, product-oriented structure and matrix structure.
 79

 Functional organizational structure is present to some extent in most of the major

pharmaceutical manufacturing plants.
 Each function within the plant is organized separately and each function reports to a
specific function/department head.
 Some of the functional departments in a pharmaceutical industry include
manufacturing department, sales department, marketing departments, research
department and others.

President

Finance Research and Manufacturing Marketing Sales

Development

Basic Structure of Pharmaceutical Manufacturing Plant

Senior Most Level Job Positions:

In a pharmaceuticals manufacturing plant, the senior most levels job positions are
occupied by administrators, owners, board of directors and other important employees who
are responsible for the overall management and operation of the organization. The senior
position people decide and set the goats for the rest of the employees to achieve and are
responsible for handling financial issues which is an important part of any industry.

Middle Level Job Positions:

The middle level executives and employees who work under senior level people
execute the plans and projects planned and assigned by the senior level employees. They
supervise and guide the lower-level employees and make sure that the company and its
operations run smoothly.

Entry Level Job Positions:

The people working at entry level for an authority is concerned don't hold important
roles but are a vital part of the industry and are responsible for day-to-day tasks and
functions. The entry level positions are held by those who are not much experienced.
 80

Pharmaceutical Company Hierarchy

Senior most level job Middle level job Entry level job
positions positions positions

Company director Department manager Pharmaceuticals

sales executive
Chief company executive Regional managers
Pharmaceutical’s
Senior company supervisor Company manager trainee
Head of the pharmaceutical Associate company Pharmaceutical’s
company department manager assistant
National pharmaceutical Pharmaceutical company Pharmaceutical’s
company head team leader secretary
Chief medical officer Pharmaceutical company Pharmaceuticals
PR associate intern
Zonal company head Pharmaceutical’s
Marketing manager
Pharmaceutical senior manufacturing clerk
company supervisor Sales manager Pharmaceuticals
Company manager District pharmaceutical company
company head representative
General manager
Quality control manager Organizational
Executive director
Warehouse manager Structure of
Pharmaceutical Manufacturing Plant

Layout
Once decided on where to locate pharmaceutical plant, the next step is to plan a
suitable layout because efficiency and performance of good machines and sturdy building
depend on the layout of a plant. Plant layout is defined as the method of allocating
machines and equipment, various production processes and other necessary service
involved in transformation process of a product with the available space of the plant, so as
to perform various operations in the most efficient and convenient manner that provides
output of high quality and minimum cost. While designing a plant layout, it is important
 81

to understand and follow the basic regulatory requirements for the construction of plant
building.
According to National Agency for Food and Drug Administration and Control (NAFDAC
layout and design of pharmaceutical manufacturing plant should aim at minimizing the risks
of errors and permit effective cleaning and maintenance in order to avoid cross
contamination, build-up of dust or dirt and any adverse effect on the products. This goal car
be achieved by designing the layout in such a way that it follows a logical Order
corresponding to the steps of the manufacturing operations.
In designing plant layout, it is important to understand the manufacturing processes and
conduct the facility programming. This is to perform various unit operations involved in the
manufacturing of dosage forms in a cost-effective manner and with minimum handling it
processing the product, starting from the receipt of raw material through the distribution of
the finished product for selling. Plant layout must be an integrated design that satisfies the
process requirements, personnel flows, material flows, and equipment layout, operational
access and maintenance access requirements.

Power Production Sewage

backup block treatment
Administrative
Parking
block

Utilities
Warehouse block

Factory road

Garden Canteen Scrap yard

Main Road
Pharmaceutical Plant Layout
Architectural design must consider proper room finishes, environmental and safety
considerations, and must ensure that design is compliant with building codes and fire
regulations. Structural framework and building exterior finishes must take into account the
interior room environment. That means, use of columns and expansion joints within the
cleaner areas of manufacturing facility are minimized wherever possible. Conceptual layout
is derived from accommodation schedule and equipment sizing needs. Building blocks of
equipment lines are developed and blocks of rooms are assembled based on necessary
adjacencies and process requirement.
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Planning the layout of a pharmaceutical plant is an important decision as it

represents long-term commitment. It is a continuous process as there are always
chances of making improvements over the existing arrangement. It should be so
designed that the functioning of plant would become very efficient by providing
optimum relationship among output, floor area and manufacturing process. A good
layout results in comforts, convenience, safety, efficiency, compactness and profits
whereas a poor layout results in congestion, waste, frustration and inefficiency.
Although pharmaceutical plant layout differs from plant to plant, the basic principles
governing pharmaceutical plant layout are more or less same.

Characteristics:
A good pharmaceutical plant layout should possess the following characteristics:
1. There should be adequate floor space for machines installation and utilization.
2. Machines should be properly arranged to facilitate minimum material
handling necessary for low-cost processing.
3. The layout should facilitate smooth and continuous flow of production process
from one point to another to avoid delays.
4. It must incorporate adequate health, safety and security features, for example,
first aid box, fire extinguisher, emergency exit and access points, etc.
5. The layout should allow effective supervision, coordination and control of the
production processes.
6. There should be room for adjustment and modifications whenever the need
arises.
7. There should be sufficient space for the workers to perform their functions.
8. The store facility for in-process material should be designed to minimize
material handling.

Advantages:
A good layout can provide a number of advantages to workers and management. The
advantages of a good pharmaceutical plant layout include but are not limited to:
1. Easy administration and communication amongst the departments.
2. Optimum use of available floor space for production operations.
3. Improved quality of product due to reduced chances of cross contamination.
4. Efficient arrangement for receipt, transportation, storage, and delivery of raw
material and finished goods.
5. Low cost of material handling and minimized loss due to waste and spoilage.
6. Conducive working conditions resulting in improved efficiency.
7. Increased productivity with reduced risk of human error and occupational
hazards.
8. Minimized cost and efforts in supervision, coordination and control over
production processes.

Sections
1. Security Office:
The pharmaceutical plant employs Safety Officers as specified in Factory Act. It is
one of the most diverse fields with a board range of potential security vulnerabilities.
Facilities protection requires highest level of security services related to access control,
ingress and egress monitoring, after-hours protection and alarm monitoring. Security
guards maintain a book which contains name or in and out time of the person. They are
responsible for safety of people working in plant premises.
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2. Garden:
Horticulture is the industry and science of plant cultivation including the process of
preparing soil for the planting of seeds, tubers or cutting. In pharmaceutical plants,
gardens are maintained surrounding the facility. Trees are planted at proximity of the
facility, clarified water from effluent treatment can be used for watering the gardens.

3. Vehicle Parking:
Parking is an essential component of the transportation system. Generally, it is
located at the periphery of the premises. Separate area provided for parking vehicles of
the employee's and the visitors. Separate areas are allocated for parking of 2-wheelers
and 4-wheelers. Allotment of parking area depends on industry's size, scope and
operations.

4. Power Backup:
Fuel is required in pharmaceutical industries for generating power during
interruption of regular power supply. Generally, coal, diesel can be used as an
alternative during electrical supply failures whereas canteen requires LPG for cooking.
Storage for these resources is located near the generator room. Constant check is kept
on the quantity of the material stored and utilized. As these substances are highly
inflammable, protection from fire is a basic requirement. Fire safety equipment’s are
placed in vicinity of such facility and people are trained in handling of the same.

5. Administrative Block:
Administrative block has cabins for Heads of various departments. This block
consists of conference rooms and a meeting room with different seating capacities. It
also comprises library, pantry and crockery storage. In addition, this block also has
offices for accounts and finance, general plant administration, and production, planning
and control Heads, cabins for production, QA, QC, engineering and maintenance Heads,
etc. Other amenities of this block include rest room, medical services and wash rooms. If
building is multi-storey there are toilets and wash rooms on each floor.

6. Production Block:
The type of facility in this block depends on budget, how many products are to be
made, and what batch sizes are to be produced. Fortunately, while designing the
pharmaceutical manufacturing plant, optimal efficiency is achieved through the use of
International Building Code (IBC). This allows for future expansion of biggest buildings.
Broadly speaking, pharmaceutical production facilities come in three main types:
A. Single-floor facilities: These are cheapest to build, but ceiling height can
impose constraints on materials handing solutions, However, even with small,
single-floor buildings, IBCs can be used to achieve full batch transfer from one
process to another, that reduce waste product. Creative use of frameworks can
enable the use of efficient gravity-fed vertical transfer systems.
B. Two-floor facilities: These facilities though more expensive to build, can be
used to separate materials handling and blending on the top floor, from tableting
and packing procedures on the lower floor. This is particularly important for
GMP, where isolating potential contaminants and maintaining quality are
priorities.
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C. Multiple-floor facilities: These are expensive, but with lots of available space
these are highly flexible. However, space can be wasted if due consideration is
not given to the plant layout and overall production flow. These facilities
provide an opportunity to incorporate new technologies to maximize the
efficiency of each production area.
No matter the size or shape of production facility materials handling solutions can
increase efficiency, productivity and revenue, if considered early in the design of a
pharmaceutical manufacturing plant.

7. Sewage Treatment:
In pharmaceutical plant most of wastewater is produced by washing equipment
at the end of the production process and it depends on the production rate. There are
other pollutants includes rejects from reverse osmosis, cleaning of the installations,
effluents from laboratories, etc. In order to treat wastewater and purify, every plant
sets up sewage water treatment plants.

8. Utility Service Department:

The utility systems in pharmaceutical plant help to check the quality and safety of
their products and ensure they comply with the laws and statutes in the FDA dossier.
Utility services include heating: ventilation and air conditioning (HVAC), plumbing,
drainage systems, gas systems, sanitation, water, pesticides etc. Other specialized services
in a factory include compressed gases, water for pharmaceutical use, vacuum, electricity
and room air conditioning. All utilities that could affect product quality are qualified and
appropriately monitored and action is taken when these utility limits exceed.

9. Canteen:
Canteen usually located at the periphery of the industry. Area of canteen depends
on the number of workers employed. The canteen furniture will be in accordance to
GMP. Food may be provided by company which will lead to maintaining a hygienic
cooking facility in canteen. Employees can have their food in the canteen. Cooking
area has to be maintained under total hygienic condition. People involved in
preparation, serving, cleaning of area are to be well trained in each activity like
personal hygiene practices, washing of utensils, cleaning of food materials.
Sanitation is the general problem associated with canteen facility.

10. Warehouse:
The warehouse is responsible for all incoming goods including labelling and packaging
and for releasing finished products. Once a finished product is received into the warehouse, it
does not undergo any further inspections or quality control tests. The warehouse relies upon
procedures and well-trained staff to ensure that products arrive safely and with the same
quality as when they left manufacturing. It is managed and run-in compliance in order for the
plant to protect and distribute a quality product. These compliant practices include control
over receiving goods, QC, storing materials, components and products, fulfilling picking
requests and shipping the product to the marketplace.

11. Scrap Yard:

During working in the industry, large amount of waste material or scrap is generated. This
includes the empty cartons in with raw material or packaging material is plastic sheets,
discarded powders, discarded or rejected products, printed packaging materials, machinery/
equipment’s or parts of machinery/equipment’s. The most common method employed for
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destruction of these materials is incineration. All materials moved to the scrap yard are
documented systematically; and the record of destruction is maintained. Security measures
taken to prevent thefts of any material stored in scrap yard.

Activities
The pharmaceutical industry comprises of companies involved in the research and
development, manufacturing and supply, and commercialization of new therapeutic
products working to bring the right treatment to the right patient at the right time.

1. Research and Development (R&D):

R&D is one of the critical activities in drug development in the pharmaceutical plant.
The department is able to research and analyse the products other businesses are creating,
as well as the new trends within the industry. It is responsible for creating new
medications that physicians use to treat their patients.
A. Drug discovery: It is the process by which new disease or sickness-fighting
compounds are screened and identified. This is the first step in new drug
development. During this phase, compounds are identified and tested in-vitro and
through preclinical testing to demonstrate preliminary for desired efficacy, stability
and bioavailability.
B. Clinical trials: The testing phase of a new drug in human clinical trials is a lengthy
and expensive affair. The regulatory authorities demand that potential drug must pass
through these trials to demonstrate safety and baseline efficacy. The phase I and
Phase Il involve only small sample groups of volunteers while the Phase Ill involves
a sample size of thousands of volunteers. Generally, Phase Ill trials need to
demonstrate that a potential drug meets the necessary efficacy requirements with a
95% statistical certainty.
C. New drug approval: In this activity approval to new drug is obtained from
regulatory body to bring a drug to market, upon a successful round of clinical trials.
The regulators review rigorous statistical data analysis and test results produced
during the clinical trials. Some drugs may be "fast-tracked" if they treat a serious
condition that does not currently have many viable treatment options, for example,
vaccines to treat Covid-19. After a new drug has been approved, it is taken to large
scale manufacturing.
D. Post-marketing monitoring: Pharmaceutical manufacturers collect data on the
efficacy and use of a drug product after it is approved, manufactured and distributed
for use. They monitor products for safety, long-term side effects and potential
secondary uses for the drug. This activity can identify additional clinical value, such
as new methods of delivery, combination of treatments, new uses, patient targeting,
etc., for approved drug.

2. Manufacturing:
The Pharmaceutical manufacturing activity is done to produce drugs on an industrial
scale following clinical trials and regulatory approval. In manufacturing, drug substances are
converted into dosage-form products. The process of manufacturing pharmaceutical products
includes many unique components that include mixing of active drug substances with
pharmaceutical excipients, such as binders, fillers, flavouring and bulking agents,
preservatives and antioxidants, etc. These excipients may be dried, milled, blended,
compressed and granulated to achieve the desired properties before they are manufactured
into final solid, liquids and semisolids formulations. In some cases, pharmaceutical
manufacturers may produce active pharmaceutical ingredients (APIs), while other
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manufacturers might purchase APIs in bulk from a third party and prepare them for
consumption by adding certain compounds, binders and/or fillers.

3. Quality Assurance:
In a pharmaceutical manufacturing, quality assurance is involved in several activities
such as purchasing, dispatching, warehousing, operational protocols, manufacturing,
training, quality control, validation and packaging. Quality assurance involves series of
actions which collectively ensure product quality. It establishes specific activities before the
start of production which includes the control factors and product evaluation before
formation of final product. In pharmaceutical manufacturing, quality assurance ensures that
the products are designed and developed in accordance with the requirements of GMP and
GLP.

4. Quality Control:
Quality Control (QC) activity is concerned with sampling, specifications and testing as
well as the organization, documentation and release of the product procedures. This ensures
the necessary and relevant tests carried out for the release of products. The product to be
released for sale or supply should be carried out only after checking their quality. QC is not
confined to laboratory operations, but it is involved in all decisions which concern the
quality of the product. The QC activity is independent of production.

5. Warehousing:
Pharmaceutical warehousing activity preserves the integrity of drug products that affect
the health and wellbeing of people. It includes proper storage of products to prevent
contamination, and to allow for inspection and cleaning of the area. It stores drug products
in a manner that must be identified with a distinctive code, for example, the lot's status can
be identified as approved, quarantined and rejected. This activity involves designing of
written procedures to describe the distribution process, product recalls and appropriate
storage conditions for each drug, respectively. Warehousing ensures that the storage of each
drug is in line with its specific requirements.

6. Packaging:
Pharmaceutical packaging operations are performed with a series of integrated machines
and repetitive manual tasks. Finished products are packaged in different types of containers
such as plastic or glass bottles, foil blister packs, pouches or sachet tubes and sterile vials.
The mechanical equipment fills, caps, labels, cartons and packs the finished products in
shipping containers.

7. Product Education and Compliance:

The product compliance activity involves final licensing of a drug after clinical trials
and the subsequent labelling, education and information management related to that
product. It ensures that products are labelled in accordance with requirements set forth by
the FDA and fact-check marketing/promotional materials that are used to market the drug to
physicians and potential patients. In some cases, the product compliance group may audit
company operations such as manufacturing, drug testing, etc., to ensure that all operations
are in compliance with industry regulations.

8. Laboratory Activities:
Laboratory operations in the pharmaceutical industry may pose biological, chemical and
physical hazards, depending upon the specific agents, operations, and equipment and work
 87

practices employed. Lab workers may conduct scientific research to discover drug
substances, develop manufacturing processes for bulk chemical and dosage-form products
or analyse raw materials, intermediates and finished products. Lab activities are evaluated
individually, although Good Lab Practices (GLPs) are applied to many situations.

9. Cleaning and Maintenance:

Workplace and equipment surfaces may be contaminated by hazardous materials
and drug substances during manufacturing and thus requires them to be cleaned.
Cleaning activity is performed by washing or wiping liquids and sweeping or vacuuming
dusts. Wet mopping and vacuuming are usually used that reduces worker exposures to dusts
during cleaning.

10. Pharmaceutical Distribution:

The distribution activity within the pharmaceuticals industry is responsible for supplying
drugs to retail medical shops, hospitals and other healthcare facilities through Supply Chain
Management (SCM) to satisfy customer requirements as efficiently as possible. SCM
contributes in reducing cost of production and distribution through elimination of waste,
compliance with standards and quality, promoting ethical sourcing, curbing unethical
practices. In most cases, drug distribution is carried out by third parties that link
manufacturers with distributors and retailers including hospital networks.

11. Patient Assistance Programs:

Patient Assistance Programs (PAPs) are initiatives funded by pharmaceutical
manufacturers to distribute free or reduced-rate medicines to people with low to moderate
income or who are underinsured. The eligibility requirements for these programs may vary;
some programs demand that the patient be uninsured, while others require that certain
income levels are met.

QUALITY CONTROL
Quality is the degree of excellence a product possesses with respect to its design and
conformity with certain prescribed standards and specifications; so as to meet customers'
expectations most satisfactorily. Quality control (QC) is an inspection aspect of quality
management. Certain observations on the concept of quality can describe it as subjective,
relative, conditional or dynamic.

Definition:
Quality control can be defined as "part of quality management focused on fulfilling quality
requirements." QC can also be defined as "the operational techniques and activities used to
fulfil requirements for quality."
ISO 9000 defines quality control as "A part of quality management focused on fulfilling
quality requirements".

Concepts
QC involves establishment of quality standards and installation of systems to ensure that
these standards are maintained and practiced. QC analysis regularly checks various quality
parameters at each step to produce good quality products. In order to implement an effective
QC program, an organisation first decides which specific standards the product or service
must meet. Then, the extent of QC actions is determined, for example, the percentage of units
to be tested from each lot. The types of quality control include process control charts, product
quality control and process control. The data such as the percentage of units that fail at
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testing is collected and the results are reported to QC Manager. After this, corrective action is
decided and implemented.

A. Steps in Quality Control:

1. Establishing quality standards: In this step quality standards are established in
terms of size, design, durability, appearance, etc., on the basis of customers'
preferences and cost of production.
2. Selecting the manufacturing process: The selection of step in manufacturing
process permits output of the required specifications.
3. Development of measurement techniques: This step helps to ensure whether
production conforms to set specifications or not.
4. Monitoring product quality: This step of QC designs a system in order to
periodically check end products to determine deviations from set quality standards
and locates causes of such deviations.
5. Taking corrective action: This step is employed to remove causes of deviations.

B. Significance of Quality Control:

1. Cost reduction and profit maximization: QC helps to better utilize productive
resources; and eliminate all sorts of wastes. Ultimately it helps to reduce cost and
maximize profit for the organisation.
2. Increase in operational efficiency: As QC implies control over quality of raw
materials and performance of operators and equipment’s, etc., it brings about more
operational efficiency of the organisation.
3. Maximum profit and customer satisfaction: QC minimize complaints from
customers and results in maximum customer satisfaction. Quality help to bring
customers back for a repeated purchase that leads to increased sales and consequent
increased profit.
4. Image of the organisation: QC builds goodwill of the organisation in society. The
quality products offered by the organisation establishes an image in the eyes of the
public.
5. Insurance against heavy losses: QC protects the manufacturer against heavy losses
due to rejection of large quantity of sub-standard products.
6. Promotes employees' productivity: QC develops a feeling of quality consciousness
among employees; that help to promote their productivity.
7. Morale of employees: QC increases morale of employees; as they feel that they are
working for an enterprise producing goods of superior quality.

C. Techniques of Quality Control:

1. Inspection: Inspection in QC programme is concerned with checking on the
performance of items to the specifications set for it. It involves periodic checking and
measuring before, during and after the production process. Manufacturing involves
several variables; thus, inspection is a never-ending process.
i Centralized inspection: In this type of inspection, all the work from a department
is sent to the Inspection Department, before passing on to the next operation. It
ensures impartial supervision; because the inspector is not under the stress of not
rejecting the work of a person with whom he has good personal relation. It is easier
to keep records of items which are approved or rejected.
ii Floor inspection: In this inspection, inspectors visit the production floor and
inspect ongoing operations of the machines, also known as patrolling or traveling
inspection. Since work is inspected on the floor, the delay in sending work to next
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station is avoided. Inspector can immediately locate the fault and suggest
rectification. It involves minimum material handling.

2. Statistical Quality Control (SQC): SQC is a system for controlling the quality of
production within the specified -limits by means of a sampling and analysis of
inspection results. It determines the extent to which quality goods are being met
without necessarily checking every item produced and for indicating whether or not
the variations which occur are exceeding tolerance limits. SQC is not to produce a
quality product but is merely informing the management about actual status of the
operations. It helps to make decision for rejection or acceptance of a particular
product. Management takes necessary steps to eliminate the causes of variations, if
any, and ensure production of quality products. The techniques of SQC are:
i. Process control: The quality characteristics under process control are checked
with the help of charts, for example, X-Chart, R-Chart, C-Chart and "-Chart,
which help to provide visual aids. These charts are easy to prepare and give early
warning of problem. All these charts represent how quality-characteristic is
changing from one sample to another. When a plotted point falls outside the
control limits (UCL: upper control limit and LCL: lower control limit) a process is
said to be out of control and an action to check and correct the process is initiated.
ii. Acceptance sampling: Acceptance sampling is used for receipt of materials and
dispatch of finished goods. Acceptance sampling plans are best suited when the
processes used in manufacturing remain unchanged. The decisions about the
quality of batches (accept or reject) are made after inspection of samples. If the
sample from the batch of products complies with quality specifications, it is
accepted and vice-versa. There is possibility that a lot of satisfactory quality is
rejected on the basis of sample result, called producer's risk. Similarly, the
consumer may accept a lot of unsatisfactory quality, called consumer's risk.
Acceptance sampling is advantageous when 100% inspection is not possible and
useful when inspection may cause damage or complete destruction. It is less
expensive than 100% inspection,

------------------------------------------------ UCL
Quality scale

Average

LCL

0 1 2 3 4 5 6 7 8 9 10
Sample number

Control Chart

Advantages of SQC:
1. The costs of inspection are greatly reduced.
2. Gives an early warning of defects during production operations.
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3. SQC techniques are simple and require no highly skilled operators.

4. It provides continuous inspection of the product during production.
5. It enables a process to be held in a state of statistical control.

QUALITY ASSURANCE
Quality is simply stated as "Fit for use or purpose." It is all about meeting the needs and
expectations of customers with respect to functionality, design, reliability, durability, price of
the product, etc., Assurance is a positive declaration on a product or service, which gives
confidence. Assurance provides a guarantee that the product will work without any problems
as per the expectations or requirements. Together quality and assurance as Quality Assurance
(QA) focuses on improving the pharmaceutical product and its development process to make
it efficient and effective as per the quality standards defined for respective pharmaceutical
product.
According to WHO, quality assurance is a wide-ranging concept covering all matters
that individually or collectively influence the quality of a product or service. As a result, the
term Total Quality Management (TQM) was adopted in most of the industries. With regard to
pharmaceuticals, QA can be divided into development, quality control, production,
distribution, and inspections.

Definition
 QA, also called QA testing, is defined as a procedure to ensure the quality of
pharmaceutical products or services provided to the customers by an organization.
 ISO 9000 defines QA as "part of quality management focused on providing confidence
that quality requirements will be fulfilled".

Concepts
QA is any systematic process of determining whether a product or service meets
specified requirements. It helps to give high-quality product that builds trust and loyalty
with customers. The standards and procedures defined by a QA program help to prevent
product defects before they arise. QA approaches are employed during every stage of a
drug's development. The QA process includes reviewing documents, approving
equipment, calibration, reviewing training records, reviewing manufacturing records and
investigating market returns.
QA process has a defined cycle called PDCA cycle. The phases of this cycle are plan,
do, and check and act (PDCA). These steps are repeated to ensure that processes followed
in the drug's development and manufacturing are evaluated and improved periodically,
a. Plan: In this phase, organizations pain and establish the product, process and
service-related objectives and determine them to deliver a high-quality end
product.
b. Do: In this phase, product, process and services are developed and tested and
necessary changes are made (do).
c. Check: In this phase, product, process and services are monitored and modified to
check whether it meets the predetermined objectives.
d. Act: In this phase necessary actions implemented to achieve improvements in the
product, process and service.

Plan

Act Do

Check
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An organization uses QA to ensure that the product, process and services are designed and
implemented with correct procedures. This helps reduce problems and errors, in the final
product.

A. Functions of QA:
1. Technology transfer: Product design document is prepared and trial and error data
collected and evaluated. The documents are distributed, checked and approved.
2. Validation: In validation, validation master plan (VMP) for the entire system is
prepared and resource planning for execution is done. Test criteria for approval of
validating product and process are set,
3. Documentation: It controls the distribution and archiving of documents. Any change
in a document is made by adopting the proper change control procedure. It also
involves approval of all types of documents.
4. Assuring product quality: It prevents mistakes and defects in manufactured products
and avoids problems when delivering process, products or services to customers.
5. Quality improvement plans: Organizations makes to its stakeholders to improve
quality through focused targets and actions.

B. Quality Assurance Methods:

1. Failure testing: This method continually tests a product to determine if it breaks or
fails. For physical products that need to withstand stress, this could involve testing the
product under heat, pressure or vibration.
2. Statistical process control (SPC): This method is based on objective data and
analysis using statistical methods to arrange and control the production.
3. Total quality management (TQM): This method employs quantitative techniques to
continuously make improvements. It depends on facts, data and analysis to support
product planning and performance reviews.

C. Types of Quality:
1. Design Quality: Design quality refers to the level of characteristics specified for a
product. The characteristics associated with high quality product are high-grade
materials, narrow tolerances, special features and high performance. The reliability of
a product is considered in the design stage. It is the probability that a product will
perform its intended function, without failure, for a specified length of time. It
depends upon the basic design, the quality of materials and the quality of components
that go into the final product. To achieve the required reliability, designers need to
specify higher priced components. This may lead to higher price but also to higher
value for the consumer.
2. Conformance Quality: Once the level of design quality has been determined, the
product characteristics are formed into drawings and specifications. The
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manufacturing people use these drawings and specifications to develop manufacturing

specifications and design the operations necessary to produce the product. This
includes the floor layout, machinery, test sets, tools and other equipment. A plan for
the number of employees required may also be included. The quality person works
with the manufacturing person to make the quality system and maintenance of
conformance quality an integral part of the manufacturing process.

D. Quality Systems:
A quality system is a mechanism that co-ordinates and maintains the activities needed to
ensure that the characteristics of products, processes or services are within certain limits. A
quality system involves every part of an organization that directly or indirectly affects these
activities, Typically, the quality system is documented in a quality manual and in the
associated documents that specify procedures and standards. There are three basic elements
in a quality system:
1. Quality management: Quality management is the means of implementing and
carrying out quality policy. Quality management plans goals and manages activities
of QC and QA. Quality management personals monitors that alt quality goals and
objectives are implemented, and corrective actions have been taken.
2. Quality control: QC encompasses all techniques and activities of an organization
that continuously monitor and improve the conformance of products, processes or
services to specifications. QC also includes the review of processes and specifications
and makes recommendations for their improvement.
3. Quality assurance: QA describes all the planned and systematic actions necessary to
assure that a product or service will satisfy the specified requirements. Usually this
takes the form of an independent final inspection. The QA function represents the
customer and is independent of the QC function.

E. The Quality Audit:

A quality audit is an independent assessment that compares various management
activities and quality attributes to a standard. The person performing the quality audit is
not associated in any way with the activity being audited. The types of audits include
management and quality system audits (Manufacturing, software and service), product
specific audits (Manufacturing, software) and activity specific audits (service).
Organizations usually use first-party audits to evaluate their own performance. Second-
party audits are conducted by a customer on a supplier. Third party audits are conducted
by completely separate companies with no personal stake in the audited organization.
Third-party auditors are usually registrars that audit to ISO 9000 series. A customer
usually combines a quality system audit. with a product-specific audit while third-party
audits reviews management and quality system. Quality audits are conducted to assess
and ensure that:
(i) Quality plans, methods and procedures are in place.
(ii) Documents are controlled to avoid misuse.
(iii) Standards and regulations are being followed.
(iv)The data system provides accurate and adequate information.
(v) Problems are addressed and corrective actions are taken.
(vi) Products conform to specification requirements.
Audits should be conducted on a scheduled basis. There should be no surprises to the
organization being audited. This policy should include all those involved to categorize their
workloads and assign personnel to assist in the audit. The audit should not disrupt any
ongoing processes or work.
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F. Quality Management System:

Quality is a measure of excellence or a state of being free from defects, deficiencies and
significant variations. QC is an essential operation of the pharmaceutical industry. QA is
obtaining confidence that, required quality of product or service is satisfactory for their
intended use. QA is a wide concept that covers all aspects that collectively or individually
impact the quality of the product. Quality management is the act of overseeing all activities
and tasks needed to maintain a desired level (if excellence. This includes the determination
of a quality policy, creating and implementing quality planning and assurance, and QC and
quality improvement.
Quality system in the pharmaceutical industry consists of implementing the best Quality
Management System (QMS) within the industry. Quality certification is a general term use
for certifying the knowledge of individuals and certifying a company's system of quality
management- Quality certifications for individuals are available through various
organizations such as the American Society for Quality (ASQ). Certifications are granted to
show that. individuals have demonstrated and maintain knowledge in an aspect of
quality„ management, such as Certified Quality Engineer (CQE), Certified Quality Inspector
(CQI), etc.

G. Quality Assurance Certifications:

The standard ISO 9000: Quality Management Systems (QMS), first established in 1987
helps the organization to ensure quality to their customers and other stakeholders. The:
certification is issued to company upon on auditing its functions, products, services and
processes. The main objective is to review and verify whether the organization follows the
process as expected and check whether existing processes need improvement. The latest
certification in the ISO 9000 series is ISO 9001:2015. This guidance includes a stronger
customer focus, top management practices and improvements to its structure and risk-based
decision-making. This certification helps to increase the profit, improves domestic and
international trade, reduce waste and increase the productivity of the employees and provide
excellent customer satisfaction.

D. Total Quality Management (TQM):

TQM is a management philosophy implemented to all activities through which the needs
and expectations of the customer and community, and the objectives of the organization are
satisfied in the most efficient and cost-effective way by maximizing the potential of all
employees in a continuing drive for improvement. TQM is a means of satisfying customers
first time, every time; enabling the employees to solve problems and eliminate wastage; style
of working, a culture more than a management technique and philosophy of continuous
improvement, never ending, only achievable by/or through people. TQM requires that all
stakeholders in a business work together to improve processes, products, services and the
culture of the company itself. The TQM perspective views quality as the fundamental
objective of the organization.
To be successful through implementing TQM, organizations concentrate on the following
key elements:
1. Focus on the customer: It is essential to identify the organization's customers.
External customers use the organization's product or service. Internal customers are
employees who receive the output of other employees.
2. Employee involvement: Since the quality is considered in the work and
responsibility of all employees, employees should be involved in quality initiatives.
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The leader employees have the closest contact with external customers and thus can
make the most valuable contribution to quality. Therefore, employees must have the
authority to innovate and improve quality.
3. Continuous improvement: The pursuit for quality is a never-ending process in
which people continuously work to improve the performance, speed and number of
features of the product or service. Continuous improvement means that small,
incremental improvement that occurs on a regular basis will eventually add up to
huge improvement in quality.

CURRENT GOOD MANUFACTURING PRACTICES (CGMP)/GOOD

MANUFACTURING PRACTICES (GMP)
 GMP is a part of quality management that ensures that products are consistently
manufactured and analysed as the quality standards appropriate for use and as
required by the marketing authorisation, clinical trial authorisation, or product
specification.
 GMP should be followed by the production department as well as by the quality
control unit.
 GMP is mainly concerned with the management and minimisation of the inherited
risks in pharmaceutical manufacturing, thus ensures the quality, safety and efficacy of
products.

Parts of GMP:
Part I: Good manufacturing practices for premises and materials.
Part IA: Specific requirements for manufacture of sterile parenteral and ophthalmic
preparations.
Part 1B: Specific requirements for manufacture of oral solid dosage forms.
Part IC: Specific requirements for manufacture of oral liquids.
Part ID: Specific requirements for manufacture of topical products.
Part IE: Specific requirements for manufacture of metered dose inhalers.
Part IF: Specific requirements of premises, plant and materials for manufacture of
drugs.
Part Il: Requirements of plant and equipment.

Under GMP:
i. All the processes involved in manufacturing of pharmaceutical products clearly are
defined, systematically reviewed for associated risks according to the scientific
knowledge and experience.
ii. Thus, GMP also ensures that current manufacturing process is capable of
manufacturing pharmaceutical products of required quality that comply with their
specifications.
iii. Qualification and validation of the product are performed.
iv. All required resources are provided, including
a. A qualified and trained personnel,
b. Sufficient space and adequate premises,
c. Required equipment and services,
d. Appropriate materials, containers, and tables,
e. Approved procedures and instructions,
v. The personnel are trained to carry out all the manufacturing processes correctly.
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vi. During manufacturing processes, records are either made manually or by recording
instruments to describe that the steps taken are as per the defined procedures and
instructions, and even the quantity and quality of the product are as expected.
vii. Any significant deviations are recorded and investigated with their root cause. Along
with this, appropriate corrective and preventive measures are implemented.
viii. Records of manufacturing and distribution are maintained in an accessible form so
that the complete history of a batch can be traced.
ix. Proper storage conditions and distribution of the products reduce any risk to their
quality and takes account of Good Distribution Practices (GDP).
x. A system is available to recall any batch of product from sale or supply.

Introduction to Concept of Calibration

 Calibration is a set of operations that establishes relationship between the values
indicated by an instrument or system for measuring (e.g., weight, temperature, and
pH), recording, and controlling, or the values represented by a material measure and
the corresponding known values of a reference standard, under specified conditions.
 Acceptance limits for the results of measuring should also be established.

Important Definitions:
i Calibration procedure: A documented, verified, and validated process that describes
a set of operations in accordance with a given method.
ii Calibration provider: Laboratory or facility including personnel that performs
calibration in an established location.
iii Errors: Result of a measurement minus the true value of the measurand.
iv Reference standard: Measurement standard having the highest metrological quality
available in an organization.
v Uncertainty of measurement: Dispersion of values that can be attributed to the
measurand.

General Principles of Calibration

Calibration is the process of adjusting an instrument or equipment as per the manufacturer's
specifications. Calibration is also defined as the process of issuing data including a report or
certificate of calibration that ensures an end user of a product's conformance with its
specifications.

Calibration Procedure:
The calibration procedure involves comparison of the instrument against primary or
secondary standards. Sometimes, it is sufficient to calibrate a device against another device
of known accuracy. After the calibration of a device or a process, future operation is
considered to be error bound for a given period of time under similar operational conditions.
The process of calibration is carried out in a hierarchical order.
i Highest level
ii Second level
iii Third level

Calibration Purpose:
i If the instrument reads in the same units as the reference standards, the purpose of
calibration is to eliminate biases and minimize the instrumental errors.
ii If the instrument reads in different units than the reference standards, the calibration
serves the purpose of converting the instrument readings to the units of interest.
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Advantages of Calibration:
1. It determines validity of measurements before the calibration.
2. It assures consistency and compatibility with those made elsewhere.
3. It helps to test repeatability and reproducibility features of the instruments and
processes.
4. It provides confidence that products meet their specifications and are of desired
quality, thus reducing costs and legal liability.
5. It increases process and product efficiency through correct measurements.
6. Calibration of devices in the process industry help to assure that the processes are
well controlled and that the products meet set specifications.
Calibration Personnel:
The calibration is conducted by trained and skilled personnel who are essential to the
precision of the calibration. Personnel performing equipment calibration is certified to have
the qualifications necessary to perform the required calibration. These qualifications are
based on training and experience. Calibration personnel may need to have appropriate
clothing (static free clothing, gloves, face masks, etc.,) for safety as well as to avoid the
possibility of contamination.

Calibration services:
All the testing and measuring instruments are calibrated at reputed laboratories which
have a set of precise reference standard, instruments and facilities backed up with well
qualified and experienced personnel. These institutes provide good, most accurate and
reliable calibration services with due traceability. Some of them provide facilities such as
identification of instruments for calibration, at site calibration, single window calibration
service, calibration of special instruments and after calibration service. In order to calibrate
instruments through outsourcing details such as name and type of the instruments, make,
model and the year of manufacturing, operational range with least count and accuracy,
relevant standards or calibration procedure (specialized and critical instruments) and general
information about customer organization must be provided.

Costs of Calibration:
A successful calibration process re-quires hardware and software, special equipment,
and manpower; hence the costs vary depending on intensity of use of these variables. The
cost of calibration depends on what is calibrated and who is calibrating it. In simple cases
where a one-off instrument is involved, cost can be lower than one hundred rupees, but
complex cases can cost thousands of rupees. Calibration cost depends on whether the
calibration is carried out on the premises of calibrating laboratories or on the factory floor
being outsourced to third parties.

Introduction to Concept of Validation

 Validation is the establishment of documented evidence to provide a high degree of
assurance that a planned process will perform according to the intended specified
outcomes without failing.
 These guidelines cover the general principles of validation and qualification, and also
appendices on validation and qualification (e.g., cleaning, computer and computerised
systems, equipment, utilities and systems, and analytical methods).

The following principles apply:

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i. Execution of validation should be in compliance with regulatory expectations.

ii. Quality, safety and efficacy should be designed and built into the product,
iii. Quality cannot be inspected or tested into the product,
iv. Quality risk management principles should be applied in determining the need, scope
and extent of validation, and
v. On-going review should ensure that the validated state is maintained and
opportunities for continuing improvement are identified.

Importance and Scope of Validation

 Validation is a systematic approach where it is confirmed that any process in a
pharmaceutical facility will operate within the specified parameters as per the
requirement.
 This is possible by collecting and analysing data.
 Validation assures that the processes will produce reliable and repeatable results
within the predetermined specifications.
 Validation verifies whether or not a product in every pharmaceutical facility is
conforming to the quality standards and compliance.
 It also establishes that the facility is following the CGMP guidelines set for the
industry by the authorised regulatory bodies.
 Validation is thus a documented evidence of the process conducted as per the
predetermined specifications.

Departments and Authorities for Validation:

i. Site validation committee: To develop site master pair,
ii. Manufacturing department: To prepare batches and assist in data collection,
iii. QA department: To approve the process protocol, review and ensure documentation,
procedure and reports are in place and compliances.
iv. QC department: To perform testing and generate reports.
v. R&D department: Designing the product and its development.
vi. Engineering department: Installation of equipment’s, ensure quality and certify plant,
facilities, equipment and support systems,
The authorities responsible for validation to execute are Heads of QA, QC and Production,
and Validation departments.

Types of Validation
i. Process Validation
ii. Cleaning Validation
iii. Method Validation:
iv. Computer system Validation
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CHAPTER-7
NOVEL DRUG DELIVERY SYSTEMS

Introduction
Novel drug delivery system (NDDS) is for delivery of drug other than conventional drug
delivery system. NDDS refers to the approaches, formulations, technologies, and systems for
transporting drugs in the body as needed to safely achieve its desired therapeutic effects.
NDDS are carriers which maintain the drug concentration in therapeutic range for longer
period of time within the body. It is a combination of advance technique and new dosage
forms which are superior to conventional dosage forms. These systems are net result of
outcome in search of efficacious treatment of severe diseases.
Advantages of NDDS include optimum dose at the right time and right location, efficient
use of expensive drugs and excipients, and reduction in production cost, beneficial to
patients, better therapy, improved comfort and standard of living. Basic modes of NDDS are
targeted, controlled and modulated drug delivery systems. Factors affecting the design of
controlled release products include physicochemical properties of a drug, route of
administration, acute / chronic therapy, target sites, the patient and the disease state/level.

Classification
Sustained and Controlled Release Drug Delivery
i. The rate at which a drug is released from resonate is dependent on several factors. In
various cases, to control the resultant effect or sustain the release of medicine over
several hours, the rate is made suitably slow.
ii. Further medication can be attained by the use of coatings that limit the release.
iii. Control the site of release Dextromethorphan (coated), diclofenac and nicotine are
examples of the drugs using this technique.
iv. Another advantage of this technology is that the drug does not needs to be in
crystalline form.

Microencapsulation
i. Microencapsulation is a process where small droplets or particles of solid or liquid
substances are covered by a nonstop film of polymeric materials.
ii. By delivering the active agent at optimal rate to the target tissue and causing slight
toxicity and east side effects, the maximum therapeutic value can be attained Delivery
of a drug in a sustained controlled release way is done by microsphere as carriers for
drugs.
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iii. In the microencapsulation, the covering of the particles is reaching dimensionally

from some tenths [of a micron to 5000-micron size.

Parenteral Controlled Release System

i. The parenteral route of administration is the most common and effective way for
delivering drugs with low bio availability and fine therapeutic index.
ii. Therefore, the drug therapy will not only benefit compliance, but also improve the
quality of the therapy when the frequency of injection will be reduced.
iii. This reduction in the entire number of drug dosing is reached by the use of a
formulation technology that promises the release of the drug is in a controlled manner
twice monthly or even less frequently.
iv. In addition, humanising patient comfort and reducing the frequency of injection of
drugs in the form of depot formulation are the objective of parenteral controlled
release system.
v. The depot formulations are likely to not only boost the therapeutic profit but also to
lessen unwanted side effect.

Buccal Drug Delivery System

i. Buccal region deals with suitable route of administration for systemic drug delivery
from the various transmucosal available sites.
ii. For the purpose of delivery of the therapeutic agents for both Buccal as well as
systemic delivery used as retentive dosage forms, buccal cavity mucosa is the most
convenient and available site.
iii. Mucosa is relatively permeable because of rich blood supply.
iv. The Buccal drug delivery system includes fast dissolving tablets, sublingual tablets,
chewing gum, buccal patches.

Transdermal Drug Delivery Systems

i. Transdermal drug delivery system delivers the drug through the skin at a controlled
rate to the systemic circulation when distinct dosage forms is applied on the intact
skin.
ii. Topical use has been applicable for centuries, mostly in the treatment of localised skin
ailments.
iii. Native treatment requires only the drug permeation through the outer layer of the skin
to treat the diseased state, hoping that this occurs with slight or no systemic
accumulation.

Ocular Drug Delivery System

i. The complication of the eye provides unique difficulties to drug delivery plans,
Conventional eye drops, used for treating many ocular diseases has several
disadvantages.
ii. Elderly patients, children and even practised users injure their eyes upon contacting
with the bottle tip leadings to bacterial contamination.
iii. Preservatives also cause morphological alterations to vital parts of the eye such as
conjunctiva, cornea and tendon resulting in alteration of scarring behaviour after
glaucoma surgery.
iv. For maintaining chemical stability of the drugs used preservatives and pH regulations
are added. Both of them lead to enhance tear flow causing poor pharmacokinetics of
eye drops due to dilution of the active moiety.
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v. Preservatives persuade irritation like tearing, stinging. hyperaemia, burning and

allergy and punctuate dermatitis, a common ocular reaction of usual eye drops.
vi. In common drug supply devices like the NODS (new ophthalmic drug delivery
system) an accuser is demonstrated to be harmless and tolerated in the human eye and
are proficient delivery system.

Nasal Drug Delivery Systems

i. Nasal administration provides an interesting and promising different technique for
reaching the systemic drug effect to the parenteral route Now a day, as compared to
oral administration many drugs have improved systemic availability through the nasal
route.
ii. Biotechnological expansion has led to the development of new and large amount of
protein and peptide frogs for managing several ailments Oral administration is not
possible because drugs knowingly degrade in the GIT or rendered metabolised by first
pass effect in the liver.
iii. Intranasal drug delivery provides a capable alternative of administration route for
such drugs.
iv. Nasal drug delivery systems are suitable when confined and hitched blood brain
barrier has to be crossed so that drug can be supplied to the biphasic of CNS.
v. It is also used for the administration of vaccines.
vi. It is used for therapeutic purposes as it provides rapid systemic drug absorption and
quick onset of action because of anatomical, physiological and histological
characteristics of the nasal cavity.

Pulmonary Drug Delivery Systems

i. Pulmonary route is used to treat respiratory diseases for centuries.
ii. The use of leaves from plants, vapours from aromatic plants, balsams and myrrh was
done in ancient inhalation therapies.
iii. The development of a safer inhalation therapy depends on the pharmacological
activity of molecule and the delivery system applications.
iv. The respiratory tract is open to a fairly very huge number of biological and non-
biological particles.
v. A characteristic of the effective lung defence mechanism is that healthy people's
lungs are sterile below the larynx.
vi. In the management of obstructive respiratory disease.
vii. The pulmonary route is the best alternative to other routes since it can minimize the
required dose.
viii. At its worst, it can be a barrier for patient compliance with the specific drug regime
vital to most effectively treat the disease, since certain patients pick irregular
treatment or no treatment at all when encountered with recurrent injections.

Intra-Uterine Drug Delivery Systems (IUD)

i. IUD is a little plastic contraceptives device that is gently introduced into the uterus
(womb) by either a physician or nurse practitioner IUD are about 98- 99% operational
in avoiding pregnancy and one type of IUD stays place for up to 10 years before
needing to be replaced
ii. Once inserted, the IUD is instantly effective and when removed, its contraceptive
effect is instantly stopped The IUD may affect the manner the sperm or egg moves
and it prevents the egg and sperm from uniting (fertilization).
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iii. The copper IUD causes thickening of the cervical mucus, forming a barrier that averts
sperm from entering the uterus.
iv. For most women, IUD is very safe and effective: The IUD is an excellent choice for
a female who has children and wants long term, but not permanent contraception.
v. The IUD is a good choice for females who cannot take birth control pills, use DEPO
power or Norplant and who choose not to use a barrier method of contraception like
diaphragm or vaginal foam.

Gastrointestinal Drug Delivery System

i. Not all drugs are absorbed consistently throughout the GIT is chief limit in orally
controlled release drug delivery system However, some drugs are absorbed habitually
through gastrointestinal tract.
ii. Some drugs are absorbed in exact proportion of gastrointestinal tract or to an altered
extent in several segments of gastrointestinal tract Such drugs have an " absorption
window".
iii. So, the drug released in the region proceeding and in close nearby area to the
absorption window is accessible for absorption.
iv. Later crossing the absorption window, the released drug goes to waste with slight or
no absorption.
v. This severely reduces the time available for drug absorption and bounds the victory of
delivery system These concerns have led to the growth of oral Gastro Retentive
Dosage Forms (GRDF) possessing gastric retention capability.
vi. One of the most viable approaches is to regulate the gastric residence time (GRT)
using GRDF that offer a new and better choice in drug therapy for achieving a
prolonged and expected drug delivery profile in gastrointestinal tract.
vii. Dosage forms that can hold in stomach are called gastro retentive drug delivery
system.

Targeted Drug Delivery System

i. It is for delivery of drugs to part or organ or the receptors of body to supply the drug
entirely. Two distinct approaches based on this definition are:
a. The drug is directly selected for the target site where it is concentrated and
shows its reaction.
b. The chemical agent is steadily offered but is active and/or activated only at the
target site.
ii. Targeted drug delivery study is done on area that concentrates on the development
and estimation of systems with precise features.
iii. The features can be of selective or regional drug delivery, controlled drug delivery, or
the combination of all.
iv. Targeted delivery system is made available for routine use.
v. It is important to critically establish the evaluation procedures and the benefit over a
conventional dosage form, if any, is documented.
vi. The progress of preclinical estimation of microsphere, drug conjugates, liposomes and
alike systems.

Brain Targeting Drug Delivery System

i. It is aiming of drug to a specific site of the brain for the preferred duration to obtain
pharmacological action.
ii. The brain is a gentle and composite organ in the human body and progress has built
extremely capable ways to guard it.
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iii. It would not add up for brain to become the site of infection and immune response.
iv. Incredible improvements in brain targeting research in the world's leading cause of
disability, brain and central nervous system disorders comprise new hospitalisations
and prolonged care than other diseases altogether.

Nanocarriers Drug Delivery System

i. In about 90% of all drugs, the active elements are in the form of the particles.
ii. Now it is possible to prepare drug nanoparticles by a range of new ways with the
expansion in nanotechnology.
iii. Nanotechnology is often useful in fibre, textiles, agriculture, electronics, forensic
science, space and medical therapeutics namely disease discovery.
iv. Controlled drug delivery, as biosensors in tissue engineering and so on.
v. Nanoparticles drug formulation decreases the patient costs and risks of toxicity.
vi. Nano capsulation of drugs (nanomedicines) raises drug efficacy, specificity, and
therapeutic index of corresponding drugs,
vii. New drug delivery pathways can be used to enhance drug efficacy and reduce side
effect. For better growth of the nanoparticulate systems, it is vital to know the
pharmaceutically relevant properties of nanoparticles.

Proteins and Peptides

i. The most common route of protein and peptide drug delivery is parenteral However,
the route is related to pain on administration causing poor patient compliance and the
preparation needs to be sterile.
ii. Drugs inserted by the gastrointestinal route are likely to undergo acid hydrolysis and
extensive gut and/or hepatic first-pass metabolism
iii. Thus, these protein drugs may show poor oral bioavailability Non- invasive mucosal
and transdermal delivery route is partial to potent drugs while lipophilic composites
do not give rapid blood levels and are less permeable than oral mucosa Various
absorption mucosa have been known and explored for systemic drug delivery
including nasal, ocular, pulmonary, rectal vaginal mucosa.

Implantable Drug Delivery System

i. These are present beneath the skin as a tiny colloid particle and are unknown to the
patient.
ii. They are intended to permit the drugs and fluids into the bloodstream without the
constant inclusion of needles.
iii. Two approaches to this problem appear possible and realistic.
iv. The use of implant electrically driven pumps that can be restocked by simple drug
injection through septum into the pump reservoir is the most important approach.
v. The main disadvantage is the huge size of the device and the requirement for surgical
implantation having the risk of infection.
vi. The use of polymeric systems in future as implants needs more input from polymer
chemistry and allied fields.

Advantages
i. Controlled delivery by sustaining desired drug concentration and controlled rate.
ii. Precise dosing.
iii. Improved efficacy and safety.
iv. Site / Target specific delivery of drug with an optimum dose.
v. Reduced toxicity/side effects.
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vi. Helpful to patients for better comfort and standard of living.

vii. Reduce in the incidence and severity of both local and systemic side effects.

Challenges
i. Delivery of poorly soluble drugs and bioavailability hurdles for poorly soluble
clinical candidates are the major challenges in Drug Delivery Systems.
ii. There are some Novel tactics in the delivery.
iii. Overcoming bioavailability difficulties and Rationale formulation design of poorly
soluble drugs.
iv. Other major challenges in drug delivery are protein drug delivery, paediatric and
geriatric drug supply Self-Emulsifying Drug Delivery Systems (SEDDS) retains
unparalleled potential in refining oral bioavailability of poorly water- soluble drags.
v. The event Pharmaceutical 2016 took dosage form into condemn making it a dosage
form meeting. Despite of having a vast freedom and advantages of NDDS, it also has
some downsides and limitations.
vi. The administration and implementation cost of Nanomedicine is much more costly.
vii. Cytotoxicity of the nanoparticles develops a threat for future.
viii. Due to their much greater cost and complexity.
ix. Nano product is facing greater difficult. For a large number of users, partial
availability and lesser production rate of personalised medicine and device are
challenging.
x. Some innovative and non-invasive supplies improve the patient approval by dropping
the marketed price and production cost which marks product degradation & quality
issue.
xi. Novel drugs given through the oral cavity must possess the risk of enduring acid or
enzymatic degradation or hydrolysis.
xii. Certain medical devices like Nano shell. Nanotube, and Nanopores are difficult to
introduce in the body of some patients, babies, or old people.
xiii. All kinds of drugs or medicines cannot be given through the nanoparticles, carriers or
devices as they cannot be merged in the polymer matric or they can be changed.
xiv. But the scientists and researchers are always trying to overcome the downsides
through their inventions.
xv. It helps in blocking drug supply in tutors.
xvi. It overcomes the challenges and barriers of ocular drug delivery.
xvii. It helps in poorly soluble drugs preparation design.
xviii. It helps in vegetative preparation.
xix. It helps in drug release testing and pharmaceutical equipment.
xx. It is helpful in academy and in industry perspective.