BP 502 T.

Industrial Pharmacy-I (Theory) Introduction-

• According to USP, Tablet is defined as a compressed solid dosage form containing
UNIT-II
medicaments with or without Excipients.
Tablets: • 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
a. Introduction, ideal characteristics of tablets, classification of tablets. Excipients, Formulation
drugs, with or without diluents
of tablets, granulation methods, compression and processing problems. Equipment’s and tablet
Advantages of tablet dosage form over other oral drug delivery systems
tooling.
From patients stand point:
b. Tablet coating: Types of coating, coating materials, formulation of coating composition, • They are easy to carry, easy to swallow and they are attractive in appearance.
methods of coating, equipment employed and defects in coating. • Unpleasant taste can be masked by sugar coating and they do not require any
measurement of dose.
c. Quality control tests: In process and finished product tests
• Some of the tablets are divided into halves and quarters by drawing lines during
Liquid orals: manufacturing to facilitate breakage whenever a fractional dose is required.
From the standpoint of manufacturer:
Formulation and manufacturing consideration of syrups and elixirs suspensions and emulsions;
• An accurate amount of medicament, even if very small, can be incorporated.
Filling and packaging; evaluation of liquid orals official in pharmacopoeia.
• 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
Prepared By-
is relatively low, hence economical.
Dr Nabin Karna • They are in general the easiest and cheapest to package and ship among all oral dosage
Professor, Department of Pharmaceutics forms.
The Pharmaceutical College Barpali • 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 (3) Sustained action tablets:
• Dispensing tablets These are the tablets which after oral administration release the drug at a desired time and
• Hypodermic tablets prolong the effect of the medicament. These tablets when taken orally release the medicament
• Tablet triturates 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.
(a) Tablets ingested orally- e.g. Diclofenac SR tablets.
(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).
(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.

(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 (5) Sugar coated tablets:
necessary excipients are compressed over the previously compressed tablet. • 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 (2) Sublingual tablets:
hydroxy propyl cellulose, hydroxy propyl methyl cellulose and ethyl cellulose. • These tablets are to be placed under the tongue where they dissolve or disintegrate
• The film coating protects the medicament from atmospheric effects. Film coated tablets are quickly and are absorbed directly without passing into GIT. e.g. tablets of nitroglycerin,
generally tasteless, having little increase in the tablet weight and have less elegance than isoproterenol hydrochloride or erythrityl tetranitrate.
that of sugar coated tablets.

(7) Chewable tablets: (3) Lozenges tablets:

• These are the tablets which are required to be broken and chewed in between the teeth • These tablets are designed to exert a local effect in the mouth or throat. These tablets
before ingestion. These tablets are given to the children who have difficulty in are commonly used to treat sore throat to control coughing in common cold. They may
swallowing and to the adults who dislike swallowing. contain local anaesthetics, antiseptics, antibacterial agents and astringents.
• These tablets should have very acceptable taste and flavour. Ex- Antacid tablets
(Digiene). • 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.

(b) Tablets used in oral cavity

(1) Buccal tablets:
(4) Dental cones:
• 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 • These are compressed tablets meant for placement in the empty sockets after tooth
into the alimentary canal. extraction. They prevent the multiplication of bacteria in the socket following such
extraction by using slow-releasing antibacterial compounds or to reduce bleeding by
• Therefore, they are formulated and compressed with sufficient pressure to give a hard containing the astringent.
tablets. e.g. Progesterone tablets.
 • These tablets contain an excipient like lactose, sodium bicarbonate and sodium (d) Tablets used to prepare solutions
chloride. These cones generally get dissolved in 20 to 40 minutes time.
(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)

(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 (2) Dispensing tablets:
hormones such as testosterone steroids for contraception. These tablets are very
usefully exploited for birth control purpose in human beings. • 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
• The disadvantages of implant tablets are their administration, changing rate of release small quantities. these tablets are supplied primarily as a convenience for
with change of surface area and possibility of tissue reactions. 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.

(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 (3) Hypodermic tablets:
action of a specified antimicrobial agent. The contains easily soluble components like
• Hypodermic tablets are soft, readily soluble tablets and originally were used for the
lactose or sodium bicarbonate.
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.
  Increase stability
 Enhance bioavailability
 Modifying drug release
 Assist product identification
 Increase patient acceptability
 Facilitate dosage form design
(4) Tablet triturates (Moulded tablets):
1. Diluents
• 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 Definition- Diluents are fillers used to make required bulk of the tablet when the drug dosage
diluent. itself is inadequate to produce the bulk.

• Since they are intended to disintegrate very quickly in contact with moisture, water Secondary reason is to provide better tablet properties such as improve cohesion, to permit use
insoluble adjuncts are avoided. The name ‘tablet triturate’ is appropriate because they of direct compression manufacturing or to promote flow.
usually contain triturations (trituration = dilution with an inert substance).
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

Tablet Ingredients/ Excipients-
• They must be nontoxic and acceptable to the regulatory agencies in all countries where
In addition to active ingredients, tablet contains a number of inert materials known as additives the product is to be marketed.
or excipients. Different excipients are:
• They must be commercially available in an acceptable grade in all countries where the
1. Diluent / Filler product is to be manufactured.
2. Binder and adhesive • They must be cheap compared to the active ingredients and must be physiologically
3. Disintegrants inert.

4. Lubricants and glidants • They must be chemically stable alone and/or in combination with the drug(s) and/or
other tablet components.
5. Colouring agents
• They must be color-compatible (should not produce any off-color appearance).
6. Flavoring agents
• They must have no negative effects on the bioavailability of the drug(s) in the product
7. Sweetening agents
Commonly used tablet diluents-
Function of excipients-
1- Lactose-anhydrous and spray dried lactose
 Impart weight, accuracy, & volume.
2. Directly compressed starch-Sta Rx 1500
 Improve solubility
 3. Hydrolyzed starch-Emdex and Celutab salts are excellent diluents for water-sensitive drugs. It is superior to anhydrous diluent,
which has a moderate to high moisture demand.
4. Microcrystalline cellulose-Avicel (PH 101and PH 102)
Disadvantages:
5. Dibasic calcium phosphate dehydrate
• Tetracycline products made with calcium phosphate diluent had less than half the
6. Calcium sulphate dihydrate
bioavailability of the standard product. Divalent cation (Ca++) form insoluble
7. Mannitol and Sorbitol 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-
8. Sucrose- Sugartab, DiPac, Nutab
administered with these drug).
9. Dextrose
Spray dried lactose
Lactose
Advantages:
• Lactose is the most widely used diluent for tablet formulation. It is obtained in hydrous
• It is used for direct compression (containing drug + diluent + disintegrant + lubricant).
and anhydrous form. The anhydrous form, picks up moisture when exposed to elevated
In addition to the direct compression properties, spray dried lactose also has good flow
humidity. Such tablets should be packed in moisture proof packets or containers. When
characteristics. It can usually be combined with as much as 20 to 25% of active
a wet granulation method is employed, the hydrous form of lactose should generally be
ingredients without losing these advantageous features.
used.
Disadvantages:
• Two grades of lactoses are commercially available:
• If spray dried lactose is allowed to dry out and the moisture content falls below the
(i) A 60 to 80 mesh – coarse
usual 3% level, the material loses some of its direct compressional characteristics.
(ii) a 80 to 100 mesh – regular grade
• Spray-dried lactose is especially prone to darkening in the presence of excess moisture,
Advantages: amines, and other compounds owing to Maillard reactions. Hence, a neutral or acid
lubricant should be used.
• Lactose has no reaction with most of the drugs, whether in hydrous or anhydrous form.
Starch
• 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 • Starch may be obtained from corn, wheat or potatoes and rice. It is occasionally used
in tablet hardness. as a tablet diluent. USP grade of starch is usually possesses moisture content between
11 to 14%.
• It is a low cost diluent.
• Specially dried types of starch that have a standard moisture level of 2-4% are available,
Disadvantages:
but are costly. Use of such starches in wet granulation is wasteful since their moisture
• Lactose reacts with amine drug bases in presence of alkaline lubricants e.g. metal level increase to 6-8% following moisture exposure.
stearates (e.g. magnesium stearate) and gradually discolours (dark brown) with time
Directly compressible starches
due to the formation of furaldehyde. This reaction is called Maillard reaction.
• Sta–Rx 1500– free flowing, directly compressible starch. It is used as diluent, binder,
Calcium salts ((DCP/TCP)
disintegrant.
Dibasic calcium phosphate dihydrate (or dicalcium orthophosphate) (DCP) [CaHPO4, 2
• Emdex and Celutab – are two hydrolyzed starches – contains dextrose 90–92%
H2O], Calcium sulfate dihydrate (CaSO4 , 2H2O).
and maltose 3–5%
Advantages:
• free flowing and directly compressible and may be used in place or mannitol in
• Diluents that exist in their common salt form as hydrates, containing appreciable bound chewable tablets because of their sweetness and smooth feeling in the mouth.
water as water of crystallization. This bound water of calcium sulfate is not released
Dextrose (D–Glucose)
below 800C. They possess very low concentration of unbound moisture. Hence, these
 • Available in two forms: as hydrates and anhydrous forms. Objective of incorporating binders
• Dextrose may sometimes be combined in formulation to replace some of the spray- • They impart a cohesiveness to the tablet formulation (both direct compression and wet–
dried lactose, which may reduce the tendency of the resulting tablets to darken. granulation method) which insures the tablet remaining intact after compression.

Mannitol • They improves the free-flowing qualities by the formation of granules of desired size
and hardness.
Advantages
Characteristics of binder
• 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. Method-I
• It is relatively non-hygroscopic and can be used in vitamin formulations. • Binders are used in dry form in the powder and then moistened with a solvent (of the
binder) to form wet lumps.
• Low calorie content and non-carcinogenic.
Method-II
Disadvantages
• Binders are often added in solution form. It requires lower concentration of binder.
• Costly and has poor flow characteristics and usually require fairly high lubricant level.
• By Method-I the binder is not as effective in reaching and wetting each of the particles
Sorbitol
within the mass of the powder. Each of the particle in a powder blend has a coating of
• It is an optical isomer of mannitol and is sometimes combined with mannitol adsorbed air on its surface, and it is this film of air which must be penetrated before the
formulations to reduce the diluent cost. powder can be wetted by the binder solution.

• Disadvantages:- It is hygroscopic at humidities above 65%. Method-III

Sucrose • In direct compression method MCC, microcrystalline dextrose, amylose and PVP are
used – those have good flow property and cohesiveness as well.
• Some sucrose based diluents are:
• It has been postulated that MCC is a special form of cellulose fibril in which individual
• Sugar tab– 90 to 93% sucrose + 7 to 10% invert sugar
crystallites are held together largely by hydrogen bonding. The disintegration of tablets
• Di Pac – 97% sucrose + 3% modified dextrins containing the cellulose occurs by breaking intercrystallite bonds by the disintegrating
medium.
• Nu Tab– 95% sucrose + 4% invert sugar + small amount of corn starch + Mg-stearate
Starch paste
Advantages: They are all used for direct compression.
Corn starch is often used in the concentration of 10–20%.
Disadvantages: All are hygroscopic when exposed to elevated humidity.
Method of preparation:- Corn starch is dispersed in cold purified water to make a 5 to 10%
Microcrystalline cellulose (MCC)
w/w suspension and then warming in water both with continuous stirring until a translucent
• Trade Name : Avicel – is a directly compression material paste is formed.. (Actually hydrolysis of starch takes place.)

• Two grades are available PH 101  powder Liquid glucose:- 50% solution in water is fairly common binding agent.

PH 102 granules Sucrose solution:- 50% to 74% sugar solution is used as binder. They produce hard but brittle
granules. Their cost is low.
• Advantages: It acts as diluent and disintegrating agents.
Gelatin solution
2. Binders and Adhesive
• Concentration 10–20% aqueous solution
Definition- Agents used to impart cohesive qualities to the powdered material are referred to
as binders or granulators. • Should be prepared freshly and added in warm condition other wise it will become
solid.
Method of preparation • Sodium starch glycolate swells 7 to 12 folds in less than 30 seconds.
• The gelatin is dispersed in cold water and allowed to stand until hydrated. The hydrated Other materials
mass is warmed in water bath to dissolve.
• Methyl cellulose, Agar, Bentonite, Cellulose, Alginic acid, Guargum, and
Cellulosic solutions Carboxymethyl cellulose.
• HPMC (Hydroxy propyl methyl cellulose) Soluble in cold water. • Sodium lauryl sulfate is a surfactant. It increases the rate of wetting of the tablet, thus
decreases the disintegrating time.
Method of preparation: HPMC is dispersed in hot water, under agitation. The mixture is cooled
as quickly as possible and as low as possible 4. Lubricant and Glidants
• HEC (Hydroxy ethyl cellulose), HPC (Hydroxy propyl cellulose) are other successful Objectives:
binders.
• Prevents adhesion of the tablet material to the surface of dies and punches.
• PVP (Polyvinylpyrollidone) Used as an aqueous or alcoholic solution. Concentration
• Reduce inter-particular friction, improve the rate of flow of tablet granulation.
2% and may vary.
• Facilitate ejection of the tablets from the die cavity.
3. Disintegrants
Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and
Definition:- A disintegrant is a substance to a mixture of substances, added to tablet to facilitate
punches, reduce inter particle friction and may improve the rate of flow of the tablet
its breakup or disintegration after administration in the GIT. The active ingredients must be
granulation.
released from the tablet matrix as efficiently as possible to allow for its rapid dissolution.
Example: Stearic acid, Stearic acid salt - Stearic acid, Magnesium stearate, Talc, PEG
Disintegrants can be classified chemically as: Starches, clays, celluloses, alginates, gums and
(Polyethylene glycols), Surfactants.
cross-linked polymers.
Glidants are intended to promote flow of granules or powder material by reducing the friction
Starch
between the particles.
• Corn starch, potato starch.
Example: Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal silicas such
• For their disintegrating effect starches are added to the powder blends in dry state. as Cab-O- Sil, Syloid, Aerosil in 0.25-3% conc.
Mode of action: 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.
• Starch has a great affinity for water and swells when moistened, thus facilitating the
rupture of the tablet matrix. 5. Coloring agent

• Others have suggested that the spherical shape of the starch grains increases the porosity Objectives of using colors that (i) It makes the tablet more esthetic in appearance and (ii)
of the tablet, thus promoting capillary action. Colour helps the manufacturer to identify the product during its preparation. Colorants are
obtained in two forms dyes and lakes.
• Normally 5% w/w is suggested and for rapid disintegration 10 – 15% w/w may be
taken. 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
Superdisintegrants
approach is to adsorb the dye on starch or calcium sulfate from its aqueous solution; the
Super disintegrants like Croscarmelose - cross linked cellulose, Crospovidone - cross linked resultant powder is dried and blended with other ingredients.
polyvinyl pyrrolidone and Sodium starch glycolate- cross linked starch
Color lakes are dyes which are adsorbed onto a hydrous oxide of a heavy metal (like
Mode of action aluminium) resulting in an insoluble form of the dye.

• Croscarmelose swells 4 to 8 fold in less than 10 seconds 6. Flavours and Sweeteners

• Crospovidone acts by wicking or capillary action.

Flavours are usually limited to chewable tablets or other tablets intended to dissolve in the Percolation Segregation:- air void Ex- Tea & Coffee jar.
mouth. Flavor oils are added to tablet granulations in solvents, are dispersed on clays and other
Trajectory Segregation:- kinetic energy Ex- powder heap
adsorbents or are emulsified in aqueous granulating agents (i.e. binder).
(a) Wet Granulation-
The use of sweeteners is primarily limited to chewable tablets. E.g. Sugar
Step-I Milling of the drug and excipients
• Mannitol– 72% as sweet as sugar, cooling & mouth filling effect
• Milling of the active ingredients, excipients etc. are milled to obtain a homogeneity in
• Saccharin– Artificial sweetener, 500 times sweeter than sucrose
the final granulation.
Disadvantages (i) it has a bitter after taste and (ii) carcinogenic
• If the drug is given in solution then during drying it will come up to the surface. To
• Cyclamate– either alone or with saccharin– it is banned avoid this problem drug is mixed with other excipients in fine state.
• Aspartame (Searle) – widely replacing saccharin Step-II Weighing
Disadvantage – lack of stability in presence of moisture • Weighing should be done in clean area with provision of air flow system.
Manufacturing of Tablets • In the weighing area all the ingredients must not be brought at a time to avoid cross-
contamination.
Manufacture of tablets involves certain well defined steps: namely:-
Step-III Mixing Commonly used blenders are:
 Pulverization and mixing.
(a) Double cone blender
 Granulation.
(b) V – blender
 Compression.
(c) Ribbon blender
 Coating (if required)
(d) Planetary mixer
Pulverization and mixing-
Any one of the blender may be used to mix dry powder mass.
• In this step the different solid / powder ingredients are reduced to the same particle size
since particles of different sizes will segregate while mixing. Step-IV Wet Massing
• Various equipments like Cutter mill, Hammer mill, Roller mill and Fluid energy mill is • Wet granulation forms the granules by binding the powders together with an adhesive.
required to reduce the large lumps.
• Binder solutions can be added in two methods:
Granulation Technology-
Method-I Method-II
Granulation: It is the process in which primary powder particles are made to adhere to form
Drug + Diluent Drug + Diluent
large multi-particle entities.
Dry binder is added Binder Solution is added
Range of size: 0.2 mm to 4 mm. (0.2 mm to 0.5 mm)
Blended uniformly
Objectives:-
 To enhance the flow of powder.
Suitable solvent is added to activate the dry binder
 To produce dust free formulations and produce uniform mixtures.
Blended in a Sigma - mixer or Planetary mixer till properly wet mass is formed
 To improve compaction characteristics.
Therefore, when
 To eliminate poor content uniformity of mix.
• (i) a small quantity of solvent is permissible, method-I is adopted and
 To avoid powder segregation. As Segregation may result in weight variation.
 • (ii) a large quantity of solvent is required method-II is adopted. 7.0/16 or larger # 12
However, method-II will give more cohesiveness than method-I if the amount of binder Step-VIII Lubrication of granules
remains constant.
• After dry granulation, the lubricant is added as a fine powder. It usually, is screened
• If granulation is over-wetted, the granules will be hard, requiring considerable onto the granulation through 60 or 100 mesh nylon cloth to eliminate small lumps as
pressure to form the tablets, and the resultant tablets may have a mottled appearance. well as increase the covering capacity of the lubricant.
• If the powder mixture is not wetted sufficiently, the resulting granules will be too soft, • The lubricant is blended very gently using tumbling action to maintain the uniform
breaking down during lubrication and causing difficulty during compression. granule size.

Step-V -Wet Screening • Too much fine powder is not desirable because fine powder may not feed into the die
uniformly causing variation in weight and density.
Wet screening process involves converting the moist mass into coarse, granular aggregates by
• Since, the very nature of lubricant produce hydrophobic surface on the particle hence
• (i) passage through a hand screen (in small scale production) or,
over blending prevents the inter granule bonding that takes place during compression.
• (ii) passage through an oscillatory granulator of hammer mill equipped with screens
(b) Dry Granulation
having large perforations (# 6 – 8 mesh screen).
Dry granulation is followed in situations where (i) the effective dose of a drug is too high
• Purpose (i) Increase particle contact point
for direct compaction and (ii) if the drug is sensitive to heat, moisture or both, which
(ii) Increase surface area to facilitate drying. precludes wet granulation. e.g. many aspirin and vitamin formulations are prepared for
tableting by compression granulation.
Step-VI Drying
Steps of granulations
• Drying is usually carried out at 600C. Depending on the thermolabile nature of the drug
the temperature can be optimized. Milling Weighing  Screening  Blending  Slugging  Granulation (Dry) 
Lubrication Compaction.
• 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 Slug:
moisture (1 – 4 %) is left within the granules – known as the residual moisture.
Slug may described as poorly formed tablets or, may be described as compacted mass of
Methods: Drying can be carried out powdered material.
Tray dryers – it may take 24 hrs of drying Purpose: To impart cohesiveness to the ingredients, so as to form tablets of desired properties.
Truck dryers – the whole cabinet can be taken out of the dryer Method: It is done either by (i) high capacity heavy duty tablet press
Fluid-bed dryer – carry out drying in 30 mins. (ii) Chilsonator roller compactor.
Step-VII Dry Screening Advantages of dry granulation over wet granulation
After drying, the granules are make monosize by passing through mesh screen.  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.
For drying granules the screen size to be selected depends on the diameters of the punch. The
calcium lactate cannot be used by wet granulation. (Aspirin, Vitamin C).
following sizes are suggested:
 Dry granulation involves less steps and hence less time is required than that of wet
• Tablet diameter upto Mesh Size
granulation.
3/16 ” # 20
 Less steps requires less working space and energy.
3.5 / 16 – 5/16” # 16
 Since popularity of wet granulation is more that dry granulation because former will
5.5/16 – 6.5/16” # 14 meet all the physical requirement for the compression of good tablets.
Direct Compression Method- Feed frame- Guiding the granules from hopper to dies.

Milling Weighing Sieving Blending Compression Upper turret- Holds the upper punchs.
Advantages: (i) It is much more quicker than any of the previous process Lower turret- Hold the lower punchs.
(ii) Minimum number of steps are required. Die table- Contain the dies.
• Modified diluents, binders etc. are available in the market which assure spherical shape Single station – stamping press
of the granules to modify flow property. However, they are not used extensively.
Multi- station- Rotary press
• 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. Fig. 1. Tablet Compression Machine.

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. Fig.2. Sequence of events involved in the formation of tablets.
Cam tracks – Guiding the movement of punches.
 Tablet machine out put is regulated by three basic characteristic like:-
Fig.3. A single punch tablet press.
 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
Fig.4. Schematic diagram for the formation of tablets with rotary press.
Tablet Tooling Set

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
 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
• Its gives definite size, shape of tablet and certain identification marking. one or more of the following factors:

• For this purpose different types of punches are used- I. Formulation design

 Flat faced bevel edged. II. Tableting process

 Shallow concave (Round / Capsule shaped) III. Machine

Capping
 Standard concave (Round / Capsule shaped)
 Deep concave (Round / Capsule shaped) Lamination
Process
 Extra deep. Related
Cracking
 Modified ball
Chipping
Auxillary Equipment-
• Mechanized feeder: Due to short D Well time (Monestry granulation feeding device) Visual Sticking
Defects
• Mechanized hopper loading equipment: Formulation
Picking
Related
• Bulk granulation container:
Binding
• Electronic monitoring device: To maintain fixed force
Machine Double
Tablet Processing Problems and its remedies- Related Impression

An ideal tablet should be free from any visual defect or functional defect. With the development 1. Capping and Lamination
of technology, the production process had become more simplified and more mechanized.
Capping is the partial or complete separation of the top or bottom crowns of a tablet from
But now the tablet punching machines are all mechanized, the mechanical feeding of feed from the main body of the tablet.
the hopper into the die, electronic monitoring of the press, but tablet process problem still
persist. • 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.
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
 • Detection: Subjecting tablets to the friability test is the quickest way to reveal such • During compression heat is generated and
problems.
(a) low m.p. lubricants e.g. stearic acid may produce sticking.
Reason and Remedies
Remedy: Low melting point lubricant are replaced with high melting point lubricants (e.g. Poly
a) Reason: Entrapment of excess air in the granules during compression. If the granules ethylene glycol)
are light and fluffy this type of problems are encountered frequently.
(b) Low m.p. substances, either active ingredients or additives may soften sufficiently form the
Remedies: Increasing the density of granules by adding more binder or changing the heat of compression to cause sticking.
solvent of binder.
Remedies:
(b) Reason: New set of punches and dies are very tightly fitted; i.e. the clearance is very
• Dilution of active ingredient with additional high m.p. diluents.
negligible hence air cannot come out.
• Increase in the size of tablet.
Remedy: In that case punch diameter should be reduced by 0.005” (i.e. 5 thou)
• If a low m.p. medicament is present in high concentration then refrigeration of the
(c) Reason: Granules should not be completely dried. if over dried or under dried then
granules and then compressing may be the order or using fette compression machine.
capping may take place.
3. Mottling
Remedy: So moisture content should be kept within 1 – 4%.
Mottling is an unequal distribution of color on a tablet, with light or dark patches in an
(d) Reason: Tooling set used for longer period of time will form claw-shaped curve on tip
otherwise uniform surface.
of the punch or wear ring in die in compression area – this form capping.
Cause: Migration of water soluble dyes to the surface while drying.
Remedy: Punches and dies are changed.
Remedies:
2. Picking and Sticking
• Change the solvent system and change the binder system
• Picking: -When some portion of the surface of the tablet is removed – it is termed as
picking. • Reduce the drying temperature
• Sticking: - Sticking refers to tablet materials adhering to the die wall. Serious sticking • Grind to a smaller particle size.
at ejection cause chipping.
• Use lakes instead of water-soluble dyes.
Causes and Remedies of picking
Quality Control Tests for Tablets-
Cause: When punch tips have engraving or embossing, usually of letters B, A, O are difficult
• General appearance: - Size, shape, and thickness: This is important to facilitate
to manufacture cleanly. These may produce picking.
packaging and to decide which tablet compressing machine to use.
Remedy:
• Organoleptic properties: which include color, odor and taste of the tablets.
(i) Lettering should be designed as large as possible, particularly on punches of small
• Weight uniformity and Content uniformity: The tablet should contain the correct
diameter.
dose of the drug.
(ii) Plating of the punch faces with chromium produces smooth, non-adherent face.
• Dissolution test: Drug should be released from tablet in a controlled and reproducible
(iii) Colloidal Silica (Cab-o-sil) is added as polishing agent that makes the punch faces way.
smooth; so that material does not cling to them.
• Weight variation, thickness & diameter: The appearance of tablet should be elegant
Causes and Remedies of Sticking & its weight, size & appearance should be consistent.
Causes: Excessive moisture may be responsible for sticking. • Hardness & friability: The tablet should show sufficient mechanical strength to
withstand fracture & erosion during manufacture & handling.
Remedy: Further drying of the granulation is then required.
 • These factors must be controlled during production and verified after production, hence  In potent drug the medicament is less in amount in comparison to the other excipients.
called In-process control 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
Official Standards as per I.P.
by content uniformity test.
A) Uncoated tablet:
• In this test 30 tablets are randomly selected for sample, and at least 10 of them are
 Uniformity of container content and Content of active ingredient. assayed individually according to the official assay method.
 Uniformity of weight and Uniformity of content. • 9 of the 10 tablets must have potency within  15 % of the labelled drug content. Only
 Disintegration test. 1 tablet may be within  25%.

B) Enteric coated tablet: • 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.
 Disintegration test.
3) Disintegration Test of Tablets
C) Dispersible tablet:
• The time a tablet takes to disintegrate is the disintegration time.
 Uniformity of dispersion.
• To test the disintegration time one tablet is placed in each tube, and the basket rack
 Disintegration test. assembly is positioned in a 1-litre beaker of water, simulated gastric fluid or simulated
D) Soluble tablet: intestinal fluid, at 370C20C, such that the tablet remains 2.5 cm from the bottom of
the beaker.
 Disintegration test.
• A standard motor moves the basket up and down through a distance of 5 to 6 cm at a
E) Effervescent tablet: frequency of 28 to 32 cpm (cycles per minute).
 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
4) Dissolution Test
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.” • 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.
2) Content Uniformity test
• Rate of dissolution is directly related to the efficacy of the drug. Rate of dissolution is
Weight variation test is applicable when the amount of medicament in the tablet is high. a good index for comparing the bioavailability of two tablet products of the same drug.
 Apparatus-I (Basket) Objective of friability test:
• In general, a single tablet is placed in a small wire mesh basket and immersed in the This apparatus is designed to evaluate the ability of the tablet to withstand abrasion, in
dissolution medium (as specified in the monograph) contained in a 1000 ml flask at handling, packaging and shipping operation.
370  0.50C. Generally it is rotated at 50 rpm unless otherwise specified.
Method: 20 tablets, previously weighed are taken in the plastic chamber of the laboratory
Apparatus-2 (Paddle) 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
• The same equipment is used. Instead of basket a paddle is introduced as the stirring
dedusted and reweighed.
element. The tablet is allowed to sink at the bottom of the flask before stirring.
Limit: - For conventional compressed tablet the weight loss should be within 0.5 to 1.0 %.
• 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 Tablets Coating
USP/NF is not less than 75% dissolved in 45 minutes.
Reasons Behind Coating of Tablets:
5) Tablet Hardness
 To mask the taste, odour or colour of the drug. Improving the product appearance,
The resistance of the tablet to chipping, abrasion or breakage under conditions of storage, particularly where there are visible differences in tablet core ingredients from batch to
transportation and handling before usage depends on its hardness. batch.

Method:  Provide physical protection, facilitates handling, particularly in high speed packaging /
filling lines.
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 provide chemical protection from its surrounding environment (particularly air,
to possess proper hardness. moisture and light).

Instruments used:  To control the release of drug from the tablet e.g. sustained release tablets, repeat action
tablets.
a) Monsanto Hardness Tester
 To protect the drug from the gastric environment of the stomach with an acid resistant
b) Strong Cobb Hardness Tester -Manual mode.
enteric coating.
c) Pfizer Hardness Tester.
Components Considered in Tablet Coating
d) Erweka Hardness tester. – Automatic.
Tablet Properties: - Shape, Tolerance, Surface area.
e) Schleuniger Apparatus. – Operates without manual involvement.
 Tablet to be coated must possess the proper physical characteristics like spherical shape
Hardness of a tablet: and uniform surface.

The hardness at which the tablet crushes is the hardness of the tablet.  To tolerate attrition of tablets during coating process they must be resistant to abrasion
and chipping.
• Unit of hardness: Kg/sq.in. or lb/ sq.in
 As the tablet surfaces that are brittle and soften in presence of heat or effected by
• Limit: Generally maximum 5 kg/sq.in. hardness is required.
coating composition and tend to become rough in the early stages of coating process
6) Friability are unacceptable for film coating.

Tablet hardness is not an absolute indicator of strength since some formulations, when Coating process: -
compressed into very hard tablets may produce chipping, capping and lamination problems.
A. Coating equipment
Therefore, another measure of tablet strength i.e. friability is often measured, i.e. the friability.
B. Coating parameters.
Instrument: Roche Friabilator
C. Facility & ancillary equipment.
 D. Automation of coating process. Ingredients-Mixtures of waxes (like beeswax, carnauba wax, candella wax or hard
paraffin).
Coating composition: - which involves polymers, color, plasticizer, solvent.
Method-Either this mixture of waxes is applied as powder or as dispersions in various
Types of Coating-
organic solvents in a polishing pan (canvas line pan).
(A) Sugar Coating.
6) Printing-In order to identify sugar-coated tablets often it is necessary to print them,
1) Sealing- using pharmaceutical grade ink, by means of a process of offset rotogravure.

Objectives- (i) To prevent moisture penetration into the tablet core, a seal coat is applied (B) Film Coating
and (ii) To strengthen the tablet core without a seal coat, the over wetted tablets would
Film coating adds 2 to 5% to the tablet weight. Film coating is a complex process that involves
absorb excess moisture, leading to tablet softening, and may affect the physical and
the application of thin (in the range of 20-200 μm) polymer-based coatings to an appropriate
chemical stability.
substrate (tablets, pellets, granules, capsules, powders, and crystals) under conditions that
Ingredients permit:

• Alcoholic solutions of Shellac (10 – 30% solid) or alcoholic solution of zein, 1. Balance between (and control of) the coating liquid, addition rate and drying process.

• Alcoholic solution of cellulose acetate phthalate (CAP) or alcoholic solution of 2. Uniformity of distribution of the coating liquid across the surface of product being
polyvinyl acetate phthalate. coated.

2) Sub-coating- 3. Optimization of the quality (both visual and functional) of the final coated product.

Objectives-To round the edges and build up the tablet size. Sugar coating can increase the Advantage-
tablet weight by 50 to 100% at this step.
 Substantial reduction in quantity of coating applied (2-4% for film coating, compared
Method:- The sub-coating step consists of alternately applying a sticky binder solution to with 50-100% for sugar coating).
the tablets followed by a dusting of sub-coating powders and then drying. Subsequent
 Faster processing times and Improvement in process efficiency and output.
coatings are applied in the same manner until the tablet edges have been covered and the
desired thickness is achieved.  Greater flexibility in optimizing formulations as a result of the availability of a wide
3) Smoothing (Syruping)- range of coating materials and systems.

Objectives-To cover and fill in the imperfections in the tablet surface caused by the sub-  Ability to be applied a wide range of pharmaceutical products.
coating step. Types-
Ingredients-Simple syrup solution (approximately 60–70%(w/w)). Often the smoothing 1) Pan-pour method-
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. 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
4) Color coating- drying.
Objective-To impart an elegant and uniform colour. Disadvantages:
Ingredient-Syrup (60 – 70% sucrose) containing the desired color. • The method is relatively slow and it relies heavily on the skill of the operator.
Method-Syrup solutions containing the dyes are coated upto 60 individual applications • Tablets always require additional drying to remove the latent solvent.
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. • Aqueous film coating is not suitable for this method because localized over wetting will
produce physicochemical instability.
5) Polishing-
2) Pan-spray method-
Objective-To produce the desired luster on the surface of the tablet.
Coating material is sprayed over the tablet bed from nozzles and hot air is passed through the (d) Process air variables (temperature, volume, rate) are required for optimum drying of the
tablet bed to dry it. The variables to be controlled is pan-spray film coating process are: 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
(a)Pan variables:
(C) Enteric Coating
Uniform mixing is essential to deposit the same quantity of film on each tablet.
1) Pan-pour method.
1. Pan design or baffling: Some tablet shapes mixes freely while other shapes may require a
specific baffling arrangement to ensure adequate mixing. 2) Pan-spray method.
Disadvantages: Baffles may produce chipping and breakage if not selected properly. 3) Fluidized bed process (air suspension coating)

(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.
Oral Liquids- (3) Preservatives
Oral Liquids are homogeneous liquid preparations, usually consisting of a solution, an (4) Stabilizers
emulsion or a suspension of one or more medicaments in a suitable vehicle. Liquid dosage
(5) Organoleptic agents
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. (1)Vehicles
Liquid preparations for oral use are either supplied in the finished form or, with the exception Solvents: In liquid pharmaceutical formulations, vehicles are major components used as a base
of Oral emulsions, may also be prepared just before issue for use by dissolving or dispersing in which drugs and other excipients are dissolved or dispersed. They function by breaking of
granules or powder in the vehicle stated on the label. bond and reducing effective charge on ions thus increasing solute-solvent forces of attraction
The vehicle for any liquid preparation for oral use is chosen having regard to the nature of the which are eventually greater than solute-solute and solvent-solvent forces of attraction. Eg:
active ingredient(s) and to provide organoleptic characteristics appropriate to the intended use water, hydro-alcoholic liquid systems, polyhydric alcohols, acetic acid, ethyl acetate and
of the preparation. Liquid preparations for oral use may contain suitable antimicrobial buffers. These may be thin liquids, thick syrupy liquids, mucilage or hydrocolloid bases. The
preservatives, antioxidants and other excipients such as dispersing, suspending, thickening, oily vehicles include vegetable oils, mineral oils, organic oily bases or emulsified bases etc.
emulsifying, buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents and Co-solvent: are defined as water- miscible organic solvents that are used in liquid drug
authorized colouring matter. formulations to increase the solubility of poorly water soluble substances or to enhance the
Classification of Liquid Orals 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
Liquid dosage forms are broadly classified into two groups: that will cover this range is a water/ethanol blend. It should not cause toxicity or irritancy when
a) Monophasic liquid dosage forms b) Biphasic liquid dosage forms administrated for oral or parental use. Other co-solvents are sorbitol, glycerol, propylene glycol
and syrup.
1.Monophasic liquids dosage forms are mixtures, elixirs, syrups, linctuses, draughts and drops
etc. 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
2. Biphasic liquids dosage forms are suspensions and emulsions. bicarbonates, organic impurities are either soluble or insoluble state. Microorganism is other
Advantages of Liquid Dosage Forms 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
i) They are the most suitable dosage form for infants, children and geriatric patients. neutral with slight deviation in pH due to dissolved solids and gases. Purified water IP is
ii) The unpleasant taste of the drugs can be masked by adding sweetening and flavouring commonly used as vehicle or as a component of vehicle for aqueous liquid formulations but
agents. 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
iii) It is attractive in appearance and gives beneficial psychological effects. generally used as hydro-alcoholic mixture to dissolve water and soluble drugs and excipients.
iv) The drug is rapidly available for absorption. 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
Disadvantages of Liquid Dosage Forms
soluble substances Glycerol is called glycerin is a clear, colorless liquid with thick, syrupy
i) The liquid dosage forms have less stability when compared to solid dosage forms. 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
ii) Liquids are bulky and therefore inconvenient to transport and store
than 95% of absolute glycerin. It is soluble in all proportions, in water or alcohol; also soluble
iv) Accidental breakage of the container results in loss of whole dosage form. 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.
Formulation consideration:
(2) Solubilizers: To increase the solubility of the drug
The common excipients used in liquid formulation are
pH adjustment : By addition of buffer to the formulation .buffers act by binding hydrogen
(1) Vehicles
formulations to control potential changes in the pH. Buffers act by binding hydrogen ions in
(2) Solubilizers 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 Preservatives must have following criteria: Effective against broad spectrum of
the buffer, and compatibility between the buffer and container. The stabilizing effect of buffers microorganisms. Physically, chemically and microbiologically stable for lifetime of the
determines the potential reaction between excipients and drug. For example, buffers containing product. Non toxic, non sensitizing, soluble, compatible and with acceptable taste and odour.
carbonate, citrate, tartarate and phosphate salts may precipitate with calcium ions by forming
Types of Preservatives
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 Acidic: phenol, benzoic acid, sorbic acid
pH of acetate buffers is known to increase with temperature, whereas the pH of boric acid
Neutral preservatives: Chlorobutanol, benzyl alcohol
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 Quarternary ammonium compounds: Benzalkonium chloride
of base or acids, respectively will create system in which the drug can act as a buffer Eg:
(4) Stabilizers
phosphate buffers, acetate buffers, citric acid phosphate buffers etc.
Oxidation, photolysis, solvolysis and dehydration are common transformations taking place in
Co-solvency: By addition of water miscible solvent in which drug has good solubility.
liquid dosage forms. Amongst them for oxidation and photodecomposition of drug are very
The solvent known as co-solvent.
common pathways of drug decomposition and are very difficult to control due to low activation
Complexation: Drug-complexing agent complexation formed when complexing agent is energies. Trace amounts of impurities, which are invariably present in the drug or excipient
added to solution. It increase solubility of drug on the basis of Le Chatelier’s principle or “ intitates the oxidation reaction. Drugs exists in reduced form show increased susceptibility
The equilibrium law”. Eg disodium EDTA, dihydroxy ethyl glycine, citric acid. 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
Micronization: The processes involve size reduction of drug particle 1 to 10microns either by
oxidation
spray drying or fluid energy mill.
Physical stability: A stable formulation retains its viscosity, color, calarity, taste and odour
Hydrotrophy : Drug dissolve in the cluster of hydrotropic agent. Also there is drug-
throughout its shelf life Color can be measured spectrophotometrically. Clarity can be
hydrotrophy agent complexation formation to increase drug solubility.
determined by measurement of its turbidity or light scattering equipment. Viscosity can be
Wetting agents and surfactants: measured by use of viscometers. Taste and odour can be determined either by pharmaceutical
investigator or by a panel of unbiased, taste sensitive individuals.
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 Chemical stability of the formulation is affected by pH, temperature, Ionic Strength, Solvent
vehicle into pores and capillaries of the particles. For non-aqueous based formulations mineral effects, Light, Oxygen. Instability can be prevented by use of: Buffering agents, Antioxidants,
oils are commonly we use wetting agents because hydrophobic drug particles are difficult to Proper packaging (eg: use of amber bottle for light sensitive products)
wet even after the removal of adsorbed air. In such cases it is necessary it is necessary to reduce
Antioxidants act as chain terminators where it reacts with free radicals in solution to stop the
the surface tension between the particles and the liquid vehicles. Surface active agents that
free-radical propagation cycle. A combination of chelating agents with antioxidants is often
work as wetting agents, comprises of branched hydrophobic chains with central hydrophilic
used to exert synergistic effect. This is because many of these agents act at differing steps in
groups or short hydrophobic chains with hydrophilic end groups.
the oxidative process. Oxidation of formulation component leads to products with an
For example- Sodium lauryl sulphate is one of the most commonly used surface-active agents unpleasant odor taste appearance, ppt, discoloration or even a slight loss of activity. Some
as a wetting agent. When dissolved in water, it lowers the contact angle of water and support substances prone to oxidation include unsaturated oils/fats, compounds with aldehyde or
in spreading of water on the particles surface to remove the air layer at the surface and replace phenolic groups, colors, flavors, sweeteners, plastics and rubbers, the latter being used in
it with the liquid phase. containers for products. Eg: acetone sodium bisulfite, acetylcysteine, ascorbic acid, thiourea.
(3) Preservatives Emulsifying agents which prevent coalescence of the dispersed globules. Forms barriers at
interface, and reduce interfacial tension Eg sodium lauryl sulphat, cetrimide, macrogols
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- Antifoaming agents: the formation of foams during manufacturing processes or when re
organisms during production and over storage time. In fact, it is desirable to develop a constituting the liquid dosage forms can be undesirable and disruptive. Antifoaming agents are
preservative-free formulation to avoid unwanted effects of these excipients. The majorities of effective at discouraging the formation of stable foams of stable foams by lowering surface
preservatives are of both acid and non-acid types and are bacteriostatic rather than bactericidal.
tension and cohesive binding of the liquid phase. Eg: Simethicone, organic phosphates, Coloring agent: A distinction should be made between agents that have inherent color and
alcohols, paraffin oils etc. 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
Suspending and Viscosity Enhancing Agents: The selection of an appropriate suspending
sulfate (blue), ferrous sulfate (bluish green) cyanocobalamin (red) and red mercuric iodide
agent is one of the most crucial factors in formulating a pharmaceutical suspension. Suspending
(vivid red) have inherent color and not thought of as pharmaceutical colorants in the usual
agents impart viscosity and thus regard particle settling. Other factors considered in the
sense of the term. Although most pharmaceutical colorants in use today are synthetic, a few
selection of the appropriate suspending and viscosity enhancing agent include desired
are obtained from natural mineral and plant sources. For example, red ferric oxide is mixed in
reheological property supendability in the system, chemical compatibility with other
small proportions with zinc oxide powder to give calamine its characteristic pink color, which
excipients, pH stability, hydration time, reproducibility, and the cost. Eg: clays, natural gums,
is intended to match the skin tone upon application. The age of the intended patient should also
synthetic gums In many formulations these excipients are employed in combination for
be considered in the selection of the flavorings agent, because certain age groups seem to prefer
enhanced effects.
certain flavors. Children prefer sweet candy-like preparations with fruity flavors, but adults
Humectants: are hygroscopic substances that help to retard evaporation of aqueous vehicles seem to prefer less sweet preparation with a tart rather than a fruit flavor.
from dosage forms. These excipients are used at 5% strength in aqueous suspension and
Manufacturing Consideration-
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. The manufacturing process for liquid preparations for oral use should meet the requirements
It also helps to prevent cap-locking caused by condensation onto neck of container-closure at of Good Manufacturing Practice (GMP). The following information is intended to provide
first opening Eg propylene glycol, glycerol, polyethylene glycol. broad guidelines concerning the critical steps to be followed during production of liquid
preparations for oral use.
Flocculating agents: prevent caking. Addition of an electrolyte reduces the magnitude of zeta
potential of dispensed particles Eg: Starch, sodium alginate. In the manufacture of liquid preparations for oral use, measures are taken to:
Chelating agents: are substances that form complexes with metal ion in activating their • ensure that all ingredients are of appropriate quality
catalytic activity in oxidation of medicaments. These agents are capable of forming complexes • minimize the risk of microbial contamination
with the drug involving more than one bond it’s a complex compound contains one or more • minimize the risk of cross-contamination
ring in its structure. Protect drug from catalysts that accelerate the oxidative reaction. Eg
Steps of Liquids Manufacturing Process
Disoium EDTA, dihydroxy ethyl glycine, citric acid and tartaric acid
1. Planning of Material Requirements: Research and development of protocols and selection
(5) Organoleptic properties
of materials; acquisition and analysis of raw materials; physical plant design, building, and
Flavouring agents: are agent in liquid pharmaceutical products is added to the solvent or installation; equipment selection and acquisition; personnel selection and initial training; and
vehicle component of the formulation in which it is most soluble or miscible. That is water monitoring information system.
soluble flavors are added to the aqueous component of a formulation and poorly water soluble
Raw Materials : Incoming raw materials should be tested as per specifications that is identity,
flavors are added to the alcoholic or other non-aqueous solvent component of the formulation.
purity, uniformity and microbial contamination .
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 Equipments : The following types of equipments may be used in the manufacture of liquid
solvent. formulations:
Sweetening agents: Sucrose enhances viscosity of liquids and also gives a pleasant texture in 1. Mixing tanks (SS 316 Stainless Steel) equipped with an agitator.
the mouth. The term sugar free solution include sweetening agents such as sorbitol, mannitol,
2. Measuring devices for large and small amount of solids and liquids. 3. Afiltration system
saccharin and aspartame as alternative to sugar such as sucrose, fructose. In addition to sucrose,
e.g. filter press
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 Cleaning of equipments
over the safety by the FDA and restriction to their use and sale in fact in 1969, FDA banned
• All equipments must be thoroughly cleaned and sanitized before use.
cyclamates from use in US. Sucralose is most popular due to its excellent sweetness, non-
• Disinfectants used: Dilute solutions of H2O2, phenol derivatives.
cariogenic, low calorie wide and growing regulatory acceptability but is relatively expensive
• Sterilized by:Alcohol, boiling water, autoclaving, steam or dry heat.
 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
2. Liquid Preparation: Research and development of protocols concerning liquid
handling to maintain product stability; relations with health insurance companies and health
compounding; scale - up of the bulk product compounding; physical plant control and
care professionals; educational materials for patient counseling; and customer service system
maintenance; equipment maintenance and renovation; continuous training of personnel and
reports.
personnel compensation plan; and supervision of system reports.
Elixirs
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 Elixirs are clear, flavoured, sweetened, hydroalcoholic preparations for oral administration.
maintenance; equipment maintenance and renovation; continuous training of personnel and They are more stable than mixtures. Elixirs are classified into two classes.
personnel compensation plan; and supervision of system reports.
a) Non medicated elixirs: These elixirs do not contain any medicament but contain some
Filling and Packing 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
Gravimetric Volumetric Constant Level
ingredients.
Containers are filled Containers are filled with Filled amount is verified
with liquids to a given liquids to a given volume. by adjusting the height Syrups
weight. to which the container is
Filled amount is Syrups are liquid oral preparations in which the vehicle is a concentrated solution of sucrose
to be filled.
Usually limited to large measured by the stroke or other sugars in water. The concentration of sugar in syrup is 66.7 % W/W. Syrups are further
container filling or of the piston and Variation in container classified into 2 classes.
highly viscous cylinder assembly. dimension may result in
products. variations in the net fill a) Simple syrups: The simple syrups do not contain any medicament, but contains some
Problems may arise pleasantly flavoured substances. These syrups are used as a medium for other liquid
per unit.
Cannot be used in high when containers used
preparations.
speed, automatic are not dimensionally
equipment uniform. b) Medicated syrups: These syrups contain some medicinal substance along with other
ingredients.
Techniques of Filling
Advantages of syrups
• Syrups prevent oxidation and decomposition of drugs.
Vacuum filling Gravity vacuum filling Pressure vacuum filling
• Syrups are sweet in taste and therefore bitter taste of drugs can be reduced.
Vacuum developed Bulk liquid tank is Pressure applied to
within the container placed above filling bulk liquid tank and Disadvantages of syrups
causes liquid to stem so that liquid vacuum developed in
• Syrups are not preferred for diabetic patients.
flow from tank to flows to the the container results
container. container due to in pressure difference • On continuous take syrup promote dental decay.
force of gravity. so that liquid flows to
the container. Suspensions
Suspensions are the biphasic liquid dosage form of medicament in which the finely divided
4. Sales of Drug Products: Research and development of protocols concerning product
solid particles are suspended or dispersed in a liquid or semisolid vehicle with the help of
storage; distribution process; continuous training of personnel and personnel compensation
suspending agent.The solid particle is the ‘dispersed phase’ or ‘discontinuous phase’ whereas
plan; and supervision of system reports.
the liquid vehicle is the ‘continuous phase’.
The solid particles act as disperse phase whereas liquid acts as a continuous phase. The Suspension in which particles settle slowly and eventually form a sediment in which
medicaments that are insoluble or poorly soluble are formulated as suspensions. Suspensions aggregation occurs with the resultant formation of a hard cake which is difficult to resuspend.
contain a suspending agent. A suspending agent is a substance that is added to the preparation
Stability of suspensions:
to suspend the insoluble particles in the preparation. It can be classified into four groups.
A stable suspension can be redispersed homogenously throughout its shelf life.The more stable
a) Oral suspensions: These suspensions are to be consumed by oral route.
pharmaceutical suspensions are flocculated i.e.,the suspended particles are bonded together
b) Parenteral suspensions: The suspensions which are administered by parenteral route are physically to form a loose cake.
called parenteral suspensions.
Packing of Suspensions
c) Ophthalmic suspensions: These are used for instilling into the eye.
Suspensions can be packed in narrow mouth screw caped colour less plain bottle. Suspensions
d) Suspensions for external use: These are used for external applications. that are very thick require a container with wide mouth. Suspensions should be stored in a cool
place.
Advantages:
Evaluation of suspension stability:
 Can improve chemical stability of certain drugs.
 Higher rate of bioavailability, as order of bioavailability is: The following are commonly used for evaluating the physical stability of suspensions:
Solution>Suspension>Capsules>Compressed tablets
1.Sedimentation method.
Disadvantages:
2.Rheological method.
 Physical stability, sedimentation and compaction.
3.Electrokinetic method.
 Bulky, handling require care.
 Uniform drug delivery cannot be achieved sometimes. 4.Micromeritic method.
Ideal properties of suspensions: 1.Sedimentation method:
1. The dispersed particles should not settle readily and the settled particles should redisperse It is determined by keeping a measured volume of suspension in a graduated cylinder in an
immediately on shaking. 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
2. The particles shouldn‘t form a cake on settling.
volume of sediment (V0) to the original volume of the sediment (VU) before settling.
3. The viscosity should be such that the preparation can be easily poured. Sedimentation volume F=V0/VU
4. It should be chemically stable. 2.Rheological method:
5. Suspensions for internal use must be palatable and suspension for external use must be free  It provides information about settling behaviour.
from gritty particles.  The arrangement of the vehicle and the particle structural features.
 Brookfield viscometer is used to study the viscosity of the suspension. If viscosity of
Types of suspensions:
the suspension increases, the stability of the suspension increases.
Depending upon particle nature/dispersed particle nature the suspensions are of two types:
3.Electrokinetic method:
1. Flocculated suspensions
The determination of surface electric charge or zeta potential is helpful to find out the stability
2. Non-flocculated/deflocculated suspensions. of suspension. Zeta potential can be calculated from the migration of particle measured by the
electrophoretic method.
Flocculated suspensions:
4.Micromeritic method:
Suspension in which particles are weakly bonded, settle rapidly, don’t form a cake and are
easily resuspended with a minimum of agitation. 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.
Deflocculated suspensions:
So, any change in particle size distribution with reference to time gives a stable suspension. i) Emulsions for oral administration
The particle size can be studied by microscopy or coulter countered method.
Some medicaments are unpleasant in taste. For example fish liver oil, we can mask this
Emulsions unpleasant taste by converting it into an emulsion and can be given orally.
An emulsion is defined as a dibasic or heterogenous liquid preparation immiscible liquids ii) Emulsions for external use
which is dispersed as a minute globules in another liquid by adding emulsifying agent.
The external preparation of emulsion consists of three classes. Applications, lotions and
Medicines having an unpleasant taste and order can be made more palatable for oral liniments, these emulsions can be either oil in water or water in oil.
administration in the form of an emulsion. Emulsions protect drugs against oxidation or
iii) Emulsions for parenteral use
hydrolysis.
Some patients are unable to ingest food in the normal way. We can administer oil in water
• Emulsions are less stable.
emulsions of nutritive oils and fats to these patients. Vitamin K that prevents blood clotting is
• They are susceptible to microbial growth. injected in this form.

Classification of emulsions: iv) Emulsions for rectal use

Emulsions can be classified into the following types: 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-
1. Oil in water (o/w) type of emulsion.
solid emulsions are aqueous creams. Creams are easy to apply and are less greasy.
2. Water in oil (w/o) type of emulsion.
Preparation of emulsions:
3. Microemulsions
The emulsions are prepared by two methods:
4. Multiple/double emulsion.
1. Small scale method
Advantages:
a) Dry gum method
 Mask the unpleasant taste.
b) Wet gum method
 Sustained release medication.
 Inert and chemically non-reactive. c)Bottle method.
 Reasonably odourless & cost effective.
2. Large scale method.
Disadvantages:
Identification tests:
 Packing, handling & storage is difficult.
The type of emulsion can be determined by the following tests:
 Thermodynamically unstable & have short shelf life.
 Leads to creaming & cracking. 1. Dilution test.
 Leads to phase inversion.
2. Conductivity test.
Packing of Emulsions
3. Dye test.
Emulsions can be packed in narrow mouth screw caped colourless plain bottle. Emulsions that
4. Fluorescence test.
are very thick require a container with wide mouth. Emulsions should be stored in a cool place.
5. Cobalt chloride test (CoCl2).
a) Oil in water type: This type of emulsion is the one in which the oil is dispersed in the water
1.Dilution test: This test is based on the solubility of external phase of emulsion.
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  o/w emulsion can be diluted with water.
for oral administration, ii) emulsion for external uses, iii) emulsion for parenteral uses, and iv)  w/o emulsion can be diluted with oil.
emulsion for rectal use.
2.Conductivity test: The basic principle of this test is that water is a good conductor of Creaming may be defined as the upward movement of dispersed globules to form a thick layer
electricity. Therefore in case of o/w emulsion this test will be +ve as water is the external phase. at the surface of emulsion. The creaming depends on “Stokes law”, the rate of creaming
In this test, an assembly is used in which a pair of electrodes connected to an electric bulb is depends on the various factors. V=2r2(d1-d2)g/9n
dipped into an emulsion. If the emulsion is o/w type, the electric bulb glows.
2.Cracking:
3.Dye test: When an emulsion is mixed with a water soluble dye such as amaranth and observed
Cracking means the separation of two layers of dispersed phase and continuous phase due to
under the microscope.
coalescence of dispersed phase globules. Cracking may be due to the following reasons:
 If the continuous phase appears red, then it means that the emulsion is o/w type as water
a) By addition of emulsifying agent of opposite type.
is the external phase.
 If the scattered globules appear red and continuous phase is colourless, then it is w/o b) By decomposition of emulsifying agent.
type.
c) By addition of common solvent.
4.Fluorescence test:
d) By microorganisms.
Oil gives fluorescence under UV light, while water doesn't. Therefore, o/w emulsion shows
e) Changes in temperature.
spotty pattern when observed under UV, while w/o emulsion fluoresces.
3. Phase inversion:
5.Cobalt chloride test:
Phase inversion means change of one type of emulsion into the other type i.e., o/w emulsion
When a filter paper soaked in cobalt chloride solution is dipped into an emulsion and dried, it
changes into w/o type and vice versa. It may be due to following reasons:
turns from blue to pink, indicating that the emulsion is o/w type.
a) By the addition of an electrolyte. b) By changing the phase volume ratio. c)By temperature
Evaluation of emulsions:
change. d)By changing the emulsifying agent.
1. Size distribution analysis.
2. Rate of phase separation.
Reference
3. Viscosity & rheological study.
1. Lieberman HA, Rieger MM, Banker GS. “Pharmaceutical Dosage Forms: Disperse
4. Measurement of dielectric constant. System”, vol.3; Second Edition,473-511
5. Conductivity measurement. 2. The theory and practice of industrial pharmacy by Leon Lachman, Herbert A.
Liberman, Joseph L. Kanig; Third edition
6. Influence of temperature.
3. Aulton, ME. “Pharmaceutics, The Science of Dosage Form Design”, 2nd edition,
7. Microwave radiation.
Churchill Livingstone, London, 2002, pp 309-322.
8. Microelectrophoretic measurement.
4. Lachman L, Lieberman HA, Kanig JL. “The Theory and Practice of Industrial
Stability of emulsions: Pharmacy”, 3rd edition, Varghese Publishing House, Bombay, 1991, pp 457-477.
The following three changes usually occurs during the storage of emulsion: 5. Niazi SK. “Handbook of Pharmaceutical Manufacturing Formulation: Liquid
products”, CRC Press LLC, 2004.
1. Creaming.
6. Remington-The science and practice of pharmacy 21st edition pg 323,740-744.
2. Cracking.
7. Lachman L, Lieberman HA, Kanig JL. ‘Theory and Practice of Industrial pharmacy’-
3. Phase inversion.
Varghese publishing house, third edition-pg no-511.
1.Creaming:
8. Edward J, Pittsburgh B, Pennsylvania,’ Pharmaceutical Packaging Handbook’ USA
Informa health care.