PHARMACEUTICS

By PHARMAGLIMPS
SAHADEV PARMAR
Sahadevparmar_22@yahoo.com
 Milling
Milling is a mechanical process to reduce the particle size of solids. It includes the terms like grinding,
pulverization, crushing, dispersion etc. the size of the solid particles conventionally expressed in mesh size i.e.
numbers of the pores per inch of screen.

Coarse milling produces particles longer than 20 mesh

Intermediate milling 20-200 mesh

Fine milling > 200 mesh

Milling is essential in pharmaceuticals and playing an important role in

1. Smaller the size, large is the surface area and faster will be the dissolution.

Specific surface = surface area / weight

The specific surface is increased on size reduction resulting in increasing the area of contact between solid
and dissolving fluid e.g. griseofulvin
2. Increase in area contact due to size reduction between solid and solvent ,reduce the time for extraction.
3. Particles size in inhalational aerosols determines the position and retension of particles in
bronchopulmonary systems.

But milling sometimes may alter the crystalline structure and can cause chemical changes in some materials like
starch, amylopectin and povidone structure is broken down to lower molecular weight polymers. Pure C12 and C16
fatty acids may be decarboxylated and converted to hydrocarbons containing one carbon less by ball mill.

Methods to determine particle size

a. Sieving method
b. Microscopy
c. Sedimentation
d. Electrical Conductivity method
e. Light and X-ray scattering

Sieving method:

Particle size (Micron) Mesh size

2000 10
850 20

600 30

400 40

300 50

250 60

200 70

175 80

150 100

75 200

37 400

b. Microscopy method: can measure particle size up to 05 µm -150 µm and generally 625 particles are counted

c. Sedimentation method: can measure particle size up to 1 µm- 200 µm and uses Andreasen pipette. Generally 1
% suspension of powder is placed and on the basis of Stroke’s law

x/t = dp2 (ρp- ρo).g

18η

x/t = Rate of sedimentation or settling velocity (distance / time )

dp = Particle diameter, η = Viscosity of the medium, (ρp- ρo) = Density gradient , g = Acceleration due to gravity

Most commonly mills used for size reduction

1. Hammer mill Almost for all drugs

2. Roller attrition Soft material
3. Fluid energy mill Moderately hard and friable ( like dried ) material
4. Cutter mill Fibrous material
5. Colloid mill Emulsions
6. Ball mill
• Hammer mill is mostly used for wet granulation. The material is feed at the top and thrown out
centrifugally and the sieved material is collected after passing through perforated screen present on the
lower portion of casing. The particle of the discharged material is smaller than the screen pore.
• Ball mill: The optimum volume of balls should be 50% of volume of the mill. Balls of different size can
be used for fine production of particles. Smaller balls give fine grinding. Ball mill uses both impact and
attrition. The speed is very important because if the ball mill is rotating at slow speed then the balls rolls
and cascade over one another providing attrition action. As the speed is increased balls are carried up and
fall down freely onto the material with an impact action which is responsible for most of size reduction. But
if the speed is further increased then the balls just begin to centrifuge with the mill is called as critical
speed and at critical speed or above critical speed there is no significant size reduction occurs. So the
critical speed id dependent upon the weight of balls and its angular velocity. Generally the ball mills are
operated at 60-85% of critical speed.
• Fluid energy mill: uses both impact and attrition. Here the micronized material is carried with high
velocity of air that follows an elliptical path in cyclone separator, the fine particles pass through a discharge
outlet and go into bag collector. While the larger particles are carried by centrifugal force to periphery
where they are further exposed to attrition. It can produce the particle size 2-20µ.
• Colloid mill: mostly used for production of emulsions and not used for dry particles. Colloid mill uses
a rotor with rpm 2000-20000. The space between the rotor and stator is adjusted to get the desired size
of globules of emulsions.
Drying
Drying is done to minimize bacterial growth, chemical stability, increase in stability, reduction of cost etc.

Non thermal methods of drying:

1. Adsorption of water from solvent by using desiccants like anhydrous CaCl2, silica gel
2. Absorption of moisture from gases by passing through H2So4 acid column.
3. Extraction of liquid from solid by use of solvent.
4. Squeezing

Hygroscopic: Natural tendency to absorb moisture e.g. glycerin, conc. Sulphuric acid, absolute alcohol

Deliquescent: Natural tendency to absorb water and liquefy e.g. Calcium chloride

Efflorescent: Natural tendency to lose water e.g. caffeine, borax etc.

Psychrometry: determines the vapor concentration and carrying capacity of a gas like air or nitrogen by passing
over the drying material.

Psychrometric chart: is relationship between temperature and humidity of air-water vapor system at constant
pressure.

Humidity of gas: concentration of water vapor in gas

Absolute humidity: Weight of water vapor / Unit weight of dry air

Saturation humidity: is the absolute humidity at which partial pressure of water vapor in air equal to vapor

pressure of free water at same temperature. Under these conditions air is completely saturated with moisture
and humidity does not change when it is in contact with liquid water at same temperature.

Relative humidity: Partial pressure of water vapor in Air

Vapor pressure of free water

So saturation humidity have 100% RH

Water activity: Water vapor pressure of exerted by Material

Vapor pressure of pure water

Dew point: A temperature to which given mixture of air and water vapor must be cooled to become saturated
i.e. it holds the maximum amount of moisture without condensation taking place. But if the mixture is cooled to
temperature below then dew point then water vapor condenses to produce two phase system of saturated air and

droplets of free water.

Wet -Bulb temperature: is the equilibrium temperature reached by evaporating surface when the rate of heat
transferred to surface by convection is equal to the rate of heat lost by evaporation.

Rate of heat transferred by convection = Rate of hear lost by evaporation

It is called as wet-bulb temperature because it is measured by the means of thermometer whose bulb is covered by a
wick of saturated with water. So wet-bulb is function of temperature and humidity of air used for evaporation.

Dry-bulb temperature: Actual temperature of air measured by ordinary temperature thermometer is called as dry-
bulb temperature.

Humidity of air can be determined by:

1. Dew point
2. Gravimetric method: is the most accurate method in which a known amount of air is passed over previously
weighed moisture absorbing material like phosphorus pentaoxide and the resultant increase in weight of
chemical is measured.

% Moisture content = Weight of water in sample / Weight of dry sample

% Loss on drying (LOD) = Weight of water in sample / Weight of wet sample

e.g. if 5g of moist solid is brought to a constant dry weight of 3g

% Moisture content = 5-3 / 3 = 66.7 %

% Loss on drying (LOD) = 5 - 3 / 5 = 40 %

Critical moisture content: During the drying both heat and mass transfer occurs. The point at which first dry spot
appears then the moisture content at this point is called as critical moisture content and the rate of drying begins to
fall off at this point.

Equilibrium moisture content: At this point no mass transfer occurs because it is the moisture content of material
at which water vapor pressure of material equal to the vapor pressure of surrounding atmosphere.
 *

Some important dryers:

Fluidized bed dryers: Uses a gas (mostly air) that is allowed to flow upward through a bed of particulate solids at
velocity greater than the sedimentation or settling velocity of particles, so the solids particles are buoyed up and
become partially suspended in gas stream. These are mostly used for drying the granules of wet granulation.

Pneumatic dryers: They can handle the fluids materials like solution, slurries and thin pastes. Here the fluid is
first dispersed in to fine droplets by pneumatic atomizers and these fine droplets comes in contact with hot moving
air and velocity of air is greater is greater than settling velocity of solids (more than used in fludized bed
dryer), so they evaporate rapidly and go along with the hot air into cyclone separator to give dried material in the
form of intact spheres which are than collected. The temperature of the air is generally 10 0C more than the
boiling point of the liquid present in the sample feed. So the time contact is very less so suitable for thermo
labile substances. The pneumatic dryers includes

1. Spray drying and spray congealing: Spray congealing is most suitable for heat-sensitive material and
encapsulation of solid and liquid particles.
2. Flash dryers: drying is for extremely short time because temperature of stream is 3000F - 13000F

Freeze drying / Drying by sublimation / Lyophilization: is mostly used for heat sensitive or material get oxidized
to oxygen as carrier gas. In this method the sample is first frozen into and then subjected under high vacuum
to heat. The frozen material is sublimized leaving only solid as dried component. The sublimation can take place
at pressure and below than triple point. The triple point for water is 4.579 mmHg and 0.099 0C. Mostly

freeze drying is done at a temperature – 10 0C to – 40 0C for most of the pharmaceuticals. Samples like
bacterial culture, blood samples, plasma, and antibiotics are dehydrated by freeze drying. The dried product can be
rapidly redissolved or resuspended by addition of water to prior use and this process is called as reconstitution.
 *

Compression: means reduction of bulk volume of materials as a result of displacement of gaseous phase.

Consolidation: is increase in mechanical strength of material resulting from particle-particle interaction.

True volume (Vt) : is total volume of solid particles. True density or true volume is measured by
Helium pycnometer.

Granular volume (Vg) : True volume + volume occupied by intraparticulate voids. Granule
volume is measured by liquid displacement method using mercury or benzene as liquid or other liquid which
do not readily wet the powder.

Bulk volume (Vb) : True volume + volume occupied by intraparticulate voids + volume

occupied by interpaticulate voids. Bulk volume is measured by standard tamping method.

Intraparticulate void means the space present within the particle while interpaticulate means the space present
between the particles.

% Porosity = Void volume (Inter + Intraparticulate) = Vb - Vt ‫٭‬100

Bulk Volume Vb

Free surface energy: atoms or the ions located at the surface of any solid particles are exposed to a different
distribution of intermolecular and intermolecular bonding forces than those within the bulk of particles. So these
unsatisfied attractive forces at the surface give the term called as free surface energy which plays an important role
in adsorption, cohesion, adhesion, rate of dissolution, rate of crystallization etc. e.g. in initial stage of wet
granulation ,the granulating liquid forms a film at their surface which combine to give liquid bridges at points of
contact.
 Surface active agents

Water and oil are immiscible and interface exists between them because the forces of attraction between water and
oil is weak, so interface exits. But if the strong attractive forces exits between oil and water molecules than two
liquids will be miscible and no interface would exist.

Surface active agents are either

1. Absorbed on interface between oil water or air water

2. They may form a orient clusters in aqueous phase (Micelles)

These surface agents effect the following properties

1. Decrease the interfacial / surface tension

2. Increase the osmotic pressure but at higher concentration become constant
3. Increase the detergency i.e. ability to solution to dissolve oil after threshold concentration
4. Increase the light scattering properties become significant after threshold concentration i.e. after
CMC

Surface active agents are classified on the basis of charge of hydrophilic region

Concerning the name, a surfactant which dissociates in water and releases cation and anion (or zwitterions) is
termed ionic (cationic, anionic, zwitterionic) surfactant. On the other hand, a surfactant which does not dissociate
is called a nonionic surfactant

a. Anionic : negative charge hydrophilic grp e.g. SDS, Sodium stearate. Examples of anionic surfactants are
generally called ―soap‖(fatty acid soap), alkylsulfonic acid salts (the main component of synthetic
detergent, such as linear alkyl benzene sulfonate (LAS)), fatty alcohol sulfate (the main component of
shampoo or old neutral detergents), etc
b. Cationic: Positive charge hydrophilic grp e.g. Cetyltrimethyl ammonium bromide and Benzalkonium
chloride. These are mostly used as antimicrobial compounds.
c. Non-ionic: Hydrophilic region has either ether (Tweens) or ester (Spans) grp.

Polysorbate 80 (commercially also known as Tween 80 is a nonionic surfactant and emulsifier derived from
polyethoxylated sorbitan and oleic acid. Polysorbate 80 is a viscous, water-soluble yellow liquid. The
hydrophilic groups in this compound are polyethers also known as polyoxyethylene groups which are
polymers of ethylene oxide. In the nomenclature of polysorbates, the numeric designation following
polysorbate refers to the lipophilic group, in this case the oleic acid. Polysorbate 80 is used as an emulsifier.
 Sorbitan monostearate (also known as Span 60) is an ester of sorbitan (a sorbitol derivative) and stearic acid
and is sometimes referred to as a synthetic wax. It is primarily used as an emulsifier to keep water and oils
mixed. Sorbitan monostearate is a non-ionic surfactant with emulsifying, dispersing, and wetting properties.

HLB SCALE

1-3 Antifoaming agents

4-6 W/O emulsifying agents

7-9 Wetting agents

9-16 O/W emulsifying agents

13-15 Detergents

16-18 Hydrotrope / Solublizing agents (To solublize hydrophobic compounds)

Methods to determine HLB

HLB is determined by water loving portion of surfactant. Generally the hydrophilic grps are polyhydric alcohols or
ethylene oxide while lipophilic grp are generally fatty acid or fatty alcohol.

1. HLB = % Mole of Hydrophilic grp

2. HLB = 20 (1- Saponification value (SV) / Acid value (AV))

3. HLB = 20. Molecular weight of hydrophilic grp (MH) / Molecular weight of

whole molecule (MT)

4. HLB = 7 + mHh – nHL

m = no. of hydrophilic grps

n= no. of lipophilic grps

Hh= value of hydrophilic grps

HL= value of lipophilic grp

 Micelles

A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution
forms an aggregate with the hydrophilic "head" regions in contact with surrounding solvent, sequestering the
hydrophobic single tail regions in the micelle centre.

As the concentration of the surface active agent go on increasing then at particular concentration these surface
agents are no more orient at the interface and no more further reduction in surface / interface tension because now
the surface active agents will go in bulk of liquid and these surface active agents will self associate to form colloidal
sized aggregates called as micelles which dominates above Critical Micelle Concentration or threshold
concentration. Critical micelle concentration (CMC) is defined as the concentration of surfactants above which
micelles are spontaneously formed. I the aqueous solution the aggregates have hydrophilic region in contact with
water and hydrophobic / lipophilic grp is shielded from water. Below CMC the surface active agents are exists in
monomers. The shape of micelle depends upon the concentration, temperature, ionic strength and type of the
surface active agent. Micelle is known as a normal phase micelle (oil-in-water micelle). Inverse micelles have the
headgroups at the centre with the tails extending out (water-in-oil micelle). Micelles are approximately spherical in
shape. Other phases, including shapes such as ellipsoids, cylinders, and bilayers are also possible.

The Krafft temperature (also known as Krafft point or critical micelle temperature) is the minimum
temperature at which surfactants form micelles. Below the Krafft temperature, there is no value for the critical
micelle concentration (CMC), i.e., micelles cannot form.

Normal Micelle Reverse Micelle

Generally the surface agent molecules present in micelle are believed to be in the range of 50-100 molecules. So
these aggregated surface active agents are characterized by aggregation number.

• Aggregation number in aqueous solution increases as the hydrophobic region increases i.e. –CH2
part. So higher the lipophilic nature of surface active agent lower will be CMC. But branching in
 lipophilic region interferes with close packing of surface active agents needed for Vander walls attraction

of hydrocarbons chains thus results in increase in CMC.

• In case of ionic surface active agents the addition of some electrolyte results in increase of aggregation
number because it will diminish the repulsive charge effect.
• Ionic surface active agents have much higher CMC than non-ionic because repulsive forces between
charged grps that resists close packing necessary for micelle formation.
 Wetting

Wetting is the ability of a liquid to maintain contact with a solid surface, resulting from intermolecular
interactions when the two are brought together. The degree of wetting (wettability) is determined by a force
balance between adhesive and cohesive forces. Adhesive forces between a liquid and solid cause a
liquid drop to spread across the surface. Cohesive forces within the liquid cause the drop to ball up and
avoid contact with the surface. The contact angle is determined by the resultant between adhesive and
cohesive forces. The tendency of a drop to spread out over a flat, solid surface increases as the
contact angle
decreases. Thus, the contact angle provides an inverse measure of wettability.

Wetting of different fluids. A shows a fluid with very little wetting, while C shows a fluid with more wetting. A
has a large contact angle, and C has a small contact angle

Contact angle (cos θ) Degree of Strength of interaction Strength of interaction

wetting between between
S /L L /L

θ=0 Perfect wetting strong weak

0 < θ < 90° High wettability strong strong

weak weak

90° ≤ θ < 180° Low wettability weak strong

Perfectly
θ = 180° weak strong
non-wetting

• A contact angle equal to 00 perfect wetting and means that adhesive forces between S/L is more
that the cohesive forces between L/L.
• A contact angle less than 90° (low contact angle) usually indicates that wetting of the surface is very
favorable, and the fluid will spread over a large area of the surface.
 • Contact angles greater than 90° (high contact angle) generally means that wetting of the surface is
unfavorable so the fluid will minimize contact with the surface and form a compact liquid droplet.

To measure the efficiency of wetting agents DRAVE’s TEST is done.

Young–Dupre equation:

Which relates the surface tensions between the three phases: solid, liquid and gas.

Spreading parameter S

When S > 0, the liquid wets the surface completely (complete wetting). When S < 0, there is
partial wetting
 Clarification and filtration

Clarification is the term used when sold content donot exceed 1 % and filtrate is primary product.

Metafilter: is a pressure filter mainly used for the clarification of syrups, filtration of injections solutions, and
clarification of insulin liquors.

Filtration is a mechanical or physical operation which is used for the separation of solids from fluids (liquids or
gases) by interposing a medium through which only the fluid can pass. Two main types of filter media are employed
in the chemical laboratory— surface filter, a solid sieve which traps the solid particles, with or without the aid of
filter paper (e.g. Büchner funnel, Membrane filters, Belt filter, Rotary vacuum-drum filter, Crossflow filters), and a
depth filter, a bed of granular material which retains the solid particles as it passes (e.g. sand filter, Sintered and
ceramic filter). For the cake filtration rotary drum filter and filtering centrifuge are used.

Pressure filter: Plate and frame filters (Filter press)

Vacuum filter: Filter leaf

Rotatary drum filter: Large scale and continuous

Theories of filtration:

a. Dracy’s equation : dV / dt = K A ∆P
ηL
b. Kozeny- Carmen equation
c. Poiseuillie’s law = πr4 ∆P
8 ηL

Membranes filters: have 80% pore of uniform size out of total filter medium volume. They have 400-500 millions
pores per square cm of filter membrane. These membrane filters are made up of esters of cellulose or nylon, Teflon,
polyamide etc. Cellulosic membrane filter papers can be attacked by bacteria.

Pore size Particles removed

0.22µ All bacteria
0.45 µ All colliform grp bacteria
0.8 µ Air borne particles
1.2 µ All non-living particles considered dangerous in I.V fluids
5µ All significant cells from body fluids
Filter aids: ―Filter Aids‖ is a group of inert materials that can be used in filtration pretreatment. There are two
objectives related to the addition of filter aids. One is to form a layer of second medium which protects the basic
medium of the system. This is commonly referred to as “precoat”. The second objective of filter aids is to improve
the flow rate by decreasing cake compressibility and increasing cake permeability. This type of usage is termed as
“admix” or "body feed". The common filter aids are diatomaceous earth (DE skeleton of ancient diatoms ),
perlite (silica plus aluminium silicate), cellulose (highly compressible), asbestos (Aluminosilicates) and others.

Membrane integrity of membrane filters is tested by

a. Bubble point test

b. Diffusion testing
c. Forward flow test

Ultrafiltration (UF) Pore size for ultra filtration is 10-100Å. It uses hydraulic pressure that reverses the
normal osmosis. UF is a variety of membrane filtration in which hydrostatic pressure forces a liquid against a
semipermeable membrane. Suspended solids and solutes of high molecular weight are retained, while water and low
molecular weight solutes pass through the membrane. This separation process is used in industry and research for
purifying and concentrating macromolecular (103 - 106 Da) solutions, especially protein solutions. Ultrafiltration
is effective to remove the pyrogens.

Microfiltration: Pore size 0.1 to 10 microns

 *

Mixing

A. Mixing of liquids
a. Impellers e.g. Propellers, Turbines, Paddles
b. Air jet
c. Fluid jet
d. Baffles
B. Mixing of immiscible liquids
a. Colloid mill
b. Silversion homogenizer
c. Ultrasonic emulsifier (Only used for low viscosity fluids)
C. Mixing of semi-solids
a. Agitator mixer e.g. sigma mixer , Planetary mixer
b. Shear mixer e.g. Triple roller mill (Continuous), Colloid mill
D. Mixing of solids
a. Fludized mixer
b. Barrel type and zig-zag (continuous and large scale use)
c. Double cone blander
d. Sigma blander
e. Planetary
 TABLETS

Are Unit dosage form, tamperproof solid dosage form.

Manufacture of Granulations

Direct Compression granulation Wet granulation

Compression

e.g. NaCl, KBr etc.

Direct compression: Some crystalline substances which can be compressed directly. A directly compressible
diluents added e.g. microcrystalline cellulose.

Disadvantages:

9 Differences in particle size & bulk density between drug & diluents leads to stratification within granulation
resulting in poor content of uniformity of drug in compressed tablet.
9 In direct compression diluents may interact with the drug e.g. Milard’s reaction that is yellow discolouration
between amine groups and hydrous lactose.
9 Because of dry nature of direct compression a static charge develops which may prevent uniform distribution of
drug in the granulation.
9 The maximum percentage of non compressible content in direct compression can be upto 30%.

Compression granulations: Used when drug is sensitive to heat, moisture (wet granulations) e.g. vitamins, aspirin
etc.
Powder blend slugs ՜ Screened or milled to produce granular form

Equipments:

1. Roller Compactor

2. Chilsonator

3. Hut’s compactor

3. Wet granulations: Forms the granules by binding the powder together with an adhesive, instead of by
compaction.

Equipment used for wet granulation:

 i. Sigma blade (mixture)
ii. Nauta mixer
iii. Fluidised bed dryer (Dryer)
iv. Littleford lodige mixture (mixer/granulator)
v. Diosna mixer/granulator
vi. Gral mixer/granulator

Why granulation

1) To improve flow by increasing particle size since larger particles flow more readily than smaller ones.
2) To prevent the segregation which is mainly due to differences in the particle size of API and excipients
because granulation produces a homogenous mixture, as in granulation particles get stuck together and cannot
separate.
3) Improves the compressive characteristics.
4) It reduces the dust.

Wet granulation:

API + Diluent/Filler Mixing

Binding

Water Wetting

Granulation

Drying

Sieving
Lubricant Glidant
Disintegrating agent

Mixing

Compression
 *

Direct compression:

API
Diluent Weighing and Mixing
Lubricant
Glidant
Disintegrating agent Compression

• No drying stage/heating, no moisture involvement. Tablet disintegrates into primary particles rather than
granular aggregates, which results in increase in surface area available for dissolution resulting in faster drug
release.
• The one limitation of direct compression is that it depends upon the fluidity & compressibility of tablet
diluents. So it cannot be used for the drug which have low potency i.e. high dose of active ingredients, in such
cases the incorporation of the diluents (at least 30% of the formula) required for direct compression leads to
larger tablets which are unacceptable.
• Most widely used diluents in directly compressible tablet is Avicel/microcrystalline cellulose (aggregates of
microcrystals isolated from α-wood cellulose by acid hydrolysis) due to its excellent flow & superior
compressibility.
 Tablet excipients

A. Diluents/Fillers

They are used to produce tablet of reasonable size i.e. minimum diameter of 3 mm.

Potent drug < 60 mg

(A) Lactose: It is disaccride & α-lactose monohydrate (Wet granulation) is most widely used, hydrous lactose
can cause Maillard reaction → interaction of amine drugs with hydrous lactose in the presence of
lubricant like magnesium stearate resulting in yellowish discolouration time to time. Spray dried lactose
(3% moisture): It is diluents used for direct compression. But it is prone to darkening in presence of
excess of moisture, amines, furaldehyde.

Hydrous lactose → Wet granulations

Anhydrous lactose → No Millard’s reaction/direct compression

(B) Starch: It may give rise to soft tablets. Moisture content 11-14%. Sta- Rx – 1500 free flowing & directly
compressible. It is diluents, binder, disintegrating agent and self lubricating, glidant (0.25%). Emdex & celutab
(contains 90-92% dextrose, 3-5% maltose) are hydrolyzed starches & are free flowing and directly compressible.
They are sweet in taste & can be used in replace of mannitol.

(C) Dextrose: It is sometimes used to replace the spray dried lactose to reduce the tablet to darken.

(D) Mannitol: Negative heat of salvation, its slow solubility & pleasant feeling in mouth, used mainly in the
chewable tablets. It is non-hygroscopic so can be used in vitamin formulation which are moisture sensitive. But
Mannitol have poor flow so require high amounts of lubricants.

(E) Sorbitol: It is optical isomer of Mannitol but is hygroscopic above humilities 65%.

(F) Sugar based diluents:

Sugar tab → 90-92% sucrose + 7-10% invert sugar

Dipac → 97% Sucrose + 3% dextrins

Nutab → 95% sucrose + 4% invert sugar with small amount of corn starch & magnesium stearate.

(G) Microcrystalline Cellulose (Avicel) Direct compressible

Avicel – 101 → Powder

Avicel – 102 → Granules

This produces cohesive compacts, disintegrating agent

(H) Calcium Slats: DCP (Dibasic calcium phosphate) and calcium sulfate have low concentration of unbound
moisture. The bound water of calcium sulfate is not released upto 800 C.

DCP is virtually insoluble in water and hence used in conjunction with disintegrating agent.

Calcium based diluents can cause interaction with tetracyclines API.

A. Binders & Adhesives

Sugars Natural Synthetic/Semisynthetic

e.g. Sucrose, e.g. Starch paste, e.g. HPMC, PEG, Poly vinyl
Glucose Acacia, Tragacanth, pyroolium, Poly vinyl
Gelatin, Alginates alcohol

Acacia & Tragacanth → 10-25%

Starch → 5-10%

Gelatin → 5-20%

Glucose → 50%

Sucrose → 70%

Acacia & Tragacanth: Natural origin so variable in composition easily attacked by microorganism.

Starch paste: Prepared by dispersing starch into water when heated. The paste must be translucent rather than
clear. On heating starch hydrolyzed to dextrin & glucose. While clear paste indicates complete conversion to
glucose.

Methyl cellulose, Hydroxy propyl methyl cellulose (HPMC), Hydroxy propyl cellulose (HPC) [for both
alcoholic & aqueous solution], are common binder for direct compression & their aqueous solution is adhesive.

Polyvinyl pyrrolidone (PVP) → It is adhesive in either aqueous or alcoholic solution. Its concentration used is 0.5-
3%.

Ethyl cellulose → It is used only with solution alcoholic & it can retard the disintegration & dissolution of drugs.

C. Disintegrants
 *

Starch → Most commonly used (5-20%).

Modified starch primogel and explotab are low substituted carboxy methyl starches (1-8%).

Clays & bentonite → 10% but can give off white appearance.

AC-Di- Sol → Internally cross linked sodium carboxymethyl cellulose i.e. Na CMC.

Cross linked polyvinyl pyrrolidone. These two are called super disintegrants. E.g. sodium starch glycoate, cros
carmellose (cross linked CMC), cros povidone, palacrillin K+ → It is a cation exchange resin.

Sodium glycine carbonate: Source of CO2 for effervescent tablets.

D. Lubricants, Antiadherants & Glidants

Lubricants: They are intended to reduce the friction during tablet ejection between walls of the tablet and walls of
the die cavity in which tablet was formed. E.g. Magnesium stearate but not glidant.

Antiadherents: They are used to reduce the sticking & adhesion of any of tablet granulation/powder to the
punches of die wall.

Glidants: They are intended to promote flow of the tablet granules from hoper & reducing the friction between the
particles. E.g. colloidal silicon dioxide [No lubricant activity, Aerosil, cab-O-Sil, Soluble].

Calcium & Magnesium Stearates → 0.25 – 1%.

Talc (5%) Both glidant + lubricant activity (Contains Iron, so carefully used if any formula contains drug which
breakdown is catalysed by Fe2+)

PEG
Colloidal silicas → 0.25 – 5%
Starch
Liquid Paraffin → 5%

Lubricants based upon fatty acids are insoluble in water & hence can retard the disintegration & dissolution time.
Water soluble lubricants: PEG 6000, [Macrogol 6000 or carbowax], Magnesium Lauryl Sulfate, Fumaric acid.

Microcrystalline cellulose/Avicel: Low coefficient of friction, when compressed mcc particles deform physically
and surfaces form H-bonding. MCC is hygroscopic & water causing the weaking of interparticulate hydrogen
bonds.
Mechanism of disintegrants:
¾ Those that enhance the action of capillary forces in producing rapid intake of aqueous liquids. So
disintegrant have porous structure & show low interfacial tension towards aqueous fluids. Rapid penetration
by water in the tablet matrix resulting in breakup of tablet. E.g. Starch, MCC, Cationic resins, sodium starch
glycolate
¾ Those which swells on contact with water. E.g. Acacia, Tragacanth. One problem can be they produce
sticky/gelatinous mass that resists break up of tablet, so optimize concentration within granulation.
Gas Production: They are sensitive to small changes in humidity levels. They are disintegrants mainly in the
effervescent tablets. The most common are mixture of citric acid & tartaric acid plus carbonates/bicarbonates,
Sodium glycine carbonate.

Glidants: They get absorbed or interposing their particles between those of other components which results in
reduction of adhesive tendencies or lower the interparticular friction system. So they are also called as flow
promoters. E.g. colloidal SiO2, Starch, talc.

¾ Calcium stearates (Lubricant) can cause Maillard reaction with amine drugs like aminophylline with lactose.
¾ A common mistake during the tablet granulation is adding both disintegrant & lubricant in one mixing
step. This results in disintegrant to be coated with lubricant & often results in both decrease in disintegrants
porosity & decrease in the efficiency of disintegrants.

E. Colors, Flavors & Sweeteners

Lakes: They are dyes that has been absorbed on hydrous (Al(OH)3) oxide and usually employed as dry powders for
coloring. They contain 10-30% of pure dye & maximum upto 50%.
¾ During the wet granulation, care must be taken to prevent colour migration during drying (mottling) [mainly
with soluble dyes]. Colorant should not be more than 2%. Flavor oil maximum upto 0.5-0.75%.
¾ Mannitol is 72% solvent as sucrose.
¾ Saccharin 500 times sweeter than sucrose but it is carcinogenic in nature.
¾ Aspartame (dipeptide aspartic acid + Phenylalanine) replace saccharin but this aspartame lack stability in
the presence of moisture and it is hygroscopic.

Wetting agents: They are used to increase water uptake and enhancing disintegration and assisting dissolutions.
E.g. sodium Lauryl sulphate (LSL) or Docussate sodium known to enhance the dissolution as it is anionic
surfactant which causes destruction of membrane of intestines. These wetting agents are added when drug is
hydrophobic.
 Tablet coating
1) Used to mask taste, odor, and color to provide physical and chemical protection.
2) To control the release of drug from tablet.
3) To protect the drug from gastric environment of stomach with acid resistant enteric coating.
4) To incorporate another drug/formula adjuvant in coating to avoid chemical incompatibility and sequential drug
release.
A. Sugar Coating
Skilled person requirement & tablet are deep convex surfaces with thin round edges. Sugar coating increase the
50-52% thickness of tablets.
Steps involved are:
(i) Sealing: Water proof coating because without it tablets would absorb excess moisture leading to tablet
softening/disintegration.
Shellac: It is mostly sealant but undergo aging due to polymerization resulting in lengthening or increase in
tablet disintegration and dissolution time.
Zein: Alcohol soluble protein derivative from corn is also effective sealant.
(ii) Sub coating: To round the edges & build up the tablet size. Sugar coating increase the tablet weight by
52%. Sub coating steps consists of alternatively applying a sticky binder (acacia/gelatin) solution to tablets
followed by a dusting of sub coating (Talc, CaCO3) powders & then drying. The process is repeated until
desired thickness is achieved (3-4 sub coats).
(iii) Syrup coating/colour coating: It is to cover & fill the imperfections in tablet surface caused by sub
coating step and impart desired colour to the tablet. This step requires most skill person. The first syrup
coats usually contain some suspended powders called as grossing syrups. No colour should be added until
tablets become smooth.
(iv) Polishing: It is done by powdered wax i.e. beeswax or carnauba wax or warm solution of these waxes in
naphtha or suitable volatile solvents.

B. Film coating (Weight gain is only 2-6%)

Film formers: The solubility is the one of the important parameter e.g. free water solubility, slow water solubility
(for controlled release), pH dependent solubility (Enteric coating)

A. Non-enteric film formers: (Mostly cellulose derivatives)

a. HPMC (Hydroxy propyl methyl cellulose): Mostly used

Alkali treated cellulose + CH3Cl → Introduce methoxy groups To introduce propylene glycol ether

Different grades are available depending upon the viscosity, generally low grades are preferred. When used alone,
the polymers have tendency to bridge or fill the debased tablet surfaces.
Ethyl cellulose: It is totally water insoluble & GIT fluids polymer & pH independent so should not be used alone.
It is mostly used for delayed/sustained release tablets in combination with water soluble additives.
Povidone: It is 1-vinyl 2-pyrrolidinone. It also acts as binder & hence improves the dispersion of colorants in
coating solution for uniformity.
4 viscosity grades given by K values i.e. K-15 [10000], K30 [40000] (tablet binder & tablet coating), K45 & K 60.
Hydroxy propyl cellulose (HPC): It is soluble in H2O below 400 C & insoluble above 450 C. It produces the
film extremely tacky.

Sodium carboxymethyl cellulose: Water soluble polymer easily dispersed in water to form colloidal solution but it
is insoluble in most of organic solvents.
PEG: PEG – 200-600 molecular weight. Liquid at room temperature & used as plasticizer for coating solution
filtrate.
PEG 900-8000 are white waxy solids at room temperature. These polymers used in combination with other
polymers to modify the film properties.
¾ Combination PEG waxes + Cellulose acetate phthalate (CAP) provides films are soluble in gastric fluids. So
used for non enteric coating process.

Acrylate polymers or carbopol: e.g. Eudragit E is a cationin polymer.

Dimethyl aminoethyl methacrylate + methacrylic acid ester.

Eudragit E → is only Eudragit material that is freely soluble in gastric fluid up to pH 5.

Eudragit RL & RS → pH independent polymers so for delayed release.

Eudragit L & S → Enteric coating & soluble above pH 6 & 7 respectively.

Eudragit E → non enteric coating

Mostly these polymers are available in Isopropanol solvents.

B. Enteric Coating Polymers

Mostly esters of phthalates, So protect acid-labile drugs from gastric fluid e.g. enzymes and antibiotics, to prevent
the gastric distress e.g. sodium salicylate, to deliver the drugs intended for local action in intestine. E.g. Shellac,
phalates & Eudragit L & S.
The pH of stomach contents varies from pH 1.5-4.
The pH of the material approaching pylorus (last part of stomach) is nearly 5. So an ideal eneteric polymer should
dissolve or become permeable near and above pH 5.
The above pH these polymers with CAP, HPMCP, Polyvinyl, acetate phthalate [which are dicarboxylic acid,
pthalic acid] in partially esterified form starts to lose their film integrity due to ionization of carboxylic group on
chain and subsequent hydration. Further the presence of esterases in intestinal fluid breakdown ester linkage of
polymer chains.

a. Cellulose acetate phthalate (CAP): Dissolves above pH 6, it is hygroscopic, films are brittle, usually
formulated with hydrophobic film (to prevent hygroscopic) forming material for better enteric films. E.g.
Diethyl phthalate. Aqueous enteric coating called as aquateric, used with colloidal dispersion of latex
particles + CAP.
b. HPMCP: Hydroxy propyl methyl cellulose phthalate. E.g. HP 50, 55.
HPMC + Pthalic anhydride → HPMCP
Dissolves at pH 5-5.5 (pylorus pH)

Polyvinyl acetate phthalate (PVAP):

Supplied as ready to use or ready to disperse enteric systems.

Acrylate polymers:
Eudragit L → Soluble at pH 6
Eudragit S → Soluble at pH 7

Solvents for film coating: To dissolve or disperse the polymers & other additives. Small concentrations of
polymers i.e. 2-10%. Should not result in extremely viscous solution system i.e. > 300 cps, it should have rapid
drying rate i.e. the ability to coat 300 kg load in 3-5 hrs.

Water- Drugs can hydrolyse, increase in viscosity of coating solution or the drug must require initial seal coat with
non aqueous solvent based coating.
Isopropanolol, acetone, C2H5OH, CH3OH, Methyl ethyl ketone.

Plasticizers:
Isothermal plasticizing technique: It is the chemical modification of basic polymer that alters the physical
properties of the polymer. E.g. degree of substitution, type of substitution, chain length etc. polymer properties are
varied.

External plasticizing techniques: Here a plasticizer is added to achieve desired effects. The external plasticizer can
be non-volatile liquid or another polymer which when incorporated with the primary polymeric film former, changes
the flexibility, tensile strength or adhesion property of the resulting film.
Plasticized range from 1-50% by weight of a film former. Commonly used plasticizer are – castor oil, PEG 200 –
400 and surfactants like Polysorbates (tween), sorbitan esters (Spans).

For aqueous coating mostly water soluble plasticizer used are PEG & PPG (poly propylene glycol) Castor oil &
spans are used for organic solvents based coating solutions.

Colorants: To achieve proper distribution of suspended colorants in coating solution requirement uses of fine
powdered colorants < 10 µ. Lakes are dyes absorbed on Al(OH)3 or Talc become choice for sugar and film coating
systems.

Natural coloring materials: Anthocyanins, caramel, carotenoids, carminic acid, Indigo, Flavones etc.

Opaquant: Provide white coating or more pastel colors. E.g. Titanium dioxide (TiO2), Talc, Al(OH)3

Film Defects
1. Sticking and Picking: Due to over wetting or excessive film tackiness causes tablets to stick each other or with
coating pan.
2. Orange Peel Effect: Due to inadequate spreading of coating solution before drying causes a bumpy or
orange peel effect indicates that spreading is impeded by too rapid drying or high viscosity coating solution.
3. Bridging & filling: During drying the film may shrink& pull away from sharp corners or bisect resulting in
bridging. It can be overcome by increasing plasticizer content.
4. Filling: It is caused by applying too much solution resulting in a thick film that fills & narrow the monogram
or bisect.
5. Blistering: When coated tablets require further drying in ovens, too rapid evaporation of solvent from the
care which affect the strength, elasticity and adhesion properties of film results in blistering. So milder drying
conditions are used.
6. Hazing/Dull film/Bloom: Loss of glass mainly due to high processing temperature or high humid condition.
Dulling is particularly with cellulosic polymers.
7. Mottling: It is migration of dyes (soluble), plasticizer & other additives during drying. Use lake dyes.
8. Cracking: It occurs when internal stress in the film exceeds the tensile strength of the film. Tensile strength of
the film can be increased by using high molecular weight polymers or polymer blends.
 Coating Equipment

Standard Coating Perforated Coating Pan Fluidized bed colour (Air

Pan Suspension)
Accela – cota
Immersion sword Hi‐Coater
Pellegrini Crlatt Coater
 Tablet defects
a. Capping: Means partial or complete separations of the top or bottom crowns of tablet from body.
b. Lamination: Separation of tablet into two or more distinct layer which is also due to entrapment of air.

1. Mainly due to air entrapment which is itself actually due to high compression force. When force
compression crosses the zero voidage. So beyond zero voidage particles behave elastic in nature when
they compressed and after removal of compression force due to elastic in nature particles try to regain
original shape which results in air entrapment.
2. Both capping & lamination are due to deep concave punches so can be avoided by flat punches which
eliminate additional shear stress.
3. A certain % of moisture is often essential for good compaction & granulations that too dry tends to cap or
laminate. So an additional hygroscopic substance like sorbitol, PEG 400, methyl cellulose help to
maintain a proper moisture level.
4. Capping & Lamination may be due to direct compression because some powder or fines may not be
compressible or may have poor compression properties. So higher concentration of times should not be
used.
5. Capping may also be when dies develop wear ring in the area of compression. Dies of tungsten carbide
inserts so used to prevent it.

c. Picking and sticking: Picking is particular concern when punches tips have engraving or embossing. So
small areas like those found in letters B,A & O are difficult to manufacture cleanly.

d. Sticking: It mainly refers to tablet material adhere to die wall. When sticking occurs, additional force is
required to overcome the friction between tablet & die wall during ejection. Serious sticking at ejection can
cause chipping at tablet edges & produce rough edge.
i. Also sticking problem does not allow lower punches free movement & therefore unusual stress on the cam
tracks & punches heads resulting in their damage. Plotting of punch faces with chromium is method to
produce smooth, non adherent force to prevent picking.
ii. Some low melting point substances either active or additives like stearic acid and PEG may soften from
heat of compression resulting to cause sticking. So low melting point lubricant replaced with high melting
point lubricant.
iii. Excessive moisture may be responsible for sticking.

e. Mottling: unequal distribution of colour on tablet, with light or dark areas .

(i) It can be due to when drug color differs from color of tablet excipients or drug whose degradation products
are colored.
 (ii) A dye can cause mottling by migration to the surface of granulation during drying. So to overcome this
change the solvent system reduces drying temperature; grind to smaller particles.
(iii) Certain colored adhesive gel solution may not be distributed well because they must be hot when added to
much cooler powder mixtures. The adhesive then precipitates from solution & carries most of the colour
with it.
(iv) Therefore , generally incorporate fine powder adhesives such as acacia and tragacanth into the product
before adding granulating fluid.

f. Weight variation: Poor flow (Add glidant like Talc, Colloidal silica). Depending upon the shape of
hopper causes of poor flow either arching and rat-holing. When poor flow occurs, it is controlled by
vibrator attached to the hopper sides. But sometimes these vibrations induce segregation and
stratification. The larger particles tend to drift upward while smaller particles sift downward, which leads
to weight variation with poor content of uniformity because the drug is not distributed between larger and
smaller particles.

Punches variation: i.e. when lower punches are unequal lengths because die fill is volumetric.

Tapped density
Hausner ′s ratio
Bulk density or pored density
< 1.25 Good flow
1.25-1.5 Moderate
>1.5 Poor

% Compressibility/Carr’s Index

5-15% Excellent
12-16% Good
18-22% Fair
24-35% Poor
> 40% Extremely poor
Official tests Unofficial tests
¾ Weight variation or uniformity of weight Size & shape
¾ Disintegration time Tablet thickness
¾ Dissolution testing
Color uniformity
¾ Content uniformity
Unique identification markings
Hardness
Friability
Porosity (Film coating test)
Physical stability

Tablet Diluents
Diluent Comment
Calcium Carbonate Insoluble in water
Glucose Hydroscopic, reducing sugar
Calcium Hydrogen Phosphate Insoluble in water good flow properties
α-lactose Inexpensive, inert and most common diluents
Mannitol Popular for chewable tablets, freely soluble in water, cool taste
Sodium chloride Freely soluble, used in solution tablet taste problem
Sucrose Hygroscopic, sweet taste used in lozenges in conjuction with lactose
Microcrystalline cellulose Excellent compression propertical, highly stables also disintegration
therapy.

Directly compressible tablet diluent

Microcrystalline cellulose
Microfine cellulose
Modified starch
Dextrates
Sucrose-dextrin coprecipitate
Calcium hydrogen phosphate
Anhydrous lactose
Spray dried lactose
Binders and Granulating fluid
 *

Substance Concentration
Acacia mucilage Up to 20%
Glucose Up to 50%
Gelatin 5-20%
Providone (PVP) 2-10%
Starch mucilage 5-10%
Sucrose Up to 70%
Tragacanth mucilage Up to 20%
Tablet Disintegrants
Alginic acid, sodium alginate 2-10%
Aluminium magnesium silicate carbon dioxide Up to 10%
Sodium carbonyl methyl cellulose or carmellose, sodium
Cationic exchange resins Up to 10%
Microcrystalline cellulose (CMC) Starch Up to 10%
Modified starch 2-10%
Sodium starch glycollate, cross carmellose sodium 1-10%
Crospovidone 2%
Tablet Glidants
Glidant Concentration (%)
Colloidal silica 0.1-0.5
Talc 1-2%

Tablet Lubricants
Substance Concentration in tablet (%w/w) Comments
Fumaric acid 5 Water soluble
Hydrogenated vegetable oil 0.5-2.0 Lubritab
Liquid paraffin Upto 5 Dispersion problems
Magnesium lauryl sulphate 1-2 Water soluble
Macrogol 4000 and 6000 2-5 Water soluble
Sodium benzoate 5 Water Soluble, taste problems
Sodium lauryl sulphate 0.5-5.0 Wetting agent, often used in
conjuction with stearates
Sodium Stearyl fumarate 1-2 Soluble in hot water
Stearates calcium magnesium stearic 0.25-1.0 Very effective lubricants, prolong
acid distintegration time blet crushing
strength.
Film formers
1. Hydroxypropyl methylcellulose
2. Methyl hydroxyethyl cellulose
3. Ethylcellulose
4. Hydroxypropylcellulose
5. Povidone
6. Sodium Carboxymethylcellulose
7. Polyethylene glycols
8. Acrylate polymers

Classification of Powders
Coarse Powder Powder passing through Mesh aperture of 1700 micrometer (Sieve number 10) and not
more than 40% by weight pass through a sieve with normal aperture of 355 micrometer
(Sieve number 44)
Moderately Coarse All the particles pass through sieve with nominal mesh aperture of 710 micrometer (22) and
not more than 40% by weight pass through the sieve with nominal mesh aperture of 250
micrometer (60)
Moderately fine All particles pass through a sieve with nominal mesh aperture of 355 micrometer (44) and
powder not more than 40% by weight pass through size with nominal mesh aperture of 180
micrometer (85).
Fine powder All particles passes through a sieve with nominal mesh aperture of 180 micrometer (85)
and not more than 40% by weight pass through a sieve with nominal mesh aperture of 125
micrometer (120)
Very fine powder All the particles passes through a sieve with nominal mesh aperture of 125 micrometer
(120) and not more than 40% by weight passes through the sieve with nominal mesh
aperture of 45 micrometer (325).
Microfine powder A powder of which is not less than 90% by weight of particles passes through a sieve with
nominal mesh diameter of 45 micrometer (325).
Superfine powder A powder with not less than 90% by number are less than 10 micrometer in size.

Difference between lakes & Dyes

Characteristics Lakes Dyes
Solubility Insoluble in most solvents Soluble in water, propylene glycol
and glycerin
Method of coloring By dispersion By solution
Pure dye content 10-40% Primary colors – 90-93%
 *

Rate of Use 0.1 – 3% 0.01-0.03%

Particle Size < 0.5 micrometer 12-200 mesh
Stability
Light Better Good
Heat Better Good
Cooling Strength Not proportional to dye content Directly proportional to pure dye
content
Shades Varies with pure dye content Constant
 Quality control of Tablets

A. Uniformity of weight: This test is not applicable to coated tablets other than film-coated tablets and to
tablets that are required to comply with the test for uniformity of content for all active ingredients. Weigh
20 tablets selected at random and calculate the average weight. Not more than two of the individual
weights deviate from the average weight by more than the percentage shown in table and none
deviates by more than twice that percentage

B. Uniformity of content: This test is applicable to tablets that contain less than 10 mg or less than 10%
w/w of active ingredient. For tablets containing more than one active ingredient carry out the test for each
active ingredient that corresponds to the aforementioned conditions. The test for Uniformity of content is
not applicable to tablets containing multivitamins and trace elements.

Determine the content of active ingredient(s) in each of 10 tablets taken at random using the method given in the
monograph or by any other suitable analytical method. The tablets comply with the test if not more than one (9
tablets out of 10) of the individual values thus obtained is outside the limits 85 to 115% of the average value
and none is outside the limits 75 to 125% of the average value. If two or three of the individual values are outside
the limits 85 to 115% of the average value and none is outside the limits 75 to 125%, repeat the determination using
another 20 tablets. The tablets comply with the test if in the total sample of 30 tablets not more than three of the
individual values are outside the limits 85 to 115% and none is outside the limits 75 to 125% of the average value.

C. Disintegration: This test is not applicable to modified-release tablets and tablets for use in the mouth.

The water medium at 37± 20C. Basket move up and down through a distance of 5-6 cm at a
frequency of 28-32 cycles/ min

1. Uncoated tablets disintegrate within 15 minutes

2. Coated tablets Operate the disintegration apparatus for 30 minutes for film-coated tablets and for 60
minutes for other coated tablets unless otherwise directed in the individual monograph. For coated
tablets other than film-coated tablets, if any of the tablets have not disintegrated, repeat the test on a
further 6 tablets, replacing the water in the vessel with 0.1M hydrochloric acid. The tablets comply with
the test if all 6 tablets have disintegrated in the acid medium.
3. Enteric coated tablets If the tablet has a soluble external coating, immerse the basket in water at room
temperature for 5 minutes. Suspend the assembly in the beaker containing 0.1M hydrochloric acid and
operate without the discs for 120 minutes, unless otherwise stated in the individual monograph. Remove
the assembly from the liquid. No tablet shows signs of cracks that would allow the escape of the contents of
disintegration, apart from fragments of coating. Replace the liquid in the beaker with mixed phosphate
buffer pH 6.8, add a disc to each tube and operate the apparatus for a further 60 minutes. Remove the
assembly from the liquid. The tablets pass the test if all six have disintegrated.
4. Dispersible and Soluble Tablets: Disintegrate within 3 minutes when examined by the disintegration
test for tablets and capsules, using water at 24o to 26o, unless otherwise stated in the individual
monograph.
5. Effervescent Tablets: Place one tablet in a 250-ml beaker containing water at 20o to 30o; numerous gas
bubbles are evolved. When the evolution of gas around the tablet or its fragments has ceased the tablet shall
have disintegrated, being either dissolved or dispersed in the water so that no agglomerates of particles
remain. Repeat the operation on a further 5 tablets. The tablets comply with the test if each of the 6 tablets
disintegrates in the manner prescribed within 5 minutes, unless otherwise stated in the individual
monograph.

D. Uniformity of color and gloss on tablet surface is measured by micro reflectance photometer.
E. Crown thickness is measured by micrometer or sliding caliper.
F. Hardness tester: 2 kg ----------------- Soft

4kg --------------------Good

6kg---------------------Hard
Monsanto Hardness‐Tester

(Compressible spring held b/w two plungers) Strong –Cobb Hardness tester (uses Hydraulic pressure )

Pfizer – Hardness tester Erweka Hardness tester

Schleuniger Hardness Tester (Most widely used )

 G. Roche Friability tester: the plastic chamber revolves at 25 rpm. Normally preweighed tablet sample is
placed in friabilator which is then operated for 100 revolutions. The tablets that less than 0.5-1% of
their weight is generally acceptable.
H. Tablet thickness should be controlled within ± 5 % variation of standard value. It is important for
tablet packaging.

DISINTEGRATION TEST FOR TABLETS AND CAPSULES

This test determines whether tablets or capsules disintegrate within a prescribed time when placed in a liquid
medium under the prescribed experimental conditions.

For the purpose of this test, disintegration does not imply complete solution of the tablet or capsule or even its active
constituent. Disintegration is defined as that state in which no residue of the tablet or capsule remains on the
screen of the apparatus or, if a residue remains, it consists of fragments of insoluble coating of the tablets or
of capsule shells or is a soft mass with no palpable core. If discs have been used with capsules, any residue
remaining on the lower surfaces of the discs consists only of fragments of shells.

Apparatus
 a. A rigid basket-rack assembly supporting six cylindrical glass tubes, 77.5 ± 2.5 mm long, 21.5 mm in
internal diameter and with a wall thickness of about 2 mm.

b. The tubes are held vertically by two superimposed transparent plastic plates, 90 mm in diameter and 6 mm
thick perforated by six holes having the same diameter as the tubes. The holes are equidistant from the
centre of the plate and are equally spaced from one another. Attached to the underside of the lower plate is
a piece of woven gauze made from stainless steel wire 635 mm in diameter and having nominal mesh
apertures of 2.00 mm. The upper plate is covered with a stainless steel disc perforated by six holes,
each about 22 mm in diameter, which fits over the tubes and holds them between the plastic plates. The
holes coincide with those of the upper plastic plate and the upper open ends of the glass tubes.

c. The plates are held rigidly in position and 77.5 mm apart by vertical metal rods at the periphery and a metal
rod is also fixed to the centre of the upper plate to enable the assembly to be attached to a mechanical
device capable of raising and lowering it smoothly at a constant frequency of between 28 and 32
cycles per minute through a distance of 50 to 60 mm. The design of the basket-rack assembly may be
somewhat different provided specifications for the glass tubes and the screen mesh size are unchanged.

d. A cylindrical disc for each tube, each 20.7 ± 0.15 mm thick in diameter and 9.5 ± 0.15 mm thick, made of
transparent plastic with a relative density of 1.18 to 1.20, and pierced with five holes, each 2 mm in
diameter, one in the centre and the other four spaced equally on a circle of radius 6 mm from the centre of
the disc. Four equally-spaced grooves are cut in the lateral surface of the disc in such a way that at the
upper surface of the disc they are 9.5 mm wide and 2.55 mm deep and at the lower surface 1.6 mm square.

e. The assembly is suspended in the liquid medium in a suitable vessel, preferably a 1000-ml beaker. The
volume of liquid is such that the wire mesh at its highest point is at least 25 mm below the surface of the
liquid, and at its lower point is at least 25 mm above the bottom of the beaker.

f. A thermostatic arrangement for heating the liquid and maintaining the temperature at 37° ± 2°C.

Method

Unless otherwise stated in the individual monograph, introduce one tablet or capsule into each tube or total six
tablets and, if directed in the appropriate general monograph, add a disc to each tube. Suspend the assembly in the
beaker containing the specified liquid and operate the apparatus for the specified time. Remove the assembly from
the liquid. The tablets or capsules pass the test if all of them have disintegrated.

If 1 or 2 tablets or capsules fail to disintegrate, repeat the test on 12 additional tablets or capsules; not less than 16 of
the total of 18 tablets or capsules tested disintegrate.

If the tablets or capsules adhere to the disc and the preparation being examined fails to comply, repeat the test
omitting the disc. The preparation complies with the test if all the tablets or capsules in the repeat test disintegrate.
 *

DISSOLUTION TEST FOR TABLETS AND CAPSULES

Use Apparatus 1 unless otherwise directed. All parts of the apparatus that may come into contact with the
preparation being examined or with the dissolution medium are chemically inert and do not adsorb, react or interfere
 *
with the preparation being examined. All metal parts of the apparatus that may come into contact with the
preparation or the dissolution medium must be made from stainless steel, type 316 or equivalent or coated with a
suitable material to ensure that such parts do not react or interfere with the preparation being examined or the
dissolution medium.

No part of the assembly, including the environment in which the assembly is placed, contributes significant motion,
agitation or vibration beyond that due to the smoothly rotating element.

An apparatus that permits observation of the preparation being examined and the stirrer during the test is preferable.

Apparatus 1 Basket type (for tablet or capsule)

An assembly consisting of the following:

a. A cylindrical vessel, A, made of borosilicate glass or any other suitable transparent material, with a
hemispherical bottom and with a nominal capacity of 1000 ml (see Fig.7.3-1). The vessel has a flanged
upper rim and is fitted with a lid that has a number of openings, one of which is central.

b. A motor with a speed regulator capable of maintaining the speed of rotation of the paddle within 4% of that
specified in the individual monograph. The motor is fitted with a stirring element which consists of a drive
shaft and blade forming a paddle, B (see Fig. 7.3-2). The blade passes through the diameter of the shaft so
that the bottom of the blade is flush with the bottom of the shaft. The shaft is positioned so that its axis is
within 2 mm of the axis of the vessels and the lower edge of the blade is 23 to 27 mm from the inside
bottom of the vessel. The apparatus operates in such a way that the paddle rotates smoothly and without
significant wobble.

c. Water -bath set to maintain the dissolution medium at 36.5° to 37.5°. The bath liquid is kept in constant
and smooth motion during the test. The vessel is securely clamped in the water-bath in such a way that the
displacement vibration from other equipment, including the water circulation device, is minimized.

Apparatus 2 Paddle type

The assembly is the same as in Apparatus 1 except that in the stirring element the paddle is replaced by a basket, D
(see Fig 7.3-3 and 7.3-4). The metallic shaft rotates smoothly and without significant wobble. The basket consists of
two components. The top part, with a vent, is attached to the shaft C. it is fitted with three spring clips, or other
suitable means, that allow removal of the lower part for introduction of the preparation being examined and that
firmly hold the lower part of the basket concentric with the axis of the vessel during rotation. The lower detachable
part of the basket is made of welded-steam cloth, with a wire thickness of 0.254 mm diameter and with 0.381mm
square openings, formed into a cylinder with narrow rim of sheet metal around the top and the bottom. The basket
may be plated with a 2.5m m layer of gold for use with acidic media. The distance between the inside bottom of the
vessel and the basket is maintained at 23 to 27mm during the test.
Dissolution medium: Use the dissolution medium specified in the individual monograph. If the medium is a
buffered solution, adjust the solution so that its pH is within 0.05 units of the pH specified in the monograph. The
dissolution medium should be deaerated prior to testing.

Time: Where a single time specification is given in the monograph, the test may be concluded in a shorter period if
the requirement for the minimum amount dissolved is met. If two or more times are specified, specimen are to be
withdrawn only at the stated times, within a tolerance of ± 2%.

Method: Introduce the stated volume of the dissolution medium, free from dissolved air, into the vessel of the
apparatus. Warm the dissolution medium to between 36.5° and 37.5°. Unless otherwise stated use one tablet or
capsule.

When Apparatus 1 is used, allow the tablet or capsule to sink to the bottom of the vessel prior to the rotation of the
paddle. A suitable device such as a wire of glass helix may be used to keep horizontal at the bottom of the vessel
tablets or capsules that would otherwise float. Care should be taken to ensure that air bubbles are excluded from the
surface of the tablet or capsule. When Apparatus 2 is used, place the tablet or capsule in a dry basket at the
beginning of each test. Lower the basket into position before rotation. Operate the apparatus immediately at the
speed of rotation specified in the individual monograph. Within the time interval specified, or at each of the times
stated, withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the
rotating blade or basket, not less than 10mm from the wall of the vessel. Except in the case of single sampling, add a
volume of dissolution medium equal to the volume of the samples withdrawn. Perform the analysis as directed in the
individual monograph. Repeat the whole operation five times. Where two or more tablets or capsules are directed to
be placed together in the apparatus, carry out six replicate tests.

For each of the tablet or capsule tested, calculate the amount of dissolved active ingredient in solution as a
percentage of the stated amount where two or more tablets or capsules are placed together, determine for each test
the amount of active ingredient in solution per tablet or capsules and calculate as a percentage of the stated amount.
If the results do not conform to the requirements at stage S1 given in the accompanying acceptance tablet, continue
testing with additional tablets or capsules through stages S2 and S3 unless the result conform at stage S2.

Where capsule shells interfere with the analysis, remove the contents of not less than 6 capsules as completely as
possible, and dissolve the empty capsule shells in the specified volume of the dissolution medium. Perform the
analysis as directed in the individual monograph. Make any necessary correction.
 CAPSULES
Capsules are solid unit dosage form in which the drug substance is enclosed within either a hard or soft gelatin shell.
The capsules may be regarded as a container drug delivery system that provides a tasteless / odorless dosage form
without the need of any secondary coating step which is required in tablets.

Soft gelatin capsules (SGC) Hard gelatin capsules (HGC)

1. They are sometimes referred as soft gels as they are 1. They are less plasticized then SGC.
made from the more plasticized gelatin film. 2. HGC contains two parts one is called as Cap
2. They are completely sealed dosage form and cannot and other is body.
be opened without destroying the shell. 3. They are most widely used for the filling of
3. With some exceptions, generally the formulations powders, granules and pellets.
that enclosed in the SGC are mostly liquids like 4. They are manufactured by dipping method,
suspensions or solutions of drug that do not which involves the step: Dipping, Rotation,
solublize the gelatin shell. Drying, Striping, Trimming and joining.
4. The most common method for preparation of SGC But nowadays they process is fully
is automated.
i. Rotary die process So it is a two step process in which first
ii. Plate process empty capsule shells are manufactured
iii. Bubble method separately after then different equipments are
iv. Accogel (for filling of powders or used for filing purpose.
granules in SGC)
Depending upon the machine tooling they may spherical,
oval, oblong , tube etc.

Formulation of Hard Gelatin Capsules (HGC)

A. Gelatin is prepared by the hydrolysis of collagen obtained from animal connective tissue, bone, skin. This long
polypeptide chain yields on hydrolysis 18 amino acids, the most prevalent of which are glycine and alanine.
Gelatin can vary in its chemical and physical properties depending on the source of the collagen and the manner of
extraction. There are two basic types of gelatin. Type A (Acid hydrolysed gelatin), which is produced by an acid
hydrolysis, is manufactured mainly from pork skin. Type B (Base hydrolysed) gelatin, produced by alkaline
hydrolysis, is manufactured mainly from green bones. The two types can be distinguished by isoelectric point as
Gelatin A has isoelectric point near to pH 9 while Type B has isoelectric point near to pH 4.7
B.

Opacifing agents used in HGC: Titanium dioxide. Opaque capsules are employed for either protection from light
or to conceal the contents.

C. Preservatives: Methyl paraben (Lipid soluble) and propyl Parabens (aqueous soluble)

D. lubricants added less than 2%

E. Moisture content: Finished HGC normally contain equilibrium moisture content 12-15%. It is determined
by toluene distillation method. This moisture content is critical for the physical properties of the shell as lower
more content < 12 % cause gelatin film brittle or moisture content >18 % cause capsules to become soft. It is
necessary to avoided of extreme temperature so these capsules are kept on relative humidity 40-60% during and
temp. 210C - 240C during handling and sorting of capsules.

Test for gelatin includes

1. Picric acid test
2. Tannic acid test which give white ppt of gelatin because it is protein and tannins ppt the protein.
Advantages of HGC:
Gelatin shell dissolves rapidly and ruptures which results in the rapid release of drug and there is no
compression force used which is used in tablets. So it gives more bioavailability of capsules those tablets.

Solubilities limits of empty capsules are:

(a) Water resistance: Fails to dissolve in H2O at 20-300 C in 15 minutes.
(b) Acid solubility: Dissolve in less than 5 minutes in 0.5% aqueous HCl at 36-380 C.

Disadvantages of HGC:
Highly soluble salts like iodides, bromides, chlorides generally should not be dispensed in HGC. Their rapid
release may cause gastric irritation due to formation of high drug concentration in localized areas.

Nowadays some non-gelatin capsules are prepared made up of HPMC and starch.
HGC filling:

Rectification is empty capsules are oriented so that they can be in the same direction i.e. body end down words.
Then there will be separation of caps from the body as upper plate slides towards left leaving the lower plate
exposed to the filling. Then the feed from the hopper fills the capsule body then the last step is replacement of caps
on body and ejection of filled capsules from the die. Then de-dusting polishing and printing is done.
Equipments for filling of HGC:

1. Lilly Park devis

2. Rotofil
3. Hofliger
4. Macofar
5. MG2
6. Osaka
7. Zanasi
8. Perry/ Accofil

In case of farmatic, Rotofil, Macofar, MG2, Zanasi equipment the power must be sufficient cohesiveness to retain
slug or pellet during the delivery to the capsules.
Equipment for de-dusting of HGC:

1. Rotosort: Mechanically sorts out unfilled joined capsules, loose caps

2. Erweka KEA: For both de-dusting and polishing
3. Seidender equipment: Uses a belt for visual inspection

Two machines are used to determine the weight of the capsule:

(i) Rotoweigh
(ii) Vericap 1200 machine

Rotatory Bottle Method: is used for dissolution rate studies in capsules.

In evaluation of capsules, following terms are used:

Soft spot: The site at which capsule lie next to the tray or against another capsule, dries slowly. This is called soft
spot.
Bloating: If capsule are stored at high humidity (60%) then capsule size enlarges (bloated).
Foreign capsule: Unfilled capsules are called foreign capsules.

Soft gelatin capsules (SGC)

Soft gelatin capsules (SGC): contain a drug that is encapsulated dissolved, solublize or suspended in liquid vehicle.
In suspension that has to be filled in SGC uses wetting agent is lecithin.

Composition of SGC:

A. Gelatin shell plasticized by using the plasticizer, sorbitol, glycerin, propylene glycol. The ratio of dry
plasticizer to dry gelatin measures the hardness of the capsule shell.

Hardness of gelatin shell = Dry weight of plasticizer / Dry weight of gelatin

0.4 / 1 = Hard
0.6 / 1 = Medium
0.8 / 1 = Soft

The basic gelatin formulation from which the plasticized films are cast usually consists of one part of gelatin, one
part of water and 0.6-0.8 part of plasticizer. This will be the gelatin shell with moisture content 6-10%.

B. Preservatives: in the concentration of 0.2% and most common combination is 4 parts of methyl
paraben and 1 part of propyl paraben.
C. Opacifier: Titanium dioxide in the concentration range 0.2-1.2 %
 *

D. 1 % Fumaric acid: To increase the acid solubility and reduces the aldehydic tanning of gelatin.
E. 5 % Sugar: To produce chewable shell and taste
F. Essential oils : 2% for odour and taste
• Iron content should not be more than 15 ppm. Iron comes in the gelatin during the hot extraction. If it is
greater than 15 ppm then it can react with colorants the resulting in the color spots.
• 0.15 % sulfur dioxide (SO2) treatment is done to prevent the decomposition of gelatin.
• Formaldehyde retards the dissolution of gelatin shell as it cause the cross-linkage of gelatin molecule
initiated by aldehyde.
• Various coating like Salol, shellac, CAP also modifies the solubility of gelatin.

The physicochemical properties of gelatin of most interest to shell manufacturers are the
1. Bloom strength
2. Viscosity.

1. Bloom strength is an empirical gel strength measure, molecular weight of gelatin, which gives an indication of
the firmness of the gel i.e. cohesive strength or internal cross linking. It is measured in a Bloom Gelometer, which
determines the weight in grams required to depress a standard plunger (0.5 inches in diameter) a fixed distance into 4
mm deep into 6.66% w/w gel held at 10 0C for 17 hr. Those gelatins that are produced from the first extraction of
the raw materials have the highest bloom strength. Bloom strengths in the range of 150-280 g are considered
suitable for capsules.

2. Viscosity of gelatin measures the chain length of gelatin. The viscosity of gelatin solutions is vital to the control
of the thickness of the cast film or essential for the manufacturing characteristic of gelatin film. Viscosity is
0
determined using 6.66% w/w of gelatin solution in water at 60 C using capillary pipette. The range must be in
25-45 mill poise.

3. Sealing temperature of the Gelatin film is between 37-400 C.

4. Minimum fill volume in capsulation is calculated from specific gravity of liquid.
5. Capsules at equilibrium with 20-30% Relative humidity at 21-240 C are considered dry and the shell
of such capsule contains 6-10% water depending upon the Gelatin formula used.
6. Moisture content of the shell is determined by toluene distillation method.

Disadvantages of SGC:

1. There is more intimate contact between shell and liquid contents than exists with dry-filled HGC which
increases the possibility of interactions. E.g. chloral hydrate formulated with oily vehicle exerts a
proteolytic effect on gelatin shell; however this effect cab be reduced by replacing the vehicle with PEG.
 2. Drugs can migrate from oily liquid vehicle to the gelatin surface depending upon their partition coefficient
because gelatin shell has certain % of moisture. E.g. 4-hydroxybenzoic acid encapsulated solutions.
3. pH of the liquid can be between 2.5 – 7.5. Liquids with more acidic pH would tend to cause leakage
by hydrolysis. pH > 7.5 and aldehydes decrease shell solubility by tanning of the gelatin.
4. Aqueous emulsions cannot be filled chances to release of water which can affect the shell.

Base absorption and M/G or Minimum per gram factor: is determined when the soft gelatin shell contains
suspension then it become crucial to find Minimum quantity of base / inert liquid / vehicle is required to
prepare the suspension. If the concentration of solids is on the higher side then the flow of material to the injection
wedge is hindered.

Base absorption is defined as the minimum amount of base or vehicle in grams required per gram of solid
drug to form a mixture which easily can be encapsulated in SGC. So it is a unit less valve because both parameters
are in grams.

Base absorption = Weight of base (grams) / weight of drug (1 gram)

The drug is taken in a beaker and the vehicle or wetting agent used is 5% lecithin is added at the rate of 1ml/min
each time and triturated (at an angle of 450C) till the uniform flow achieved then stop adding oil and measure the
volume of oil consumed. The value depends upon

1. Particle size and distribution

2. Density of drug
3. State of drug i.e. crystalline, amorphous
4. Hydrophobicity and hydrophilicity of drug

Minimum per gram factor: The above uniform mixture obtained is homogenized in a colloid mill and subjected to
deaeration in desiccator and find out the specific gravity / density.

M / G factor = BA + S × 16.23 minims

BA: Base absorption value

S: Solid drug

D: Density of mixture

1 ml = 16.23 minims
 *
M / G factor is defined as volume of mixture in minims required for a solid drug to produce a mixture which can
be encapsulated e.g. M / G = 50 mean 1 g of drug in a mixture occupies 50 minims.

PARENTERALS
(Intradermal, Subcutaneous, Intramuscular, Intraspinal, Intravenous)
 *

Maximum volume for single dose container up to = 1000 ml

For multi-dose container up to = 30 ml unless otherwise mentioned
Maximum volume for intradermal/intracutaneous 0.2 ml
Maximum volume for subcutaneous 1 ml
Maximum volume for intramuscular 2 ml (5ml)
Maximum volume for Intraspinal, intracardic, intra arterial 10 ml (without any bactericide)
Maximum volume for intravenous 1 liter
Intracorneal, sub-conjuctival, intravitreous not exceeding more than 1 ml
Volume not more than 20 ml should be administered by syringe
• Parenterals suspensions should not be given by intravenous (danger of blockage of small blood
vessels ) and subcutaneously (very painful and irritating)

¾ Excluded intravenous injections i.e intravascular route (100% bioavailability), with other nonvascular
injections like Intraspinal, intramuscular, subcutaneous, intradermal ,the absorption is affected by size and
number of blood vessels supplying the tissue, physicochemical properties of drug like dosage form whether
it is solution, suspension or emulsion, nature of vehicle and its pH. [Hyaluronidase] sometimes used an
adjunct to increase the absorption of injected drugs

¾ Mostly the vehicle for intravenous and Intraspinal preparations is aqueous because there is danger in
blockage of brain capillaries. While in case of intramuscular, subcutaneous, intradermal the preparations
can be solutions, emulsions, suspensions.

I. VEHICLES FOR STERILE PREPARATIONS

Mostly water and tests for quality of water are-

1. Total solid content (not more than 10 ppm for water for injection)
2. Gravimetric analysis of dissociated and undissociated (Endotoxins are a class of pyrogens which are
lipopolysaccrides, soluble in water and are components of the cell wall of Gram-negative bacteria) organic and
inorganic substances present in water. Reverse osmosis and distillations mainly remove the inorganic
dissociated substances.
3. Electrolytic measurement of conductivity (measuring the specific conductance of water) or ionic content as a
part of ppm of NaCl (for water for injection conductivity should not be more than 1 micromho or ionic part 0.1
ppm of NaCl)

• Water for Injection (WFI) is water purified by distillation or 2 stage reverse osmosis." It does not need to
be sterile but not contain more than 0.25 USP endotoxin units.
• Sterile Water for Injection or pyrogen free water for injection, USP is a sterile, nonpyrogenic
preparation of water for injection intended only for dilution purposes which contains no Bacteriostatic,
antimicrobial agent or added buffer and is supplied only in single-dose containers to dilute or dissolve
 drugs for injection. For I.V. injection, add sufficient solute to make an approximately isotonic solution.
[Presence of pyrogen is detected by LAL test]
• Bacteriostatic water for injection U.S.P. Water that serves the same purposes as Sterile Water for
Injection, it meets the same standards, with the exception that it may be packaged in either single-dose
or multiple-dose containers of not larger than 30-mL size. Bacteriostatic water for injection
Bacteriostatic agent like benzyl alcohol and combination of methyl and propyl parabens.

Water for Sterile water for injection Bacteriostatic

injections water for
injection
Total solid 10 ppm 40 ppm for vial < 30 ml 40 ppm
content 30 ppm for vial >30 but <100 ml
20 ppm > 100 ml
pH 4.5- 7 4.5- 7.5 (5.4) 4.5- 7
pyrogens should sterile and pyrogen free sterile and
not be more than pyrogen free
0.25 endotoxin
units
Method of distillation or 2 Reverse osmosis, ion exchange, a
preparation stage reverse solid matrix filter containing
osmosis activated carbon and zeta
adsorbent, a final 0.1 micron
pore-size sterilizing filter.

METHOD TO REMOVE PYROGENS

(Not necessary for the ophthalmic preparations because pyrogens are not absorbed systematically from eye). The
minimum volume required to test pyrogen is 15 ml.

1. Ultrafilteraion (0.1 µm)

2. Use of reverse osmosis, ion exchange, a solid matrix filter containing activated carbon and zeta
adsorbent, a final 0.1 micron pore-size sterilizing filter.
3. By treating potable water at a temperature of at least 230° C can produce pyrogen-free in 5 seconds or
less and at a pressure at least equal to the pressure of saturated steam at said temperature.
 4. The addition of an oxidant, in the form of a gas, a liquid, or a solid, further decreases the required
treatment time to less than 0.05 second.

Containers can be rendered through pyrogens by heating at 2100 C for 3-4 hrs.

Co-solvents’ like [Diloxanes, dimethyl acetamide], ethyl alcohol, PEG 400 and 600 are used when the drug
dissolved in water undergoes hydrolysis, oxidation, decarboxylation, and racemization which markedly
affected by pH of the solution.

¾ Epinephrine undergoes racemization and oxidation, but if the pH of the solution is maintained at pH less 3
little reaction occurs. The oxidation reaction can be reduced by displacing atmospheric oxygen with inert
gas or adding 0.1% sodium metabisulphite as an antioxidant.
¾ Atropine sulfate rapidly hydrolyses in aqueous solution but if pH 3-4 is maintained than little reaction
occurs.
¾ Barbituric acid and its derivatives hydrolyzed rapidly in water particularly at low pH

Ethyl alcohol for C.glycosides, Propylene glycol for barbiturates, Propylene glycol alkaloids and certain
antibiotics, Ethylenediamine to solublize theophylline, Sodium benzoate to solublize caffeine , Glycerol to
solublize ergotamine

Water immiscible solvents

Fixed oils, ethyl oleate, isopropyl myristate, benzyl benzoate, sesame oil, cotton seed oil

¾ [Sesame oil also has antioxidant property]

™ Most widely used nonaqueous solvents other than water are propylene glycol and polyethylene
glycol.

II. Additives in parenterals

Local anesthetics: [Benzyl alcohol and procaine] in parenterals is commonly used as local anesthetic

I. Antioxidants: prevent autoxidation by blocking the oxidative reactions like, ascorbic acid, gallic acid,
etc.
Antioxidant (reducing agents): sodium bisulfite, sodium metabisulfite, thiourea
Antioxidants (blocking agents): ascorbic acid, BHT, BHA. BHA and BHT are mostly used in non-
aqueous parenteral preparations.
 Synergists: citric acid, tartaric acid, citraconic acid

[Sodium bisulfate] can be absorbed from peritoneal dialysis solutions. So it generally NOT used as
antioxidant in Intraspinal injections.

II. Buffers: change in the pH can occur during the storage as a result of dissolving the glass constituents
into the product, release of constituents from rubber closures or plastic components in contact with
product. Lactic acid, Adipic acid, maelic acid etc
Citrates pH 2-6
Acetates pH 4-6
Phosphates pH 6-8
III. Tonicity modifiers: Isotonicity is most important for Intraspinal injections and intravenous, in
case of Intraspinal injections because the circulation of the cerebrospinal fluid is slow and slight
disturbance of osmotic pressure quickly cause headache and vomiting. For intracutaneous injections
nonisotonic can cause irritation Isotonicity is for comfort of patient but not essential for
subcutaneous and intramuscular injections. Isotonic solution is one which does not cause
hemolysis.
¾ For rapid absorption of drugs from intramuscularly a hypertonic solution is used because increase the
effusion rate of tissue fluids.
¾ The compounds contributing to the isotonicity of a product reduce the pain of injection in the area with
nerve ending. Sorbitol, Mannitol, lactose, glycerin, and sodium sulphate is mainly used tonicity
modifiers.
Method to determine isotonicity
1. Freezing point depression
2. Hemolytic method using RBC because isotonicity depends upon the permeability of living
semipermeable membrane that separates solutions from biological cell system. The membrane
concerned is one enclosing the RBC.

IV. Solublizer, wetting agents or emulsifiers :

¾ [Lecithin, Polysorbate 80 (Tweens)], sodium deoxy cholate, theophylline
V. Stabilizers : Creatinine, glycine, sodium caprylate
VI. Chelating agents: release of heavy metals from the rubber closers etc can react with the main
medicament of the preparation, to prevent chelating agents mainly trisodium or calcium disodium salt
of ethylene diamine tetra acetic acid.
¾ Thiomerosal a Bacteriostatic agent used in poliomyelitis vaccine is unstable in presence of
cupric ions and the breakdown of products destroys the Antigenicity of the vaccine.
 ¾ Sometimes complexation may occur between added ingredient and macromolecule. E.g.
polysorbate 80 can form complex with methyl and propyl esters of p-hydroxybenzoic acid,
reducing the antibacterial activity.
III. Plastic Containers : Polypropylene and polyethylene are most widely used in parenterals plastic
containers
¾ Low density polyethylene & Polystyrene are generally not autoclavable.
¾ Polyamides and Polystyrene have high reactivity due to sorption as they have high permeability for
water vapors.
¾ Flexible polyvinyl chloride is used for intravenous solutions
¾ Polyethylene containers for ophthalmic solutions

Test procedure for evaluating toxicity of plastic materials*** implanting small pieces of plastic material to
intramuscularly in rabbits

IV. Glass containers : principally glass is silicon dioxide tetrahedron whose physicochemical properties
are altered by adding oxides of sodium, iron, magnesium etc. sometimes oxides may hydrolyze to raise in
pH, catalyze reactions or glass flakes may be produced.
Test for evaluating chemical resistance test
Type Highly resistant Powered For buffered & unbuffered aqueous
1 borosilicate glass glass test solutions, powders
Type Treated (sulfur dioxide Water For buffered aqueous solution with pH
2 fumes) soda lime glass attack test below 7 & for dry powders, oleaginous
solutions
Type Soda lime glass Powered For dry powders, oleaginous solutions
3 glass test
Type General purpose soda lime Powered Not for parenterals & for suspensions,
4 glass glass test emulsions, oral solutions

¾ Ultraviolet rays are completely filtered by using amber color bottles which mainly contains iron oxide.
V. Parenterals Suspensions: solid content is 0.5 - 5% but may go up to 30% in antibiotic preparation.
¾ Stabilizing agent used to reduce the interfacial tension between the solid and vehicle is polysorbate 80 and
lecithin.
¾ For increasing the viscosity of parenterals suspensions mainly Sorbitol and protective colloid is used.
¾ To increase the stability of flocculated parenterals suspensions Monosodium citrate is added as
increase the surface charge of the solid particles may cause them to form fluffy aggregates which are
necessary to prevent packing of dense cake.
 Partical size must be small and uniform because-

1. Small and uniform particles to give sow uniform rates of sedimentation and predictable rates of
dissolution and drug release.
2. Small and uniform particles reduce the tendency of larger crystal growth during the storage, as small
crystals tend to disappear and larger crystals grow larger in a mixture.

e.g procaine penicillin injection, insulin zinc suspension etc.

Small and uniform partical size can be achieved by micropulverization, fluid energy grinding, ultrasonic insonation
of shock cooled saturated solution.

VI. Emulsions: uniform droplets 1µ - 5µ in size of internal phase. Mostly emulsifier used in parenterals
emulsion is [oxyehtyleneoxypropylene polymer and lecithin]. With emulsions separation of phase does
not occurs rapidly as suspensions because the difference in density between oil and water is relatively
small. Emulsion must be stable to autoclaving. Elevated temperature can produce coalescence of dispersed
phase and excess shaking can cause acceleration of the rate of creaming.

VII. Osmolality and Osmolarity: Solutions that have same osmolarity as that of RBC are isotonic.
Units of osmolarity are osmols/milliosmoles/mosmol. Osmolarity measures the osmotic potential of a
solution i.e. potential to move water through semi-permeable membrane from a solution of lower osmotic
potential. [Osmolarity of plasma as reported is 306 mosmol/liter]. Intravenous injections with hypotonic
solutions cause swelling of erythrocytes and hemolysis, while hypertonic solution can cause crenation of
erythrocytes. Glucose 5% infusion has osmolarity 280 mosmol/liter and sodium chloride an
osmolarity 308 mosmol/liter. Other large volume intravenous solutions have osmolarity between 260-
340 mosmol/liter. If parenterals solution is hypotonic then osmolarity adjustment is made by NaCl,
glucose, Mannitol to make isotonic.

Osmolality: is the mass of solute which is dissolved in kilogram of water, will exert an osmotic equal to that
exerted by a gram molecular weight of an ideal unionized substances dissolved in kilogram in water. So Osmolality
is milliosmol/ kg.

Osmolarity: is the mass of solute which is dissolved in sufficient solvent to produce a liter of solution, will exert
an osmotic equal to that exerted by a gram molecular weight of an ideal unionized substances dissolved in liter of
solution. So osmolarity = Osmolality (density – gram of solute / ml)

Osmoticity: is a general term and refer osmotic state without stipulating osmolarity or Osmolality.
 When an

alternative excipients is used for adjusting tonicity, e.g Mannitol then sodium chloride equivalent of
excipient is calculated Ce = (9 - CmXm) Xe

Ce concentration of excipients (g/l)

Xe sodium chloride equivalent of the excipients

Cm concentration of medicament (g/l)

Xm sodium chloride equivalent of the medicament

VIII. Quality control

¾ Leaker test: [is intended to detect incompletely sealed ampuls (leakers)] so that they may be discarded.
Leakers usually detected by producing a negative pressure within an incompletely sealed ampule in a
vaccum chamber, ampuls are submerged in deeply colored solution of 0.5 – 1% methylene blue. Vials
and bottles are not subjected to leaker test because rubber closures are not rigid.

Pyrogen test: presence of pyrogenic substances in parenterals preparations is determined by qualitative in vivo
biologic test based on fever response in vein of rabbits (within 3 hrs) as they show slow physiologic response to
pyrogens similar to that of human beings.

The test involves measurement of the rise in body temperature of rabbits following the intravenous injection of
a sterile solution of the substance being examined. It is designed for products that can be tolerated by the test rabbit
in a dose not exceeding 10ml per kg injected intravenously within a period of not more than 10 minutes.

LAL test is in vitro test (5 – 10 times more sensitive than rabbit test) method for pyrogens which utilize the
gelling property of lysate of the amebocytes of limulus polyphemus (horseshoe crab) in the presence of
pyrogenic Endotoxins from gram negative bacteria with in 60 min when incubated at 370C.

The bacterial endotoxins test (BET) or LAL test measures the concentration of bacterial endotoxins that may be
present in or on the sample of the article to which the test is applied using a lysate derived from the hemolymph
cells or amoebocytes from the horseshoe crab, Limulus polyphemus. The Indian horseshoe crab also yields
amoebocte lysate having similar activity. The addition of a solution containing endotoxins to a solution of the
lysate produces turbidity, precipitation or gelation of the mixture. The rate of reaction depends on the
concentration of endotoxin, the pH and the temperature. The reaction requires the presence of certain bivalent
cations, a proclotting enzyme system and clottable protein all of which are provided by the lysate. The quantities of
endotoxins are expressed in defined Endotoxin Units (EU).

HEPA filters can remove at least 99.97% of airborne particals of 0.3 µm in diameter
DOP (Di-octyl phthalate) test to determine the efficiency of HEPA filters. Di-octyl phthalate smoke of
average size particals of [0.3)