UNIT-2 (Industrial Pharmacy-I)

Introduction-
• According to USP, Tablet is defined as a compressed solid dosage form containing
medicaments with or without Excipients.
• According to the Indian Pharmacopoeia, Pharmaceutical tablets are solid, flat or
biconvex dishes, unit dosage form, prepared by compressing a drug or a mixture of
drugs, with or without diluents
Advantages of tablet dosage form over other oral drug delivery systems
From patients stand point:
• They are easy to carry, easy to swallow and they are attractive in appearance.
• Unpleasant taste can be masked by sugar coating and they do not require any
measurement of dose.
• Some of the tablets are divided into halves and quarters by drawing lines during
manufacturing to facilitate breakage whenever a fractional dose is required.
From the standpoint of manufacturer:
• An accurate amount of medicament, even if very small, can be incorporated.
• Tablets provide best combined properties of chemical, mechanical and
microbiological stability of all the oral dosage forms.
• Since they are generally produced on a large scale, therefore, their cost of production
is relatively low, hence economical.
• They are in general the easiest and cheapest to package and ship among all oral
dosage forms.
• Some specialized tablets may be prepared for modified release profile of the drug.
• Product identification is potentially the simplest and cheapest requiring no additional
processing steps when employing an embossed or monogrammed punch face.
Disadvantages of tablet dosage form
 Difficult to swallow in case of children and unconscious patients.
 Drugs with poor wetting, slow dissolution properties, optimum absorption high in
GIT may be difficult to formulate or manufacture as a tablet that will still provide
adequate or full drug bioavailability.
 Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to
oxygen may require encapsulation or coating. In such cases, capsule may offer the
best and lowest cost.
 Some drugs resist compression into dense compacts, owing to amorphous nature, low
density character.
Types of tablets-
(a) Tablets ingested orally:
• Compressed tablets
• Multiple compressed tablets
• Enteric coated tablets
• Sugar coated tablets
• Film coated tablets
• Chewable tablets
(b) Tablets used in the oral cavities:
 • Buccal Tablets
• Sublingual tablets
• Lozenges
• Dental cones
(c) Tablets administered by other routes:
• Implantation tablets
• Vaginal tablets
(d) Tablets used to prepare solutions:
• Effervescent tablets
• Dispensing tablets
• Hypodermic tablets
• Tablet triturates
(a) Tablets ingested orally-
(1) Compressed tablets:-
• These tablets are formed by compression and contain no special coating. They are
made from powdered, crystalline or granular materials, alone or in combination with
suitable excipients.
• These tablets contain water soluble drugs which after swallowing get disintegrated in
the stomach and its drug contents are absorbed in the gastrointestinal tract and
distributed in the whole body. e.g. Aspirin (Dispirin) paracetamol tablets (Crocin).

(2) Multiple compressed tablets / Layered tablets-

• These are compressed tablets made by more than one compression cycle. Such tablets
are prepared by compressing additional tablet granulation on a previously compressed
granulation. The operation may be repeated to produce multilayered tablets of two or
three layers.
• To avoid incompatibility, the ingredients of the formulation except the incompatible
material are compressed into a tablet and then incompatible substance along with
necessary excipients are compressed over the previously compressed tablet.
(3) Sustained action tablets:
These are the tablets which after oral administration release the drug at a desired time and
prolong the effect of the medicament. These tablets when taken orally release the medicament
in a sufficient quantity as and when required to maintain the maximum effective
concentration of the drug in the blood throughout the period of treatment.
e.g. Diclofenac SR tablets.

(4) Enteric coated tablets:

• These are compressed tablet meant for administration by swallowing and are designed
to by-pass the stomach and get disintegrated in the intestine only.
• These tablets are coated with materials resistant to acidic pH (like cellulose acetate
phthalate, CAP) of the gastric fluid but get disintegrated in the alkaline pH of the
intestine.

(5) Sugar coated tablets:

• These are compressed tablets containing a sugar coating. Such coatings are done to
mask the bitter and unpleasant odour and the taste of the medicament. The sugar
coating makes the tablet elegant and it also safeguard the drug from atmospheric
effects.
(6) Film coated tablets:
• The compressed tablets having a film coating of some polymer substance, such as
hydroxy propyl cellulose, hydroxy propyl methyl cellulose and ethyl cellulose.
• The film coating protects the medicament from atmospheric effects. Film coated tablets
are generally tasteless, having little increase in the tablet weight and have less elegance
than that of sugar coated tablets.

(7) Chewable tablets:

• These are the tablets which are required to be broken and chewed in between the teeth
before ingestion. These tablets are given to the children who have difficulty in
swallowing and to the adults who dislike swallowing.
• These tablets should have very acceptable taste and flavour. Ex- Antacid tablets
(Digiene).

(b) Tablets used in oral cavity

(1) Buccal tablets:
• These tablets are to be placed in the side of the cheek (buccal pouch) where they
dissolve or erode slowly and are absorbed directly in the buccal cavity without
passing into the alimentary canal.
• Therefore, they are formulated and compressed with sufficient pressure to give a hard
tablets. e.g. Progesterone tablets.
(2) Sublingual tablets:
• These tablets are to be placed under the tongue where they dissolve or disintegrate
quickly and are absorbed directly without passing into GIT. e.g. tablets of
nitroglycerin, isoproterenol hydrochloride or erythrityl tetranitrate.

(3) Lozenges tablets:

• These tablets are designed to exert a local effect in the mouth or throat. These tablets
are commonly used to treat sore throat to control coughing in common cold. They
may contain local anaesthetics, antiseptics, antibacterial agents and astringents.
• These are prepared by compression at a high pressure by the moulding process and
generally contain a sweetening agent, flavouring agent and a substance which roduces
a cooling effect. e.g. Vicks lozenges, Strepsils.

(4) Dental cones:

• These are compressed tablets meant for placement in the empty sockets after tooth
extraction. They prevent the multiplication of bacteria in the socket following such
extraction by using slow-releasing antibacterial compounds or to reduce bleeding by
containing the astringent.
 • These tablets contain an excipient like lactose, sodium bicarbonate and sodium
chloride. These cones generally get dissolved in 20 to 40 minutes time.

(c) Tablets administered by other routes

(1) Implantation Tablets:
• These tablets are placed under the skin or inserted subcutaneously by means of minor
surgical operation and are slowly absorbed. These may be made by heavy
compression but are normally made by fusion. The implants must be sterile and
should be packed individually in sterile condition. Implants are mainly used for the
administration of hormones such as testosterone steroids for contraception. These
tablets are very usefully exploited for birth control purpose in human beings.
• The disadvantages of implant tablets are their administration, changing rate of release
with change of surface area and possibility of tissue reactions.

(2) Vaginal tablets:

• These tablets are meant to dissolve slowly in the vaginal cavity. The tablets are
typically ovoid or pear shaped for the ease of insertion. these tablets are used to
release steroids or antimicrobial agents. the tablets are often buffered to promote a pH
favorable to the action of a specified antimicrobial agent. The contains easily soluble
components like lactose or sodium bicarbonate.
(d) Tablets used to prepare solutions
(1) Effervescent tablets:
• These tablets along with the active medicament contain ingredients like sodium
bicarbonate, citric acid and tartaric acid which react in the presence of water liberating
carbon dioxide and producing effervescence leading to disintegration of the tablet,
thus fastens solution formation and increase the palatability. Eg. Histac (Ranitidine)

(2) Dispensing tablets:

• These tablets provide a convenient quantity of potent drug that can be readily convert
into powders and incorporate into liquids, thus circumventing the necessity to weigh
small quantities. these tablets are supplied primarily as a convenience for
extemporaneous compounding and should never be dispensed as dosage form.
• e.g. The drugs commonly incorporated are mild silver potentiate, bichloride of
mercury merbromin an quarternary ammonium compounds.

(3) Hypodermic tablets:

• Hypodermic tablets are soft, readily soluble tablets and originally were used for the
preparation of solutions to be injected. These tablets are dissolved in sterile water or
water for injection and administered by parenteral route. these tablets are not
preferred now-a-days because the resulting solution is not always sterile.
(4) Tablet triturates (Moulded tablets):
• These are powders moulded into tablets. They are flat, circular discs, usually
containing a potent substance mixed with lactose, lactose and sucrose, dextrose, or
other suitable diluent.
• Since they are intended to disintegrate very quickly in contact with moisture, water
insoluble adjuncts are avoided. The name ‘tablet triturate’ is appropriate because they
usually contain triturations (trituration = dilution with an inert substance).

Tablet Ingredients/ Excipients-

In addition to active ingredients, tablet contains a number of inert materials known as additives
or excipients. Different excipients are:
1. Diluent / Filler
2. Binder and adhesive
3. Disintegrants
4. Lubricants and glidants
5. Colouring agents
6. Flavoring agents
7. Sweetening agents

Function of excipients-
 Impart weight, accuracy, & volume.
 Improve solubility
  Increase stability
 Enhance bioavailability
 Modifying drug release
 Assist product identification
 Increase patient acceptability
 Facilitate dosage form design

1. Diluents
Definition- Diluents are fillers used to make required bulk of the tablet when the drug dosage
itself is inadequate to produce the bulk.
Secondary reason is to provide better tablet properties such as improve cohesion, to permit use
of direct compression manufacturing or to promote flow.

A diluent should have following properties:

1. They must be non-toxic and low cost.
2. They must be commercially available in acceptable grade
3. They must be physiologically inert, physically & chemically stable by themselves
& in combination with the drugs.
4. They must be free from all microbial contamination.
5. They do not alter the bioavailability of drug.
6. They must be color compatible.

Characteristics of an ideal diluents

• They must be nontoxic and acceptable to the regulatory agencies in all countries
where the product is to be marketed.
• They must be commercially available in an acceptable grade in all countries where the
product is to be manufactured.
• They must be cheap compared to the active ingredients and must be physiologically
inert.
• They must be chemically stable alone and/or in combination with the drug(s) and/or
other tablet components.
• They must be color-compatible (should not produce any off-color appearance).

• They must have no negative effects on the bioavailability of the drug(s) in the product

Commonly used tablet diluents-

1- Lactose-anhydrous and spray dried lactose
2. Directly compressed starch-Sta Rx 1500
 3. Hydrolyzed starch-Emdex and Celutab
4. Microcrystalline cellulose-Avicel (PH 101and PH 102)
5. Dibasic calcium phosphate dehydrate
6. Calcium sulphate dihydrate
7. Mannitol and Sorbitol
8. Sucrose- Sugartab, DiPac, Nutab
9. Dextrose

Lactose
• Lactose is the most widely used diluent for tablet formulation. It is obtained in
hydrous and anhydrous form. The anhydrous form, picks up moisture when exposed
to elevated humidity. Such tablets should be packed in moisture proof packets or
containers. When a wet granulation method is employed, the hydrous form of lactose
should generally be used.
• Two grades of lactoses are commercially available:

(i) A 60 to 80 mesh – coarse

(ii) a 80 to 100 mesh – regular grade

Advantages:
• Lactose has no reaction with most of the drugs, whether in hydrous or anhydrous form.

• Lactose formulations show good release rates. Their granulations are readily dried,
and the tablet disintegration times of lactose tablets are not strongly sensitive to
variations in tablet hardness.
• It is a low cost diluent.

Disadvantages:
• Lactose reacts with amine drug bases in presence of alkaline lubricants e.g. metal
stearates (e.g. magnesium stearate) and gradually discolours (dark brown) with time
due to the formation of furaldehyde. This reaction is called Maillard reaction.

Calcium salts ((DCP/TCP)

Dibasic calcium phosphate dihydrate (or dicalcium orthophosphate) (DCP) [CaHPO4, 2
H2O], Calcium sulfate dihydrate (CaSO4 , 2H2O).

Advantages:
• Diluents that exist in their common salt form as hydrates, containing appreciable
bound water as water of crystallization. This bound water of calcium sulfate is not
released below 800C. They possess very low concentration of unbound moisture.
Hence, these
 salts are excellent diluents for water-sensitive drugs. It is superior to anhydrous diluent,
which has a moderate to high moisture demand.
Disadvantages:
• Tetracycline products made with calcium phosphate diluent had less than half the
bioavailability of the standard product. Divalent cation (Ca++) form insoluble
complexes and salts with number of amphoteric or acidic functionality antibiotics,
which generally reduces their absorption (which is also why milk should not be co-
administered with these drug).

Spray dried lactose

Advantages:
• It is used for direct compression (containing drug + diluent + disintegrant + lubricant).
In addition to the direct compression properties, spray dried lactose also has good
flow characteristics. It can usually be combined with as much as 20 to 25% of active
ingredients without losing these advantageous features.
Disadvantages:
• If spray dried lactose is allowed to dry out and the moisture content falls below the
usual 3% level, the material loses some of its direct compressional characteristics.
• Spray-dried lactose is especially prone to darkening in the presence of excess
moisture, amines, and other compounds owing to Maillard reactions. Hence, a neutral
or acid lubricant should be used.

Starch
• Starch may be obtained from corn, wheat or potatoes and rice. It is occasionally used
as a tablet diluent. USP grade of starch is usually possesses moisture content between
11 to 14%.
• Specially dried types of starch that have a standard moisture level of 2-4% are
available, but are costly. Use of such starches in wet granulation is wasteful since
their moisture level increase to 6-8% following moisture exposure.

Directly compressible starches

• Sta–Rx 1500– free flowing, directly compressible starch. It is used as diluent, binder,
disintegrant.
• Emdex and Celutab – are two hydrolyzed starches – contains dextrose 90–92%
and maltose 3–5%
• free flowing and directly compressible and may be used in place or mannitol in
chewable tablets because of their sweetness and smooth feeling in the mouth.

Dextrose (D–Glucose)
 • Available in two forms: as hydrates and anhydrous forms.

• Dextrose may sometimes be combined in formulation to replace some of the spray-

dried lactose, which may reduce the tendency of the resulting tablets to darken.

Mannitol
Advantages
• Because of the negative heat of solution (cooling sensation in the mouth) its slow
solubility, and its pleasant feeling in the mouth, it is widely used in chewable tablets.
• It is relatively non-hygroscopic and can be used in vitamin formulations.

• Low calorie content and non-carcinogenic.

Disadvantages
• Costly and has poor flow characteristics and usually require fairly high lubricant level.

Sorbitol
• It is an optical isomer of mannitol and is sometimes combined with mannitol
formulations to reduce the diluent cost.
• Disadvantages:- It is hygroscopic at humidities above 65%.

Sucrose
• Some sucrose based diluents are:

• Sugar tab– 90 to 93% sucrose + 7 to 10% invert sugar

• Di Pac – 97% sucrose + 3% modified dextrins

• Nu Tab– 95% sucrose + 4% invert sugar + small amount of corn starch + Mg-stearate
Advantages: They are all used for direct compression.
Disadvantages: All are hygroscopic when exposed to elevated humidity.

Microcrystalline cellulose (MCC)

• Trade Name : Avicel – is a directly compression material

• Two grades are available PH 101  powder

PH 102 granules

• Advantages: It acts as diluent and disintegrating agents.

2. Binders and Adhesive

Definition- Agents used to impart cohesive qualities to the powdered material are referred to
as binders or granulators.
Objective of incorporating binders
• They impart a cohesiveness to the tablet formulation (both direct compression and
wet– granulation method) which insures the tablet remaining intact after compression.
• They improves the free-flowing qualities by the formation of granules of desired size
and hardness.

Characteristics of binder
Method-I
• Binders are used in dry form in the powder and then moistened with a solvent (of the
binder) to form wet lumps.
Method-II
• Binders are often added in solution form. It requires lower concentration of binder.

• By Method-I the binder is not as effective in reaching and wetting each of the
particles within the mass of the powder. Each of the particle in a powder blend has a
coating of adsorbed air on its surface, and it is this film of air which must be
penetrated before the powder can be wetted by the binder solution.

Method-III
• In direct compression method MCC, microcrystalline dextrose, amylose and PVP are
used – those have good flow property and cohesiveness as well.
• It has been postulated that MCC is a special form of cellulose fibril in which
individual crystallites are held together largely by hydrogen bonding. The
disintegration of tablets containing the cellulose occurs by breaking intercrystallite
bonds by the disintegrating medium.
Starch paste
Corn starch is often used in the concentration of 10–20%.

Method of preparation:- Corn starch is dispersed in cold purified water to make a 5 to 10%
w/w suspension and then warming in water both with continuous stirring until a translucent
paste is formed.. (Actually hydrolysis of starch takes place.)
Liquid glucose:- 50% solution in water is fairly common binding agent.
Sucrose solution:- 50% to 74% sugar solution is used as binder. They produce hard but
brittle granules. Their cost is low.

Gelatin solution
• Concentration 10–20% aqueous solution

• Should be prepared freshly and added in warm condition other wise it will become
solid.
Method of preparation
• The gelatin is dispersed in cold water and allowed to stand until hydrated. The
hydrated mass is warmed in water bath to dissolve.
Cellulosic solutions
• HPMC (Hydroxy propyl methyl cellulose) Soluble in cold water.

Method of preparation: HPMC is dispersed in hot water, under agitation. The mixture is
cooled as quickly as possible and as low as possible
• HEC (Hydroxy ethyl cellulose), HPC (Hydroxy propyl cellulose) are other successful
binders.
• PVP (Polyvinylpyrollidone) Used as an aqueous or alcoholic solution.
Concentration 2% and may vary.

3. Disintegrants
Definition:- A disintegrant is a substance to a mixture of substances, added to tablet to
facilitate its breakup or disintegration after administration in the GIT. The active ingredients
must be released from the tablet matrix as efficiently as possible to allow for its rapid
dissolution.
Disintegrants can be classified chemically as: Starches, clays, celluloses, alginates, gums and
cross-linked polymers.
Starch
• Corn starch, potato starch.

• For their disintegrating effect starches are added to the powder blends in dry state.

Mode of action:
• Starch has a great affinity for water and swells when moistened, thus facilitating the
rupture of the tablet matrix.
• Others have suggested that the spherical shape of the starch grains increases the
porosity of the tablet, thus promoting capillary action.
• Normally 5% w/w is suggested and for rapid disintegration 10 – 15% w/w may be
taken.

Superdisintegrants
Super disintegrants like Croscarmelose - cross linked cellulose, Crospovidone - cross linked
polyvinyl pyrrolidone and Sodium starch glycolate- cross linked starch
Mode of action
• Croscarmelose swells 4 to 8 fold in less than 10 seconds

• Crospovidone acts by wicking or capillary action.

 • Sodium starch glycolate swells 7 to 12 folds in less than 30 seconds.

Other materials
• Methyl cellulose, Agar, Bentonite, Cellulose, Alginic acid, Guargum, and
Carboxymethyl cellulose.
• Sodium lauryl sulfate is a surfactant. It increases the rate of wetting of the tablet, thus
decreases the disintegrating time.
4. Lubricant and Glidants

Objectives:
• Prevents adhesion of the tablet material to the surface of dies and punches.

• Reduce inter-particular friction, improve the rate of flow of tablet granulation.

• Facilitate ejection of the tablets from the die cavity.

Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and
punches, reduce inter particle friction and may improve the rate of flow of the tablet
granulation.
Example: Stearic acid, Stearic acid salt - Stearic acid, Magnesium stearate, Talc, PEG
(Polyethylene glycols), Surfactants.
Glidants are intended to promote flow of granules or powder material by reducing the friction
between the particles.
Example: Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal silicas
such as Cab-O- Sil, Syloid, Aerosil in 0.25-3% conc.
Antiadherents are used for the purpose of reducing the sticking or adhesion of any of the
tablet ingredients or powder to the faces of the punches or to the die wall.
5. Coloring agent

Objectives of using colors that (i) It makes the tablet more esthetic in appearance and (ii)
Colour helps the manufacturer to identify the product during its preparation. Colorants are
obtained in two forms dyes and lakes.
Dyes are dissolved in the binding solution prior to the granulating process. However, during
drying their color may migrate to the surface and may produce mottling of the tablet. So
another approach is to adsorb the dye on starch or calcium sulfate from its aqueous solution;
the resultant powder is dried and blended with other ingredients.
Color lakes are dyes which are adsorbed onto a hydrous oxide of a heavy metal (like
aluminium) resulting in an insoluble form of the dye.
6. Flavours and Sweeteners
Flavours are usually limited to chewable tablets or other tablets intended to dissolve in the
mouth. Flavor oils are added to tablet granulations in solvents, are dispersed on clays and
other adsorbents or are emulsified in aqueous granulating agents (i.e. binder).
The use of sweeteners is primarily limited to chewable tablets. E.g. Sugar
• Mannitol– 72% as sweet as sugar, cooling & mouth filling effect

• Saccharin– Artificial sweetener, 500 times sweeter than sucrose

Disadvantages (i) it has a bitter after taste and (ii) carcinogenic

• Cyclamate– either alone or with saccharin– it is banned

• Aspartame (Searle) – widely replacing saccharin

Disadvantage – lack of stability in presence of moisture

Manufacturing of Tablets
Manufacture of tablets involves certain well defined steps: namely:-
 Pulverization and mixing.
 Granulation.
 Compression.
 Coating (if required)

Pulverization and mixing-

• In this step the different solid / powder ingredients are reduced to the same particle
size since particles of different sizes will segregate while mixing.
• Various equipments like Cutter mill, Hammer mill, Roller mill and Fluid energy mill
is required to reduce the large lumps.

Granulation Technology-
Granulation: It is the process in which primary powder particles are made to adhere to form
large multi-particle entities.
Range of size: 0.2 mm to 4 mm. (0.2 mm to 0.5 mm)

Objectives:-
 To enhance the flow of powder.
 To produce dust free formulations and produce uniform mixtures.
 To improve compaction characteristics.
 To eliminate poor content uniformity of mix.
 To avoid powder segregation. As Segregation may result in weight variation.
Percolation Segregation:- air void Ex- Tea & Coffee jar.
Trajectory Segregation:- kinetic energy Ex- powder heap

(a) Wet Granulation-

Step-I Milling of the drug and excipients
• Milling of the active ingredients, excipients etc. are milled to obtain a homogeneity in
the final granulation.
• If the drug is given in solution then during drying it will come up to the surface. To
avoid this problem drug is mixed with other excipients in fine state.

Step-II Weighing
• Weighing should be done in clean area with provision of air flow system.

• In the weighing area all the ingredients must not be brought at a time to avoid cross-
contamination.
Step-III Mixing Commonly used blenders are:
(a) Double cone blender
(b) V – blender
(c) Ribbon blender
(d) Planetary mixer
Any one of the blender may be used to mix dry powder mass.

Step-IV Wet Massing

• Wet granulation forms the granules by binding the powders together with an adhesive.

• Binder solutions can be added in two methods:

Method-I Method-II
Drug + Diluent Drug + Diluent
Dry binder is added Binder Solution is added
Blended uniformly

Suitable solvent is added to activate the dry binder

Blended in a Sigma - mixer or Planetary mixer till properly wet mass is formed
Therefore, when
• (i) a small quantity of solvent is permissible, method-I is adopted and
 • (ii) a large quantity of solvent is required method-II is adopted.

However, method-II will give more cohesiveness than method-I if the amount of binder
remains constant.
• If granulation is over-wetted, the granules will be hard, requiring considerable
pressure to form the tablets, and the resultant tablets may have a mottled appearance.
• If the powder mixture is not wetted sufficiently, the resulting granules will be too soft,
breaking down during lubrication and causing difficulty during compression.

Step-V -Wet Screening

Wet screening process involves converting the moist mass into coarse, granular aggregates by
• (i) passage through a hand screen (in small scale production) or,

• (ii) passage through an oscillatory granulator of hammer mill equipped with screens
having large perforations (# 6 – 8 mesh screen).
• Purpose (i) Increase particle contact point

(ii) Increase surface area to facilitate drying.

Step-VI Drying

• Drying is usually carried out at 600C. Depending on the thermolabile nature of the
drug the temperature can be optimized.
• Drying is required in all wet granulation procedures to remove the solvent, but is not
dried absolutely because it will pose problems later on. Hence, certain amount of
moisture (1 – 4 %) is left within the granules – known as the residual moisture.
Methods: Drying can be carried out
Tray dryers – it may take 24 hrs of drying
Truck dryers – the whole cabinet can be taken out of the dryer
Fluid-bed dryer – carry out drying in 30 mins.

Step-VII Dry Screening

After drying, the granules are make monosize by passing through mesh screen.

For drying granules the screen size to be selected depends on the diameters of the punch. The
following sizes are suggested:

• Tablet diameter upto Mesh Size

3/16 ” # 20
3.5 / 16 – 5/16” # 16
5.5/16 – 6.5/16” # 14
 7.0/16 or larger # 12

Step-VIII Lubrication of granules

• After dry granulation, the lubricant is added as a fine powder. It usually, is screened
onto the granulation through 60 or 100 mesh nylon cloth to eliminate small lumps as
well as increase the covering capacity of the lubricant.
• The lubricant is blended very gently using tumbling action to maintain the uniform
granule size.
• Too much fine powder is not desirable because fine powder may not feed into the die
uniformly causing variation in weight and density.
• Since, the very nature of lubricant produce hydrophobic surface on the particle hence
over blending prevents the inter granule bonding that takes place during compression.
(b) Dry Granulation
Dry granulation is followed in situations where (i) the effective dose of a drug is too high
for direct compaction and (ii) if the drug is sensitive to heat, moisture or both, which
precludes wet granulation. e.g. many aspirin and vitamin formulations are prepared for
tableting by compression granulation.

Steps of granulations
Milling Weighing  Screening  Blending  Slugging  Granulation (Dry) 
Lubrication Compaction.

Slug:
Slug may described as poorly formed tablets or, may be described as compacted mass of
powdered material.
Purpose: To impart cohesiveness to the ingredients, so as to form tablets of desired properties.
Method: It is done either by (i) high capacity heavy duty tablet press
(ii) Chilsonator roller compactor.

Advantages of dry granulation over wet granulation

 No application of moisture (required in wet granulation) and heat (for drying). So the
drugs susceptible to either moisture or heat or both can be made by dry granulation.
e.g. calcium lactate cannot be used by wet granulation. (Aspirin, Vitamin C).
 Dry granulation involves less steps and hence less time is required than that of wet
granulation.
 Less steps requires less working space and energy.

 Since popularity of wet granulation is more that dry granulation because former will
meet all the physical requirement for the compression of good tablets.
Direct Compression Method-
Milling Weighing Sieving Blending Compression
Advantages: (i) It is much more quicker than any of the previous process
(ii) Minimum number of steps are required.
• Modified diluents, binders etc. are available in the market which assure spherical
shape of the granules to modify flow property. However, they are not used
extensively.
• If active medicament is less in amount then there will be no problem but in case of
high dose large amount of active ingredient is to be replaced by specially treated
vehicles to improve flow property or compressibility.
• These specially treated materials are

costly. Tablet Compression

It can reduce the volume by apply pressure, particle in die are re-arrange, resulting a closer
packing structure and reduce space and at certain lode reduced space and increase inter-
particulate friction will prevent farther interparticulate friction.
Elastic deformation:- Either whole or a part can change their shape temporarily.
Plastic deformation:- Change shape permanently.
Particle fragmentation:- Fracture into a number of smaller discrete particles.

Find new position- decrease the volume of powder bed- when force increase new particle
again under go deformation-particle particle bonds can formed.
Time of loading:- Deformation of particle are time independent process in Elastic & Plastic
deformation.
Deformation is time dependent, when its behavior is referred to Viscoelastic & Viscous
deformation.
Degree of deformation:- Some quantitive chang in shape.
Mode of deformation:- type of shape change.
Basic Component of Compression Machine
Head- Contain upper punchs, dies, lower punchs.
Body- Contain operating machinaries.
Hopper- Holding feeding granules.

Dies- Define size, shape of tablet.

Punches – For compression with in dies.
Cam tracks – Guiding the movement of punches.
Feed frame- Guiding the granules from hopper to dies.
Upper turret- Holds the upper punchs.
Lower turret- Hold the lower punchs.
Die table- Contain the dies.
Single station – stamping press
Multi- station- Rotary press

Fig. 1. Tablet Compression Machine.

Fig.2. Sequence of events involved in the formation of tablets.

 Fig.3. A single punch tablet press.

Fig.4. Schematic diagram for the formation of tablets with rotary press.

A- Feed frame, B- Die, C- Pull down cam, D- Wipe off blade, E- Weight control cam, F –
Lower compression roll, G- Upper compression roll, H- Rising cam, I- Ride up cam
Tablet machine out put is regulated by three basic characteristic like:-
 No of tooling sets
 No of compression station
 Rotational speed of press.
Rotary presses are engineered for fast & economical production of all kind of tablet.

Ex- The monestry nova rotary tablet press.

Gradually modification made in machines by using hydraulic or pneumatic pressure to
control pressure roll in place of spring for smoother pressure.
Special type machine:-
Fette machine- Chill the compression(For low MP substance like wax)
Versa press- For multi-layer tablet

Tablet Tooling Set

 • Its gives definite size, shape of tablet and certain identification marking.

• For this purpose different types of punches are used-

 Flat faced bevel edged.

 Shallow concave (Round / Capsule shaped)
 Standard concave (Round / Capsule shaped)
 Deep concave (Round / Capsule shaped)
 Extra deep.
 Modified ball

Auxillary Equipment-
• Mechanized feeder: Due to short D Well time (Monestry granulation feeding device)

• Mechanized hopper loading equipment:

• Bulk granulation container:

• Electronic monitoring device: To maintain fixed force

Tablet Processing Problems and its remedies-

An ideal tablet should be free from any visual defect or functional defect. With the
development of technology, the production process had become more simplified and more
mechanized.
But now the tablet punching machines are all mechanized, the mechanical feeding of feed
from the hopper into the die, electronic monitoring of the press, but tablet process problem
still persist.
An industrial pharmacist usually encounters number of problems during manufacturing.
Majority of visual defects are due to inadequate quality or inadequate moisture in the
granules
ready for compression or due to faulty machine setting. Functional defects are due to faulty
formulation.

Basic
Problems

Mechanical Release
Weight Content
Strength Profile Visual defects
Variation Uniformity
Related Altered

Hardness Friability

The Imperfections known as: ‘VISUAL DEFECTS’ are either related to Imperfections in any
one or more of the following factors:
I. Formulation design
II. Tableting process

III. Machine
Capping

Lamination
Process Related

Cracking

Chipping

Visual Defects Sticking

Formulation Related
Picking

Binding

Machine Related Double Impression

1. Capping and Lamination

Capping is the partial or complete separation of the top or bottom crowns of a tablet from
the main body of the tablet.
• Lamination is the separation of tablet into two or more distinct layers. Usually these
problems are apparent immediately after compression, or even hour or days later.
 • Detection: Subjecting tablets to the friability test is the quickest way to reveal such
problems.

Reason and Remedies

a) Reason: Entrapment of excess air in the granules during compression. If the granules
are light and fluffy this type of problems are encountered frequently.
Remedies: Increasing the density of granules by adding more binder or changing the
solvent of binder.
(b) Reason: New set of punches and dies are very tightly fitted; i.e. the clearance is very
negligible hence air cannot come out.
Remedy: In that case punch diameter should be reduced by 0.005” (i.e. 5 thou)

(c) Reason: Granules should not be completely dried. if over dried or under dried then
capping may take place.
Remedy: So moisture content should be kept within 1 – 4%.

(d) Reason: Tooling set used for longer period of time will form claw-shaped curve on
tip of the punch or wear ring in die in compression area – this form capping.
Remedy: Punches and dies are changed.

2. Picking and Sticking

• Picking: -When some portion of the surface of the tablet is removed – it is termed as
picking.
• Sticking: - Sticking refers to tablet materials adhering to the die wall. Serious sticking
at ejection cause chipping.

Causes and Remedies of picking

Cause: When punch tips have engraving or embossing, usually of letters B, A, O are difficult
to manufacture cleanly. These may produce picking.
Remedy:
(i) Lettering should be designed as large as possible, particularly on punches of small
diameter.
(ii) Plating of the punch faces with chromium produces smooth, non-adherent face.

(iii) Colloidal Silica (Cab-o-sil) is added as polishing agent that makes the punch
faces smooth; so that material does not cling to them.
Causes and Remedies of Sticking
Causes: Excessive moisture may be responsible for sticking.
Remedy: Further drying of the granulation is then required.
 • During compression heat is generated and

(a) low m.p. lubricants e.g. stearic acid may produce sticking.

Remedy: Low melting point lubricant are replaced with high melting point lubricants (e.g.
Poly ethylene glycol)
(b) Low m.p. substances, either active ingredients or additives may soften sufficiently form
the heat of compression to cause sticking.

Remedies:
• Dilution of active ingredient with additional high m.p. diluents.

• Increase in the size of tablet.

• If a low m.p. medicament is present in high concentration then refrigeration of the

granules and then compressing may be the order or using fette compression machine.

3. Mottling
Mottling is an unequal distribution of color on a tablet, with light or dark patches in an
otherwise uniform surface.
Cause: Migration of water soluble dyes to the surface while drying.

Remedies:
• Change the solvent system and change the binder system

• Reduce the drying temperature

• Grind to a smaller particle size.

• Use lakes instead of water-soluble dyes.

Quality Control Tests for Tablets-

• General appearance: - Size, shape, and thickness: This is important to facilitate
packaging and to decide which tablet compressing machine to use.
• Organoleptic properties: which include color, odor and taste of the tablets.

• Weight uniformity and Content uniformity: The tablet should contain the correct
dose of the drug.
• Dissolution test: Drug should be released from tablet in a controlled and reproducible
way.
• Weight variation, thickness & diameter: The appearance of tablet should be
elegant & its weight, size & appearance should be consistent.
• Hardness & friability: The tablet should show sufficient mechanical strength to
withstand fracture & erosion during manufacture & handling.
 • These factors must be controlled during production and verified after production,
hence called In-process control

Official Standards as per I.P.

A) Uncoated tablet:
 Uniformity of container content and Content of active ingredient.
 Uniformity of weight and Uniformity of content.
 Disintegration test.

B) Enteric coated tablet:

 Disintegration test.

C) Dispersible tablet:
 Uniformity of dispersion.
 Disintegration test.

D) Soluble tablet:
 Disintegration test.

E) Effervescent tablet:
 Disintegration/Dissolution/Dispersion test.

1. Weight Variation
This test is based on the fact that, if the weight variation is within the limits then it can be said
that the amount of medicament will uniform considerably. Conversely, if the weight variation
is not in limits then it can be concluded that the active medicament will ununiform
considerably.

Sources of weight variation

Weight variation is solely dependent on the poor flow property of granules and filling
of die cavity. Poor flow properties arise from: (a) improper lubrication, (b) size of granules
and
(c) adjustment of lower punch.

Weight variation test

The U.S.P. weight variation test is run by weighing 20 tablets individually, calculating
the average weight, and comparing the individual tablet weights to the average. The tablets
meet the USP test if “not more than 2 tablets are outside the percentage limit and if no tablet
differs by more than 2 times the percentage limit.”

2) Content Uniformity test

Weight variation test is applicable when the amount of medicament in the tablet is high.
  In potent drug the medicament is less in amount in comparison to the other excipients.
The weight variation may meet the pharmacopoeial limitation but this will not ensure
the correct variation of potency. hence, in this case the weight variation test is
followed by content uniformity test.
• In this test 30 tablets are randomly selected for sample, and at least 10 of them are
assayed individually according to the official assay method.
• 9 of the 10 tablets must have potency within  15 % of the labelled drug content.
Only 1 tablet may be within  25%.
• If this condition is not met then the tablets remaining from the 30 must be assayed
individually and none may fall outside  15% of the labeled content.

3) Disintegration Test of Tablets

• The time a tablet takes to disintegrate is the disintegration time.

• To test the disintegration time one tablet is placed in each tube, and the basket rack
assembly is positioned in a 1-litre beaker of water, simulated gastric fluid or simulated
intestinal fluid, at 370C20C, such that the tablet remains 2.5 cm from the bottom of
the beaker.
• A standard motor moves the basket up and down through a distance of 5 to 6 cm at a
frequency of 28 to 32 cpm (cycles per minute).

4) Dissolution Test
• Disintegration test simply identifies the time required for the tablet to break up under
the condition of the test but it does not ensure the drug release in the bulk of the fluid.
• Rate of dissolution is directly related to the efficacy of the drug. Rate of dissolution is
a good index for comparing the bioavailability of two tablet products of the same
drug.
 Apparatus-I (Basket)
• In general, a single tablet is placed in a small wire mesh basket and immersed in the
dissolution medium (as specified in the monograph) contained in a 1000 ml flask at
370  0.50C. Generally it is rotated at 50 rpm unless otherwise specified.

Apparatus-2 (Paddle)
• The same equipment is used. Instead of basket a paddle is introduced as the stirring
element. The tablet is allowed to sink at the bottom of the flask before stirring.

• Limit: A value of t90% (i.e 90% drug release) within 30 minutes is often considered
satisfactory and is an excellent goal since a common dissolution tolerance in the
USP/NF is not less than 75% dissolved in 45 minutes.
5) Tablet Hardness

The resistance of the tablet to chipping, abrasion or breakage under conditions of storage,
transportation and handling before usage depends on its hardness.
Method:
A tablet is taken between the 2nd and 3rd finger and pressing it with the thumb as fulcrum. If
the tablet breaks with a “sharp snap”, yet, it does not break when it falls on the floor – is said
to possess proper hardness.

Instruments used:
a) Monsanto Hardness Tester
b) Strong Cobb Hardness Tester -Manual mode.
c) Pfizer Hardness Tester.
d) Erweka Hardness tester. – Automatic.
e) Schleuniger Apparatus. – Operates without manual involvement.

Hardness of a tablet:
The hardness at which the tablet crushes is the hardness of the tablet.
• Unit of hardness: Kg/sq.in. or lb/ sq.in

• Limit: Generally maximum 5 kg/sq.in. hardness is required.

6) Friability

Tablet hardness is not an absolute indicator of strength since some formulations, when
compressed into very hard tablets may produce chipping, capping and lamination problems.
Therefore, another measure of tablet strength i.e. friability is often measured, i.e. the
friability.
Instrument: Roche Friabilator
Objective of friability test:
This apparatus is designed to evaluate the ability of the tablet to withstand abrasion, in
handling, packaging and shipping operation.
Method: 20 tablets, previously weighed are taken in the plastic chamber of the laboratory
friability tester. In the plastic chamber the tablets are subjected to abrasion and shock by
rotating the plastic chamber at 25 rpm for 4 mins (i.e. total 100 revolutions). The tablets are
dedusted and reweighed.
Limit: - For conventional compressed tablet the weight loss should be within 0.5 to 1.0 %.

Tablets Coating
Reasons Behind Coating of Tablets:
 To mask the taste, odour or colour of the drug. Improving the product appearance,
particularly where there are visible differences in tablet core ingredients from batch to
batch.
 Provide physical protection, facilitates handling, particularly in high speed packaging
/ filling lines.
 To provide chemical protection from its surrounding environment (particularly air,
moisture and light).
 To control the release of drug from the tablet e.g. sustained release tablets, repeat
action tablets.
 To protect the drug from the gastric environment of the stomach with an acid resistant
enteric coating.
Components Considered in Tablet Coating
Tablet Properties: - Shape, Tolerance, Surface area.
 Tablet to be coated must possess the proper physical characteristics like spherical
shape and uniform surface.
 To tolerate attrition of tablets during coating process they must be resistant to
abrasion and chipping.
 As the tablet surfaces that are brittle and soften in presence of heat or effected by
coating composition and tend to become rough in the early stages of coating process
are unacceptable for film coating.

Coating process: -
A. Coating equipment
B. Coating parameters.
C. Facility & ancillary equipment.
 D. Automation of coating process.
Coating composition: - which involves polymers, color, plasticizer, solvent.
Types of Coating-

(A) Sugar Coating.

1) Sealing-

Objectives- (i) To prevent moisture penetration into the tablet core, a seal coat is applied
and (ii) To strengthen the tablet core without a seal coat, the over wetted tablets would
absorb excess moisture, leading to tablet softening, and may affect the physical and
chemical stability.
Ingredients
• Alcoholic solutions of Shellac (10 – 30% solid) or alcoholic solution of zein,

• Alcoholic solution of cellulose acetate phthalate (CAP) or alcoholic solution of

polyvinyl acetate phthalate.
2) Sub-coating-

Objectives-To round the edges and build up the tablet size. Sugar coating can increase the
tablet weight by 50 to 100% at this step.
Method:- The sub-coating step consists of alternately applying a sticky binder solution to
the tablets followed by a dusting of sub-coating powders and then drying. Subsequent
coatings are applied in the same manner until the tablet edges have been covered and the
desired thickness is achieved.
3) Smoothing (Syruping)-
Objectives-To cover and fill in the imperfections in the tablet surface caused by the sub-
coating step.
Ingredients-Simple syrup solution (approximately 60–70%(w/w)). Often the smoothing
syrups contain a low percentage of titanium dioxide (1–5%) as an opacifier. This gives a
very bright and reflective background for the subsequent coloring step.
4) Color coating-
Objective-To impart an elegant and uniform colour.
Ingredient-Syrup (60 – 70% sucrose) containing the desired color.

Method-Syrup solutions containing the dyes are coated upto 60 individual applications
until the desired color is achieved. After each application of color, the coatings are dried.
In the finishing step a few clear coats of syrup may be applied.
5) Polishing-
Objective-To produce the desired luster on the surface of the tablet.
 Ingredients-Mixtures of waxes (like beeswax, carnauba wax, candella wax or hard
paraffin).
Method-Either this mixture of waxes is applied as powder or as dispersions in various
organic solvents in a polishing pan (canvas line pan).
6) Printing-In order to identify sugar-coated tablets often it is necessary to print them,
using pharmaceutical grade ink, by means of a process of offset rotogravure.
(B) Film Coating
Film coating adds 2 to 5% to the tablet weight. Film coating is a complex process that
involves the application of thin (in the range of 20-200 μm) polymer-based coatings to an
appropriate substrate (tablets, pellets, granules, capsules, powders, and crystals) under
conditions that permit:
1. Balance between (and control of) the coating liquid, addition rate and drying process.

2. Uniformity of distribution of the coating liquid across the surface of product being
coated.
3. Optimization of the quality (both visual and functional) of the final coated product.

Advantage-
 Substantial reduction in quantity of coating applied (2-4% for film coating, compared
with 50-100% for sugar coating).
 Faster processing times and Improvement in process efficiency and output.
 Greater flexibility in optimizing formulations as a result of the availability of a wide
range of coating materials and systems.
 Ability to be applied a wide range of pharmaceutical products.
Types-
1) Pan-pour method-
Viscous coating materials are directly added from some container into the rotating pan
moving with the tablet bed. Tablets are subjected to alternate solution application, mixing and
then drying.

Disadvantages:
• The method is relatively slow and it relies heavily on the skill of the operator.

• Tablets always require additional drying to remove the latent solvent.

• Aqueous film coating is not suitable for this method because localized over wetting
will produce physicochemical instability.

2) Pan-spray method-
Coating material is sprayed over the tablet bed from nozzles and hot air is passed through the
tablet bed to dry it. The variables to be controlled is pan-spray film coating process are:
(a) Pan variables:

Uniform mixing is essential to deposit the same quantity of film on each tablet.

1. Pan design or baffling: Some tablet shapes mixes freely while other shapes may require a
specific baffling arrangement to ensure adequate mixing.
Disadvantages: Baffles may produce chipping and breakage if not selected properly.

(b) Pan speed

• Pan speed affects mixing and the velocity at which the tablet pass under the spray.

• Too slow speed cause localized over-wetting resulting in tablets sticking to each other
or to the pan.
• Too high speeds may not allow enough time for drying before the same tablets are
reintroduced to the spray. This results in a rough coating appearance on the tablets.
Optimum pan speed: 10 – 15 rpm for nonaqueous film coating.
3 – 10 rpm for aqueous film coating

3) Fluidized bed process (air suspension coating)

This process have been successfully used for rapid coating of tablets, granules and capsules.

Process variables are as follows: (a) Chamber design and air flow rate controls the
fluidization pattern, (b) Tablet shape, size and density, (c) Volume and rate of air flow either
too high rate produce attrition and breakage of tablets or too low rate  mass does not move
fast enough through the spray region  over-wetting occurs and (d) Inlet and exhaust air
temperature.
Examples-

Non-enteric materials: e.g. Hydroxypropyl methylcellulose (HPMC), Methyl hydroxy ethyl

cellulose (MHEC), Ethyl cellulose (EC), Polyvinyl pyrrolidone (PVP), Sodium
carboxymethyl cellulose (Sod. CMC), Polyethylene glycols (PEG), Acrylate polymers e.g.
Eudragit E
Enteric materials: e.g. Cellulose acetate phthalate (CAP), Acrylate polymers (Eudragit L, S),
Hydroxypropyl methylcellulose phthalate (HPMCP), Polyvinyl acetate phthalate (PVAP).
(c) Spray variables

1) Rate of liquid application.

2) Spray pattern.
3) Degree of atomization

These three spray variables are interdependent. For spraying two types of systems are there:
(a) High-pressure, airless system and (b) low-pressure, air atomization system.
(d) Process air variables (temperature, volume, rate) are required for optimum drying of the
coating by evaporation of the solvent. The balance between the supply and exhaust air flow
should be such that all the dust and solvent are confined within the coating system

(C) Enteric Coating

1) Pan-pour method.
2) Pan-spray method.
3) Fluidized bed process (air suspension coating)
Oral Liquids-
Oral Liquids are homogeneous liquid preparations, usually consisting of a solution, an
emulsion or a suspension of one or more medicaments in a suitable vehicle. Liquid dosage
forms are either monophasic or biphasic. A monophasic liquid dosage form is one which
contains only one phase. A biphasic liquid dosage form contains two phases.
Liquid preparations for oral use are either supplied in the finished form or, with the exception
of Oral emulsions, may also be prepared just before issue for use by dissolving or dispersing
granules or powder in the vehicle stated on the label.
The vehicle for any liquid preparation for oral use is chosen having regard to the nature of the
active ingredient(s) and to provide organoleptic characteristics appropriate to the intended use
of the preparation. Liquid preparations for oral use may contain suitable antimicrobial
preservatives, antioxidants and other excipients such as dispersing, suspending, thickening,
emulsifying, buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents
and authorized colouring matter.

Classification of Liquid Orals

Liquid dosage forms are broadly classified into two groups:
a) Monophasic liquid dosage forms b) Biphasic liquid dosage forms

1. Monophasic liquids dosage forms are mixtures, elixirs, syrups, linctuses, draughts and
drops etc.
2. Biphasic liquids dosage forms are suspensions and emulsions.

Advantages of Liquid Dosage Forms

i) They are the most suitable dosage form for infants, children and geriatric patients.

ii) The unpleasant taste of the drugs can be masked by adding sweetening and flavouring
agents.
iii) It is attractive in appearance and gives beneficial psychological effects.
iv) The drug is rapidly available for absorption.
Disadvantages of Liquid Dosage Forms
i) The liquid dosage forms have less stability when compared to solid dosage forms.
ii) Liquids are bulky and therefore inconvenient to transport and store
iv) Accidental breakage of the container results in loss of whole dosage form.
Formulation consideration:
The common excipients used in liquid formulation are
(1) Vehicles
(2) Solubilizers
(3) Preservatives
(4) Stabilizers
(5) Organoleptic agents

(1) Vehicles

Solvents: In liquid pharmaceutical formulations, vehicles are major components used as a

base in which drugs and other excipients are dissolved or dispersed. They function by
breaking of bond and reducing effective charge on ions thus increasing solute-solvent forces
of attraction which are eventually greater than solute-solute and solvent-solvent forces of
attraction. Eg: water, hydro-alcoholic liquid systems, polyhydric alcohols, acetic acid, ethyl
acetate and buffers. These may be thin liquids, thick syrupy liquids, mucilage or hydrocolloid
bases. The oily vehicles include vegetable oils, mineral oils, organic oily bases or emulsified
bases etc.
Co-solvent: are defined as water- miscible organic solvents that are used in liquid drug
formulations to increase the solubility of poorly water soluble substances or to enhance the
chemical stability of a drug. Co-solvent increases the solubility of a drug. An ideal co-solvent
should possess values of dielectric constant between 25 and 80. The most widely used system
that will cover this range is a water/ethanol blend. It should not cause toxicity or irritancy
when administrated for oral or parental use. Other co-solvents are sorbitol, glycerol,
propylene glycol and syrup.
Water : They contain large number of dissolved and suspended particles as impurities like
inorganic salts sodium, potassium, calcium, magnesium and iron as chlorides, sulfates and
bicarbonates, organic impurities are either soluble or insoluble state. Microorganism is other
impurities present in water. Drinking water contains less than 0.1 % of total solid. For the
preparation in pharmaceutical formulation IP refers water as clear, odorless, colorless and
neutral with slight deviation in pH due to dissolved solids and gases. Purified water IP is
commonly used as vehicle or as a component of vehicle for aqueous liquid formulations but
not for those intended for parenteral administration. Ethanol, frequently referred as alcohol is
the most commonly used solvent in liquid pharmaceutical formulation next to water. It is
generally used as hydro-alcoholic mixture to dissolve water and soluble drugs and excipients.
Diluted ethanol is prepared by mixing equal volumes of ethanol IP and purified water IP is a
most useful solvent in various pharmaceutical processes and formulations to dissolve poorly
soluble substances Glycerol is called glycerin is a clear, colorless liquid with thick, syrupy
consistency, oily to the touch, odorless, very sweet and slightly warm to taste. They are
prepared by the decomposition of vegetable or animal fats or fixed oils and containing not
less than 95% of absolute glycerin. It is soluble in all proportions, in water or alcohol; also
soluble in a mixture of 3 parts of alcohol and 1 part of ether, but insoluble in ether,
chloroform, carbon di-sulphide, benzene, benzol, and fixed or volatile oils.
(2) Solubilizers: To increase the solubility of the drug

pH adjustment : By addition of buffer to the formulation .buffers act by binding hydrogen

formulations to control potential changes in the pH. Buffers act by binding hydrogen ions in
acids and donating hydrogen ions in bases. The selection of as suitable buffer should be
based
on suitability of acid-base form for use in oral liquids, stability of the drug and excipients in
the buffer, and compatibility between the buffer and container. The stabilizing effect of
buffers determines the potential reaction between excipients and drug. For example, buffers
containing carbonate, citrate, tartarate and phosphate salts may precipitate with calcium ions
by forming sparingly soluble salts. The other factors that may affect the solution pH include
temperature, ionic, strength, dilution and the amount and the type of co-valents presents. For
example the pH of acetate buffers is known to increase with temperature, whereas the pH of
boric acid buffers decreases with temperature. It is important to know that the drug in
solution may itself act as a buffer. If the drug is a weak electrolyte such as salicyclic acid or
ephedrine, the addition of base or acids, respectively will create system in which the drug can
act as a buffer Eg: phosphate buffers, acetate buffers, citric acid phosphate buffers etc.
Co-solvency: By addition of water miscible solvent in which drug has good solubility.
The solvent known as co-solvent.
Complexation: Drug-complexing agent complexation formed when complexing agent is
added to solution. It increase solubility of drug on the basis of Le Chatelier’s principle or “
The equilibrium law”. Eg disodium EDTA, dihydroxy ethyl glycine, citric acid.
Micronization: The processes involve size reduction of drug particle 1 to 10microns either
by spray drying or fluid energy mill.
Hydrotrophy : Drug dissolve in the cluster of hydrotropic agent. Also there is drug-
hydrotrophy agent complexation formation to increase drug solubility.
Wetting agents and surfactants:
In pharmaceutical formulations wetting agents are routinely used, they air adsorbed at solid
particles surfaces keep them away from vehicles which ultimately promotes penetration of
the vehicle into pores and capillaries of the particles. For non-aqueous based formulations
mineral oils are commonly we use wetting agents because hydrophobic drug particles are
difficult to wet even after the removal of adsorbed air. In such cases it is necessary it is
necessary to reduce the surface tension between the particles and the liquid vehicles. Surface
active agents that work as wetting agents, comprises of branched hydrophobic chains with
central hydrophilic groups or short hydrophobic chains with hydrophilic end groups.
For example- Sodium lauryl sulphate is one of the most commonly used surface-active agents
as a wetting agent. When dissolved in water, it lowers the contact angle of water and support
in spreading of water on the particles surface to remove the air layer at the surface and
replace it with the liquid phase.
(3) Preservatives

Microbial contamination is major problem encountered by aqueous based liquid dosage

forms. Use of preservatives becomes unavoidable in such cases to prevent the growth of
micro- organisms during production and over storage time. In fact, it is desirable to develop a
preservative-free formulation to avoid unwanted effects of these excipients. The majorities of
preservatives are of both acid and non-acid types and are bacteriostatic rather than
bactericidal.
Preservatives must have following criteria: Effective against broad spectrum of
microorganisms. Physically, chemically and microbiologically stable for lifetime of the
product. Non toxic, non sensitizing, soluble, compatible and with acceptable taste and odour.

Types of Preservatives
Acidic: phenol, benzoic acid, sorbic acid
Neutral preservatives: Chlorobutanol, benzyl alcohol
Quarternary ammonium compounds: Benzalkonium chloride

(4) Stabilizers

Oxidation, photolysis, solvolysis and dehydration are common transformations taking place
in liquid dosage forms. Amongst them for oxidation and photodecomposition of drug are very
common pathways of drug decomposition and are very difficult to control due to low
activation energies. Trace amounts of impurities, which are invariably present in the drug or
excipient intitates the oxidation reaction. Drugs exists in reduced form show increased
susceptibility when it is consistently exposed an open environment. The pH of the solution
may contribute in the oxidation of drugs because ionized forms of these drugs at particular
pH are very prone oxidation
Physical stability: A stable formulation retains its viscosity, color, calarity, taste and odour
throughout its shelf life Color can be measured spectrophotometrically. Clarity can be
determined by measurement of its turbidity or light scattering equipment. Viscosity can be
measured by use of viscometers. Taste and odour can be determined either by pharmaceutical
investigator or by a panel of unbiased, taste sensitive individuals.
Chemical stability of the formulation is affected by pH, temperature, Ionic Strength, Solvent
effects, Light, Oxygen. Instability can be prevented by use of: Buffering agents,
Antioxidants, Proper packaging (eg: use of amber bottle for light sensitive products)
Antioxidants act as chain terminators where it reacts with free radicals in solution to stop the
free-radical propagation cycle. A combination of chelating agents with antioxidants is often
used to exert synergistic effect. This is because many of these agents act at differing steps in
the oxidative process. Oxidation of formulation component leads to products with an
unpleasant odor taste appearance, ppt, discoloration or even a slight loss of activity. Some
substances prone to oxidation include unsaturated oils/fats, compounds with aldehyde or
phenolic groups, colors, flavors, sweeteners, plastics and rubbers, the latter being used in
containers for products. Eg: acetone sodium bisulfite, acetylcysteine, ascorbic acid, thiourea.
Emulsifying agents which prevent coalescence of the dispersed globules. Forms barriers at
interface, and reduce interfacial tension Eg sodium lauryl sulphat, cetrimide, macrogols
Antifoaming agents: the formation of foams during manufacturing processes or when re
constituting the liquid dosage forms can be undesirable and disruptive. Antifoaming agents
are effective at discouraging the formation of stable foams of stable foams by lowering
surface
tension and cohesive binding of the liquid phase. Eg: Simethicone, organic phosphates,
alcohols, paraffin oils etc.
Suspending and Viscosity Enhancing Agents: The selection of an appropriate suspending
agent is one of the most crucial factors in formulating a pharmaceutical suspension.
Suspending agents impart viscosity and thus regard particle settling. Other factors considered
in the selection of the appropriate suspending and viscosity enhancing agent include desired
reheological property supendability in the system, chemical compatibility with other
excipients, pH stability, hydration time, reproducibility, and the cost. Eg: clays, natural gums,
synthetic gums In many formulations these excipients are employed in combination for
enhanced effects.
Humectants: are hygroscopic substances that help to retard evaporation of aqueous vehicles
from dosage forms. These excipients are used at 5% strength in aqueous suspension and
emulsion for external application. They are also used to prevent drying of the product after
application to the skin as well as prevent drying of product from the container upon opening.
It also helps to prevent cap-locking caused by condensation onto neck of container-closure at
first opening Eg propylene glycol, glycerol, polyethylene glycol.
Flocculating agents: prevent caking. Addition of an electrolyte reduces the magnitude of
zeta potential of dispensed particles Eg: Starch, sodium alginate.
Chelating agents: are substances that form complexes with metal ion in activating their
catalytic activity in oxidation of medicaments. These agents are capable of forming
complexes with the drug involving more than one bond it’s a complex compound contains
one or more ring in its structure. Protect drug from catalysts that accelerate the oxidative
reaction. Eg Disoium EDTA, dihydroxy ethyl glycine, citric acid and tartaric acid
(5) Organoleptic properties

Flavouring agents: are agent in liquid pharmaceutical products is added to the solvent or
vehicle component of the formulation in which it is most soluble or miscible. That is water
soluble flavors are added to the aqueous component of a formulation and poorly water
soluble flavors are added to the alcoholic or other non-aqueous solvent component of the
formulation. In a hydro-alcoholic or other multi-solvent system, care must be exercised to
maintain the flavorants in solution. This is accomplished by maintaining a sufficient level of
the flavorants solvent.
Sweetening agents: Sucrose enhances viscosity of liquids and also gives a pleasant texture in
the mouth. The term sugar free solution include sweetening agents such as sorbitol, mannitol,
saccharin and aspartame as alternative to sugar such as sucrose, fructose. In addition to
sucrose, a number of artificial sweetening agents have been used in food and pharmaceuticals
over the years. Some of these including asparatame, saccharin, and cyclamate have faced
challenges over the safety by the FDA and restriction to their use and sale in fact in 1969,
FDA banned cyclamates from use in US. Sucralose is most popular due to its excellent
sweetness, non- cariogenic, low calorie wide and growing regulatory acceptability but is
relatively expensive
Coloring agent: A distinction should be made between agents that have inherent color and
those that are employed as colorants. Colors used in liquid dosage form must be certified by
FDA as per D&C Act 1940. Certain agents- sulphur (yellow), riboflavin (yellow), cupric
sulfate (blue), ferrous sulfate (bluish green) cyanocobalamin (red) and red mercuric iodide
(vivid red) have inherent color and not thought of as pharmaceutical colorants in the usual
sense of the term. Although most pharmaceutical colorants in use today are synthetic, a few
are obtained from natural mineral and plant sources. For example, red ferric oxide is mixed in
small proportions with zinc oxide powder to give calamine its characteristic pink color, which
is intended to match the skin tone upon application. The age of the intended patient should
also be considered in the selection of the flavorings agent, because certain age groups seem to
prefer certain flavors. Children prefer sweet candy-like preparations with fruity flavors, but
adults seem to prefer less sweet preparation with a tart rather than a fruit flavor.
Manufacturing Consideration-
The manufacturing process for liquid preparations for oral use should meet the requirements
of Good Manufacturing Practice (GMP). The following information is intended to provide
broad guidelines concerning the critical steps to be followed during production of liquid
preparations for oral use.
In the manufacture of liquid preparations for oral use, measures are taken to:
• ensure that all ingredients are of appropriate quality
• minimize the risk of microbial contamination
• minimize the risk of cross-contamination

Steps of Liquids Manufacturing Process

1. Planning of Material Requirements: Research and development of protocols and
selection of materials; acquisition and analysis of raw materials; physical plant design,
building, and installation; equipment selection and acquisition; personnel selection and initial
training; and monitoring information system.
Raw Materials : Incoming raw materials should be tested as per specifications that is identity,
purity, uniformity and microbial contamination .
Equipments : The following types of equipments may be used in the manufacture of liquid
formulations:
1. Mixing tanks (SS 316 Stainless Steel) equipped with an agitator.

2. Measuring devices for large and small amount of solids and liquids. 3. Afiltration system
e.g. filter press
Cleaning of equipments
• All equipments must be thoroughly cleaned and sanitized before use.
• Disinfectants used: Dilute solutions of H2O2, phenol derivatives.
• Sterilized by:Alcohol, boiling water, autoclaving, steam or dry heat.
2. Liquid Preparation: Research and development of protocols concerning liquid
compounding; scale - up of the bulk product compounding; physical plant control and
maintenance; equipment maintenance and renovation; continuous training of personnel and
personnel compensation plan; and supervision of system reports.
3. Filling and Packing: Research and development of protocols concerning filling and
packing; scale-up of the finished drug product filling and packing; physical plant control and
maintenance; equipment maintenance and renovation; continuous training of personnel and
personnel compensation plan; and supervision of system reports.

Filling and Packing

Gravimetric Volumetric Constant Level

Containers are filled Containers are filled Filled amount is verified
with liquids to a given with liquids to a given by adjusting the height
weight. volume. to which the container is
Usually limited to to be filled.
Filled amount is
large container filling measured by the stroke Variation in container
or highly viscous of the piston and dimension may result in
products. cylinder assembly. variations in the net fill
Cannot be used in high per unit.
Problems may arise
speed, automatic when containers used
equipment are not dimensionally
uniform.

Techniques of Filling

Vacuum filling Gravity vacuum filling Pressure vacuum filling

Vacuum developed Pressure applied to

Bulk liquid tank is
within the bulk liquid tank and
placed above filling
container causes vacuum developed in
stem so that liquid
liquid to flow from the container results
flows to the
tank to container. in pressure difference
container due to
force of gravity. so that liquid flows to
the container.

4. Sales of Drug Products: Research and development of protocols concerning product

storage; distribution process; continuous training of personnel and personnel compensation
plan; and supervision of system reports.
5. Vendor Handling: Research and development protocols concerning precautions to
maintain product stability; control of vendor stock; and sales system reports.
6. Customer Service: Research and development of protocols concerning home storage and
handling to maintain product stability; relations with health insurance companies and health
care professionals; educational materials for patient counseling; and customer service system
reports.

Elixirs
Elixirs are clear, flavoured, sweetened, hydroalcoholic preparations for oral administration.
They are more stable than mixtures. Elixirs are classified into two classes.
a) Non medicated elixirs: These elixirs do not contain any medicament but contain some
aromatic or pleasantly flavoured substances. These are used as solvents for other liquid
preparations.
b) Medicated elixirs: These elixirs contain some medicinal substance along with other
ingredients.
Syrups
Syrups are liquid oral preparations in which the vehicle is a concentrated solution of sucrose
or other sugars in water. The concentration of sugar in syrup is 66.7 % W/W. Syrups are
further classified into 2 classes.
a) Simple syrups: The simple syrups do not contain any medicament, but contains some
pleasantly flavoured substances. These syrups are used as a medium for other liquid
preparations.
b) Medicated syrups: These syrups contain some medicinal substance along with other
ingredients.
Advantages of syrups
• Syrups prevent oxidation and decomposition of drugs.
• Syrups are sweet in taste and therefore bitter taste of drugs can be reduced.

Disadvantages of syrups
• Syrups are not preferred for diabetic patients.
• On continuous take syrup promote dental decay.

Suspensions
Suspensions are the biphasic liquid dosage form of medicament in which the finely divided
solid particles are suspended or dispersed in a liquid or semisolid vehicle with the help of
suspending agent.The solid particle is the ‘dispersed phase’ or ‘discontinuous phase’ whereas
the liquid vehicle is the ‘continuous phase’.
The solid particles act as disperse phase whereas liquid acts as a continuous phase. The
medicaments that are insoluble or poorly soluble are formulated as suspensions. Suspensions
contain a suspending agent. A suspending agent is a substance that is added to the preparation
to suspend the insoluble particles in the preparation. It can be classified into four groups.
a) Oral suspensions: These suspensions are to be consumed by oral route.

b) Parenteral suspensions: The suspensions which are administered by parenteral route are
called parenteral suspensions.
c) Ophthalmic suspensions: These are used for instilling into the eye.
d) Suspensions for external use: These are used for external applications.
Advantages:
 Can improve chemical stability of certain drugs.
 Higher rate of bioavailability, as order of bioavailability is:
Solution>Suspension>Capsules>Compressed tablets
Disadvantages:

 Physical stability, sedimentation and compaction.

 Bulky, handling require care.
 Uniform drug delivery cannot be achieved sometimes.

Ideal properties of suspensions:

1. The dispersed particles should not settle readily and the settled particles should redisperse
immediately on shaking.
2. The particles shouldn‘t form a cake on settling.
3. The viscosity should be such that the preparation can be easily poured.
4. It should be chemically stable.

5. Suspensions for internal use must be palatable and suspension for external use must be free
from gritty particles.
Types of suspensions:
Depending upon particle nature/dispersed particle nature the suspensions are of two types:
1. Flocculated suspensions
2. Non-flocculated/deflocculated suspensions.

Flocculated suspensions:
Suspension in which particles are weakly bonded, settle rapidly, don’t form a cake and are
easily resuspended with a minimum of agitation.

Deflocculated suspensions:
Suspension in which particles settle slowly and eventually form a sediment in which
aggregation occurs with the resultant formation of a hard cake which is difficult to resuspend.
Stability of suspensions:
A stable suspension can be redispersed homogenously throughout its shelf life.The more
stable pharmaceutical suspensions are flocculated i.e.,the suspended particles are bonded
together physically to form a loose cake.
Packing of Suspensions
Suspensions can be packed in narrow mouth screw caped colour less plain bottle.
Suspensions that are very thick require a container with wide mouth. Suspensions should be
stored in a cool place.

Evaluation of suspension stability:

The following are commonly used for evaluating the physical stability of suspensions:
1.Sedimentation method.
2.Rheological method.
3.Electrokinetic method.
4.Micromeritic method.
1.Sedimentation method:
It is determined by keeping a measured volume of suspension in a graduated cylinder in an
undisturbed position for a definite period of time, the ultimate volume (V0) and the initial
volume (Vu) of the sediment is to be noted. Sedimentation volume is a ratio of the ultimate
volume of sediment (V0) to the original volume of the sediment (VU) before settling.
Sedimentation volume F=V0/VU
2. Rheological method:

 It provides information about settling behaviour.

 The arrangement of the vehicle and the particle structural features.
 Brookfield viscometer is used to study the viscosity of the suspension. If viscosity of
the suspension increases, the stability of the suspension increases.
3. Electrokinetic method:

The determination of surface electric charge or zeta potential is helpful to find out the
stability of suspension. Zeta potential can be calculated from the migration of particle
measured by the electrophoretic method.

4. Micromeritic method:

The stability of suspension depends on the particle size of the disperse phase. The size of the
particle in a suspension may grow and ultimately leads to the formation of clumps or caking.
So, any change in particle size distribution with reference to time gives a stable suspension.
The particle size can be studied by microscopy or coulter countered method.
Emulsions
An emulsion is defined as a dibasic or heterogenous liquid preparation immiscible liquids
which is dispersed as a minute globules in another liquid by adding emulsifying agent.
Medicines having an unpleasant taste and order can be made more palatable for oral
administration in the form of an emulsion. Emulsions protect drugs against oxidation or
hydrolysis.
• Emulsions are less stable.
• They are susceptible to microbial growth.

Classification of emulsions:
Emulsions can be classified into the following types:
1. Oil in water (o/w) type of emulsion.
2. Water in oil (w/o) type of emulsion.
3. Microemulsions
4. Multiple/double emulsion.

Advantages:
 Mask the unpleasant taste.
 Sustained release medication.
 Inert and chemically non-reactive.
 Reasonably odourless & cost effective.

Disadvantages:
 Packing, handling & storage is difficult.
 Thermodynamically unstable & have short shelf life.
 Leads to creaming & cracking.
 Leads to phase inversion.

Packing of Emulsions
Emulsions can be packed in narrow mouth screw caped colourless plain bottle. Emulsions
that are very thick require a container with wide mouth. Emulsions should be stored in a cool
place.
a) Oil in water type: This type of emulsion is the one in which the oil is dispersed in the water

b) Water in oil type: This type of emulsion is the one in which the water is dispersed in the
oil. Emulsions may be liquid or semi-solid. Liquid emulsions can be classified as i) emulsions
for oral administration, ii) emulsion for external uses, iii) emulsion for parenteral uses, and
iv) emulsion for rectal use.
i) Emulsions for oral administration

Some medicaments are unpleasant in taste. For example fish liver oil, we can mask this
unpleasant taste by converting it into an emulsion and can be given orally.
ii) Emulsions for external use

The external preparation of emulsion consists of three classes. Applications, lotions and
liniments, these emulsions can be either oil in water or water in oil.
iii) Emulsions for parenteral use

Some patients are unable to ingest food in the normal way. We can administer oil in water
emulsions of nutritive oils and fats to these patients. Vitamin K that prevents blood clotting is
injected in this form.
iv) Emulsions for rectal use

Some emulsions are given by rectal route. Semi-solid emulsions are water in oil or oil in
water type. The water in oil type semi-solid emulsions are oily creams while the oil in water
semi- solid emulsions are aqueous creams. Creams are easy to apply and are less greasy.

Preparation of emulsions:
The emulsions are prepared by two methods:
1. Small scale method
a) Dry gum method
b) Wet gum method
c)Bottle method.
2. Large scale method.

Identification tests:
The type of emulsion can be determined by the following tests:
1. Dilution test.
2. Conductivity test.
3. Dye test.
4. Fluorescence test.
5. Cobalt chloride test (CoCl2).
1. Dilution test: This test is based on the solubility of external phase of emulsion.

 o/w emulsion can be diluted with water.

 w/o emulsion can be diluted with oil.
2. Conductivity test: The basic principle of this test is that water is a good conductor of
electricity. Therefore in case of o/w emulsion this test will be +ve as water is the external
phase. In this test, an assembly is used in which a pair of electrodes connected to an electric
bulb is dipped into an emulsion. If the emulsion is o/w type, the electric bulb glows.
3. Dye test: When an emulsion is mixed with a water soluble dye such as amaranth and
observed under the microscope.
 If the continuous phase appears red, then it means that the emulsion is o/w type as
water is the external phase.
 If the scattered globules appear red and continuous phase is colourless, then it is w/o
type.
4. Fluorescence test:

Oil gives fluorescence under UV light, while water doesn't. Therefore, o/w emulsion shows
spotty pattern when observed under UV, while w/o emulsion fluoresces.
5. Cobalt chloride test:

When a filter paper soaked in cobalt chloride solution is dipped into an emulsion and dried, it
turns from blue to pink, indicating that the emulsion is o/w type.
Evaluation of emulsions:
1. Size distribution analysis.
2. Rate of phase separation.
3. Viscosity & rheological study.
4. Measurement of dielectric constant.
5. Conductivity measurement.
6. Influence of temperature.
7. Microwave radiation.
8. Microelectrophoretic measurement.

Stability of emulsions:
The following three changes usually occurs during the storage of emulsion:
1. Creaming.
2. Cracking.
3. Phase inversion.

1. Creaming:
Creaming may be defined as the upward movement of dispersed globules to form a thick
layer at the surface of emulsion. The creaming depends on “Stokes law”, the rate of creaming
depends on the various factors. V=2r2(d1-d2)g/9n

2. Cracking:

Cracking means the separation of two layers of dispersed phase and continuous phase due to
coalescence of dispersed phase globules. Cracking may be due to the following reasons:
a) By addition of emulsifying agent of opposite type.
b) By decomposition of emulsifying agent.
c) By addition of common solvent.
d) By microorganisms.
e) Changes in temperature.

3. Phase inversion:

Phase inversion means change of one type of emulsion into the other type i.e., o/w emulsion
changes into w/o type and vice versa. It may be due to following reasons:
a) By the addition of an electrolyte. b) By changing the phase volume ratio. c)By temperature
change. d)By changing the emulsifying agent.