PHARMACEUTICS

CHAPTER 1 – HISTORY OF PHARMACY PROFESSION AND PHARMACOPOEIA

 The word pharmacy was taken from Greek word “pharmakon” meaning drug.
 Various programs are offered in the pharmacy field like B.Pharm, D.Pharm, M.Pharm, MS Pharm
etc.
 Father of Pharmacy – William Procter Jr. He is an American Pharmacist.
 Father of Indian Pharmacy – Mahadev Lal Schroff.
 In ancient period it was believed that physician performed the pharmaceutical work, prepare
the prescription or supervise the preparation of the prescription.
 London Pharmacopoeia became available in India in 1824. This controlled the pharmaceutical
activities in India, therefore Indian community was forced to import drugs from overseas.
 Pharmacy courses were started in India in 1842 in Goa.
 In 1868, first Indian Pharmacopoeia was published.
 In 1939, first issue of Indian Journal of Pharmacy was published.
 In 1941, a post for Hospital Pharmacist was announced at KEM Hospital, Mumbai.
 The Pharmacy Act was enacted in 1948.
 In 1949, Pharmacy Council of India was established.
 Pharmacy is a versatile, dynamic, growing and increasingly diverse professions, one which
creates an excitement because there are so many opportunities for services. It is an old age
profession which has transformed into a hub for ‘Global health Care’ and evolved as
multidisciplinary and multifaceted field in recent times.

PHARMACY AS A CAREER

There is a huge scope in pharmacy field as career –

 ACADEMICS – pharmacists as teachers have various roles to play in teaching institution,
they can teach students, do the research work etc. There is a lot of demands of qualified
teachers in the upcoming time. Teachers make time to get exposure to the
pharmaceutical industry and the practical settings to keep themselves updated.
 REGULATORY AFFAIRS – pharmacists can work in the Drug Control Department in
various sections. The CDSCO (CENTRAL DRUGS STANDARD CONTROL ORGANIZATION) is
the central body in India for drug control. Their task is to ensure the standards of drug
from its making to supply. Drug Inspectors, Drug Controllers etc are there to give
manufacturing approval, market approval for any drug. They also work in drug testing
laboratories with the head department.
 CLINICAL RESEARCH – Clinical Research Organization (CROs) in India provide many job
oppurtunities. They are staffed with highly skilled clinicians, pharmacologists,
pharmacists etc. They do the clinical trials of various drugs, they monitor the
manufacturing of drugs and do the quality assurance of them and also manage the data
of global trials.
  CONSULTANCY – this service can be provided by the highly qualified and experienced
pharmacists. They can provide consultation to various departments regarding
manufacturing, documentation, research, surveys, sales etc.
 MEDICAL TRANSCRIPTION – The B Pharm graduate can work with medical practitioners
to maintain the patient treatment history, the drugs to which the patient is allergic.
 SALES AND MARKETING – pharmacists with pleasant personality and having good
communication skills can opt the job of medical sales representative. Companies also
prefer pharmacy graduates as they have good knowledge of drugs and their effects.
 COMMUNITY PHARMACY – pharmacist act as a mediator in between the patient and the
doctor. Therefore, he can also provide counseling to the patient and can also provide
training to the patient regarding self medication etc.

PHARMACOPOEIA

 Pharmacopoeia is derived from two words “pharmakon” means drug and “poiea” means
to make.
 It is a legal and official book that is issued by recognized authorities that is usually
appointed by government of each country.
 It has list of pharmaceutical substances and formulas along with their description and
standards.
 Many advanced countries publish their own Pharmacopoeia, for example Indian
Pharmacopoeia (I.P.), British Pharmacopoeia (B.P) etc.
 The first Indian Pharmacopoeia (IP) was published in 1955.

INDIAN PHARMACOPOEIA

 Indian Pharmacopoeia is a formally accepted document that contains overall quality and all the
details of drugs or products marketed in India. It also contains specifications of drugs.
 It is published by Indian Pharmacopoeia Commission (IPC).
 During checking the quality of drugs or at the time of any dispute in court, the standards
mentioned in I.P are considered acceptable.
 Indian Pharmacopoeia Headquarter - Ghaziabad (Uttar Pradesh)

S.No of Editions Year of Publication Year of addendum

released
First 1955 1960

Second 1966 1975

Third 1985 1989 (1st) and 1991 (2nd)

Fourth 1996 2000 (1st), 2002 (2nd) and

2005 (3rd)
 Fifth 2007 2008

Sixth 2010 2012

Seventh 2014 2015

Eighth 2018 2019

Indian Pharmacopoeia Committee was formed in 1948 and they formed the Indian Pharmacopoeia in
1955.

First and Second editions in the year 1955 and 1966 respectively.

Third edition was published in 1985 and this included herbal drugs with their quality control parameters.

Fourth edition included antiretroviral drugs and those drugs which had plant origin.

Fifth edition focused on those drugs that were used in National Health Care Programs.

Sixth Edition had 3 volumes, volume 1 had notices, preface, acknowledgements, introductions etc.
Volume 2 contained notices, dosage forms, drug substances, pharmaceutical aids (A to M) etc. Volume 3
contained notices, dosage forms, pharmaceutical aids (N to Z), vaccines, herbal products, blood and
blood related products etc.

Seventh edition had 4 volumes and contained biotechnology products, herbal products, vaccines etc.

Eighth edition is the latest edition of pharmacopoeia. It has 4 volumes having 220 new monographs that
are as follows –

- 170 chemical monographs

- 15 herbal monographs
- 10 blood and blood related products
- 2 vaccines and immunosera for human use monographs
- 3 radiopharmaceutical monographs
- 6 biotechnology derived therapeutic products
- 14 veterinary monographs
- 366 revised monographs and 7 omissions.

BRITISH PHARMACOPOEIA

 It is published annually and contained standards required for maintaining of quality of medical
substances of United Kingdom.
 Its 1st edition was published in 1864.
  Volumes of B.P. –
1. VOLUME 1 and 2 – It consists of medicinal substances.
2. VOLUME 3 – it consists of formulated preparation, blood related preparations,
immunological products, surgical materials, homeopathic preparations etc.
3. VOLUME 4 – it consists of appendices, index, infrared reference spectra.
4. VOLUME 5 – it has veterinary preparations.
5. VOLUME 6 – it consist of CD-ROM version, British Approved names etc.
 The newest edition of B.P was effective from January 2021.
 It contains –
1. 30 new BP monographs
2. 171 amended BP monographs
3. It has much clear design
4. Brief guide on “how to use the BP”

UNITED STATES PHARMACOPOEIA

 It is published annually by the UNITED STATES PHARMACOPOEIA CONVENTION.

 It is published in a combined volume with National Formulary as USP-NF.
 It acts as an official public standard for setting an authority over all the prescriptions, OTC drugs,
healthcare products.

MARTINDALE – THE EXTRA PHARMACOPOEIA

 It is a reference book that has around 6000 drugs and medicines that are being used worldwide,
180,000 preparations, 700 disease treatment reviews etc.
 It was published by Pharmaceutical Press.
 Its latest edition has over 120 monographs including –
1. New antibacterials
2. New antivirals
3. New treatment options for migraine
4. New antidiabetic
5. Antineoplastic agents
6. Novel drugs etc.
CHAPTER 2 – PACKAGING MATERIALS

 Packaging is the science, art and technology of enclosing or protecting the products for
distribution, sale and use.
 Packaging also refers to the process of design, evaluation and production of packages.

COMPONENTS OF PACKAGES –

 CONTAINER – It contains the drug or the material and always remain in the direct contact with
the material.
 CLOSURE – It helps in closing up the material and make sure to eradicate all the air inside it so
that material will not get spoiled and hence helps in the better transportation of it.
 CARTON – It is any box or any other thing in which containers are placed.
 BOX – it is made up of wood, thick material that carries multiple carton or products to prevent
any damage to the internal product.

FUNCTIONS OF PACKAGING –

 Product Identification – packaging helps in better identification of products.

 Product Protection – packaging protects the contents from spillage, breakage or any leakage.
 Product Promotion – packaging also helps in promotion of the products as better packaging
attracts the customers.
 Marketing – packaging and labels can be used by marketers to encourage potential buyers to
purchase the product.
 Convenience – packaging can helps in better distribution, handling, stacking, display sale,
dispensing, and ease of disposal.
 Barrier Protection – it acts as a barrier from oxygen, water, dust etc. It will help in increasing the
overall shelf life of the product.
 Security – packaging seals the products so maintain its overall genuineness and if it gets
tempered it will indicate that something abrupt was done with it.

IDEAL PROPERTIES OF PACKAGING

 They must protect the preparation from environmental conditions.

 They must not be reactive with product.
 They must not impart tastes or odor to the product.
 They must be non-toxic.
 They must meet applicable tamper- resistant requirements.
 They must not cause any product degradation.
 They should ease the product identification.
 They must be according to the size of products.
 They must be easily removable and replaceable.

Selection Criteria –
  On the facilities available – for example pressurized dispenser requires special filling
equipments.
 On the ultimate use of products – the product is packages based on its consumer like some are
used by professionals in hospitals and some are to be used at home.
 On the physical form of the product – for example, solid and liquid drugs need different
packaging materials.
 On the route of administration – for example oral, parenteral, etc.
 On the cost of product – costly products need more sophisticated packaging than others.

TYPES OF PACKAGING MATERIALS

 Glass
 Metals
 Plastic
 Rubber
 Foils
 Fibrous materials, etc.

GLASS AS A PACKAGING MATERIAL

 Glass has been widely used as a drug packaging materials.

 It is composed of sand, soda ash, limestone and cullet.
 Si, Al, Na, K, Ca, Mg, Zn are generally used in preparation of glasses.
 Advantages –
1. They are hygienic and can be sterilized.
2. They are relatively non reactive.
3. They can be easily labeled.
4. They have good protection power.
5. They are transparent.
6. They are available in various size and shapes.
7. They can withstand variety of temperatures.
8. They are economical and easily available.
9. They do not deteriorate with age.
 Disadvantages –
1. It is relatively heavy.
2. Glass is fragile so easily broken.
3. Photosensitive drug cannot be protected in the transparent glass container. Only amber
colored glass can protect photosensitive drugs.
4. Once broken it cannot be joined back.

Types of Glasses –

1. TYPE 1 – BOROSILICATE GLASS –

  It is produced by replacing the sodium oxide by boric acid (B2O2) and some lime by aluminium.
 It is least reactive
 It has high melting point and can withstand high temperature.
 It is resistant to chemical substances.
 Mostly ampoules and vials are made up of this glass.

2. TYPE 2 – TREATED SODA LIME GLASS –

 It is made up from commercial soda lime glass that has been de-alkalized or treated to remove
surface alkali.
 The de-alkalizing process is known as “sulfur treatment”.
 Higher chemical resistance but not as type 1
 Cheaper than type 1
 It is used to make containers for buffered, aqueous solutions with pH below 7.0, dry powders.

3. TYPE 3 – SODA LIME GLASS –

 It is ordinary glass prepared from silicon dioxide, soda ash and lime stone and is generally called
as soda lime glass.
 It is cheapest in quality.
 It is not suitable for alkali products.
 Has average resistance.

4. TYPE NP – GENERAL PURPOSE SODA LIME GLASS –

 It is general purpose glass used for oral and topical preparation.

 It has lowest hydraulic resistance.
 It is suitable for solid products, some liquids and semi solid but not for parenterals.

PLASTIC AS A PACKAGING MATERIAL

 There are mainly two types of plastic one is thermoplastic and other is thermosetting plastic.
 Thermoplastic – on heating they become soft and on cooling they again become solidified. They
are cheap. Example – polyethylene, PVC, polypropylene etc.
 Thermosetting – when heated they become soft but don’t become liquid. Example – phenol
formaldehyde, urea formaldehyde etc.
 Advantages –
a) Low in cost.
b) Light in weight
c) Durable
d) Unbreakable
e) Pleasant to touch
f) Flexible
g) Ease of transportation
 h) Good protection power
i) Leak proof
j) Odorless
k) Able to retain shape
l) Resistant to inorganic chemicals.
 Disadvantages –
a) Low mechanical strength
b) Not completely impermeable to moisture, gases etc.
c) Liable to attract dust and dirt.
d) Can be permeable
e) It can cause adsorption or absorption
 POLYETHYLENE –
a) This is used as high density or low density.
b) Low density is used as squeeze bottle.
c) High density is less permeable to gases and more resistant to oils, chemicals.
d) It is prone to stress cracking in presence of surfactants or vegetable oils, also it lacks in
clarity.
 POLYPROPYLENE –
a) Good resistance
b) Colorless, odorless, with excellent tensile strength.
c) Low permeability
d) Suitable for use in closures, tablet containers, IV bottles.
 POLYVINYL CHLORIDE (PVC) –
a) Inexpensive, clear and stiff
b) Used in rigid packing materials and main component of intravenous bags.
c) Can be easily processed.
d) Poor resistance

METALS AS PACKAGING MATERIAL

 Metal containers are used for canning mainly.

 They are used solely for medicinal products for non-parenteral administrations.
 It is resistant to high and low temperatures.
 It forms an excellent tamper evident container.
 Advantages –
a) They are durable
b) They do not allow light, moisture, gases to pass through them.
c) They are lighter in weight than glass.
 Disadvantages –
a) They are costly
b) They may cause adulteration by shedding particles in the product.
 Metals used for packaging –
 a) ALUMINIUM – it is light yet strong in nature. It provide barrier to light and chemicals.
They are impermeable and easy to work with.
b) TIN – tin containers are preferred for food, pharmaceutical etc. It is most chemically
inert of all the metals.
c) LEAD – lowest cost from all other metals. It is widely used for non-food materials such as
packing ink, paints etc.

RUBBER AS A PACKAGING MATERIAL

 It is excellent material for forming seals, and used to form closures.

 Categories of rubber –
a) NATURAL RUBBERS – it is suitable for multiple use closures for injectable products as
rubber re-seals after multiple insertion of needle. Natural rubber can further classified
as soft rubber and hard rubber. Soft rubber is naturally occurring polymer of monomeric
isoprene, soft rubber when added with carbon black give hard rubber which can be used
for making tyres, tubes etc. Hard rubber is formed by process of vulcanization in which
soft rubber is mixed and warm with sulphur and set into given shape.
b) SYNTHETIC RUBBERS - this rubber is resistant to oxidation, oils and other chemicals.
 Advantages –
a) Provide resistance against acids, alkalis.
b) Helps in better closure of products.
 Disadvantages –
a) Can be oxidized by oils, solvents etc.
CHAPTER 3 – PHARMACEUTICAL AIDS

The substances, which have little or no therapeutic value, but essentially used in manufacturing or
compounding of various pharmaceuticals are known as pharmaceutical aids.

They may be obtained by many sources like animal, vegetables, minerals, synthetic. They are not API
(active pharmaceutical ingredient).

CHARACTERISTICS OF IDEAL PHARMACEUTICAL AIDS:

 Non-toxic
 Non-reactive
 Chemically stable
 Economical
 Require less equipment
 Efficient in use

CLASSIFICATION OF PHARMACEUTICAL AIDS:

A. BASED ON ORIGIN

1. Animal source – gelatin, bees wax, honey, lactose, etc.

2. Plant source – starch, turmeric, acacia, peppermint, etc.
3. Mineral source – talc, silica, calamine, paraffin, etc.
4. Synthetic source – boric acid, lactic acid, povidone, etc.

B. BASED ON DOSAGE FORM

1. SOLID DOSAGE FORMS

 Binders & adhesives – acacia, gelatin, starch paste, povidone, etc.

 Lubricants – talc, stearic acid, vegetable oil, calcium stearate, etc.
 Glidants – starch, corn starch, colloidal silicon dioxide, etc.
 Disintegrants – starch, cellulose, clays, cross-linked polymers, etc.
 Colouring Agents – dyes and lakes.
 Flavours – spray dried and other flavor syrups.
 Sweeteners – mannitol, saccharin, etc.
 Coating materials – capsule coated by gelatin, synthetic polymers, povidone, etc.

2. LIQUID DOSAGE FORMS

 Solvents – water, alcohol, acetic acid, syrups, etc.

 Buffers – phosphate buffer, acetate buffers, citric acid phosphate buffers.
 Antimicrobial preservatives – benzyl alcohol, phenol, etc.
 Antifoaming agents – organic phosphate, alcohol, paraffin oils, etc.
 Thickening agents – methyl cellulose, hydroxyethyl cellulose, etc.
 Humectants – propylene glycols, glycerol, etc.
 Chelating agents – disodium EDTA, citric acid and tartaric acid.
  Emulsifying agent – cetrimide, macrogol esters, etc.
 Sweetening agents – sucrose, sorbitol, sucralase, etc.
 Colours – amaranth, eosin, erythrosine, etc.

3. SEMI SOLID DOSAGE FORM:

 Preservatives – benzyl alcohol, sodium benzoate, propyl paraben, etc.

 Anti-oxidants – butyl hydroxy toluene, butyl hydroxyl anisole, etc.
 Solubilisers – lanolin, cholesterol, etc.
 Gelling agents – pemulen, xanthan gum, etc.

COLOURING AGENTS

Coloring agents are mainly used to impart a distinctive appearance to the pharmaceutical dosage
forms.

REASONS FOR USING COLOURING AGENTS

1. Increases acceptability

2. for identification

3. stability purpose

IDEAL PROPERTIES OF COLOURING AGENT:

 Non-toxic
 Free from harmful impurities
 Have no physiological activity
 Unaffected by light
 Unaffected by reducing or oxidizing agents
 Does not interfere with tests
 Free from taste or odor

CLASSIFICATION:

1. Organic dyes and their lakes

2. Inorganic or mineral colors
3. Natural color or vegetable and animal colors

ORGANIC DYES AND THEIR LAKES

Dyes are synthetic, chemical compounds that exhibit their coloring power when dissolved in a
solvent. Examples include Tartrazine Lemon Yellow, Erythrosine, etc.

Lakes have been defined by the FDA as the “aluminium salts of FD&C water soluble dyes extended
on a substratum of alumina.” Or simply they are the aluminium or calcium salts of any water soluble
food dye.

INORGANIC OR MINERAL COLORS

Stability towards light is an important characteristic displayed by this material. They are obtained
from inorganic materials. The most important application of mineral color in present day is the use
of mixture of red and yellow ferric oxides to give calamine a fresh color. Titanium dioxide is used to
color and opacify hard gelatin capsules.

NATURAL COLORS OR VEGETABLE AND ANIMAL COLORS

This is a chemically and physically diverse group of materials. Some of them are the products of
chemical synthesis rather than extraction from a natural source. For example, beta-carotene is
synthetic in origin.

Natural colors are not as stable to light as compared to other groups. It includes, turmeric,
chlorophyll, saffron, paprika, etc.

FLAVOR/FLAVORING AGENTS

They tend to change the disagreeable taste of drugs into agreeable taste. This will increase patient’s
compliance and make them more sweet or tasty.

This can be done by various products, such as:

 Salty – apricot, butterscotch, peach

 Bitter – chocolate, mint, passion fruit
 Sweet – vanilla, fruits, berries
 Sour – citrus fruits, raspberry

CLASSIFICATION:

 SWEETENING AGENTS:
a. Sucrose – can be used in syrups, elixir, lozengus, etc.
b. sorbitol
c. saccharin sodium
 FLAVORED SYRUPS:
a. Fruit Flavored syrup – like blackcurrant, raspberry, lemon, orange.
b. Cocoa Syrup – it is used for masking the bitter taste of drugs used in pediatrics.
 Aromatic Oils – volatile oils such as caraway, cinnamon, ginger, lemon, orange
 Synthetic Flavors – vanillin, etc.

SWEETNERS/SWEETENING AGENTS

They are added in a preparation to hide or mask the bitter taste of the mixture. Commonly we use
sugar as sweetening agent.

There are mainly two categories of sweeteners – natural and artificial sweetening agents.

- They can be used to sweeten candies, drinks, toothpaste.

- Aspartame used as a table top sweetener.
- They can also be used as preservative
- They also provide viscosity to the product.
PRESERVATIVES

They are the chemical substances used to preserve organic substance from decay or spoilage by
preventing microbial attack. They improve the shelf life or drugs by decreasing or lowering the
oxidation of active ingredients and reducing microbial production.

NEED OF PRESERVATIVE:

- To protect the drug from microbial attack

- To stabilize the product
- To increase shelf life of the product
- To enhance activity and efficacy of drug

PROPERTIES OF IDEAL PRESERVATIVE:

 Must be effective
 Odorless
 Stable
 Non-toxic and non-reactive
 High solubility
 Cost effective
 Tasteless
 Compatible with drug components

CLASSIFICATION OF PRESERVATIVE:

 On the basis of mechanism of action – a. Anti-oxidant

b. Anti-microbial agents
c. Chelating agents
 On the basis of source – a. naturally obtained
b. synthetically prepared

ANTI-OXIDANTS

They are used to reduce the oxidation of active compounds or protect the formation of free radicals
by using their self reducing activity in finished product.

TYPE DEFINITION EXAMPLE

TRUE OXIDANTS These are thought to block Butylated hydroxytoluene

chain reactions by reacting (BHT)
with free radicles.
REDUCING AGENTS They have lower redox Ascorbic Acid
potential than the drug which
they are protecting.
ANTIOXIDANTS SYNERGISTS These enhance the effects of Sodium edetate
other anti-oxidants.

ANTI-MICROBIAL PRESERVATIVES

It is added in a product to minimize risk of spoilage and to kill low levels of contamination that are
induced during storage or repeated use of multi-dose container.

These agents mainly work by inhibiting cell wall, cell membrane growth.

Preparations which contain water are at risk of microbial spoilage such as:

- Solutions
- Suspensions
- Emulsion
- Creams
- Injectable
- Eye drops

Example include benzoic acid, sodium benzoate, methylparabens, etc.

CHELATING AGENTS

They act as preservatives and protect product by forming complex with it preventing its
deterioration. Examples include EDTA, Citric Acid, etc.

NATURAL PRESERVATIVES – they are obtained from nature. Examples are neem oil, lemon, honey.

SYNTHETICALLY PREPARED – they are obtained from chemicals or by any process. Examples include
benzoate, nitrites, etc.

COMMON SIDE EFFECTS OF PRESERVATIVES:

 Hypersensitivity
 Allergy
 Asthma
 Cancer
 Neurological damage, etc.
CHAPTER 4 – UNIT OPERATIONS

Unit operations involve a physical change or chemical transformation such as separation,

crystallization, evaporation, filtration, polymerization, isomerization, and other reactions.

SIZE REDUCTION

It is the process of reducing large solid unit masses into small unit masses. This is also known as
Comminution & Grinding. When the particle size of solid is reduced by mechanical means it is called
as Milling.

The size reduction operation can be divided into two major categories depending on whether the
material is solid or liquid –

 Grinding and cutting – for solid material.

 Emulsification and atomization – for liquid material.

OBJECTIVES OF SIZE REDUCTION:

 Size reduction leads to increase in the surface area.

 Pharmaceutical capsules, insufflations, suppositories and ointments require particle size
below 60mm size.
 To increase the therapeutic effectiveness of some drugs.
 Mixing of powder with narrow size range is easier and uniform.
 Reduce bulkiness of the drug
 Make it more appealing.

FACTORS AFFECTING SIZE REDUCTION:

 HARDNESS – it is easier to break soft materials than the hard materials.

 ELASTIC/STICKINESS – some materials are sticky in nature which make them difficult to grind
as they will stick with various materials.
 HYGROSCOPIC - Certain substances absorb moisture content rapidly. This wet mass hampers
the milling process. Ex: Potassium carbonate.
 FIBROUS - These are tough in nature. A soft, tough material has more difficulty than a hard,
brittle substance. Ex: Raowulfia, Ginger. Here cutters can be used.

METHODS OF SIZE REDUCTION:

 IMPACT – this involve hammer or bar at high speed. (hammer mill)

 COMPRESSION – particles crushed between rollers by the application of force. (roller mill)
 CUTTING – the material cut by a sharp blade (cutter mill)
 ATTRITION – in this method, machine and materials rub against each other and this will lead
to shredding in the size of material. (fluid energy mill)

The common size reduction mills used in pharmaceutical industries are:

 Hammer mill
 Ball mill
  Fluid energy mill
 Disintegrator

HAMMER MILL

It is a type of mill in which large material is crushed into smaller ones.

PRINCIPLE – it operates on the principle of impact between rapidly moving hammers mounted on
rotor and the stationary powder material.

PARTS – it consist of a metal casing, enclosing a central shaft, to which 4 or more swinging hammers
are attached. Lower part of casing consists of a screen, through which material can pass and
collected in a receiver.

CONSTRUCTION & WORKING –

 It is basically a steel drum containing a vertical or horizontal rotating shaft or drum on which
hammers are mounted.
 The hammers swing on the ends or fixed to the central rotor.
 The rotor rotate at a high speed inside the drum.
 The material is put into a hopper which is connected to the drum.
 They are mainly operated at 1000 to 2500 rpm for the reduction of the large sized particles.

APPLICATIONS –

 It is used to grind various materials like sugar, herbal medicines etc.

 It is used to create powder mixtures.

ADVANTAGES –

 It is rapid in action and is able to grind various types of materials.

 They are easy to install and operate.
 There is little chance of contamination of the product.
 The particle size of the material can be easily controlled by us or speed is also controlled by
us.
  Low cost of maintenance.
 It is easy to manufacture.

DISADVANTAGES –

 Heat build up during milling is more, therefore, product degradation is possible.

 Sometimes screen may get clogged.
 They are not suitable for sticky, fibrous or hard material.

BALL MILL

It helps in grinding the drug substances into fine powders.

PRINCIPLE – it operates on the principle of impact and attrition between the rapidly moving balls
and the powder material, both enclosed in a hollow cylinder.

PARTS – it consist of a hollow cylinder mounted on a metallic frame such that it can be rotated along
its longitudinal axis. Cylinder contain balls occupying 30-50% of mill volume. Weight of ball is
constant.

WORKING –

 At low speeds, the ball roll over each other and attrition (rubbing) will be less so small
quantity of material is crushed down.
 At high speeds, balls will move towards the walls of the container, hence there will no
crushing or grinding of the material
 But at correct speed, the centrifugal force throws the ball up and down which will lead to
proper grinding and attrition between them.

APPLICATIONS –

 They are used in cement industries, and in fertilizers industries.

 They can also be used for regrinding purpose.

ADVANTAGES –

 It can produce very fine powder.

 It is used for both wet and dry grinding processes.
 Overall maintenance cost is low.
 It is a closed system, hence less chances of contamination.
 It can be easily seen from outside.
DISADVANTAGES –

 It is very noisy machine.

 It is a slow process
 The machine is of very large size.

SIZE SEPERATION

Special technique is used to separate particles of specified size which is known as the process of size
separation.

Objectives and application of size separation -

 Size reduction of solid material never gives particles of same size, it gives particles of
different size. This material must be subjected to size separation technique to obtain narrow
size ranges.
 It is used for the determination of average particle size.
 The process of size separation is very efficient quality control tool for the analysis of the
powders.
 It will help in in overall dose uniformity.

Mechanism of size separation -

Separation can be done by three methods:

 Agitation
 Brushing
 Centrifugal

Agitation method -

 Oscillation: The sieves is mounted in a frame that oscillates back and forth. It is a simple
method but the material may roll onto the surface of the sieve.
 Vibration: The sieve is vibrated at high speed by means of an electric device. The Rapid
vibration is imparted to the particles on the sieve which helps to pass the powdered material
through the sieve.
 Gyration: In this method, a system is made so that sieve is on a rubber mounting and
connected to an eccentric flywheel. This gives a rotatory movement of the particles on the
sieve, that help them to pass through the sieve.

Brushing method: In this case a brush is used to move the particles on the surface of the sieve and
to keep the meshes clear. The brush is rotated in the middle in case of a circular sieve, but spiral
brush is rotated on the longitudinal axis in case of a horizontal cylindrical sieve.

Centrifugal method: In this method a high-speed rotor fixed inside a vertical cylinder sieve so that
on rotation the particles are thrown out words by centrifugal force. The current of air can be
generated due to high speed of rotor which helps in separating the particles.

Official standards for powders -

The Indian Pharmacopoeia has laid down the standards for powders for pharmaceutical purposes.
The Indian Pharmacopoeia specifies five grades of powder which are as under:
  Coarse powder - powder of which all the particles pass through a sieve a with nominal mesh
aperture of 1.70mm (NO.10 sieve) and not more than 40% through a sieve with nominal
mesh aperture of 335µm (NO. 44 sieve) is called coarse powder.
 Moderately coarse powder - a powder of which all these particles pass through a sieve a
with nominal mesh aperture of 710nm (number 22 sieve) and not more than 40% through a
sieve with nominal mesh aperture of 250mn (no. 60 sieve) is called moderately coarse
powder.
 Moderately fine powder - if all the particles of a powder pass through a sieve with nominal
mesh aperture of 355µm (No.44 sieve) and not more than 40% through a sieve with nominal
mesh aperture of 180µm (No.85 sieve), it is known as moderately fine powder.
 Fine powder - in case all the particles pass through a sieve with a nominal mesh aperture of
180µm (no.85 sieve), it is called fine powder.
 Very fine powder - if all the particles of the Powder pass through a sieve with the nominal
mesh aperture of 125µm (no.120 sieve) it is said to be very fine powder.

SIEVES

They are constructed from wire cloth with square meshes, woven from wires of brass, bronze,
stainless steel or any other suitable material. The wires should be of uniform circular cross-section
and should not be coated or plated. There should not be any reaction between the material of the
sieve and the substance which is being passed through it.

Standards for sieves:

 Number of sieve – sieve number indicates the number of meshes in a length of 2.54cm in
each transverse direction parallel to the wires.
 Nominal size of aperture – nominal size of aperture indicates the distance between the
wires. It represents the length of the side of the square aperture. The I.P. has given the
nominal mesh aperture size for majority of sieves in mm or cm.
 Nominal diameter of the wire – wire mesh sieves are made from the wire having specified
diameter in order to give a suitable aperture size and sufficient strength to avoid distortion
of the sieve.
 Approximate percentage sieving area – this standard expresses the area of the mesh
expressed as a percentage of the total sieve area. It totally depends on the size of the wire
used for any particular sieve number. Generally the sieving area is kept within the range of
35-40% in order to give suitable strength.
 Tolerance average aperture size – some variations in the aperture size is unavoidable and
when this variation is expressed as a percentage, it is known as aperture tolerance average.

SIEVING METHOD:

In this method, the fine powder is separated from the coarse powder by using sieves of desired
number. The degree of fineness of a powder is known with the help of sieve through which the
powdered material is passed. Sieves are numbered in order to distinguish from each other. Sieves
are arranged in descending order that means the larger size sieve will be on top and smaller ones in
the bottom.

CYCLONE SEPERATOR
They are the machines that separate particulate matter from air, gas, or water stream.

PRINCIPLE – in cyclone separator, the centrifugal force is used to separate solids from fluids. The
separation depends not only on the particle size but also on the density of particles. Hence
depending on the fluid velocity, the cyclone separator can be used to separate all types of particles
or to remove only coarse particles and allow fine particles to be carried through the fluid.

CONSTRUCTION – it consists of a cylindrical vessel with a conical base. In the upper part of the
vessel, an inlet is fitted and a fluid outlet and at the base it is fitted with solid output.

WORKING –

The suspension of solid in gas (usually air) is introduced tangentially at very high velocity, so that
rotary movement takes place within the vessel. The fluid is removed from a central outlet within the
vessel. The rotatory flow within cyclone separator causes the particles to be acted on by centrifugal
force. The solids are thrown out to the walls, thereafter it falls to the conical base and discharged
out through solid outlet.

USES – they are used to separate the suspension of a sloid in gas. It can be used with liquid
suspensions of solid also.

ADVANTAGES –

 It require small space for installation.

 It has low maintenance cost.
 It can operate even on high temperatures.

DISADVANTAGES –
  Operation cost is high.
 It can’t be used for sticky materials.

MIXING

It is a process in which two or more ingredients are mixed together. It is the most important unit
operation out of all.

ADVANTAGES/APPLICATIONS OF MIXING:

 To obtain uniform composition of the mixed components.

 To enhance physical & chemical reaction of mixed components.
 To improve dissolution & diffusion of mixture.
 To get true solution after mixing two miscible liquids.
 Mixing is essential to produce emulsion when two immiscible liquids are mixed together
with emulsifying agent.
 To produce a solution after mixing a solid with liquid.
 To produce semisolid products like ointments, suppository after mixing a solid or liquid with
semisolid base.
 Mixing is essential in manufacturing of tablets & capsules to get mixture of solid powders.

TYPES OF MIXTURES:

 POSITIVE MIXTURE – mixtures formed from two or more miscible liquids or gases through
diffusion process are positive mixtures. Such mixtures require no energy & creates no
problem. E.g. solution, syrup, etc.
 NEGATIVE MIXTURE – mixtures formed from immiscible components like solid and liquid to
form suspension or emulsion are negative mixtures. Such mixtures require more energy and
may separate out. E.g. suspension, emulsion, etc.
 NEUTRAL MIXTURE – mixtures formed from different components like solid and liquid to
form static mixtures are neutral mixtures. Such mixtures do not easily mix but once mixed
they do not separate easily. E.g. paste, ointments, etc.

FACTORS AFFECTING MIXING:

 Nature of product – for mixing, particle surfaces should be smooth. Rough surface of
components lead to increase chances of entry of active ingredients into the pores of another
one which will block mixing.
 Particle size – it is easier to mix powders of same particle size. Variation in particles sizes
leads to improper mixing.
 Particle charge – some particles due to electrostatic charges exert an attractive force which
leads to separation.
 Proportion of materials – it is easy to mix powders available in equal quantities. But to mix
small quantities of powders with large quantities of ingredients is a difficult process.
 Viscosity – increase in viscosity leads to poor mixing.
 Temperature – it also affects the mixing process.
  Mixing time – the mixing time is also very important for appropriate mixing. There is always
an optimal mixing time for the specific conditions in which mixing take place.

DOUBLE CONE BLENDER

It is a machine that is used to mix or blend granules or dry powders. They are made up of stainless
steel. It has different capacities depending on the need.

PRINCIPLE – it involves axial mixing as the powder moves in different direction. The blending will
totally depend on the speed of rotation.

CONSTRUCTION – it has two cone-shaped blenders. They are joined together at the base. It is
supported by two lateral supports. One of them is connected with driving motor.

WORKING –

 In this, powder is filled upto two-third of the blender.

 Rate of rotation is 30-100rpm.
 Mixing occurs due to rotational motion.
 Product can be discharged from the bottom of the blender.
 Safety guard is applied after loading and before un-loading the blender.

ADVANTAGES –

 It can be used in various industries for mixing.

 Maintenance is easy.
 Uniform mixing is done with it.
 Large amount of material can be handled easily.

DISADVANTAGES –

 It requires large space.

 It is not suitable for particles with greater size.

TURBINE MIXER

Turbine mixer is used for mixing the low viscosity liquids and also it helps in mixing medium viscosity
liquids.
Principle - they can create a turbulent movement of the fluids by the help of centrifugal and
rotational motion.

Construction - they are made up of a circular disc which has short blades on it. The blades may vary
in the shape like they may be straight or curved or Disc type. Flat blade turbines produces radial and
tangential flow of the liquid. Axial flow is seen in pitched bleeder turbine.

Working -

Mixture is filled through an opening at its top. There is a drum with him which mixing blades revolve.
Speeds vary according to the material. The radial flow with the impeller on the vessel wall, this
caused the mixing of the material.

Application -

 They are used in chemical reaction and for extraction.

 They are also used for preparing emulsions, suspension, and syrups.

Advantages -

 They generate high shearing force even at low pumping rates.

 They are also suitable for liquids of large volumes.

Disadvantages -

 They are not preferred for solvents with very high viscosity.
 Sometimes it can cause oxidation of material being mixed.
 They are very expensive.

TRIPLE ROLLER MILL

They are used for mixing semi solids and result in preparing ointments, creams, wet masses, etc.

Principle - it generates high shear force by differential speed and narrow space between the rollers.
Due to this shear particles get crushed in order to form a semi solid base.

Construction - there are three rollers in its structure of equal diameter and they are made up of
stainless steel usually. They are arranged parallel to each other and they are fixed in a frame. A
hooper is fixed within the first two rollers and at last there is a receiver attached.
Working -

The first roller is called as receiving roller which rotates at a speed lower than the second roller.
Roller has lower speed than the third roller. The feed introduced in between the first and the second
roller. The movement of rollers aggregate and Crush the particles and finally it is converted into a
semi solid form and then released into a receiver which is present at last of the third roller.

Applications - they are used for making creams, paste, for any other Semi solid form.

Advantages -

 They prepare the semi solid form.

 They can prepare a bases for the drugs.

Disadvantages -

 They are not suitable for material whose viscosity is 5 pascals per second.

SILVERSON MIXER – HOMOGENISER

They are used for mixing the coarse particles to the fine form. They are fast and efficient. It has
variety of capacity ranging from 1 ml to 12 litre.

Principle - generate shearing force and turbulence with high speed rotors. The material circulates
within the head and due to this the fluid rapidly breaks down into smaller globules.

Construction - they consist of long supporting columns connected to a motor. Centrally located shaft
is present. Its one end is connected to the motor and the other and connected to the head. Turbine
blade are present in the head.

Working - the head of this mixer is put up in the vessel which has the coarse material. When we start
the motor, the central rotating shaft rotates the head, which rotates the turbine blades. The fluid
now moves into the head and mixing occur. A fine emulsion is obtained through the opening of the
outer cover.
Application - it is used for making creams, sauces, emulsions, etc.

Advantages -

 It has different capacities and different size so we can choose according to the material.
 It provides homogenous product.
 It can perform variety of mixing actions.

Disadvantages -

 Sometimes it may clog the pores of mesh.

 Requires high operating power.
 It may be expensive.

FILTRATION

It is defined as a process of separation of solids from a fluid by passing the same through a porous
medium that retains the solids but allows the fluid to pass through.

TERMS USED IN FILTRATION –

 SLURRY –suspension to be filtered.

 FILTER MEDIUM – porous medium used to retain solid.
 FILTER CAKE – accumulated solids on the filter.
 FILTRATE – clear liquid passing through the filter.

APPLICATIONS OF FILTRATION:

 Production of sterile products: HEPA filters or membrane filters.

 Production of bulk drugs
 Production of liquid drugs
 Effluents and waste water treatment
THEORIES OF FILTRATION –

 The flow of liquid through a filter follows the basic rules that govern the flow of any liquid
through the medium offering resistance.
 The rate of flow may be expressed as – RATE = driving force/resistance
 The rate of filtration may be expressed as volume (L) per unit time (dv/dt).
 Driving force = pressure upstream – pressure downstream.
 Resistance is not constant. It increase with an increase in the deposition of solids on the
filter medium. Therefore, filtration is not a steady process. The rate of flow will be greatest
at the beginning of filtration process, since the resistance is minimum.
 After forming of filter cake, its surface acts as a filter medium and solids continuously
deposit adding to thickness of the cake.

POISEULLIE’S EQUATION:

Poiseullie considered that filtration is similar to the streamline flow of liquid under pressure through
capillaries.

𝜋∆𝑃r4
V=
8𝐿𝜂

Where, V = rate of flow, m3/s

ΔP = pressure difference across the filter, Pa

r = radius of capillary in the filter bed

L = thickness of filter cake

𝝶 = viscosity of filtrate

DARCY’S EQUATION

𝐾𝐴𝛥𝑃
V=
𝜂𝐿
Where, K = permeability coefficient of cake, m2

A = surface area of porous bed

Other terms are same as previous equation.

KOZENY-CARMAN (K-C) EQUATION

∑ = Porosity of cake

S = specific surface area of particles comprising the cake

K = Kozeny constant (usually taken as 5)

FACTORS INFLUENCING FILTRATION:

A. Properties of solid

 Particle shape
 Particle size
 Particle charge
 Density
 Rigidity or compressibility of solid under pressure
 Tendency of particle to flocculate or adhere together

B. Properties of liquids

 Density
 Viscosity

C. Properties of solids in slurry

 Rate of formation of filter cake especially in early stage of filtration

D. Temperature

 Temperature of suspension

MEMBRANE FILTER

They are thin and porous sheets of material able to separate contaminants from water when a
driving force is applied.

CONSTRUCTION – membrane filters are made of thin and flat membranes of cellulose derivatives,
such as cellulose acetate and cellulose nitrate. These filters are brittle when in dry condition and can
be stored for an indefinite period. The filters are between 50 and 150µ thick and are available in
sized upto 60cm2.

PRINCIPLE – they are just like a sieve and traps the particles.

WORKING – a membrane filter has 400-500 million pores per square centimetre of filter surface. The
pores are absolutely uniform in size and occupy about 80% of filter volume. To avoid rapid clogging
of a membrane, pre-filtration is often required. The selection of a membrane filter for a particular
application depends on the particles to be removed.

USES – these filters are mainly used for sterilization of both aqueous and oily liquids. The membrane
filters cannot be used for filtration of organic solvents, such as alcohols, ketones, esters and
chloroform. It is used for diagnostic cytology.

MERITS –

 It is easily disposed off.

 It prevents cross-contamination.
 The rate of filtration is rapid.
 Adsorption is negligible.

DEMERITS –

 Sometimes it may get clogged.

 Cannot be used for filtration of organic solvents.

SINTERED FILTERS

CONSTRUCTION – these are made up of borosilicate glass. Borosilicate glass is finely powdered,
sieved and particle of desired size are separated. It is then packed into a disc mould and heated to a
temperature at which adhesion takes place between the particles. The disc is then fused to a funnel
of suitable shape and size.

WORKING – the sintered glass filters are available in different pore size. Hence the funnel with a
sintered filter is numbered according to pore size. The filtration is carried out under reduced
pressure. These funnel are used for bacteria filtration.

USES – sintered filters are also available in stainless steel which has a greater mechanical strength.
However these are very much liable to attack by the solutions passing through them. They are used
for parenteral injections, ophthalmic solutions.
MERITS –

 Easily cleanable
 No chance of contamination
 Negligible volume of filtrate is retained in the medium.

DEMERITS –

 Expensive
 They are fragile
 They cannot be used for large volumes.

DRYING

It is the process of removal of small amount of liquid (water/volatile liquid/moisture) by application

of heat to obtain dry solid or solid products. The equipment used for drying is called dryer.

APPLICATIONS OF DRYING:

 Preservation of drug products – crude drugs of animals and vegetable origin are dried out to
prevent their chemical decomposition, blood products are dried out to prevent the microbial
growth, etc.
 Preparation of bulk drugs – drying is the last step in preparation of bulk drugs, for example,
powdered extracts, spray-dried lactose.
 Improved handling – drying reduces the moisture content in drugs, hence drug becomes
light-weight, ease in transportation and storage.
 Improved characteristics – drying will help in improving the characteristics of the drugs. It
improves the compressing ability, nature of the material, etc.
 Reduction in transport cost – because drying helps in reducing bulkiness of the drug, hence
reduce transportation cost.
 Purification of crystalline products – when we dry the drug, it leads to better adhering of the
drug, hence leads to better purification of crystalline products.
 Prevention of corrosion – generally corrosion occurs due to presence of moisture. So if we
reduce the moisture by drying them, corrosion will be prevented.

FACTORS AFFECTING DRYING:

  PARTICULATE DIAMETER – If the size of the particulate that is to be dried is smooth or
small, drying will be quick and effective as compared to the rough or large particulate.
 MECHANISM INVOLVED IN DRYING – usually two mechanisms are responsible for the
process of drying and that are diffusion and capillary action. Diffusion process is better
as it leads to maximum absorption of the moisture.
 SIZE UNIFORMITY – if the size of the particulate is uniform better diffusion and capillary
action mechanisms will work, hence better drying.
 PRODUCT MASS FLOW RATE – If the material is kept stationary, that means surface area
subjected to drying will not change, hence rate of drying will be less. But if we keep the
material moving in different directions, then rate of drying will be more.
 DIAMETER OF THE DRYER SECTION – diameter or size of the dryer also matters. Because
if the object is large and the dryer is small then it will increase the time taken during
drying process.
 MOISTURE CONTENT – if the moisture content is very high in any material, it will take
more time in drying out of it.

CLASSIFICATION OF DRYERS –

FLUIDISED BED DRYER

Fluid bed drying is most widely used technique for drying pharmaceutical powders and granulation.

PRINCIPLE - In this, hot air is passed at high pressure through a perforated bottom of container
containing granules to be dried. The granules are lifted from the bottom and suspended in the
stream of air. The hot gas surrounding every granule to completely dry them.
CONSTRUCTION –

There are two types of bed dryers that are vertical fluid dryer and horizontal fluid bed dryer. Vertical
fluid bed dryer is made up of stainless steel or plastic. A detachable bowl is attached at the bottom.
This bowl has perforated bottom. The upper part is equipped with a fan for the circulation of hot air.
Filter bags are placed above the drying bowl to recover the fines.

WORKING –

 When the velocity of air is greater than the settling velocity of granules, the granules remain
partially suspended in the gas stream.
 After sometime, a point of pressure is reached at which frictional drag in the particles is
equal to the force of gravity.
 The granules rise in the container because of high velocity gas and fell back in a random
boiling motion. This condition is said to be fluidized state.
 Drying is achieved at a constant rate and falling rate period is very short.

APPLICATION –

 Used for coating granules.

 Used for drying granules.
 Used to mix ingredients.

ADVANTAGES –

 It requires less time to complete drying, i.e. 20-40 minutes.

 Hot spots are not observed in the dryer, because of its excellent mixing and drying
capacities.
 The thermal efficiency is 2 to 6 times greater than tray dryer.
 It facilitates the drying of thermolabile substances, since the contact time of drying is short.
 It can be used either as batch or continuous type.
  The free movement of individual particles eliminates the risk of soluble material migrating as
may occur in static bed.

DISADVANATGES –

 Many organic powders develop electrostatic charges during drying which can be avoided by
efficient electrical earthing of the dryer.
 The turbulence of the fluidized state of granules may cause attrition of some materials
resulting in production of fines which can be avoided by using suitable binding agent.

EXTRACTION

Extraction is the method of removing active constituents from a solid or liquid by means of liquid
solvent. The separation of medicinally active portions of plant or animals tissues from the inactive or
inert components by using selective solvents.

Extracts can be defined as preparations of crude drugs which contain all the constituents which are
soluble in the solvent.

MARC – solid residue obtain after extraction

MENSTRUUM – solvent used for extraction

IDEAL PROPERTIES OF SOLVENTS:

 Be highly selective for the compound to be extracted.

 Not react with extracted compound.
 Have a low price.
 Be harmless to man and environment
 Be completely volatile
 Should have minimum viscosity.

METHODS OF EXTRACTION

 Infusion
 Decoction
 Digestion
 Maceration
 Percolation
 Continuous hot extraction

INFUSION

It is the process of extracting chemical compounds or flavours from plant material in a solvent such
as water, oil, alcohol, by allowing the material to remain suspended in the solvent over time.

DECOCTATION
Water is used as a solvent and the crude drug which is to be extracted is cut into small pieces and
boiled with water for the stated time usually 10 to 15 minutes in a vessel of enameled iron or
earthenware - counting from when the liquid starts to boil with occasional stirring.

To obtain highly concentrated decoction, boiling is continued until the liquid reduced to a certain
volume. Allow to cool to about 40 degrees celsius, press the marc and mix the resulting liquid to the
decoction. At the end of the decoction time, stain it through find muslin cloth. Then sufficient water
is passed through the strainer to produce a definite volume. It is generally used for hard drugs.

DIGESTION

It is the process in which heat as well as pressure is used for extraction. The equipment is like a
pressure cooker or autoclave and is called digester. Extraction of non thermolabile materials is more
efficient in it because of high penetration power of solvent and solubilisation rate of soluble matters
of the crude drug due to high pressure and temperature respectively.

MACERATION

Various types of maceration processes are:

 Simple maceration - a process for tinctures made from organised drugs, example, roots,
stem.
 Maceration with adjustment - a process for tinctures made from un-organised drugs such as
oleoresins and gum resins.
 Double maceration and triple maceration process - for concentrated preparations.
 Plant material (crushed
or coarse powder)

placed in a closed vessel

whole solvent added

allowed to stand for 7

days shaking occasionally

liquid strained off

marc pressed

mix strained and

expressed liquid

clarified by filtration

evaporation &
concentration

SIMPLE MACERATION:

Drug is placed in wide mouth container with the stopper to prevent the evaporation of menstruum.
The drug is placed with the whole of the menstruum in a closed vessel for seven days. During this,
shaking is done occasionally. After 7 days liquid is strained and marc is pressed. Then it is filtered to
make a clear liquid. Example include tincture of orange or lemon.

MACERATION WITH ADJUSTMENT:

The unorganised drug is placed with 4/5th of menstruum in a closed vessel for a period of 2-7 days.
Shaking is done occasionally. After the stated duration, the liquid is filtered and the final volume is
made up by passing the remaining 1/5th of the menstruum through the filter. Example, tincture of
Tolu.

DOUBLE MACERATION:

Drug is macerated twice by using the menstruum which is divided into two parts in such a manner
that the same volume is used for each maceration. The quantity of menstruum required for two
macerations are calculated as:

Volume of menstruum required for first maceration:

Total volume of menstruum - volume to be retained by drug + volume to be retained by drug

Volume of menstruum required for 2nd maceration:

Total volume of menstruum - volume of menstruum used in first maceration

Strain the liquid and press the marc. Example, concentrated infusion of orange, gelatin.

TRIPLE MACERATION:

In this process, the drug is macerated thrice by using the menstruum which is divided into three
parts in such a manner that the same volume is used for such each maceration. The quantity of
menstruum required for three maceration is calculated as:

Volume of menstruum required for 1st maceration:

Total volume of maceration - volume to be retained by the drug + volume to be retained by the drug

Volume of menstruum required for 2nd and 3rd maceration:

Total volume of menstruum - volume of menstruum used in first maceration

Press the marc lightly. Then combine the liquid obtained from second and third maceration and
evaporator it to specified extent. Mix it with liquid obtained from first maceration. Add alcohol 90%
equal to one fourth of the volume of the finished product. Adjust volume with water. Allow it to
stand for 14 days and filter.

PERCOLATION –

It is continuous downward displacement of the solvent through the bed of crude drug to get extract.
We have various percolation processes that are used for extraction:

 Simple percolation or petroleum process for tinctures.

 Percolation processes for concentrated preparation such as:
I. Reserved percolation process
II. Modified percolation process
 Continuous hot percolation or soxhelation.

SIMPLE PERCOLATION

Simple percolation process is used for the preparation of tincture. There are three stages in the
official method for the preparation of tincture:

 Imbibition
 Maceration
  Percolation

Imbibition - the Powder drug is moistened with sufficient quantity of menstruum and allowed to
stand for 4 hours in closed vessel. Pack the moistened drug into percolators and add sufficient
quantity of menstruum to saturate the material. When liquid starts coming out from outlet of
percolators, the outlet is closed. Then the sufficient quantity of menstruum is added in order to
leave a layer above the drug.

Maceration - the moistened drug is left in contact with menstruum for 24 hours. During this time,
the menstruum dissolves the active constituent of the drug and becomes almost saturated with it.

Percolation - it consists of downward displacement of saturated solution formed in maceration and

extraction of the remaining active constituent present in the drug by slow passage of the menstruum
through the column of the drug. Mix the expressed liquid with percolate. Add sufficient quantity of
menstruum to produce required volume and then filter.

PERCOLATION PROCESS FOR CONCENTRATED PREPARATION

Percolation processes for concentrated preparations are used for preparing liquid extraction solid
extracts.

 Reserved percolation process -

In this process a part of percolate generally three by fourth volume of finished preparation is
reserved

Then the percolation process is continued till the drug is completely exhausted

The percolate is subjected to evaporation or distillation to convert it into soft extract

This soft extract is dissolved in the Reserve portion of percolate and then sufficient menstruum is
added to produce required volume

 Modified percolation process:

In percolation process for preparation of tincture, the drug/ percolate (d/p) ratio is about 1:4.

The d/p ratio is reduced to 1:3 by modifying percolation process and hence there is lot of savings in
heat, time and menstruum. Percolation is a displacement process. The strong solution of active
constituent of drug formed during maceration is displaced by the fresh menstruum when
percolation process is started.

CONTINUOUS HOT PERCOLATION

When active constituent of the drug are not freely soluble in the solvent or they are difficult to be
displaced from the cells of the drug, then it becomes necessary to extract the crude by the action of
hot menstruum for considerable length of time. The fixed oils from seeds and alkaloids from the
drugs are extracted by continuous hot percolation process using Benzene, chloroform, petroleum.
 The drug to be extracted it is packed in a paper cylinder made from a filter paper and it is
placed in the body of soxhlet extractor.
 The solvent is placed in the flask and apparatus is then filled.
 When solvent is boiled on heating the flask it gets converted into vapours.
 These vapours enter into condenser through the side tube and get condensed into hot liquid
which falls on the column of the drug.
 When Extractor gets filled with the solvent, the level of Syphon tube also raises up to its top.
 The solvent containing active Pharmaceutical ingredient in the syphon tube came over and
run into the flask, thus emptying the body of Extractor.
 This altering of filling and emptying the body of Extractor goes on continuously.
 This process is repeated until drug is exhausted.
CHAPTER 5 – PHARMACEUTICAL DOSAGE FORMS

TABLETS

 Tablet is defined as compressed unit solid dosage form that contains medicaments.
 According to Indian Pharmacopoeia, pharmaceutical tablets are solid, flat, or biconvex
dishes, unit dosage form, prepared by compressing a drug or mixture of drugs with or
without diluents.
 They are very different in shape with each other and have different sizes and weight, it will
all depend on the amount of medicinal substances and the route of Administration.

Advantages -

 Cost is lowest of all oral dosage form.

 They provide accurate and stable dose with greatest precision.
 They are lighter and compact.
 Easiest and cheapest to package and strip.
 Easy to swallow with least tendency for hang-up.
 Objectionable odor and bitter taste can be masked by various techniques.
 Suitable for large scale production.
 Greatest chemical and microbial stability over all other dosage forms.
 Product identification is easy and rapid.
 They have sustained release product such as delayed-release product.
 Most stable dosage form.

Disadvantages -

 Difficult to swallow in case of children and unconscious patient.

 Some drugs resist compression into dense compact.
 Drugs with poor wetting, slow dissolution properties may be difficult to formulate or
manufacture as a Tablet.
 Bitter tasting drugs, drugs with an objectionable odor, or drugs that are sensitive to oxygen
may require encapsulation and coating. In such cases capsule may offer the best and lowest
cost.
 High dose drugs are difficult to formulate.

General properties of tablet -

 Tablet should have elegant product identity with free from defects like crack, discoloration.
 Should have sufficient strength to with stand mechanical shock during its production,
packaging, shipping, and dispensing.
 Should have the chemical and physical stability to maintain its physical attributes over time.
 The tablet must be able to release the medicinal agent in a predictable and reproducible
manner.
 It must have a chemical stability over time so as not to follow alteration of the medicinal
agents.
Different types of tablets -

A. Tablets ingested orally -

 Compressed tablet, example Paracetamol.

 Multiple compressed tablet.
 Delayed release tablet, example enteric coated bisacodyl tablet.
 Sugar coated tablet, example, multivitamin tablet.
 Film coated tablet, example, metronidazole tablet.
 Chewable tablet, example, antacid tablet.

B. Tablets used in oral cavity -

 Buccal tablet, example, vitamin C tablet.

 Sublingual tablet, example, vicks methanol tablet.
 Lozengus
 Dental cone

C. Tablets administered by other routes -

 Implantation tablet
 Suppositories, example, co-trimoxazole tablet.

D. Tablets used to prepare solution -

 Effervescent tablet, example, disprin.

 Dispensing tablet, example, enzyme tablet.
 Hypodermic tablet.

PRODUCTION OF TABLETS

Manufacturing of tablets is done by three methods mainly:

1. Direct compression
2. Wet granulation
3. Dry granulation

DIRECT COMPRESSION

 Direct compression is defined as process by which tablets are compressed directly from
powder mixture of API and suitable excipient.
 It involves only 2 unit operations powder mixing and tableting.

Advantages -

 Reduced production time and cost.

 Product stability can be improved.
 Faster drug dissolution due to fast disintegration into primary particles.
 Less number of equipment are required.
  Elimination of heat and moisture, thus increasing not only the stability but also the
suitability of the process of thermolabile and moisture sensitive API.
 The chances of batch to batch variation are negligible.

Disadvantages -

 Many active ingredients are not compressible either in crystalline form or amorphous form.
 Needs directly compressible filler that is usually expensive.
 Problems in the uniform distribution of low dose drugs.
 High dose drugs having high bulk volume, poor flowability and poor compressibility are not
suitable for this method.
 Non uniform distribution of colour.

DRY GRANULATION

 In this the drug is added to the granulator and grinded.

 The suitable diluents and excipients are added and mixed in a blender.
 After mixing the Powder mixture, it is compressed into large flat tablets or pellets about 1
inch in diameter.
 These palettes are broken down by hand or by milling.
 The granules undergo dry screening through a desired mesh for sizing.
 Finally the lubricating agent is added and mix thoroughly in a blender.
 The resultant granules are compressed by machine, table press.

Advantages -

 It needs less space and equipment.

 It is suitable for moist and heat sensitive drugs.
 It takes less time.

Disadvantages -

 It produces lots of dust.

 The prolonged compression may result in hard tablets with poor disintegration properties.
WET GRANULATION

 Drug is added to the granulator and grinded.

 The suitable diluents and other excipients added and mixed in a blender.
 Granulating liquid are added to form a damp mass of the Powder material.
 The mass is screened to form pelletes or granules.
 These granules are dried to remove excess of the liquid.
 Dry screening of granules result in size reduction.
 The lubricating agents are added and the mixture is mixed thoroughly in a blender.
 The resultant granules are compressed by machine tooling of the tablet press.

Advantages -

 Wet granulation is suitable for high dose drugs which have poor flowability.
 It is suitable for bulky and dust producing powder.
 By selecting a suitable granulating liquid, the dissolution rate of the insoluble drugs can be
enhanced.
 Proper selecting a suitable granulating liquid enables the preparation of sustained release
dosage form.

Disadvantages -

 The wet granulation require large space.

 It is unsuitable for hydrolyzable, thermolabile and moisture sensitive drugs.
 It is expensive method.
 It is difficult to transfer the material in this.
 Time consuming method.

Drying equipments -

 Drum dryer
 Spray dryer
 Freeze dryer
  Tray dryer

Drum dryer - it consists of a drum which is heated internally usually by steam and rotated on its
longitudinal axis. The liquid is applied to the surface and spread to a film. Drying rate is controlled by
using suitable speed of rotation and the drum temperature.

Spray dryer - it provides a large surface area for heat. These are sprayed into a stream of hot air so
that each droplet tries to a solid particle.

Freeze dryer - it is a process used to drive extremely heat sensitive material. In this process the
initial liquid solution is frozen, the pressure Above the Frozen state is reduced and the water
removed by sublimation.

EVALUATION OF TABLETS

Non official tests -

 General appearance - organoleptic property, size and shape.

 Hardness
 Friability

Official tests -

 Weight variation
 Content uniformity
 Dissolution
 Disintegration

General appearance:

The general appearance of a tablet, its visual identity is very much essential for consumer
acceptance. Appearance of tablet involve the measurement of tablet's:

 Size
 Shape
 Colour
 Odor
 Taste
 Surface texture

Organoleptic properties - many pharmaceutical tablets use colour as a vital means of rapid
identification and consumer acceptance. The colour of a product must be uniform within a single
tablet.

Size and shape - it is measured by micrometre or sliding caliper scale. Tablet thickness should be
controlled within ±5% variation of standard value.

Hardness -
Tablets require a certain amount of strength or hardness and resistant to friability, to withstand
mechanical shocks of handling in manufacturing, packing and shipping. Hardness thus sometimes
termed the tablet crushing strength.

Tablet hardness testers are -

 Monsanto tester
 Pfizer tester
 Strong cobb tester
 Erweka tester

Monsanto tester: It was manufactured by monsanto chemical company. It has a spring which can be
compressed by moving the screw knob forward. The tablet which is to be tested is placed between
fixed and moving jaw, apply force to it. The force applied to the tablet is gradually increased by
moving the screw knob forward until the tablet breaks. Reading is noted from the scale. 4 kg of
hardness is suitable for handling the tablets.

Pfizer tablet hardness tester: It is just as the plier. The tablet is held vertically in between the Jaws
which are pressed with the hands until the tablet breaks. Reading is noted from the middle of the
pressure dial.

Friability -

 It is official in USP but not in IP. It is also known as Roche friabilator. Tablet hardness is not
an absolute indicator of strength since some formulations when compressed into very hard
tablets.
 Pre weighed tablets placed in a friabilator.
 It is operated on 25 rotations per minute for 4 minutes.
 Tablet are then dusted and re-weighed.
 Tablets that lose less than 0.5-1% of their weight are generally acceptable.

Weight variation -
  The weight of the tablet being made is routinely measured to help ensure that the tablet
contains the proper amount of the drug.
 As per Indian Pharmacopoeia, weight 20 tablets selected at random and determine the
average weight.
 Not more than 2 of the individual weights deviate from the average weight by more than the
percentage deviation shown in the table:

I.P/B.P Limit U.S.P

80mg or less ± 10% 130mg or less

More than 80mg or less than ± 7.5% 130mg to 324mg

250mg
250mg or more ± 5% More than 324mg

Content uniformity -

 This method check that every tablet must contain the stated amount of drug within the
prescribed limit.
 The result lies within the range for the content of active ingredient stated in the monograph.
 The test is applicable to tablets that contain less than 10 mg or less than 10% w/w of the
active ingredient.
 It is not applicable to Tablet containing multivitamin and trace is element.
 10 tablets are taken at random, their content of active ingredient is determined in each of
them. And the average values calculated.
 The sample passes the test is not more than one of the individual value is outside the limit of
85 to 115% of the average value.
 And none is outside the limit 75-125% of the average value.
 If two or three of the individual tablets are outside the limit then the test is repeated using
another 20 tablets.

Dissolution -

 It is the process by which a solid solute enters a solution.

 Pharmaceutically, it may be defined as the amount of drug substance that goes into the
solution per unit time under standardized conditions of liquid or solid interface, temperature
and solvent composition.
 Dissolution kinetics is important in determining the bioavailability of the drug.
 It is carried out in:

USP dissolution Apparatus Type 1 (basket type)

USP dissolution Apparatus type 2 (paddle type)

 In general, single tablet is placed in a small wire mesh basket tied to the bottom of the shaft
connected to a variable speed motor.
  The basket is immersed in the dissolution medium (as specified in the monograph)
contained in a flask. The flask is maintained at a constant temperature of 37 degree Celsius ±
5 degree Celsius by constant temperature bath.
 The motor is adjusted to turn at the specified speed and the samples of fluid are withdrawn
at intervals to determine the amount of drug in the solution.
 For example, for methyldopa tablets, the dissolution test calls for a medium of 900 ml of 0.1
NHCl, apparatus 2, turning at 50 RPM, and time limit is 20 minute. The accepted amount
dissolved in 20 minutes is not less than 80% of the labelled amount of the methyldopa.

Disintegration -

It is the time required for the tablet to break into the particles, the disintegration test is a measure
only of the time required under a given set of conditions for a group of tablet to disintegrate into
particles.

Liquid used in disintegration -

 Water
 Simulated gastric fluid (pH = 1.2 HCl)
 Intestinal fluid (pH = 7.5)

USP method for uncoated tablets:

 Start the disintegration test on 6 tablets.

 If one or two tablets from the six tablets fail to disintegrate completely within 30 minutes,
repeat the same test on another 12 tablets. (the whole test will consume 18 tablets)
 Not less than 16 tablets disintegrate completely within the time. If more than two tablets
from the 18 tablet fail to disintegrate, the batch must be rejected.

For coated tablets:

 To remove or dissolve the coat, immerse the tablet in distilled water for 5 minutes.
 Put the tablet in the Apparatus in water or hydrochloric acid for 30 minutes at 37 degree
Celsius. If not disintegrated, put in intestinal fluid.
 If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the 18 must
disintegrate within the time.
 If two or more not disintegrated the batch is rejected.

Disintegration Time:

Type of tablet IP BP USP

UNCOATED 15 mins 15 mins 5 mins

COATED 60 mins 30 mins -

FILM 30 mins - -

ENTERIC 120 mins - 1-2 hours

VARIOUS MODIFIED TABLETS

SUSTAINED RELEASE TABLETS

Dosage form that maintain the therapeutic blood or tissue levels of the drug by continuous release
of medication for a prolonged period of time, after administration of a single dose. It is also known
as prolonged release, slow release, sustained action, prolonged action, or extended release dose.

Sustained release dose provide an amount of drug initially made available to the body to cause the
desired therapeutic responses, followed by a constant release of medication for maintenance of
activity over a period of time.

Properties of drugs that are suitable for sustained release –

 Drugs having low solubility at absorption site and pH dependent are poor candidates.
 Dose must not be greater than 500mg.
 Drug should be un-ionized, largely ionized drugs are poor candidates.
 Those drugs having short half life span are most suitable.

ADVANTAGES –

 It is better for those patients who are non-compliant.

 Low dose of drug is required.
 Minimum fluctuations are seen in the concentration.
 Improved efficiency of treatment.
 Maximum bioavailability with a minimum dose.
 Reduction in health care cost.
 Minimize drug accumulation with chronic dosing.

DISADVANTAGES –

 If any allergy or side effect occur, drug can’t be stopped.

 More costly and expensive processes and equipments are involved in manufacturing.
 Physician has less flexibility in adjusting dosage regimen as it has fixed dose.
 Need additional patient education.
 Dose dumping
 Delayed onset of action so cannot be given in emergency condition.

EXTENDED RELEASE TABLETS

  These are designed to release their medication in controlled manner, at a predetermined
rate, duration and location to achieve and maintain optimum therapeutic blood levels of
drug.
 These are taken commonly only once or twice daily while other preparation needs 3-4 times
daily administration to achieve same therapeutic effect.
 They provide an immediate release of drug that promptly produce the desired therapeutic
effect followed by gradual release of additional amounts of drug to maintain this effect over
a pre-determined period.

FAST DISSOLVING TABLETS

They are also known as mouth dissolving tablets and they are those which disintegrates or dissolves
rapidly without water within few seconds in mouth.

ADVANTAGES OF FDT –

 They have faster onset.

 They have better result and bioequivalence.
 They are convenient and very easy to use.
 They have small packaging so easy to handle.
 There is no need of water to swallow the tablet.
 It is not bitter in taste.
 No risk of choking.
 Easy for patients who refuse to swallow a tablet, such as mentally ill patients, un-
cooperative patients.

DISADVANTAGES –

 The tablets usually have insufficient mechanical strength. Hence, careful handling is
requires.
 The tablets may leave unpleasant taste if not formulated properly.
 Drugs with larger doses are difficult to formulate into FDT.

MANUFACTURING – it is generally prepared by lyophilization means drying at low temperature

under conditions that involve the removal of water by sublimation, example, antacids.

DOUBLE LAYERED TABLETS

They are also known as bi-layer tablets. It is suitable for sequential release of two drugs in
combination and also for sustained release of tablet in which one layer is for immediate release as
loading dose and second layer is maintenance dose.

It is needed for administration of fixed dose combinations of different API’s and to separate
incompatible API from each other.

ADVANTAGES –

 Low cost compared to other forms.

  Flexible concept.
 Greatest chemical and microbial stability.
 Easy to swallow.
 Fit for large scale production.
 Maximize the efficacy of combination of two drugs.
 Easy to pack and handle.
 Separation of incompatible components.

DISADVANTAGES –

 Manufacturing unit of this is expensive.

 Cross-contamination between the layers.
 Difficult to swallow in case of children and unconscious patients.
 Capsule coating is required for those which are bitter in taste.

CAPSULES

They are the solid dosage forms in which the drug substance is enclosed within either a hard or soft
double shell, usually formed from gelatin. The term capsule is derived from the Latin word capsula
meaning a small container.

The medication may be a powder, a liquid or a semi-solid mass.

Capsules are intended to be administered orally by swallowing them whole. Occasionally, capsules
are administered rectally or vaginally.

ADVANTAGES –

 Capsules are tasteless, odorless.

 They can be administered easily.
 We can use combination of powders in it.
 The drugs having unpleasant odor or taste can be enclosed within a tasteless shell.
 They can be filled quickly.
 They are economical.
 They are easy to handle and carry.
 Physician can change the dose and combination of the drug according to patient’s
requirement.
 Gelatin quickly solubilize when came in contact with gastric pH and therefore there is rapid
release of medication in the stomach.
 Can be produced in large quantities and require little excipient.

DISADVANTAGES –

 They are not suitable for liquids that dissolve gelatin, such as aqueous or hydro alcoholic
solutions.
 The concentrated solutions which require previous dilution are unsuitable for capsule
because if administered as such lead to irritation in stomach.
  They require special storage conditions.

TYPES OF CAPSULES –

 Hard gelatin capsules

 Soft gelatin capsules

HARD GELATIN CAPSULES

 The hard gelatin capsule consists of two pieces in the form of cylinders closed at one end.
The shorter piece is called the cap and this cap fits over the open end of longer piece called
body.
 Hard gelatin capsules are also known as dry-filled capsules or two piece capsules.
 The drug substance placed in the body and the caps are slided over it, hence enclosing the
drug substance.

MANUFACTURING OF HARD GELATIN CAPSULES – steps involved in making empty gelatin capsules:

 Dipping
 Spinning
 Drying
 Stripping
 Trimming and joining
 Polishing

DIPPING

 Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form
the caps and bodies.
 The dipping solution is maintained at a temperature of about 500o C in a heated, jacketed
dipping pan.

SPINNING

 The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the
formation of a bead at the capsule end.
DRYING

 The gelatin is dried by a blast of cool air to form a hard shell.

 The pins are moved through a series of air drying them to remove water.

STRIPPING

 A series of bronze jaws strip the cap and body portions of the capsules from the pins.

TRIMMING AND JOINING

 The stripped cap and body portions are trimmed to the required length by stationary knives.
 The cap and body lengths are precisely trimmed to a ± 0.15mm tolerance.
 After trimming to the right length, the cap and body portions are joined.
 Finished capsules are pushed onto a conveyer belt which carries them out to a container.
 Capsule quality is monitored throughout the production process including size, moisture
content, single wall thickness, and color.
 Capsules are sorted and visually inspected on specially designed inspection station.
 Perfect capsules are imprinted with the client logo on high speed.

POLISHING

 PAN POLISHING – Acela-cota pan is used to dust and polish.

 CLOTH DUSTING – capsules are rubbed with cloth.
 BRUSHING – capsules are feed under soft rotating brush.

STORAGE

 Finished capsules normally contain an equilibrium moisture content of 13-16%.

 To maintain a relative humidity of 40-60% when handling and storing capsules.
FILLING OF A HARD GELATIN CAPSULE –

HAND OPERATED METHOD –

 It consist of a bed having 200-300 holes, a loading tray having 200-300 holes, a powder tray,
a pin plate having a rubber, a lever and a cam handle.
 The empty capsules are filled in the loading tray and it is placed over the bed. The cam
handle is operated to separate the capsule caps from their bodies.
 The powder tray is placed in a proper position and filled with an accurate quantity of powder
with scraper. The excess of the powder is collected on the platform of the powder tray. The
pin plate is lowered and the filled powder is pressed by moving the pin downwards.
 After pressing the pin plate is raised and the remaining powder is filled into the bodies of
capsules. The powdered tray is removed after its complete filling. The cap holding tray is
again placed in position. The plate with the rubber top is lowered and the lever is operated
to lock the caps and bodies. The loading tray is then removed and filled capsules are
collected.

PUNCH METHOD

 Powder is placed on a sheet of a clean paper or porcelain plate using spatula which is
formed into a cake having a depth of approximately one-fourth to one-third the length of
the capsule body.
 Then empty capsule body is held between the thumb and forefinger and punched vertically
into the powder cake repeatedly until filled.

AUTOMATIC FILLING MACHINE – example, Osaka capsule filling machine, macofar capsule filling
machine.

SEALING OF HARD GELATIN CAPSULE SHELLS

 Tamper evident capsules by sealing the joint between the 2 capsule parts.
 Distinctive looking capsules by sealing them with colored band of gelatin. If removed, the
band cannot be restored without expert sealing with gelatin.
 Through a heat welding process that fuses the capsule cap to the ring around the capsule
where heat welded.
  Capsule may also be sealed through a heat welding process that fuse capsule cap to the
body.
 Lightly coating the inner surface of the cap with a warm gelatin solution immediately prior to
placement on the filled capsule body.

The excipient used in filling of hard gelatin capsule –

 DILUENTS – they are used to increase the powder bulk and to ease out the filling process.
Example, corn starch, lactose, etc.
 DISINTEGRANTS – they are used to break down the powder bulk. Example, corn starch,
sodium starch glycolate, etc.
 GLIDANTS – they are used to reduce inter-particle attraction, example, talc.
 LUBRICANTS – they are used to minimize the contact between powder particles, example,
magnesium and other metals.
 SURFACTANTS – they are used to reduce surface tension and also to promote powder
wetting, example, sodium lauryl sulphate.

ADVANTAGES –

 They have simpler manufacturing process.

 They have few production steps.
 Granules, powders, liquids, semi-solid formulations and mini tablets can easily be filled alone
or in combination.
 Reduces stability problem with sensitive drugs.
 Printing options provide greater possibilities in branding.
 They hide the unpleasant taste and odor of few medicines.
 Identification is easy.

DISADVANTAGES –

 Drugs which can dissolve the capsule cannot be put up in a capsule.

 Sometime it became very difficult to ingest large dose capsule.
 It cause rapid release of drugs hence can cause irritation in stomach.

SOFT GELATIN CAPSULE

They are one piece, air tight sealed, and are made up of gelatin in which glycerine or polyhydric
alcohol added, containing liquid, suspension, or semisolid enclosed in a matrix.

They are mainly composed of gelatin, plasticizer, preservative, colouring, and opacifying agents,
flavouring agents and sugars. They have thicker shells then the hard capsules.

Formulation -

 Formulation for soft capsules involve liquid rather than powder Technology.
 Materials are generally formulated to produce the smallest possible capsule consistent with
maximum stability, therapeutic effectiveness and manufacture efficiency.
 The liquids are limited to those that do not have an adverse effect on gelatin walls.
Manufacture of soft gelatin capsule -

It is manufactured by these methods:

 Plate process
 Rotary die process
 Acco-gel capsule machine

PLATE PROCESS

 Place the gelatin sheet over a die plate containing numerous die pockets.
 Application of vacuum to draw the sheet into the die pockets.
 Fill the pockets with liquid or paste.
 Place another gelatin sheet over the field pockets.
 Sandwich under a die press where the capsules are formed and cut out.

ROTARY DIE PROCESS

 In this machine the soft gelatin capsules are prepared and then filled immediately with liquid
medicaments. It has two hoppers and two rotating dies.
 Liquid mixture is placed in 1 Hopper and the liquid medicament in another hopper.
 The two rotating dies rotate in opposite directions when the fluid gelatin mixture enter the
machine from the Hopper it produces two continuous ribbons.
 The half shell of the capsule is formed.
 At this stage the measured quantity of the Medicament is filled into it with the stroke of a
pump with the subsequent movement of the dies, the other half capsule is formed.
 The two halves of the capsule are sealed together by the heat and pressure of the rotating
dies.
 As the die rolls rotate, the convergence of the matching die pockets seals and cut outs the
filled capsule.

ACCO-GEL CAPSULE MACHINE

It consists of mainly three parts:

 Measuring roll
 Die roll
 Sealing roll

As the measuring roll and die roll rotate, the measured doses are transfer to the gelatin linked
pockets of the die roll.

The continued rotation of the filled die converges with the rotating sealing roll where a second
gelatin sheet is applied to form the other half of the capsule.

Pressure developed between the die roll and sealing roll seals and cut out capsule.

Base adsorption (BA) in soft capsules -

It is defined as the number of Grams of liquid base required to produce capsule mixture when mixed
with 1 gram of solid. It is influenced by many factors such as size and shape of solid, physical state,
density, moisture content, etc. The formula to calculate base adsorption is -

Weight of base/ weight of solid = base adsorption.

ADVANTAGES -

 Easy to administer
 Easy to manufacture
 Liquids can be encapsulated.
 Small to large size possible
 Elegance and portability
 Ready availability of drug, hence faster action.
 Specialised dosage forms can be made.
 Can be used for ophthalmic preparations, vaginal preparations.

DISADVANTAGES -

 It cannot be used for acidic drugs, ketones.

 Cannot be used for those drugs that can cause stomach irritation.

DIFFERENCE BETWEEN HARD AND SOFT CAPSULES

HARD CAPSULE SOFT CAPSULE

Contain 4 to 5 times less gelatin than the soft Require 4 to 5 times more gelatin than the hard
capsule. capsule.

Require No other additives. Require addition of glycerine for softening

purposes.

Allow step-by-step filling of two different Have to be sealed immediately after filling one
formulation. substance.

Heat resistant: Allow filling of thermostable Filling temperature limited to about 35 degree
substances up to 75 degree Celsius. celsius.

They are stable in hot climates. Tend to stick together and become gluey.

Disintegrate faster due to the capsule wall being Will disintegrate slower due to the thickness of
5 times thinner than the walls of soft capsules. gelatin wall.

Less product migration into the shell. Glycerine acts as a plasticizer by disrupting the
gelatin structure, so therefore there will be
higher migration of the product into the shell.
Constant external dimension. Dimensions vary according to weight.

LIQUID ORAL PREPARATIONS

It contains one or more soluble chemical substances dissolved in a specified solvent.

Liquid dosage form prepared by dissolving active ingredients in an aqueous or non-aqueous solvent
by suspending the drug or by incorporating the drug into one of the two phases of an oil and water
system. It includes solutions, syrup, suspensions, elixir, and concentrates.

ADVANTAGES –

 Immediately available for absorption.

 Easy administration.
 Easy to change the dosage regimen.
 Easy to colour, flavour, sweeten.
 The drug in solution is uniformly distributed.
 Easier to swallow.

DISADVANTAGES –

 Bulky than tablets or capsules.

 Less stable
 Less accuracy in dose as patient use different household devices such as tsp, tablespoon.
 Accident breakage of container.
 Shorter lifespan.
 Growth of microorganisms are easy because of the liquid media, addition of preservative is
must.

CLASSIFICATION –

They are classified on the basis of their phases -

1. MONOPHASIC

2. BIPHASIC

MONOPHASIC LIQUID DOSAGE FORMS

It refers to liquid preparation containing two or more components in 1 phase system, it is

represented by true solution. A true solution is a clear homogenous mixture that is prepared by
dissolving solute in a suitable solvent.

The component of the solution which is present in large quantity is known as solvent whereas the
component present in small quantity is termed as solute.

ADVANTAGES –

 It is easier to swallow, therefore easier for children and old age people.
 Facilitate absorption of drug faster than solid dosage from as drug is already in solution
form.
 It is homogenous therefore give uniform dose than suspension or emulsion which need
shaking.
  Simple to formulate.
 It can be administered by various routes – oral, parenteral, enema, otic, nasal and
ophthalmic preparation.

DISADVANTAGES –

 They are bulky, so difficult to transport and store.

 Water is commonly used as vehicle, which is prone to microbial growth.
 When expose to direct sunlight it may undergo hydrolysis, so need to store in cool and dark
place.
 Drug stability reduce by hydrolysis or oxidation. So, they have shorter expire date than solid
dosage forms.
 Other major signs of drug instability are color change, precipitation, microbial growth, etc.

CLASSIFICATION

It is majorly divided into two types –

1. liquids meant for internal administration – syrups, mixtures, elixirs, linctuses.

2. liquids meant for external administration –

 Liquids applied to skin – lotions, liniments, collodions, paints.

 Liquids used in mouth – gargles, mouthwashes, throat paints.
 Liquid instilled into body cavities – douches, ear drop, nasal drops, eye drops, enemas.

SYRUPS

Syrup is sweet, viscous, concentrated or nearly saturated aqueous solution of sucrose containing
66.7% w/w of sugar.

COMPOSITION OF SYRUP:

 Sugar
 Preservative
 Flavourants and colorants
 Thickeners or stabilizers

TYPES OF SYRUPS:

 Simple syrup – when purified water is used in making the solution of sucrose.
 Medicated syrup – when syrup contains medicinal substance, example, cough syrup.
 Flavoured syrup – syrups that has flavoring agent but not the medicinal substances.

ADVANTAGES –

 It retard the oxidation because it partly hydrolyzed into dextrose and levulose, so hence
prevent decomposition of many substances.
 It prevent the growth of micro-organisms.
  It is palatable, hence easily used.

PREPARATION OF SYRUP:

It is prepared using these techniques –

 Solution by heat – this method is suitable if the constituents are not volatile or degraded by
heat. Purified water is heated at 80-850 C and then it is removed from the heat. Then add
sucrose with agitation. Other components are added to hot syrup, then allow it to cool and
adjust the volume by adding more water. If we want to add any flavoring or coloring agent
that is volatile in nature, then add it after cooling to avoid evaporation.
 Agitation without heat – this is used for those substances that degrade on heating or get
evaporated with heat.
 Percolation – in this, either purified water or source of medicinal component is passed
slowly through a bed of crystalline sucrose, thus dissolving it and forming a syrup, example,
ipecac syrup.

ELIXIRS

They are clear sweetened, hydroalcoholic preparations intended for oral use and usually flavored for
palatability. Alcohol content vary from 10-12% and upto 40%.

NEED OF ELIXIR –

 Some drugs are insoluble in water so in this case we cannot use syrup or suspension.
 We have to make a dosage form which could dissolve non-polar compounds.

TYPES – medicates elixirs and non-medicated elixirs.

 NON-MEDICATED ELIXIR – these are simple elixirs that do not contain medicated agents.
They contain – alcohol, sweetening agent, coloring agent.
 MEDICATED ELIXIR – they are solution of active ingredient dissolved in water and an alcohol
often along with other excipients such as preservatives.

METHOD OF PREPARATION –

 Alcohol soluble and water soluble components are generally dissolved separately in alcohol
and water.
 Aqueous solution is added to the alcoholic solution, so minimal separation of alcohol soluble
components occurs.
 Mixture is made up to volume by the specific solvent or vehicle.
 Talc to remove excess amount of oil.
 Filter the preparation.
 Pour it in clean bottle.
 Label the bottle suitably.

STORAGE – they should be stored in tightly closed and light resistant container away from direct
heat and sunlight.
BIPHASIC LIQUID DOSAGE FORM

It contain 2 phases, including undissolved drug and the solvent system (vehicle). Undissolved phase
is distributed throughout a vehicle and they are used for oral administration.

In this, first phase is called as “dispersed phase” and the vehicle is called as “dispersed medium”. It is
also known as internal phase or external phase respectively.

There are two types of biphasic liquid:

 SUSPENSION
 EMULSION

SUSPENSION –

They are those preparations that contain finely divided drug particles distributed somewhat
uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.

The range of solid particles in suspension from 0.5 to 5 micron. They are chemically stable than
solution.

CLASSIFICATION –

 Based on general class:

1. Oral suspension – example, paracetamol suspension.
2. Externally applied suspension – example, calamine lotion.
3. Parenteral suspension – example, insulin zinc suspension.
 Based on size of particles:
1. Coarse suspension – suspensions having particle size of greater than 1 micron in
diameter are called coarse suspension.
2. Colloidal suspension – suspensions having particle sizes of suspended solid less than
1 micron in size are called colloidal suspensions.
 Based on electrokinetic nature of solid particles:
1. Flocculated suspension - in this individual particles are in contact with each other to
form loose aggregate and create network like structure. They will sediment loosely.
But when we shake it can Re-disperse easily and Reform the original suspension.
2. Deflocculated suspension - in this the individual particle exist as separate entities.
When shaking it can be read disperse easily and form the cake.

ADVANTAGES –

 Suspension can improve chemical stability of certain drugs, example, procain penicillin G.
 Drug in suspensions exhibits higher rate of bioavailability than other dosage forms.
 Duration and onset of action can be controlled.
 Suspension can hide the bitter taste of drugs.

DISADVANTAGES –

 Physical stability, sedimentation and compaction can cause problems.

  It is bulky.
 Sufficient care must be taken during handling and transportation.
 Uniform and accurate dose may not be achieved.

FORMULATION OF SUSPENSION:

 Medicament
 Flocculating agent - these are chemical additives that cause suspended solids to form
aggregate. In order to prepare a suspension, flocculating agent is added. Flocculation occurs
when the particle carry an opposite charge to the surfactant, so due to this opposite charge
neutralization will occur and hence floccules will form.
 Electrolytes: They decrease the electrical barrier between the particles so that they can get
linked together. For example sodium salts of acetate, phosphates and citrates.
 Surfactants: It neutralize the overall charges on the particles and hence floccules will form.
 Polymers: They hold the dispersed particles in a flocculated way to form their network.
Example, starch, cellulose.
 Deflocculating agent - By any chance the particles carry the same charge as that of the
surfactant, they will repel each other, and they will remain separate from each other which
will cause deflocculation.
 Wetting agent - They minimise the tension between the solid and the liquid medium and
increase the affinity of the particle towards the medium so that they can make a good
suspension.
 Preservatives - They preserve the overall quality of the suspension so that no microbial
growth will take place. Benzoic acid can be used as preservative.
 Organoleptic additives -
1. Flavouring agent: They will give flavour to the suspension, example, vanilla, strawberry,
pineapple.
2. Sweetening agents: They provide sweetness to the suspension, example, sucrose,
aspartame.
3. Colouring agent: They provide colour to the suspension. Example, tartrazine, sunset yellow.
4. Perfumes: They will provide fragrance to the suspension. Example, rose water.
 Suspending agents - They act as vehicle. They will help in settling down the particles.

Natural polysaccharides: Acacia, Tragacanth - 0.2% concentration, Alginates

Semi synthetic: Methyl cellulose - 0.5-2% concentration, Sodium carboxymethyl cellulose - 0.25-1%
concentration.

Inorganic agents: Bentonite - 3% concentration, Magnesium aluminium silicate - 5% concentration.

Synthetic compounds: Colloidal Silicon dioxide - 4% concentration.

PREPARATION -

 First the particle size is reduced to a desired size with the help of mill or other equipments.
 The insoluble materials are grinded to a smooth paste with a vehicle containing the wetting
agent.
  All soluble ingredients are dissolved in same portion of the vehicle and added to the smooth
paste to get slurry.
 If preparing on small scale, the slurry is then transferred to a graduated cylinder and mortar
is rinsed with successive portion of vehicle.
 If preparing on industrial scale, then slurry is transferred to a colloid mill or a disperser or
any other equipment to completely wet the particles.
 Then a deflocculated suspension is obtained.
 Decide whether the solids are – suspended in a structured vehicle, flocculated or flocculated
and then suspended.
 Add the vehicle containing the suspending agent or flocculating agent.
 Make up the dispersion to the final volume.
 Thus suspension is prepared.

INSTABILITIES IN SUSPENSION –

 Sometimes insoluble solid particles settle down at the bottom which is known as caking.
 Light-sensitive preparations may change their colour in the presence of light.
 Sometime due to alteration in temperature, pH, there is growth of microbes in the
suspension.
 If we store the suspension for a prolonged time period, drug degradation may occur, change
in flavour may occur, also there will be changed in the viscosity.

EMULSIONS

 Emulsions contain two immiscible liquids. The liquid which is in the form of minute globules
is the dispersed phase and the liquid containing the dispersed globules is the continuous
phase.
 If we want to disperse two immiscible liquids for a prolonged time period, an emulsifying
agent is used.

Advantages -

 More rapidly absorbed than solids.

 Two immiscible liquids can easily be incorporated.
 The poor taste of oils can be hided.

Disadvantages -

 Cracking of emulsion can occur.

 They are bulky so difficult to transport.
 If they are not shaken well prior to use can cause dose inaccuracy.

Types of emulsions -

Oil in water (o/w):

In this type, the oil will be the dispersed phase and water will be the dispersion medium. Best
example of this is milk, in this, fat globules act as dispersed phase that are suspended in water that is
the dispersion medium.

Other examples include, vitamin A in corn oil in water, liquid paraffin in water, benzyl benzoate
emulsion.

Water in oil (w/o):

In this type, water will be the dispersed phase and oil will be the dispersion medium. For example,
butter, salad dressing.

FORMULATION -

 Oil phase: This is made up of any oil like volatile oil, fixed oil, mineral oil, that is used to
prepare any kind of emulsion.
 Aqueous phase: Freshly boiled and cooled purified water is used.
 Antioxidant: It enhances the stability of the oil in the emulsion by preventing its oxidation,
example, beutylated hydroxyl anisole.
 Flavouring agent: It added flavour to the emulsion. Example, orange, chocolate, pineapple.
 Colouring agent: It provides colour to the emulsion, example erythrocin, tartrazine.
 Perfume: It provides fragrance to the emulsion.
 Preservatives: They help in reducing the microbial growth in the emulsion, example benzoic
acid, chloroform, methyl and propyl parabin.
 Emulsifying agent: These are those substances which are added to emulsion for stabilization
purposes. The various characteristic of emulsifiers are -
1. They are substances which have a hydrophilic end as well as hydrophobic end.
2. They are soluble in both water and oil.
3. They form a layer between the dispersed phase and the dispersion medium thereby
preventing the dispersed phase particles to come together to form large particles and
separate out.
4. They can be cationic, anionic.
5. It is not just the percentage of water and oil which decides whether it is oil in water or a
water in oil emulsion. On the other hand, it depends on which among water and oil can
solvate the emulsion to a large extent.
6. If the emulsifier is more soluble in water, then it will become oil in water emulsion.
7. On the other hand if the emulsifier is more soluble in oil then it will become water in oil
emulsion.
8. The commonly used emulsifiers for o/w emulsions are proteins, gum, soaps, etc.
9. The commonly used emulsifiers for w/o emulsions are heavy metal salts of fatty acid, long
chain alcohol, etc.

Preparation method -

It can be prepared by the following methods:

 Wet gum method

  Dry gum method

DRY GUM METHOD - In this method, the oil is first triturated with gum and with a little amount of
water to form the primary emulsion. The trituration is continued till a characteristic clicking sound is
heard and a thick white cream is formed. Once the primary emulsion is formed, the remaining
quantity of water is slowly added to form the final emulsion.

This method consist of: 4:2:1 formula -

 Four parts of oil

 Two parts of water
 One part of gum.

WET GUM METHOD - As the name suggests, in this method first gum and water are triturated
together to form a mucilage. The required quantity of oil is then added gradually in small
proportions with thorough trituartion to form the primary emulsion. Once the primary emulsion has
been formed remaining quantity of water is added to make the final emulsion.

This method consists of: 4:2:1 formula

 4 part of oil
 2 part of water
 1 part of gum.

Instabilities in emulsion -

 Flocculation: In this condition floccules will form.

 Creaming: In this sometime there is rising or settling of globules occur and they form a dense
layer at the surface or at the bottom of the emulsion.
 Cracking: It means the Separation of two layers of disperse and continuous phase. It may
occur due to change in temperature, creaming, microorganism presence, decomposition of
emulsifying agent.
 Phase inversion: Sometimes the phases got inverted, such as water in oil becomes oil in
water and vice versa.

Pharmaceutical application -

 Oral, rectal and topical administration of oils and oil soluble drugs.
 The unpleasant taste can be masked by emulsification.
 The absorption and penetration of medicament can be enhanced by emulsification.
 Intramuscular injections of water soluble drugs or vaccine are prepared through
emulsification.

DRY POWDER FOR RECONSTITUTION

These are the Powder mixtures that require the addition of water (reconstitution) at the time of
dispensing and are mostly for pediatric use. They are called as dry syrup, dry powder for oral
suspension, reconstituted oral suspension.
Characteristics -

 Powder blend must be uniform mixture of the appropriate concentration of each ingredient.
 During reconstitution, the Powder blend must disperse quickly and completely in aqueous
vehicle.
 It must be easily re-dispersed and poured by the patient to provide accurate and uniform
dose.
 Final product must have an acceptable appearance, odor and taste.

Formulation -

 Suspending agent
 Wetting agent
 Preservatives
 Sweeteners
 Flavouring agent
 Buffer
 Colouring agent
 Anti-caking
 Diluent
 Flocculating agent
 Antifoaming agent
 Granule Binder
 Antioxidant
 Lubricant

Reconstitution of oral suspension:

 First determine the type and volume of required diluent.

 Then shake the bottle gently before opening the cap.
 If it is antibiotic bottle with marking, cool boiled water is added carefully up to the mark. But
if it is unmarked, one should refer to the instructions on the labelling.
 Replace the cap of the bottle and then shake it until all the Powder mixes thoroughly.
 Allow it to stand for 2 to 5 minutes so that air bubbles will be free in the bottle.
 Then open the cap, add the remaining quantity of the water up to the final mark and then
close it again.
 Bottle must be inverted and shaken vigorously e for at least 5 seconds.
 Prepared suspension should be shaken well before giving each dose. Do not use kitchen
appliances such as tsp or tablespoon as they are not much accurate for dose calculation.
 Then store it in refrigerator or keep it at room temperature in a cool dry place. Do not freeze
it.
 If it is expiry then discarded immediately.

TOPICAL PREPARATIONS

OINTMENTS
They are semi solid in nature and are applied topically. Its base contain the medicament in solution,
suspension, or emulsion form.

Advantages -

 Easy to handle.
 Chemically stable.
 Most preferred route.
 Patient gets the actual drug amount because it is applied topically.

Disadvantages -

 Less stable.
 More bulky than the solid form.

TYPES OF OINTMENTS

 Hydrophobic ointment - they have the ability to absorb only small quantity of water as they
are hydrophobic. The base of this type of ointment include water insoluble hydrocarbons
like paraffin, waxes, animal fats.
 Water emulsifying ointments - they can absorb large amount of water. The base include
water in oil emulsion for example wool fat, wool alcohols, monoglycerides.
 Hydrophilic ointments - they are the mixture of solid polyethylene glycols and liquid. They
can be easily mixed in the water.

Ointment bases -

These are those substances that are the part of an ointment which serves as carrier or vehicle for
medicament.

Ideal properties:

 Inert, odourless, and smooth.

 Physically and chemically stable.
 Compatible with skin.
 Proper consistency.
 Not retard healing of wound.
 Not produce irritation.

CLASSIFICATION OF OINTMENT BASES –

Preparation of ointment -

TRITURATION METHOD:

 Finely powder the solid medicaments.

 Weight the required quantity of ointment base.
 Triturate them properly.
 Add the remaining amount of base until the medicament is uniformly mixed.

EMULSION METHOD:

 All the components are taken in required quantity.

 Fat, oil, and waxes are melted together on a water bath at a temperature of 70 degree
Celsius.
 The aqueous solution of all heat stable components are heated at same temperature.
 The solution is slowly added to the melted bases with continuous stirring until cool down
and semi solid mass known as ointment is prepared.

FUSION METHOD:

 When ointment contains a number of solid ingredients with different melting points, it is
necessary to melt them in decreasing order to their melting point.
 All the components are melted accordingly.
 The medicaments are slowly added to melted mass, continue stir them until mass cools
down and gives a homogenous product.

MIXING METHOD:

 The best result is obtained by mixing small amounts of base with the Powder to form a very
smooth mass, which eventually mixed with the remainder of base.
 The ingredients can also be mixed with Mineral oil to form a smooth paste.
 The paste is then mixed with the remainder of base.

PASTES
  They are homogenous semisolid dosage form that contains high concentration of insoluble
powder substance not less than 20% dispersed in the suitable base.
 They are less greasy, more absorptive and stiffer than the ointments.

Characteristics of paste:

 They are stiffer than other semisolid dosage forms.

 They are porous in nature.
 They are less greasy.
 They have good adhesive property.

Bases used in paste -

 Hydrocarbon bases
 Water miscible bases
 Water soluble bases

HYDROCARBON BASES

WATER MISCIBLE BASES

It includes emulsifying ointment and emulsifying wax used for the preparation of the paste.

WATER SOLUBLE BASES

They are prepared from mixture of high and low molecular weight polyethylene glycols.
Method of preparation:

They are prepared by trituration and fusion methods. Trituration method is used when the base is
liquid or Semi solid. Fusion method is used when the base is Semi solid or solid in nature.

TRITURATION METHOD -

Compound Zinc paste is prepared by both trituration and fusion method.

Procedure:

 Zinc oxide and starch powder are passed through sieve number 120.
 Soft paraffin is melted on a water bath.
 Required amount of powder is taken in a mortar, triturated with little melted base.
 Mix it until smooth and gradual mixture is prepared.
 Then add rest of the base.

FUSION METHOD:

Zinc and coal Tar paste is prepared by this method.

Procedure -

 The components are melted in decreasing order of their melting points, higher melting point
- substance should be melted first.
 The Medicament is added slowly in the melted ingredients and stirred thoroughly until the
mass cools down.

DIFFERENCE BETWEEN OINTMENTS & PASTES –

OINTMENTS PASTES

They contain medicaments which are They contain large amount of finely
generally dissolved/ suspended / emulsified powdered solids such as starch, zinc oxide,
in the base. carbonates, etc.
They are soft and semi solid preparations. They are very thick and stiff.
They are more greasy. They are less greasy.

They are simply applied on the skin. They are generally applied with the spatula.

They are less viscous. They are more viscous.

SUPPOSITORIES & PESSARIES

Suppository is a medicated solid dosage form generally intended for use in the rectum, vagina and to
a lesser extent, the urethra. After insertion they melt or soften at body temperature, whereas
vaginal suppositories sometimes called as pessaries, also made as compressed tablets that
disintegrate in body fluids.

ADVANTAGES –

 It is used in those patients whose oral routes are not useful.

 It prevents the risk of drug abuse.
 Drugs with unacceptable taste and odor can be administered through this route.
 Drug is prevented from first pass metabolism.
 It can be used in any patient, very young, very old, unconscious, mentally ill patients.
 It prevents gastric irritation and other side effects of the drugs.

DISADVANTAGES –

 It can cause mucosal irritation.

 There may be any leakage present.
 Sometime its incomplete absorption occurs.
 Traditional issues are major disadvantage.
 They are expensive from other dosage forms.

TYPES OF SUPPOSITORIES:

 Rectal suppository - for adults, weighs 2gm and are of torpedo shape. Children's suppository
weigh about 1gm.
 Vaginal suppositories/Pessaries - weight about 3-5gm and are molded in globular or oviform
shape or compressed on a tablet press into conical shape.
 Urethral suppositories - they are of pencil shaped. For males, weight is 4gm and 100-150mm
long. For females, weigh 2gm and 60-75mm in length.
 Nasal suppositories - they are introduced into nasal cavity. Weight 1gm and length 9-10cm.
 Ear cones - they are introduced into the ear. They are cut according to the sizes.
Ideal suppository base -

 Melts at body temperature or dissolve in body fluids.

 Non-toxic and non-irritant.
 Compatible with any medicament.
 Releases medicament readily.
 Easily moulded and removed.
 Easy to handle.
 Stable on storage.

Types of suppository bases -

A. Fatty bases

B. Hydrophilic suppository bases

C. Water dispersible bases

FATTY BASES

Cocoa butter (theobroma oil) -

 It is most widely used suppository base. It satisfies many requirements for ideal suppository
base.
 Cocoa butter is a triglyceride, yellowish white, solid, fat, smells and tastes like chocolate.
 Its melting point is between 30-350 C.
 It must be stored in a cool dry place protected from light.
 Two factors must be taken into consideration if we are using cocoa butter as a base -
1. Polymorphism: It has polymorphic nature that means it gets converted into metastable form
at temperature above 350 C. This overheating must be avoided so that polymorphism may
not occur.
2. Due to addition of some drugs in cocoa butter, its melting point is altered.

HYDROPHILIC SUPPOSITORY BASES

Glycerated gelatin suppository -

  This is a mixture of glycerol and water into a stiff jelly by adding gelatin.
 It is used for making jellies, suppositories, and pessaries and its proportion is changed
according to the intended purpose.
 This dissolves in body secretions and therefore is preferable to a fatty base for administering
antiseptics.
 But they are difficult to prepare and handle and their careful storage is necessary. It can also
lead to dehydration of the rectal mucosa and its irritation as well.

WATER DISPERSIBLE BASES

 There are several non-ionic surface active material. These surface active agent may be used
alone, blended or used in combination with other suppository vehicle.
 Another type of water dispersible suppository vehicle is based on the use of water soluble
cellulose derivatives. Example, methyl cellulose.

Method of manufacturing of suppositories -

Hand molding:

It is the oldest and simplest method, by rolling the suppository into the desired shape.

Steps include -

 The drug and other additives are made into a fine powder.
 It is incorporated into the suppository base by kneading with it or by trituration in a mortar.
 Then these masses are rolled into the shape of cylinder rod on the Rolling tile in presence of
lubricants to prevent the adherence of masses.
 Then cut the rods and made one end pointed.

Compression molding -

 Elegant suppository can be made by the compression of cold grated mass into the desired
shape.
 Simple and more elegant appearance is achieved than hand molding.
 The main disadvantage is that due to air sometimes its oxidation may take place.
 First powder all the required ingredients.
 Then mix it with bases.
 Prepare its mold and lubricate it.
 Place this mass in cylinder.
 Apply pressure.
 Release the suppository.
 Cool it, pack it and store it.

Heat molding -

 Most commonly used method for production of suppository both on small scale and large
scale.
 First, base is melted on a water bath.
  Then the drugs are either emulsified or suspended in it.
 Then, pour the mass into cold metal molds, which are usually chrome or nickel plated.

Automatic molding machine -

There are two types of Machines that are used:

Rotary machine -

 This machine consists of turn table in which metal molds are fitted.
 This table rotates sequentially, and the mold gets filled with drug, additives, bases.
 Before mass is filled, the molds are lubricated.
 The excess mass is removed by the scraping unit.
 Cool it and eject the suppositories.

Linear machine -

 It is similar to rotary machine.

 All the steps involved in the Rotary machine are same in this machine except the rate of
production is more higher than the Rotary machine.

LINIMENTS

They are solutions or mixtures of various substances in oil, alcoholic solutions of soap or emulsions
and may contain suitable antimicrobial preservatives. They are in liquid or semi liquid form and it is
used for external application. They are rubbed on to the affected area.

General uses of liniments -

 Antipruritic - used to relieve itching.

 Astringents - causes biological tissue to contract.
 Emollients - products that soften the skin or treat dry skin.
 Analgesics - reduce pain.
 Counter-irritant - they are applied locally to produce superficial inflammation with the
objective of reducing inflammation in deeper adjacent tissue.

Example of liniments -

 Compound Calamine liniment

 White liniment
 Camphor liniment, etc.

LOTIONS

They are liquid that are applied externally on the broken skin without friction. They have low to
medium viscosity. Hand creams and face creams are categorised under lotions.

Preparation - Homogeinser is used to triturate the ingredients and to form a smooth paste. Add
liquid to it. And lotion is prepared.
DIFFERENCE BETWEEN LOTIONS & LINIMENTS –

LOTIONS LINIMENTS

They are aqueous solution. They are liquid or semi-solid in nature.

They can be applied on broken skin. They can’t be applied on broken skin.

They are applied without friction. They are applied with friction.

Counter-irritants are absent in it. Counter-irritants are present.

Example – calamine lotion. Example – turpentine liniment.

GEL OR JELLIES

They are Semi solid in nature. They are transparent or translucent non greasy gels. In single phase
jellies, macromolecules are uniformly distributed throughout the liquid with no boundaries between
macromolecules and the liquid. In two phase jelly, it contains small separate particles also called as
magma.

Types of jellies -

 Medicated jelly: They have water in it. They can be used as vehicle for water soluble
medicaments. They are easy to use. Example, ephedrine sulphate - for nose bleeding,
pramoxine hydrochloride - acts as local anaesthetic.
 Lubricants: They are used to moisten the surface of various equipments such as catheters,
tubes. They provide sufficient smoothness and reduces irritation and friction. Example,
lignocaine.
 Miscellaneous jellies:
1. Patch testing - they are used to detect any kind of skin sensitivity.
2. Electrocardiography - electrode jelly e is used before hand for the placement of electrodes
of ECG to the skin so that they will stick to the skin and we can get ECG reading easily.

Preparation of jellies -

They are prepared by adding thickening agent. Such as tragacanth or carboxymethyl cellulose.
Thickening agent is transferred into aqueous solution in which drug has been dissolved. The mass is
triturated in mortar until a uniform product is obtained.

Following agents are used in preparation -

 Tragacanth
 Sodium alginate
  Pectin
 Starch
 Gelatin
 Cellulose derivatives

TRAGACANTH – It is commonly used for the preparation of lubricating, medicated, and

contraceptive jellies. They are also called as bassorin paste. When it is added in water it produce
lumpy product. So, dispersing agent like alcohol, volatile oil is used to get a homogenous
preparation.

SODIUM ALGINATE - They are used for lubricant and for dermatological jellies. In this, alcohol,
glycerin, they are used as dispersing agent.

PECTIN - It is very good gelling agent. It is used in various preparation of jellies including edible
jellies. Glycerin is used as dispersing agent. They are prepared with suitable preservatives.

STARCH - Starch jelly prepared with combination of gelatin and glycerin. They are prepared by
heating method or fusion method.

GELATIN - It is soluble in hot water. Very stiff medicated jellies are prepared by adding gelatin. They
are melted before use and after cooling to desired temperature. It can be applied by brush. After
applying cover it with bandage.

CELLULOSE DERIVATIVES - Methyl cellulose and sodium carboxymethyl cellulose are widely used in
the preparation of jellies. They produce natural jellies and stable. They have good resistance against
bacterial infections.

COLD CREAMS

It is an emulsion of water and certain fats, usually beeswax and various scent agents, designed to
smooth skin and remove makeup. They produce cooling effect because slow evaporation of water
present in the emulsion.

Formulation -

 Beeswax - 5%
 Liquid paraffin 45%
 White soft paraffin 10%
 Hard paraffin 7%
 Borax 0.2%
 Water 32.8%
 Perfume

Ideal properties -

 Elegant in appearance.
 Provide a smooth texture.
 Non-irritant and non-toxic
  Non-dehydrating.
 Non-greasy and non-staining.

VANISHING CREAMS

These spread easily and seem to disappear rapidly when rubbed on skin. These are an oil in water
type of emulsion. They are also known as greaseless creams or day creams.

Formulation –

 Stearic acid – protective function

 KOH or NaOH – to neutralize free fatty acids.
 Glycerin – it maintain consistency.
 Water – provide stability
 Perfume – provide fragrance.

NASAL DROPS

 They are oily solutions which are inserted into the nasal cavity to attain the desired effect
that can be antiseptic, local analgesics or vasoconstriction.
 They are in a glass bottle having a glass dropper. They are also available in plastic form. pH
lies within 5.5-7.5.
 There are various drugs that are present in the nasal drops such as antihistamine,
vasoconstrictor, decongestant.

Preparation -

 Vehicle: Purified water

 Tonicity adjuster: Sodium chloride
 Buffer: Phosphate buffer
 Preservative: Chlorobutanol, aromatic alcohols.

Dispensing -

 10 to 15 ml is the capacity of the nasal drop bottle.

 They have dropper in them.
 Squeeze the dropper and pour the drops directly into the nostrils.

Storage -

 Cool place is required for their storing.

 Do not store them for long term because there are chances of microbial contamination in
them.

Examples -

 Ephedrine hydrochloride nasal drops.

 Phenylephrine hydrochloride nasal drops.
EAR DROPS

 These are the solution that are used for installation into the ear. The solution are prepared
in water, glycerin, propylene glycol or alcohol.
 They are generally used to clear the ear, to soft the wax, and also for treating mild
infections.
 There is a technique to instill the ear drops, patient either have to lie down or tilt their head
at 45 degree angle.

Preparation -

 There are clear solution that means they do not have any particles in them.
 There are mainly two types of ear drops - Sterile ear drops and non-sterile ear drops. Both of
them have different type of preparation technique.

Sterile ear drop: It involves the presence of sterile and preserved base solution. Active ingredients
are dissolved in the base.

Non-sterile ear drops: It involves dissolution of the active Pharmaceutical ingredient and other
excipient in the vehicle.

Examples -

 Sodium bicarbonate ear drops.

 Aluminium acetate otic drops.

POWDERS & GRANULES

 Powders may be defined as solid material in a finely divided state.

 Powdered drug on its own can be a dosage form for taking orally called as simple powder,
when they are usually mixed with water first or for external application as a dusting powder.
 Granules are aggregations of fine particles of powders in a mass of about spherical shape.
Granulation is the process in which primary powder particles are made to adhere to form
larger, multiparticles entities called granules.

Types of powders -

They are classified into two categories:

Based on usage -

 Internal use
 External use

Based on quantity -

 Bulk powder
 Divided powder

INTERNAL USE –
Simple powders:

They are prepared by blending the ingredients in increasing order of their weights. The mixture that
is obtained is divided into chunks of equivalent sizes. Hence, simple powder is obtained.

Compound powders:

They are made up of two or more ingredients mixed together such as aspirin, paracetamol, and
caffeine.

Bulk powders:

They are prepared in bulk and stored in a wide mouth container so that required quantity can be
sufficiently withdrawn according to the need. Example Ginger powder, heavy magnesium carbonate.

Effervescent powder:

They have active and inert ingredients in them along with the mixture of acids and sodium
bicarbonate, that releases carbon dioxide when dissolved in water.

EXTERNAL USE –

Dusting powder:

They are applied externally on local sites. Example, starch, zinc oxide, boric acid. They can be used
for many purposes such as they work as lubricant, protectives, antiseptic, antipruritic, astringents.

Snuffs:

They are basically used for inhalation into the nostrils, they are specifically for the patient with
respiratory disorders such as asthma. It has bronchodilator action and also works as decongestant.

Douche powder:

They can be used for application in vagina, nasal, otic or ophthalmic use. They are very e fine
particles.

Dental powders:

They are generally used for the cleaning of the teeth. But it is not frequently prescribed by the
doctors.

Insufflations:

They are for the inhalation purpose. They can be used in the nose, throat, vagina. They are applied
by the help of insufflators.

Divided powders:

They are packed in folded paper and are available in envelopes, metal foil, and other containers as
well. They are prepared by blending the ingredients in increasing order of their weights. And then
mixture is prepared which is then packed according to the weight.
Advantages -

 They can be used both internally as well as externally.

 They are more stable.
 They are very easy to use.
 They are portable and easy to handle.
 It can easily be dispersed and ingested as well.
 They do not need any special equipments for the production.
 They dissolve very well in the body.

Disadvantages -

 They can be bitter in taste.

 They can be affected by atmospheric conditions such as moisture.
 Preparing them is a time consuming process.

Advantages of granules -

 They have good flowability than powders.

 They have greater compressibility rate.
 They are physically and chemically stable.
 They form the particles which are uniform in nature.

STERILE FORMULATIONS

INJECTABLES: Parenteral are the injections and its mode of administration is injection, infusion or
implantation. They are differ from pharmaceutical dosage due to some of reasons:

1) It should be sterile free of physical, chemical and biological contamination.

2) Preparations of medicine should be sterile, free from pyrogen in liquid and solid dosage.

3) Dosage should be packed in single dose or multi dose containers.

4) Administration of medicine in skin, mucus membrane into internal body.

5) In parenteral administration it bypasses the alimentary canal.

6) Diluting solution should be clear liquid for drug reconstitution.

GENERAL REQUIREMENTS FOR INJECTABLE

Parenteral formulation needs some of following considerations:

MENONIC: FICS

F Free from pyrogens

Free from foreign particles

I Isotonicity
C Chemical purity
S Stability

Sterile

Specific gravity

FORMULATION OF INJECTIONS SOLUTES

Best quality of active pharmaceutical ingredients and excipients should be used for administration
through parenteral injections. The aseptic sterilisation process was done to lower microbial level.
Non-pyrogenicity of injections was from non-pyrogenic ingredients that are used in the preparation
of injections. The GMP (Good manufacturing product) will be less in microbial and endotoxins.

During preparation of pharmaceutical some of chemical impurities are added and it should not
removed by filters/process. Some of the trace elements should cause problem in patient. So select
best quality of chemicals for preparation after their testing.

Examples: Bulk Manufacturing precautions are:

1) Cross contamination prevents the transfer of impurities by proper handling

techniques/equipments.

2) Equipment should be washed with sterile solution that are used for injection.

3) Purification should be followed by closed system.

4) Standards should be maintained overall.

Vehicles

Aqueous and non-aqueous vehicles are used in preparation.

1) Aqueous vehicles: Types are discussed below

i) Water for Injections U.S.P.:

a) It is common solvent for large scale injection manufacturing.

b) Purification of injections is mainly done by distillation /reverse osmosis process, it will be purified
as water and it should not more than 1mg/100ml of water.

c) It only free from pyrogens and its not sterile one.

d) The products should be fully sterilised after completion of preparation.

e) After preparation it was collected in sterile techniques in sterile container.

g) It will be used within a day.

ii) Sterile water for Injection U.S.P.:

a) It will be single dose container made in 1L.

b) It is free of pyrogens and accepted amount of endotoxins that will be 0.25 U.S.P endotoxins units
in per millilitre.

c) It should be free of micro-organisms.

d) Solid content should be higher compared with sterile water due to leaking occur during
sterilisation.

e) It used for sterile injections

f) It used for diluting the medicine for injection especially antibiotics which are in powder form.
example: ampicillin powder.

iii) Bacteriostatic water for injection U.S.P.:

a) Anti – microbial agents present in this sterile water.

b) Pre filled syringes and vials package contains 30ml of water which is used in injections.

c) All the container should be labelled with names and its proportion of anti-microbial agent.

d) In the preparation of medicine only small amount will be administered due to presence of anti-
microbial agents.
e) The agents should be added with multiple dose of parenteral preparation and it should be
chemically compatible.

f) This agents are avoided in neonates.

iv) Sodium chloride Injection U.S.P.:

a) It is isotonic solution in the sterile water of sodium chloride.

b) It contain 154 mEq of sodium and chloride ions in per litre and do not have anti-microbial agents,

c) Suspension of drugs in parenteral preparation made by this sterile water.

d) It was mainly used as catheter intravenous fluid flush and intravenous medications. It will be used
to flush IV line it not used more than 8 hours.

v) Bacteriostatic Sodium Chloride Injections U.S.P.:

a) It also contains Isotonic solution of sterile water of sodium chloride.

b) Anti microbial agents names are labelled in container.

c) Solution contains 0.9% of sodium chloride.

d) It is made up of compatible, preservative and sodium chloride.

e) Used as catheter or IV line flush for patency.

f) Avoided in neonates.

vi) Ringer’s Injection U.S.P.:

a) It contains sodium chloride, potassium chloride and calcium chloride in sterile water.

b) The concentration is same as physiologic fluids.

c) It used as vehicle or otherwise electrolyte replenisher and plasma volume expander.

d) Lactated Ringer’s injection U.S.P.: It contains sodium chloride, potassium chloride, calcium
chloride and lactate in sterile water.

e) Used as systemic alkaliser and also fluid and electrolyte replenisher.

2. Non –aqueous vehicles: The vehicle is added with drug has low amount of water solubility or
prone to hydrolysis. So it not used for injection. It should be limited due physical and chemical
factors.

Some of the following features are:

i) It should be non- irritating.

ii) Non –toxic in nature.

iii) Pharmacologically inert one.

iv) It should be administer in wide range of temperatures.

v) Non sensitising agent.

vi) Metabolise easily.

vii) It is less viscous to allow syringability.

viii) It permits heat sterilisation because it has high boiling point.

Examples

a) Fixed oils or vegetable oils.

b) Ethyl oleate, isopropyl myristate, benzyl benzoate and dimethylacetamide.

c) It used for steroidal hormones and oil soluble vitamins.

Additives

Formulation of parenteral products made up of some of high quality solutes.

1) MEDICAMENTS - It is active ingredients. Before parenteral formulation it should sterilised.

2) ADDITIVES - Some of the products are added to parenteral preparation to improve utility and
stability of products.

i) Solubilisers: It will increase the solubility of soluble drugs. Examples: ethyl alcohol, lecithin, castor
oil, polysorbates (20, 40, 80), PEG 300, PEG 40.

ii) Anti oxidants :Drugs in solution are degraded by oxidation process and it is mediated by free
radicals. Hydroxyl ions catalyse, hydrogen and metal are such oxidative decomposition.

For example: some of drugs are easily oxidised due to formulated in their reduced forms such are
epinephrine, morphine, ascorbic acid, menadione etc. Sometimes oxidation can be minimised due to
improve or increasing the oxidation potential.

Anti oxidants like salts of sulphur dioxide are commonly using one in aqueous parenterals. It will
keep the product in stable manner by adequately getting oxidised and it consumed throughout its
shelf life. Examples of anti oxidants:

Anti oxidants used in parenteral formulations

 S,NO Additives Concentration (%)
1 BLOCKING AGENTS
Ascorbic acid esters 0.01- 0.015
Butyl Hydroxyl Toluene(BHT) 0.005-0.02
Tocopherols 0.05-0.075
2 REDUCING AGENTS
Ascorbic acid 0.02-0.1
Sodium bisulphite 0.1-0.15
Sodium metabisulphite 0.1-0.15
Sodium formaldehyde sulphoxide 0.1-0.15
Thiourea 0.005
3 SYNERGIST AGENTS
Ascorbic acid 0.01-0.05
Citric acid 0.005-0.01
Citraconic acid 0.03-0.45
Phosphoric acid 0.005 – 0.01
Tartaric acid 0.01 – 0.02
4 CHELATING AGENTS
EDTA 0.01-0.075

iii) Chelating Agents: These are dissolve in solvent and forming complexes with metal ion, and it
prevents the metals ions from interfering in manufacturing process. Examples are

Chelating agents in parenteral formulations

S.NO Additives Concentration(%)

1 Edetate disodium 0.00368-0.05
2 Edetate calcium disodium 0.04
3 Edetate tetra sodium 001

iv) Buffers: It will be added in preparation to maintain the PH, and can change PH results in product
degradation. Examples are

Buffers in parenteral formulations

S.NO Additives Concentration (%)

1 Acetic acid 0.22
2 Adipic acid 1.0
3 Benzoic acid and sodium benzoate 5.0
4 Citric acid 0.5
5 Lactic acid 0.1
6 Maleic acid 1.6
7 Potassium phosphate 0.1
8 Sodium phosphate monobasic 1.7
9 Sodium phosphate dibasic 0.71
10 Sodium acetate 0.8
11 Sodium bicarbonate 0.115
 12 Sodium carbonate 0.06
13 Sodium citrate 4.0
14 Sodium tartrate 1.2
15 Tartaric acid 0.65

v) Stabilisers: This will be added in the formulation of parenterals to prevent rapid oxidation
process. Examples are

Stabilisers in parenteral formulation

S.NO Additives Concentration (%)

1 Creatinine 0.5-0.8
2 Glycine 1.5-2.25

3 Niacinamide 1.25-2.5

4 Sodium caprylate 0.4

5 Sodium saccharin 0.03

vi) Surfactants: It will be used in disposing water soluble drug as colloidal dispersions, for powder
wetting, prevention of growth of crystal in suspension, provide syringability, steroids solubiling and
fat soluble vitamins. Examples are

Surfactants in parenteral formulation

S.NO Additives Concentration (%)

1 Poly ethylene 0.1-0.5
2 Sorbitan monooleate 0.05-0.25

vii) Preservatives: It will maintain sterility of solution in preparation when use of multiple dose
package. Examples are

S.NO Additives Concentration (%)

1 Benzalkonium chloride 0.01
2 Benzethonium chloride 0.01
3 Benzyl alcohol 0.5-10.0
4 Benzyl paraben 0.015
5 Cholorobutanol 0.25-0.5
6 Metacresol 0.1-0.25
7 Methyl paraben 0.01-0.18
8 Phenol 0.065-0.5
9 Phenylmercuric nitarate 0.001
10 Propyl paraben 0.005-0.035
11 Thimerosal 0.001-0.02
viii) Protectants: It is used in protein formulation and protection against activity loss caused by
stress and to prevent loss of active ingredients due to absorption to primary packaging materials or
process equipment. Examples are

Protectants in parenteral formulation

S.NO Additives Concentration(%)

1 Glucose 2-5
2 Lactose 2-5
3 Maltose 2-5
4 Sucrose 2-5
5 Trehalose 2-5
6 Human serum albumin 0.1-1.0

ix) Toxicity adjusting agents: It helps to reduce level of pain or irritation of tissue. Examples are

Toxicity adjusting agents

S.NO Additives Concentration (%)

1 Lactose 0.14-5.0
2 Mannitol 0.4-2.5
3 Gelatin 1.6-2.25
4 Sodium sulphate 1.1
5 Sorbitol 2.0
6 Dextrose 3.75-5.0
7 Sodium chloride varies

PREPARATION

1) Filtration: Solution product should be filtered after its compounding. By filtration process all
microorganisms are removed whose size is less than 0.2µm in size.

2) Filling: Solution was sterilized by filtration process and it was filled by aseptic manner. For
prevention of contamination it will be stored in container. Filtration method is done to sterilize the
product or otherwise it should be done in final container. Liquid can be transferred more easily in
narrow mouth container compared to solid. For production filling heavy machinery are required.

Types of fillings method:

 Volumetric filling machines: It consists of Pistons or Peristaltic pumps.

 Time/ pressure filling: It used in filling of sterile liquids. The system of filling contains
production tank that is attached with pressure sensor. This sensor will be helps to measure
the pressure. They use nitrogen pressure for filling. Proteins are sensitive to shear forces so
they preferring time/ pressure filling.

4) Sealing: it is final aseptic procedure and it will be rapid and will prevent contamination in
container.
5) Ampoules: Neck portion of glass is melted and sealed.

There are two types: PULL SEALS and TIP SEALS.

 Tip seals are also called bead seals. In this, tip of the ampoules neck which is made up of
glass should be heated in high temperature with gas oxygen flame, neck will form like bead
to close the opening.
 Pull seals: In this heating will be done at below the tip of ampoule. In the single burner of
flame will be used in ampoule to seal. While glass gets soften, the tip should be clutched and
pulled from the body of ampoule.
 Comparison between the two seals, pull seal is slower and secure than tip seal.

6) Vials and bottles: Rubber closure will be used to close both glass and plastic container after the
process of filling it will helps to prevent from contamination. Ampoules are more risk for
contamination compare with vials. With help of the aluminium caps only the rubber stopper will be
in the correct position.

7) Sterilisation: After the final container is sealed only it is called as terminal sterilization. As soon as
possible it will done after filling and sealing. This can be done by thermal process. There are 2 types
of sterilization.

 Radiation sterilization
 Dry heat sterilization

Radiation sterilization: After finishing the parenteral product, it should done very carefully because
increase in temperature can cause alternation of stability. Some of the product like pharmaceutical
and biological product is affected due to increased temperature, so they need for sterilization in
thermal process. Ionising radiation used in terminal sterilization method. In the non-thermal process
of filtration procedure they use bacteria retaining filter for the heat labile products only. In all
process they follow strict aseptic techniques for preventing contamination into the filtrate. The
disadvantage is it can change colour and odour of radiolytic products.

Dry heat sterilization: some of the dry solids are sterilized by this method, they are not affected by
increase temperature. In this type they mainly use glass ware and metal ware for sterilization. After
the sterilization process all the equipment are pyrogen free, sterile and dry. Commonly using
sterilization method is autoclaving. It is used in both aqueous or liquid substances because it is most
effective method of sterilization.

Advantages:

1) Its action is very quick in nature.

2) Other than Oral route drugs are used in this administration.

3) In Unconscious or vomiting patients they use this type of administration.

4) it can prolong the action of duration.

5) Glucose and electrolytes (sodium chloride) are nutritive in nature can be administered through
this route.

Disadvantages:

1) it can be painful.

2) Administration of drugs should be done by trained persons

3) overdose and wrong dose can cause death as well.

EYE DROPS

It is made up of sterile liquid or suspensions or oily solutions of drug. It should be present in Doppler
and it infused into the eyes. The drops should contain drugs like anti-inflammatory, anaesthetic,
anti-septic etc.

Characteristics of eye drops are:

1) Sterile in nature

2) It should be iso-osmotic with lachrymal secretions.

3) It will be free from pathogens, foreign particles, fibres and filaments.

4) pH is neutral.

5) The preservation of drops should in bacteriocidal.

6) In storage also it should be in stable nature.

Formulation: Formulation of eye drops consists of:

i) Desired therapeutic effect was produced by active ingredients.

ii) Vehicle may be aqueous or oily in nature.

iii) Prevention from microbial contamination and maintaining stability by inert anti-microbial
preservatives.

iv) Inert adjuvants are mainly used for the tonicity, viscosity or pH to increasing the stability by active
ingredients.

v) Proper storage is necessary for maintaining the products in stable nature and it will helps to
prevent from contamination. It should be carried out in three stages like preparation, storage and
use.

Eye drops should be always in sterile in nature. Pseudomonas aeruginosa, is one of contamination in
drops leads to vision loss.

Antimicrobial Preservatives
Multiple dose eye drops are mixed or added with the some antimicrobial preservatives that
are effective and they should pass the test for efficacy. It will be helps to ensure that drops
are sterile in nature and non-contamination. Penetration of micro-organisms are prevented
in healthy eyes and sometimes microorganisms colonies are developed due to the damage
of epithelia. In eyes the cornea is avascular and any other internal structure has chance of
infection and it should be treated. Preservatives are avoided in eye drops that are used in
the intraocular surgery of eye it can lead to damage in eye.

Preservatives for eye drops

Benzalkonium Chlorhexidine Phenylmercuric nitrate

chloride(0.01%w\w) acetate(0.01%w/v) (0.002% w/v)

Atropine sulphate Cocaine Tetracaine

Carbachol Cocaine and homotropine Chloramphenicol

Cyclopentolate Fluorescein

Homatropine Hydrocortisone

And neomycin

Hyoscine Lachesine

Hypromellose Neomycin

Phenylephrine Sulphacetamide

Physostigmine Zinc sulphate

Pilocarpine Zinc sulphate and adrenaline

Prednisolone

Acetate may be used and in single dose preparation.

PREPARATION

1) Preparation of the solution: In aqueous drops, vehicle contains the antioxidant, stabiliser,
preservative, viscosity modifier or buffer, tonicity modifier with active ingredient and vehicle to
increase the volume.

2) Clarification: membrane filter or sintered glass filters and size of pores is 0.45-1.2µm is used, the
clarified solution should be poured into final container or filter directly and sealed it before of
process of heat sterilisation or any other container before filtration.

3) Sterilisation: In this autoclaving should be achieved at 115o C temperature for 30 minutes or

121oC temperature for 15 minutes of time period. Membrane filter is used for filtration into sterile
container and size of pore is 0.22µm also the best method for sterilisation. In dry heat method they
used at 160o temperature for 2 hours and it suitable method for the non-aqueous products like
liquid paraffin eye drops.

4) Each eye drop container should be closed in the breakable seal. It should be done after the
sterilisation process.

Advantages -

i) It will be used as natural moisture in eye and it helps to prevent dryness of eyes.

ii) Eye drops containing medication would help in fast recovery of eye surface. Its fluid will be helps
to flush the eye and reducing irritation.

iii) Compare with pills and injection it is very easy to administer the drops.

Disadvantage -

i) Container of eye drops should be maintain carefully for prevention of contamination and it leads
to infection and cause severe effect on it.

ii) Sometimes drops that not works on patient eye, the reason is mainly due to the continuous
administration. It leads to irritation of eye and cost expensive.

iii) For minor symptoms administer of eye drops not works. More and continuous uses of the eye
drops affect both health and wealth.

iv) For some individual it will cause gritty or burning sensation and blurred vision it mainly due to
allergic problems/season.

Uses

1) It helps to treat infection.

2) For using dilating and contracting pupils.

3) These are used before any surgical procedure or examination if eye.

4) It helps to relieve from itching, discomfort and pain.

5) For lubrication of eye.

6) It used to staining the cornea for identify scars and abrasions.

EYE OINTMENTS

In this, vehicles are used to maintaining the drug stability for prolonged time period. In ointment,
product are removed from foreign particulate matter by sterilisation through heat and filtration in
liquid phase itself.
Ophthalmic ointments should be non-irritating in nature. After sterilisation of eye ointments it
should be kept in sterile steam jacket for maintain the ointments in molten state and adding
excipients. After the process it should pass into pervious sterilised colloid mill.

Formulation - For preparation of ointment bases are used, they are

- Yellow soft paraffin 80gm.

- Liquid paraffin 10gm.
- Wool fat 10gm.

White soft paraffin: It is made by bleaching of yellow soft paraffin, so it not used. Bleaching Agents
sometimes stick on the base and cause irritation to eye after proper washing.

Wool fat: It helps in absorption of active ingredients and it was used as solution emulsification.

Liquid paraffin: It mainly for the reduce viscosity of base so it will be expelled easily from collapsible
tubes for applied on eye.

Preparation - Both yellow soft paraffin and wool fat both should be melted on heating in water bath.
Liquid paraffin was added to melted mixture and then filtration done through coarse filter paper (for
ex: Whatman 54) in heated funnel. And finally mixture is sterilised at 160oC temperature for 2 hours.
Medicament is added in eye ointment base and finally its package done in sterile container.

Advantages -

1) It have prolonged contact time and increased Stability.

2) Selection of drugs is flexible.

3) Improves stability.

Disadvantages

1) Sticking of eyelids after using.

2) Sometimes blurred vision will occur.

3) Poor patient compliance.

4) It will be interfering with attachment of new corneal epithelial cells to normal base.

5) Eyelids matting will occur.

IMMUNOLOGICAL PRODUCTS

According to WHO IMMUNISATION “THE PROCESS BY WHICH AN INDIVIDUAL IS MADE

IMMUNE OR RESISTANT TO AN INFECTIOUS DISEASE, TYPICALLY BY ADMINISTRATION OF A
VACCINE”
Administration of vaccine in the body, it will act on immune system and provide protection from the
infection or disease in the body based on the vaccine. Products (immunological) are mainly made up
of group of pharmaceutical preparation with different compositions but its purpose are same.
Vaccines, immune sera, human immunoglobulins, antibody tested therapies and diagnostics, in vivo
diagnostics, monoclonal anti bodies are currently available products.

Sera

Sera (i.e. serum in singular) are the component of blood which is neither blood cell nor clotting
factor, but it is blood plasma without fibrinogen. It contains all antibodies, antigens, electrolytes,
hormones, exogenous substance (i.e., microorganisms or drugs) and proteins.

Anti-sera (anti serum) - it is the blood serum, it contains antibodies and it will be provide the passive
immunity to person against various diseases in body. It is also called as ANTI TOXIN. This injection
provides antibodies or immunoglobulins. After administration of antigen in animal body, it will cause
disease and produce the antibodies, it will collected in the form of anti-sera. In this process
sometimes it will produce allergic reactions as it is collected from animals. It will act as curative and
also for the immediate protection from disease.

Features of anti-sera

 Antibodies are produced from animals (mainly horses).

 It will be obtained from animal serum (e.g., anti-serum of rabies).
 Anti-toxins are produced by administration of toxoid or toxin, e.g., Anti snake
venom(ASV), Anti tetanus serum(ATS), Anti diphtheria serum(ADS), Anti gas gangrene
serum (AGS), anti D sera, hepatitis B anti serum, rabies anti toxin/anti rabies, scorpion
anti venom , etc.
 The anti-toxins or anti-sera are administered in human through the parenteral route.

Manufacturing of sera

The antigen and sensitive cell of antigen of immune system get closer and there will be production
of anti-bodies occurs. This process will occur naturally during development process of human or it
will occur after the antigen administrated artificially as immunisation or vaccination. Administration
of vaccination in human will protect from infection by production of antibodies for particular
disease.

In laboratories, the anti-sera are prepared by immunisation of animal, example: rabbits. The
diagnostic or therapeutic anti sera are prepared from many animals like horse, pigs, goats, sheep for
large amount of production. In simple antigen administration in animals it will producing mono
specific antibodies, in complex or mixed antigen will produce poly specific antibodies.

The efficiency of immunisation will depend upon the route of administration, character, dose and
form. In animals, antigen is administered via intra muscular, intravenous, intra peritoneal, intra-
dermal, sub-cutaneous. In intra peritoneal and intravenous administration of antigen will reach the
spleen and liver through circulating system via blood and stimulate the lymphatic tissues of body.
The other routes like intra muscular, intra dermal and subcutaneous, it will reach the lymph nodes
and highest amount of immune response will be produced. Low titres of antibodies will produce in
simple antigen and it will give primary responses.
Auto immune processes can arise in the preparation of anti-sera against organs. Because the
immunised animals is injected with antigen having structure that will be resembles of the host tissue
and organs antigens. Due to the auto immune reaction will cause damage of inner organs and
sometimes it may lead to death also. In some other condition it will fail to act due to immunological
tolerance, which occurs when both administered antigen and host antigen looks same. So that time
take different animals for preparing anti sera.

Vaccines

 Louis Pasteur invented the term vaccine and derived from vacca (cow means), and Jenner
designed 1st vaccine for Vaccinia (cow pox virus).
 In process the Individuals are exposed to particular antigen intentionally that time disease
doesn’t affect them or not cause any infection is called Vaccination. In the process the active
immunity of individual will be induced.
 Vaccine is killed micro-organisms or live attenuated or parts or products of antigens which
will induce specific immune response.
 After the process of vaccination, it will stimulate both T and B memory cell which will yield
the T cells and B cells antibody producing cells.
 It will stimulate high amount of neutralising antibodies.
 Vaccines are prepared from killed microorganisms or weakened, or activated toxins, sub
cellular segments, toxoids derived from microorganisms or immunologically active surface
markers.
 Based on the target pathogens vaccine are bacteria or viral type.

BACTERIAL AND VIRAL VACCINES

BACTERIAL VACCINES VIRAL VACCINES

Live attenuated Bacillus calmette Guerin(BCG), Vaccinia, measles, mumps,
S.typhi (Ty21a), S.typhi (Aro A) rubella, yellow fever,
and V.cholera. polio(OPV), adeno, varicella
zoster, cytomegalo, hepatitis A,
influenza, dengue, rota virus,
respiratory syncytial, influenza,
and Japanese encephalitis.
Inactivated V. cholera, B.pertusis, S.typhi, Polio (IPV) , influenza, rabies,
V.cholerae. Japanese encephalitis, hepatitis
A.

It is administered in single agent or combination, they have routes like subcutaneous, intramuscular
intranasal, or oral, intradermal. The vaccine is effective well tolerated, inexpensive to produce,
convenient to store and easy to administer.

Types of vaccines or vaccine preparation: It contains microorganisms or its components

a) Live attenuated vaccine

These vaccines are prepared from non-virulent micro-organism and it retain its antigenicity. It will
provide lifelong permanent immunity to individual and protect from various disease. They are
unsafe in immunocompromised individual so it should be avoided in them.

B) Inactivated vaccine

These type of vaccine are made up of activated or killed pathogens with the altered antigenicity. The
organisms are killed through heat or chemical application. First primary dose of vaccine are
administered and then single or multiple booster is required. Inactivated vaccines are made by killed
form of disease causing microorganisms. Inactivated vaccine in the single dose doesn’t provide
immunity as like the live vaccines, and needed specific time interval for administration of booster
injection for continuous immunity.

C) Recombinant sub unit vaccine

These vaccines are prepared by genetic engineering. The genes collected from desired antigen of
microbe that are inserted into vectors.

D) Toxoid vaccine
This type of vaccines is prepared from the certain bacterial species producing toxins in it. Method of
preparation called as toxoiding. Removal of the toxins from bacteria is done by chemical treatment
without affecting immunogenicity. Toxoiding process utilised by different reagents. Formaldehyde is
common one.

Bacterial cell component vaccines

In this, the vaccines are prepared by purified protective components (proteins and polysaccharide)
and not from whole cells.

Disadvantage of this vaccine is that it has T cell independent antigen, they don't induce effective
protective response or immunological memory in very young individual. The problem is solved by
chemical, coupling the polysaccharide with T-cell dependent protein.

Conjugate vaccine

Based on the performance of antigens types, sometimes it will produce the inappropriate or weak
immune response. And it will be improved by chemical conjugation with more immunogenic
carriers. Peptide Protein, polysaccharide protein, alkaloid protein and lipid protein are prepared by
this process only. Conjugate vaccines are used for tumour therapy, preventing infection, treating
addictions and controlling fertility.

Viral subunit vaccines

This viral subunit vaccines have 3 available forms -

1) Two influenza vaccine

2) One hepatitis B vaccine.

Its preparation include collection of influenza particles from embryonated hen's egg which are
affected by virus of influenza. And it will be treated with surfactant (Example: non-ionic detergent)
and it disrupts the particles of virus and produce the subunits of virus. And it is concentrated and
recovered by method of centrifugation.

Hepatitis B vaccine can be removed from the hepatitis B surface antigen (HbsAg) collected from the
blood of individual who are affected with hepatitis B. Antigen from the un-natural source was
genetically engineered and expressed HbsAg after the process of fermentation.

DNA VACCINE
These vaccines are still in the research and they are similar to recombinant vaccines. Administration
of DNA is done in the animals, intramascularly, to blow the DNA into the muscle cells with help of
compressed gas.

After the introduction of the DNA, it will completely coated with gold particles. DNA will help to
stimulate the both cellular and Humoral immunity.

Production of vaccines

Vaccines are used for large population to maintain health and it was large scale production, and
challenging task.

Production of vaccines include:

 Generation of the antigens – antigen will stimulate the immune response of the body by the
following techniques –

1. For preparing live antigens, they are grown on cells, and allowed to replicate.
2. Proteins are derived from the pathogens.

 Release and isolation of the antigen – now in this step, we separate the antigens from the
pathogens.
 Purification – it will undergo ultrafiltration, gel filtration, size exclusion to separate them
properly. Then they undergo basic purification methods.
 Addition of other components – vaccines are made by adding other components which will
increase the immune response, or increase the shelf life, or help in preservation.
 Packaging – the vaccines are put up into the vials or vessels which are sealed and labelled
properly.
Chapter 6 – PHARMACEUTICAL MANUFACTURING PLANT AND QUALITY CONTROL AND QUALITY
ASSURANCE

DEFINITION AND CONCEPT OF QUALITY CONTROL

It include various techniques that are involved in the monitoring and improving the business so that
the products, services meet the standard specifications. It include reviewing the processes and all
the specifications and also make recommendations for the improvement.

The aim of quality control is to identify and eliminate the sub-standard performance.

The two major categories of quality are – quality of design and quality of conformance.

QUALITY OF DESIGN – it tells you the characteristics of any product such as high-grade materials,
special features, etc.

QUALITY OF CONFORMANCE – once we decide the quality of design, we form the characteristics of
the product into drawing and specifications. Then these drawings are used by engineers to develop
the standards and design such as floor layout, machinery, tools, etc. Quality of conformance is the
degree of adherence of the product characteristics to the design drawing and specifications.

DEFINITION AND CONCEPT OF QUALITY ASSURANCE

Quality assurance means final inspection, it include all the activities done to ensure that the product
meets the required specifications. It is basically the arrangements that are made to ensure that
pharmaceutical products are of the quality required for the intended use.

Quality assurance make sure that –

 Pharmaceutical product is developed in a way that is according to Good Manufacturing

Practice (GMP) requirements.
 Correct packaging and information is labelled on the product.
 All the calibrations and validations of the product are done.
 They are not sold before the authorized persons have certified the production.
 Quality of the product has been maintained throughout their shelf-life.
 Regular evaluations must be done.

The manufacturer of the product must takes the responsibility for the quality assurance of the
product and make sure that they are safe to use, comply with the standards, efficacy is proper.

CURRENT GOOD MANUFACTURING PRACTICES (CGMP)/ GOOD MANUFACTURING PRACTICES

(GMP)

Good manufacturing practice (GMP) is a system for ensuring that products are consistently produced
and controlled according to quality standards. It must be followed by the production department as
well as by the quality control unit.

Under GMP –

 All the processes involved in the manufacturing must be clearly defined.

  Qualification and validations of the products are performed.
 It makes sure that all the required resources are provided, that include – personnel, space,
equipments, materials, labels, containers, instructions, storage, transport, etc.
 All the instructions are in understandable language.
 Personnel are adequately trained.
 Proper records are maintained.
 System is available to recall any batch of products.
 All the complaints must be examined and changes are made accordingly.

PERSONNEL

Personnel play very important role in the manufacturing and quality assurance of the product. All
the personnel must be trained accordingly and must have adequate knowledge regarding all the
processes. Individual responsibilities must be clearly defined to all the personnel.

Personnel who supervise the pharmaceutical products must possess scientific education and
experience as mentioned in legislation. He/she should be qualified in –

- Chemistry or biochemistry
- Chemical engineering
- Microbiology
- Pharmaceutical sciences
- Pharmacology and toxicology
- Physiology, etc.

PERSONNEL TRAINING

Company should design a training program so that whenever they employ or hire any worker or
personnel, they can provide appropriate training to them. Along with this training, they must be
taught about all the GMP practices and their individual responsibilities and duties.

An in-service education program and training program should be given to them so that their
knowledge remain up to date and they can work actively and efficiently.

PERSONAL HYGIENE

All the personnel must undergo proper health examination and checkup before hiring, so that the
company got to know that they are hiring capable individuals. Also there must periodic health
checkup and examination.

Personal hygiene must be maintained by all the individuals and the training of it must be given to
them by the company itself. If a person shows any kind of symptoms then he or she should not be
allowed to handle the materials for packaging materials.

Good sanitation practices must be followed by all the employees. Education must be given regarding
the use of head cover, face mask, hand hygiene, etc., so that products must not be contaminated.

BASIC STRUCTURE OF PHARMACEUTICAL MANUFACTURING PLANT

For developing a pharmaceutical product, there should be premise that is of suitable size,
construction and location.

Site development plan must address the following -

- Overall Infrastructures such as green spaces, parking, road access, etc.

- Waste management protocol
- Security, guard Post, cameras, etc.
- Ease of maintenance and cleaning
- Good construction material
- Electricity backup, water availability.
- Layout of the building
- Appropriate Equipment placement
- Traffic flow
- Compliance with laws and regulation

Following guidelines must be followed during plant design and construction -

 Walls - walls must be noise proof so that work can be done effectively. They must be
adequately spaced. High quality concrete block or gypsum with plaster finish should be used
for making the walls. The finish of the walls must be smooth.
 Floors - they must be durable, easily cleanable, resistant to chemicals, without cracks, and
there must not be any accumulation of dusts.
 Ceilings - Ceiling must be non-brittle, non-combustible in nature. Ceiling should be seamless
and have adequate light fittings, there outlets and Returns. They are designed in such a
manner that they reduce dust accumulation.
 Lighting - lighting must be adequate and should reach every area under it. Normally 32-50
foot candles is suitable for the work environment and effective performance however few
areas demand higher foot candles along with special lighting such as in operation theatre.
 Services - there must be adequate provision of drainage, water, electricity and other services
in the building. Proper cleaning, washing and toilet facilities must be provided for the
employees.
 Utilities - required facilities must be available in the building such as adequate ventilation, air
filtration and exhaust system, proper air conditioning facility. These systems must be
installed in a way that they prevent cross contamination.
 Water - availability of water depends upon its usage, for example, if water is only needed for
the drinking purpose then we require the same amount of water but if it is required for any
production or preparation purpose then we need large amount of water. If any
manufacturer use treated water, so to achieve the quality of the water treatment processes
should be validated and monitored.
 Contaminant - if we are producing any sterile or sensitive material for example
cephalosporins then we need a separate production areas which will be having separate
equipments and we need to make sure that there will not be any type of contaminant
present at that time during the production. Proper disinfection and sterilization of that area
must be done routinely.
  Sewage and refuse - building must have proper sewage and refuse disposal norms,
containers must be provided for the disposal of waste in the building.
 Sanitation and maintenance - if you are manufacturing active Pharmaceutical ingredients
then we need to keep the area clean and well maintained. The building must be very clean.
No insects, rodents, fungus must be present because it will contaminate the material. So we
can use various insecticides, disinfectants, fungicides.
 Ancillory areas - there must be provision of changing rooms and lockers, pantry, toilet areas,
stores so that all the things can be managed easily.

LAYOUT OF PHARMACEUTICAL MANUFACTURING PLANT

If a manufacturing plant is prepared by a proper layout then it will result in efficient production and
coordination. Proper layout include all the information related to the workplace, sequence of
operations, flow pattern of materials, storage space, in process inventory, and finished goods, space
for office, toilets, etc.

Importance of plant layout -

 It will help in better operations.

 It makes economic use of building.
 It enhances safety and employees convenience.
 It gave maximum exposure to natural light and ventilation and provide comfort to the
Employees.
 It will lead to the effective utilisation of Manpower and all the areas in the building.

Types of plant layout -

 Product layout: In this all the equipments or machineries or tools that are required for the
production are arranged as per the sequence. This is also known as one line layout.
 Process layout: In this all the equipments or machineries are not arranged as per the
sequence but a specific operation like granulation or coating of the products is carried out at
a particular workstation. Departments must be located at a minimum distance to avoid long
distance movement of materials.
 Fixed position layout: In this a complete product is produced at a fixed location.
 Combined layout: It is a combination of product and process layout.

SECTIONS OF PHARMACEUTICAL MANUFACTURING PLANT

Different sections are involved in the manufacturing of Pharmaceutical products and this section
required different norms for space and supplies. The sections include purchasing of raw material,
processing, production, manufacturing, releasing, storing and shipment of the Pharmaceutical
product.

Minimum area required for each section setup for pharmaceutical manufacturing unit is given
below–

 For external preparation section - it includes making of cream, ointment, it requires at least
30 square m for the making area and 10 square m for ancillary area.
  For liquid dosage - it includes preparation of syrup, suspensions, it require at least 30 square
m area for basic installation of machinery and 10 square m for ancillary area.
 For solid dosage - it includes preparation of tablets and capsules or powder. Tablet section
need 60 square m area for installation of machinery and 20 square m area for ancillary, this
is for uncoated tablets. If coating is required, then a different area of at least 30 square m is
required. Capsule section and powder section require at least 25 square m for the
production and around 10 square m for ancillary area.
 Ophthalmic preparation - it includes production of parenteral ophthalmic solutions, so a
sterile section is mandatory. Minimum 25 square m area is required for the production and
around 10 square m of ancillary area.
 Parenteral section - it includes preparation of ampoules, injections, vials. Dry unit must be
separated from the wet unit. The area under this section varies according to the the volume
of parenteral preparation.

ACTIVITIES OF PHARMACEUTICAL MANUFACTURING PLANT

Process equipment:

All the equipments or devices must be adequately marked and special attention must be given to
them, for example, their wires are connected or not, if they are causing any harm to the
surrounding. If we are using any measuring equipment then the range must be fixed.

Maintenance and cleaning - cleaning and maintenance must be done routinely. Assign the individual
responsibility for equipment cleaning, maintain their schedule, instruct them about de-assembling
and reassembling all articles, inspection of equipments must be done prior to use.

Calibration - equipment must be calibrated according to the standard followed by the company
which are certified and records of these calibrations should also be maintained. Do not use those
equipments or instruments which do not meet the calibration criteria.

Documentation and records:

Records of equipment cleaning and use -

Whenever we are cleaning and using the equipment, record must be maintained. Record include the
date, time, product, batch number of each batch processed in the equipment, and the person who
perform the cleaning and maintenance of equipment.

Records of raw materials, intermediate, API labelling and packaging materials -

All the records must be maintained related to the above mentioned which include, the
manufacturer's name, quantity of each shipment, supplier name, number on receipt, date on
receipt, result and conclusion, final decision regarding the rejected raw material.

Batch production record -

It should be prepared for each intermediate and API. It should include all the information related to
the production and control of each batch. The record must have an identification number and must
be dated and signed while being issued.
Documentation of completion of each significant step in batch production record should include -

 Date and time

 Identity of equipments
 Weight, batch number
 Result recorded
 Sampling
 Signature of the personnel who performed and supervised each step
 Result of laboratory test
 Description of packaging and labelling
 Representative Label of API
 Any deviation noted
 Result of release testing

Laboratory control records - it include,

 Description of sample received for testing

 Raw material, name and source.
 Batch number or any code
 Quantity and date of receiving
 Test methods used
 Data of the preparation and testing
 Record of calculation performed
 Test results
 Signature of performer
 Date and signature of a second person who verify the accuracy of records.

Material Management:

The materials that are used in making, packaging, labelling, cleaning, maintaining must be noted.
The material must be of suitable grade to reduce health risk.

Receipt and Quarantine -

Once we receive the material, before accepting it each container of material must be visually
examined for correct labelling, or any damage, broken seals. We should Quarantine the material
before they are sampled or tested or released for use.

Sampling and testing of incoming production material -

If there is no certificate of analysis of a supplier we can perform test as well to evaluate the material.
A full analysis should be performed at intervals and compared with the certificate of analysis. There
is no need to test hazardous or highly toxic raw materials. And the result must be documented
appropriately.

Storage -
We can prevent the degradation and contamination of the materials by proper handling and storage.
Material must be stored in an adequate space and they must be stored in a way that their quality is
not affected at all. Arrange the materials in such a way that the oldest stock is used first. Rejected
material should be identified under a Quarantine system so that we cannot use them.

PRODUCTION AND IN-PROCESS CONTROL

In process controls (IPC), they are the checks that we do before the completion of manufacturing
process. It will help in the monitoring whether the material is according to the standards or not. It
can be performed at regular intervals or at the end of the process.

Production operations -

The material should have the following information -

 Name or item code

 Receiving number
 Measure of the material
 Date for revaluation

Time limits -

They must be specified to ensure the quality of intermediates and API. Any change in the specified
time limit must be evaluated and documented. There must be sufficient time limit for the
revaluation process for the in process control.

Contamination control -

The batches must be protected from the contamination, they got contaminated if they came in
contact with any Residue layer in the centrifuge bowl, etc. Production of the materials must be
conducted in such a way that contamination of intermediates or API by other material is prevented.
Precautions must be performed.

PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES

Intermediates:

There should be procedures in a written way that describe the identification, quarantine, sampling,
testing, and release, handling, packaging and labelling of intermediates. Records must be maintained
of each and every step.

Packaging materials:

Container must be able to provide protection against contamination or any deterioration of the
material. Container should be non-reactive, non-additive, otherwise the product will destroy.

Label issuance and control:

Authorised personnel is allowed to enter the label storage room. He is responsible for evaluating the
label so that there will not be any mix up and the product got proper identification.
Packaging and labelling operations:

Always refer to the documented procedures to ensure that suitable packaging materials and labels
are used. Labels on containers must have the name or identification code, product batch number,
and storage conditions. They must be examined before releasing the materials. And the examination
must be recorded and reported to the respected authorities.

STORAGE & DISTRIBUTION

Various individuals are involved in the process of storage & distribution.

Warehousing procedures:

It is necessary to provide suitable storage conditions to the product as mentioned in the guidelines.
And record of these conditions is mandatory. Provide separate storage spaces to the quarantined,
rejected, recalled materials.

Distribution procedures:

Once the quality control test has been done, the API and intermediate should be released for
distribution. Special conditions are required for the transportation or storage of an API or
intermediate as mentioned on the label. It is the duty of the manufacturer to make sure that the
persons involved in the storage and transportation must know about these conditions.

LABORATORY CONTROL

Quality units should have lab facilities and the laboratory controls that include all the procedures
related to sampling, testing, approval or rejection of the material and recording and storage
conditions must be documented and followed throughout the laboratory testing.

Primary reference standard -

These are those standards which are obtained from an officially recognised source and these are
tested and validated. If primary reference standard is an available then we can develop or design in-
house primary standard reference and test it.

Secondary reference standard -

These are those standards which are tested or determined prior to use by comparing against primary
reference standard.

Testing of intermediates for API:

Laboratory tests should be performed for each batch to ensure the quality. If we find any impurity
then documented immediately. The impurity profile should be compared impurity profile in the
regulatory submission or with the historical data. This help in detecting any change in the batch.

Certificates of analysis:
Certificate of analysis should be issued on request for each batch. Certificate should carry the name
of the product, its grade, batch number, date of release, expiry date, etc. It should also include the
list of test performed, result of the test obtained.

Date of expiry and retest:

After manufacturing or the production of API or any intermediate, always assign it an expiry date or
retest date.

VALIDATION

Validation provide evidence for -

 The premises, utilities, equipment, and processes that have been designed as per the
requirement for GMP. (Design qualification)
 The premises, utilities, equipment that have been installed according to the design
specification. (Installation qualification)
 The premises, supporting utilities, and equipment operation according to the design
specification. (Operational qualification)
 Processes for the production of the product according to the standards. (Process validation,
Performance qualification)

Validation policy:

Include company's policy and approaches, that how they validate a certain product. The important
parameters should be identified during the development stage, such as -

 Defining the API

 Identifying the parameters that affect the quality
 Define the processes parameter that we use for the manufacturing.

Validation documentation:

Written validation protocol will describe how we conduct the validation process. It include all the
steps and criteria that we usually follow.

Approaches to process validation:

Process validation has three approaches -

1. Prospective validation - that means validation is completed before the final drug product
manufactured from the API.

2. Concurrent validation - we are doing the validation process concurrently that means side by side
with each and every process.

3. Retrospective validation - this cannot change the process, because this can be done after the
creation of the final product.

Periodic review of validated system:

Time to time evaluation of the system is required to verify that they are operating in a valid manner.

Cleaning validation:

During early production we should validate the cleaning procedures for equipment, this should
reflect actual equipment usage patterns.

The equipment to be cleaned, procedures, materials, acceptable cleaning level, parameters to be

monitored, should be specified in the cleaning validation protocol.

REJECTION &RE-USE OF MATERIALS

Rejected material must be marked properly and they should be kept or stored separately in
restricted areas. Either we can return them to the suppliers or we can destroy them timely and
record it. In exceptional cases we can reuse the material only if the quality remains unaffected and it
is meeting the criteria. So a new batch number should be assigned to the reused batch.

COMPLAINTS & RE-CALL

Record of the complaint should include -

 Complaints name and address

 Nature of complaint
 Name and batch number of the API
 Date on which complaint is received
 Action taken initially with the dates
 Follow up action
 Response provided to the originator of complaint
 Final decision made on the API.

CONCEPT OF CALLIBRATION AND VALIDATION

Calibration is a set of operations that forms the relationship between the values indicated by an
instrument, example, weight, temperature. It generally compare the measured value and the
corresponding reference values.

Validation is an act of demonstrating and documenting that a procedure will steadily give the
desired result. It clarify the qualification of any instrument or tool. It ensures that the instrument
measures a particular thing in every scenario.

GENERAL PRINCIPLES OF CALIBRATIONS -

Calibration is a process of adjusting an instrument as per manufacturer’s specifications. The engineer

use the calibration process to determine the relationship between the values being measured and
the reference values. We can call an instrument calibrated, when it is giving the values as per the
reference data.

REASON FOR CALIBRATION

Usually instruments degrades with time and this will lead to alterations in the values being
measured. Continuing calibration ensures that equipment fulfils the desired specifications and
providing us the accurate values as per the standard. Good calibration leads to better productivity,
quality, and efficiency.

FREQUENCY OF CALIBRATION

It varies from industry to industry. Manufacturer performs the initial calibration on the equipment.
The subsequent calibrations are performed by the users as per the demand. The need to recalibrate
an instrument depends on how well the equipment performs in the application.

GENERAL PRINCIPLES OF QUALIFICATION

It is the documented evidence of premises, system, for equipment with pre-determined

specification. It is a part or the initial stage of validation, but it does not involve in the process of
validation. There are four phases of qualification –

 Design qualification – it is the first phase in which the instrument is developed, designed
and produced according to the standards. Manufacturer should maintain quality in
production and testing of the instrument. And user should confirm that this instrument is
intended to use. All the things must be documented properly. Design qualifications are the
specifications that a manufacturer used to describe any equipment. It fulfill the user
requirement specifications.
 Installation qualification - it is that verification which ensure that all the key aspects of the
equipment and ancillary system installation are as per the approved Design and Standards.
 Operational qualification - it is that verification which makes sure that all the key aspects of
the equipment and ancillary system perform as per the standard and ranges.
 Performance qualification - it is that verification which makes sure that the equipment
performed effectively and reproductive Lee to produce a product according to the
specifications and with quality.

GENERAL PRINCIPLES OF VALIDATION

Validation means that there is an evidence that tells us that the planned process will perform
according to the intended outcomes without failing.

The following principles apply -

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

 Product is of good quality, and is safe to use.
 Quality cannot be inspected and tested into the product.
 Quality risk management principles should be applied in determining the need, scope and
extent of validation.
 Ongoing review should ensure that the validated state is maintained.

TYPES OF VALIDATION

A. PROCESS VALIDATION:
It involve forming the documented evidence to provide assurance that any process will consistently
produce a product that will fulfil the specifications and quality. It occurs in 3 stages –

- Stage 1 – process design: it involve the manufacturing process is defined or the design is
defined.
- Stage 2 – process qualification: in this, the process design is evaluated to determine whether
or not the process can manufacture the product.
- Stage 3 – continued process verification: on going assurance is done during routine
production.

B. CLEANING VALIDATION:

This is conducted to ensure that no cross-contamination occurs between different batches. If the
residue of the first batch is not cleaned properly then it will contaminate the products of the second
batch and adversely affect the quality of product.

C. METHOD VALIDATION:

This is done to ensure the accuracy of analytical tests. We should first verify the test before testing
of the materials.

D. COMPUTER SYSTEM VALIDATION:

Computer systems are nowadays used for everything, it will help us in maintaining records, and
handling the data, so its validation is necessary. FDA issued a guide for validation of computer
system which was first published in 1983 and is called the BLUEBOOK.

VALIDATION MASTER PLAN

It is a document that describes the expectations, intentions, methods and approach to be used
during the validation programs. This master plan should neither be too short (4-5pages) nor too
lengthy (of 400-500 pages).

Master plan includes –

 Overview of site/facility/area
 Overview of manufacturing process
 Overview of types of cleaning method to be used
 Overview of responsibilities of various departments
 Overview of minimum requirements for cleaning validation program, including –
Necessary logics to support the program:
1. Residue selection
2. Equipment characterization
3. Product surface area calculations
4. Sample site selection
5. Product grouping, if any
6. Analytical methods’ validation
7. Sampling methods’ recover studies
  Data related to –
1. Cleaning and testing of equipments
2. Preventive maintenance
3. Visual inspection
4. Equipment quarantine
5. List of equipments subjected to cleaning validation
 Summary report.

VALIDATION CHARACTERISTICS

It include –

 Specificity
 Linearity
 Range
 Accuracy
 Precision
 Detection limit
 Quantitation limit
 Robustness
 System suitability testing

SPECIFICITY

This is done during the validation test, it will help in determining the presence of any impurities. In
this, we identify or discriminate between compounds having similar structure. Chromatogram is
used for the chromatographic procedure to demonstrate the specificity.

 If impurities are available - in this the discrimination is done in the presence of impurities.
This can be done by spiking the pure drug substance with appropriate levels of impurities
and then compare the result with the unspiked sample.
 If impurities are not available - the specificity in this case can be demonstrated by comparing
the test results of the samples containing impurities or degradation product with a second
well characterized procedure.

LINEARITY

A linear relationship should be evaluated across the range of the analytical procedure. It may be
demonstrated directly on the drug substance for separate weighings of synthetic mixtures of the
drug product components. If a linear relationship exist, test result should be evaluated by
appropriate statistical methods.

The correlation coefficient, slope of regression line, residual sum of squares and plot of data should
be submitted.

RANGE
Specified range is derived from linear studies. It is established by confirming that the analytical
procedure provides an acceptable degree of linearity, accuracy and precision when applied to the
samples containing amount of different ranges. The following specified ranges should be considered-

 Normally, 80-120% of the test concentration for the drug substance or a finished drug
product.
 A minimum of 70- t1 30% of the test concentration is for the content uniformity.
 From the reporting level of an impurity to 120% of the specification for impurity
determination, etc.

ACCURACY

Accuracy should be established across the specified range of the analytical procedure. We can
determine the accuracy by following methods -

 Comparing the result of the proposed analytical procedure with those of another well
characterized procedure with stated order defined accuracy.
 Determining accuracy after the establishment of precision, linearity and specificity.
 Accuracy should be evaluated using a minimum of 9 determinations over a minimum of
three concentration levels covering the specified range (three concentrations, three
replicates).

PRECISION

The extent to which precision should be established depend on the circumstances under which the
procedure is to be used. The applicant should establish the effects of random events on the
Precision of analytical procedure. Variations include days, equipments, etc. Standard deviation, and
confidence interval should be reported for each type of investigated precision.

DETECTION LIMIT

It can be determined by several approaches, depending on whether the procedure is instrumental or

non-instrumental.

 Based on visual examination - this can be used for non-instrumental as well as instrumental
methods. Detection limit is determined by analysing the samples with known concentrations
of analyte and by establishing the minimum level at which the analyte can be detected.
 Based on signal to noise - this can be applied to analytical procedures exhibiting baseline
noise. Signal to noise ratio can be determined by comparing the measured signals from
samples with known low concentration of analyte with those of blank samples and then
establishing the minimum concentration at which the analyte can be detected. Signal to
noise ratio between 3 or 2:1 is acceptable for estimating the detection limit.

QUANTITATION LIMIT

It can be determined by many methods, but depending on whether the procedure is non-
instrumental or instrumental.
  Based on visual examination: This can be used for non-instrumental as well as instrumental
methods, it can be determined by analysing the samples with known concentrations of
analyte and establishing the minimum level at which the analyte can be quantified with
acceptable accuracy and precision.
 Based on signal-to-noise approach: This can be applied to analytical procedures exhibiting
baseline noise. Signal to noise ratio can be determined by comparing the measured signal
from samples with known low concentration of analyte with those of blank samples and
then establishing the minimum concentration at which the analyte can be quantified.
Signal to noise ratio between 10:1 is acceptable.

ROBUSTNESS

It should be evaluated during the developmental phase. It should show the reliability of analysis with
respect to variations made deliberately in the parameters of methods. One consequence of
robustness evaluation is that a series of system suitability parameters should be established to
ensure that the validity of the analytical procedure is maintained.

SYSTEM SUITABILITY TESTING

It is an important part of analytical procedure. It is based on the concept that the equipment and
samples to be analysed form an integral system that can be evaluated. System suitability test
parameters is to be established for a particular procedure depend on the type of procedure being
validated. If the quality of the data is doubtful, meaningful conclusions about the product quality
cannot be reached and this will have serious unfavorable effect on the stability of the data and the
validation process.

Steps in method validation -

 A validation protocol for operating procedure for the validation is developed.

 The application, purpose and scope of the methods are defined.
 The performance parameters and acceptance criteria are defined.
 The validation experiments are defined.
 The relevant performance characteristics of the equipment are verified.
 The materials are qualified.
 Pre validation experiments are carried out.
 The method parameters and acceptance criteria are adjusted.
 Full internal and external validation experiments are carried out.
 The criteria for revalidation are defined
 The type and frequency of system suitability test for analytical quality control checks for the
routine are defined.
 Validation experiments and validation results are documented.

Validation report -

It includes the following things:

 Objective and scope of the method

 Type of compound and matrix
 Chemicals, reagents, reference standards and control sample preparation.
 Procedures for quality check of standards and chemicals used
 Safety consideration
 Method parameters
 Critical parameters indicated from robustness testing
 Listing of equipment and its functional and performance requirements
 Details of how the experiments were conducted and samples were prepared
 Statistical procedures and representative calculations
 Procedures for quality control in the routine
 Representative plots, example chromatograms, spectra, calibration curves.
 Method acceptance limit performance data
 Expected uncertainty of measurement results
 Criteria for revalidation
 Person who developed and initially validated the method
 Summary and conclusion.
CHAPTER 7 – NOVEL DRUG DELIVERY SYSTEM

INTRODUCTION

Novel means new. It is a new approach for drug delivery other than the conventional Drug Delivery
System. A Novel Drug Delivery System (NDDS) is an approach that combines inventive development,
formulations, new technologies, new methods for supplying drugs in the body as required to safely
achieve its anticipated pharmacological effects.

DRUG DELIVERY CARRIERS

These are the channels through which drug has been given. It include -

 Micelles: They are formed by group of amphiphilic copolymers in aqua solution. The
hydrophilic block can form hydrogen bonds with the Aqua surrounding and form a shell like
structure. So as a result the contents inside this shell is protected from hydrolysis and
enzymatic degradation.
 Liposomes: They contain layers of phospholipid. It helps in delivering the drug at a specific
site.
 Liquid crystals: They are present in liquid as well as solid state. They can form different
structures.
 Nanoparticles: They are in the solid state and can either be amorphous or crystalline. They
can adsorb the drug and hence preventing it from chemical and enzymatic degradation.
 Hydrogels: They are 3D in structure and they can absorb large amount of water. They can
deliver the drug at specific sites.

CLASSIFICATION

A. Films and strips:

The Medicament is spread over a film or strip. They are divided into three groups -

 Buccal strips - the patient is instructed to keep the strip with in the buccal mucosa or under
the tongue. It will start its action within 15 minutes. Then after this duration the strip is
removed and discarded.
 Zero order release film - these are used in topical application and as implants. Example
pilocarpine films, pilocarpine is dissolved in a 25% solution of poly-2- hydroxyethyl
methacrylate in 95% ethyl alcohol. This solution is spread over a film to get a thickness of
2mm. Then it is dried at room temperature for 1 hour, and then it is put up under the
pressure for 2 hours. Then it is cut into desired sizes.
 Sprayable bandages - they can be applied topically. They consist 0.01-90% of the drug that is
dispersed in a solvent. They are sprayed over the affected area. Example prednisolone
sprayable bandage.

B. Implants:
These are the tablets that are placed under the skin by doing a minor surgery and the drug is
released over prolonged period of time. In the market we can also find magnetically controlled in
plants, they can be placed in the upper thigh at a depth of 5mm.

C. Sustained and controlled release Drug Delivery System:

In this drug delivery system we can control the rate of release of the drug, usually the rate is slow.
Diclofenac, nicotine can be given by this technique. Benefit of this technique is that the drug does
not need to be in crystalline form.

D. Microencapsulation:

It is a process where small droplets of solid or liquid substances are covered by a non-stop film of
polymeric materials. The covering of the particle is made up by microns.

E. Parenteral controlled release system:

It is most common and effective way of delivering the drug. This will provide the drug via parenteral
route in a controlled manner, so hence prevent frequent injection dosages.

F. Ocular Drug Delivery System:

Sometimes when we are injecting eye drops, one can injured their eyes buy bottle lid and also
preservatives are used in the preparation of the eye drop so this will lead to enhance the tear flow,
hence the drug remain minimum in the eye. Now a days new ophthalmic drug delivery system is
used and it is said to be harmless and tolerated.

G. Pulmonary drug Delivery System:

It is used in case of respiratory diseases. The drug is injected into the respiratory tract and shows it
effect in the system. Pulmonary route is best alternative to other routes since it can minimise the
required dose. And also prevent from recurrent injection.

H. Intrauterine Drug Delivery System:

It is the little plastic contraceptive device that is introduced into the uterus by physician or nurse. It
helps in preventing the pregnancy, and it is an Irreversible method. It helps in thickening of the
cervical mucus hence forming a barrier that prevent sperms from entering the fallopian tube.

I. Gastrointestinal Drug Delivery System:

It is an effective method that sustain the prolonged effect of the drug and more bioavailability of it.
Because whenever the drug is in gastrointestinal system it will go to the liver for the first pass
metabolism and this will reduce the bioavailability of the drug and earlier elimination of the drug.

J. Targeted Drug Delivery System:

This system help in only targeting a certain or specific site. The drug is directly selected for the target
site where it is concentrated and shows its reaction.

ADVANTAGES –
  Can give precise dose.
 Improved efficacy and safety.
 Controlled delivery of the drug.
 Specific site target
 Reduce side effect
 Helpful for patients.

CHALLENGES –

 Poorly soluble drugs is a major challenge because they have less bioavailability.
 Nanoparticles can be cytotoxic in nature.
 These systems are of Greater cost and complexity.
 For a large number of people we have less devices as of now.
 Certain medical devices are difficult to introduce in the body of some patients.
 Every kind of medicine cannot be given through these carrier molecules.