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pharmaceutical

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hamzawi
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Pharmaceutical Technology

Tablets
Learning objectives:

At the end of this chapter the students will be able to:

1. Define and Differentiate between various types of tablet dosage forms.

2. Compare and contrast advantages and disadvantages of various types of


tablet dosage forms.

3. List categories of inert ingredients, with examples, which are employed in


the manufacture of compressed tablets
4. Describe tablet coating types and coating process. (functional vs. plain)

5. State quality standards and USP compendial requirements for tablets


Tablets:-
• According to the European Pharmacopeia, tablets are defined as unit solid
dosage forms each containing one or more active ingredient and obtained
by compressing (or molding) uniform volumes of particles with the aid of
suitable pharmaceutical excipients (crystalline vs flowability).
• Tablets are used mainly for systemic drug delivery but can also be used for
local drug action
• For systemic drug delivery, the drug must be released from the tablet then
dissolved to be absorbed through the GIT barriers to reach the systemic
circulation by which it reaches its site of action
• It can be used for local drug delivery in mouth or GIT, or can be used to
alter the pH of the stomach in case of hyperacidity (antacids)
Tablets are popular dosage forms for several
reasons (advantages)
• The oral route represents a convenient and safe way of drug
administration
• Compared to liquid dosage forms, tablets have general advantages in
terms of the chemical and microbiological stability of the dosage
form
• The manufacturing procedure enables accurate dosing of drug
• Tablets are convenient to handle and can be prepared in a versatile
way with respect to their use and the delivery of the drug (diverse
uses).
• Tablets can be produced with robust and quality-controlled
production procedures that ensure the product produced meets its
predetermined specifications.
• Tablets may be formulated to release the therapeutic agent
at a particular site within the GIT to reduce side effect,
promote absorption at that site and provide a local effect
(e.g. ulcerative colitis). This is not achieved by liquid
preparations
• Tablets may be formulated to contain more than one
therapeutic agent (even if there is an incompatibility
between each active ingredient or for staged release). By
formulation as 1. two layered tablet each layer contains
only one drug. 2. tablet inside tablet
The main disadvantages of tablets

• The problem of poor bioavailability of drugs due to


unfavorable drug properties, eg. poor solubility, poor
absorption properties Biopharmaceuticals Classes????? ,
poor wettability and instability in the gastrointestinal tract.
Besides, some drugs may cause local irritant effects or cause
harm to the GIT mucosa
• The manufacture of tablets requires a series of unit
operations and therefore there is an increased level of
product loss at each stage in the manufacturing process.
• The compression properties of certain therapeutic agents
like paracetamol are poor (high dose drugs) and may
present problems in their subsequent formulation and
manufacture as tablets

• The administration of tablets to certain groups, e.g.


children and the elderly, may be problematic due to
difficulties in swallowing

• Drugs of bitter taste/bad odor/oxygen or moisture


sensitivity require the tablet to be coated
Bio-Pharmaceutical Classes
Requirements of an ideal tablet formulation
1- It must be strong and hard enough to withstand handling (hardness)
2- The drug must be bioavailable which must be confirmed by
disintegration, dissolution and bioavailability studies
3- Must be of uniform weight and drug content (two quality control
tests are carried out to ensure those uniformities; uniformity of weight
and uniformity of content)
4- Must be elegant in shape
5- Must maintain its content of active constituents during storage
6- Freedom from defects such as cracks, contamination and
discoloration
7- Must be of suitable size for ease of administration
DIFFERENT TYPES OF TABLETS
• Immediate release tablets such as orally disintegrating,
chewable, effervescent, sublingual and buccal tablets. They
are characterized by rapid release of the drug after
administration or the tablet is dissolved and administered as
a solution.
• Modified release tablets include
1. Extended: products are designed to release there medications in a
controlled manner, at a predetermined rate, duration and location to
achieve and maintain optimum therapeutic blood levels of the drugs.
Examples-controlled release, sustained release and long acting drug products.
2. Delayed release tablets Where the drug is liberated from the tablet after passing
certain time after administration After this period has elapsed, the release is normally
rapid not extended.
• Example of this type is an enteric coated tablet.
• In case of local treatment in the lower part of intestine or in the colon, a delayed
release approach can be combined with a extended drug release to achieve better
treatment.
3. Repeat action
4. Targeted release
Types of Tablets:
1. Oral Compressed Tablets
 Also called “Peroral tablets”; tablets intended to be swallowed
with water

 Either uncoated, sugar-coated, or film coated

 May be intended for local effect in the GIT or for systemic effect
after absorption of active constituent

 May be intended for immediate (conventional), delayed (e.g.


enteric), or extended release (controlled release) of the drug

Scored or grooved surface


2. Medicated lozenges
 Compressed tablets (troche) intended to be sucked slowly to
release drug in buccal cavity (could be prepared by molding)

 Mostly contain bactericides or local anesthetics for local action


in mouth/throat, may contains vit c for systemic action.

 Must be palatable, so contain flavored sugar

Disc shape
3. Effervescent Tablets
 Compressed tablets disintegrate in water by liberation
of CO2 from acid-base reaction (disintegrants addition?).

e.g. Citric and tartaric acid and bicarbonates

 Ingredients must be anhydrous to prevent acid-base


reaction during storage, Must be manufactured, packed
and stored in dry conditions

 Drug: vitamins, analgesics, proton pump inhibitors


4. Sublingual and Buccal Tablets
 Tablets intended to be placed under the tongue or on the side of
cheek

Properties: small, flat, soft (not highly compressed), and flavored.

 Used for drugs such as glyceryl trinitrate (angina) and certain


steroids that are absorbed more rapidly from the sublingual mucosa
than stomach where they may become inactivated by enzymatic
action or by gastric acidity or first pass effect

Buccal tablet erodes slowly


5. Chewable Tablets
 Tablets intended to be chewed in mouth and dissolved in the mouth
 Disintegrate by the action of the teeth (disintegrant??).
 Sweet and flavored (e.g. using mannitol (gives cooling sensation) as
excipient)
Creamy base
 Adv:
Used by children and patients with swallowing difficulty
Convenient (no need for water to swallow)
e.g. Antacids and Vitamins
6. Solution Tablets
They should be freely soluble in water and
produce a clear solution.
 Drug(s), and excipients must be water-soluble
and the tablets should not be over-compressed,
otherwise dissolution will be retarded.
 Solution tablets are a convenient mean of
preparing antiseptic solutions, douches and gargles.
7. Hypodermic Tablets
In this type of tablets, all drugs, and excipients must be of the
highest purity, freely soluble in water to be used for preparation
of solution to be injected and the tablets must not be over
compressed.
Tablets to be dissolved in only 1-2 ml of sterile water for
injection
Manufactured under aseptic conditions.
Machine parts coming into contact with the granules of this
tablet should be also sterilized before use
8- Multiple compressed tablets
• These are compressed tablets made by more than
compression cycle. (layered or tablet inside tablet)
• This process is best when separation of active ingredients is
needed for (chemical and physical) stability issues
• Or, if the mixing process is inadequate to guarantee
uniform distribution of two or more active ingredients
• Staged drug release
• The unique appearance of the layered tablets
• https://www.youtube.com/watch?v=i5ZUS8WkUWY
9- Instantly disintegrating or dissolving tablets
Instant-release tablets (rapidly dissolving tablets or RDTs)
are characterized by disintegrating or dissolving in the mouth
within one minute, some within 10 seconds.
Oro-dispersable tablets vs. conventional
Method of preparation: (Lyophilization or freeze drying
[porous hygroscopic plug], Soft direct compression by adding
super-disintegrants and small quantity of effervescent
materials that are very water soluble)
Drug solubility?
Used by children and the elderly or patients with swallowing
difficulty
Bubble packaging, peel the back of the package for tablet
removal.
10- Vaginal tablets
Called vaginal inserts are uncoated, bullet shaped or ovoid
tablets to produce local effect.
Prepared by compression
Applied by applicator.
Used to treat bacterial or fugal infections
Tablet Formulation

Active Ingredients Non-Active Ingredients


(Drug) (Excipients or adjuncts)

For local action in the digestive system


The drug exerts local effect without being absorbed
e.g. antacids
For systemic effect
The drug must dissolve in GI fluid before absorption
Tablet Excipients
Why used?

 To facilitate tablet manufacture

 To achieve physically and mechanically


acceptable tablets

 To enhance drug bioavailability


Ideal Properties of Excipients

 Pharmacologically inert and non-toxic

Pure and free from contaminations (spx)

 Compatible with each other (no excipient-excipient


interaction) and with drug (no excipient-drug interaction)

 Not affecting the physicochemical stability of the drug

 Not inversely affecting drug absorption or efficacy

 Inexpensive
A Consideration of the Dose of Drug is the
Starting Point…
LOW DOSE (<25mg)
(Most of the tablet will be excipients)
Content Uniformity (mixing issues)
HIGH DOSE (>250mg)
(Most of the tablet will be drug)
Fluidity (flowability)
Compactibility
Tablet is a multi-component system:

• Drug
• Diluent
• Binder/Adhesive
• Glidant/lubricants/Antiadherents = (Lubricating agents)
• Disintegrants
• Coloring agents
• Flavoring agents
• Coating agent
Diluent (Filler)
• Bulking agent
• 10 – 50% Tablets weigh normally at least 50 mg.
• Must meet criteria Therefore, a low dose of drug per tablet
• Good compressibility requires the incorporation of a substance
• Must be stable into the formulation to increase the bulk
volume of the powder and hence the size of
• Physically
• Chemically the tablet.
• Must be biocompatible
Examples of Diluents (1)
Mainly CARBOHYDRATES but also some inorganic salts.
Lactose is the most common diluent in tablets.
• Properties:
• Good solubility in water
• Pleasant taste
• Non-hygroscopic (crystalline lactose)
• Non-reactive
• Good compactibility
• Available in different grades
• Very cheap
Examples of Diluents (2)
Spray processed lactose [Fast Flo lactose]
composed of lactose crystals and a small amount of amorphous
lactose
Amorphous dissolves more rapidly and has better compactibility
V. RAPID SOLUBILITY

Other sugars:
-glucose
-sucrose
-starch

Sugar alcohols (sorbitol, mannitol, xylitol)


• There are two forms of lactose: crystalline and
amorphous forms
• A- Lactose monohydrate and;
• B- Lactose (an anhydrous form) obtained by thermal
treatment of lactose monohydrate
• Amorphous lactose is produced by spray drying a lactose
solution which gives nearly completely amorphous particles.
The main disadvantage of amorphous lactose is its
hygroscopic nature which leads to less stability and
spontaneous crystallization at elevated temperature or high
relative humidity.
Examples of Diluents (3)
Cellulose: the most commonly used is microcrystalline cellulose
(MCC)
There are two commonly used grades of MCC, Avicel pH-101
(powder) and Avicel pH-102 (granules).

• [Avicel] Most compactible material available for


pharmaceutical use.

• When tablets made from mostly MCC, they showed self


disintegration and require little lubricant also works as a
binder
• Disadvantage: Hygroscopic (SWELLING) and thus can be a
problem for drugs prone to hydrolysis.
Examples of Diluent (Continued)
Dicalcium Phosphate dihydrate [ Emcompress]
 - Minigranules to increase size and improve flow which
help in mixing and feed into the die.
Dicalcium phosphates have the advantage of possessing
low concentrations of unbound moisture and having a low
affinity for atmospheric moisture. So, they are the best
diluents for water sensitive drugs like aspirin
Consider the solubility of drug in selecting a
filler

Water soluble fillers used with poorly


water soluble drugs.

Possible Incompatibilities
Classic example: Tetracycline formulated
with calcium phosphate.
DISINTEGRANTS
- Substances routinely included in tablet formulations
to promote water penetration and dispersion of the
matrix of the dosage form in dissolution fluids to
expose drug particles.
- Typically, disintegration of tablets should occur
within 15 minutes
Disintegration Process

DRUG IN SOLUTION
• There are two major mechanisms and factors affecting tablet
disintegration as follows:
A- Swelling
• Although not all effective disintegrants swell in contact
with water, swelling is believed to be a mechanism in
which certain disintegrating agents impart the
disintegrating effect, causing increase in internal
pressure of the tablet, and overcoming the
adhesiveness of other ingredients, causing the tablets
to fall apart
B: Porosity and Capillary Action (Wicking)
• Disintegrants that do not swell are believed to impart their
disintegrating action through porosity and capillary action.
• Tablet porosity provides pathways for the penetration of fluid
into tablets.
• The disintegrant particles themselves act to enhance porosity
and provide these pathways into the tablet.
• Liquid is drawn up or “wicked” into these pathways through
capillary action and rupture the interparticulate bonds
causing the tablet to break apart.
Types and Use Levels of Disintegrants
• Starch: 5-15%. (Swelling)
• Croscarmellose sodium: Modified Cellulose
(Sodium carboxymethyl cellulose which has been
crosslinked to render it insoluble). (Swelling & Wicking)
-AcDiSol®
Direct Compression: 1-3%
Wet Granulation: 2-4%
• Sodium Starch glycolate (Sodium carboxymethyl starch;
crosslinking reduces solubility) (Swelling)
SUPER DISINTEGRANTS
-Primojel®
-Explotab®
used at a concentration 4-6%
Sodium Starch Glycolate

Upon Exposure to 100% RH Air


In case of direct compression the disintegrant powder is
homogenously mixed with the other components, but when
Formulations are granulated disintegrants are best added:

•½ before granulation (intragranular)


•½ after granulation (extragranular)
OIL TO THE SYSTEM
The Three Lubricant Roles
• True Lubricant Role
• Reducing friction between
sliding surfaces, traditionally
at the tablet-die wall
interface during tablet
formation and ejection.
• Anti-adhesion Role
• Preventing sticking to
surfaces, e.g., the faces of
tablet punches.
• Glidant Role
• Improving flow by
modifying the interaction
between particles.
Lubricants
In a general sense
Lubricant Typical True Anti- Glidant
level Lubricant adherent activity
activity activity
Metallic 0.5-1% Excellent Good Poor
stearates e.g.
mag.stearate

Stearic 1-5% Good Good Nil


Acid
Colloidal 1-5% Nil Good Excellent
Silicas
Talc 1-5% Poor Excellent Good
Concept of a ‘’Lubricant System’’
• Frequently two substances are used in a tablet formulation to
maximize overall lubricant effect in all three areas; For example,
combining magnesium stearate with a colloidal silica.
• Lubricants are always added last after all other components have
been thoroughly mixed (Mixing time of 2-5 minutes).
• Water soluble lubricants are not as effective as the hydrophobic
lubricants:
• Used when a tablet must be completely water soluble (e.g.,
effervescent tablets)
• Examples: DL Leucine, sodium benzoate, polyethylene glycol
8000.

GLIDANTS (FLOW AIDS)
•Improve the Flow of powders/granules from Hoppers
and into die cavity (1%)
•POOR FLOW: IRREGULAR TABLET WEIGHT
Glidants (FLOW AIDS)
•Added to enhance the flowability of direct
compression mixtures, by reducing interparticulate
friction
•There is an optimum concentration at which the
flow is best (talc and silicas). The optimum
concentration is related to the amount needed to
just coat the bulk powder particles.
Effect of the GLIDANT: decreases the angle of
repose, which means good flow


With glidant Without glidant


BINDER (ADHESIVE)
• BINDER:‘’glues’’ the particles together into a cohesive mass
to hold the overall tablet together, and therefore Improves
Compactibility. (integrity and mechanical strength of the
tablets)
•As a dry powder: it is mixed with other ingredients before
wet granulation (binder for wet granulation) or as a solution
which is used as granulation liquid. The binder is referred to
as a solution binder (‘’glue’’).
•As a dry powder: mixed with the other ingredients before
compaction (slugging or tableting). The binder is referred to
as a dry binder.
Flavoring agents & sweeteners
- They are usually limited to chewable tablets or tablets that are intended to dissolve in mouth, to
impart pleasant taste to mask unpleasant taste.

Flavoring agents:
- Water-soluble flavours usually have poor stability. For this reason flavour oils or dry powders are
typically used.
- Oil flavors may be added to tablet granules just before compression
(WHY?) because they are sensitive to moisture and volatilization upon heating (during drying process).
- Since oils interfere with flowability and compressibility of the granules, minimum amount of the
flavouring agent (0.5% of the granulation) is used to avoid their negative effect on the tablet
characteristics.
Sweetening agents:
- Some sweeteners may come from the diluent (e.g. lactose and mannitol).
- Artificial sweeteners such as Saccharine and Aspartame may be also included.
- Saccharin is 400 times sweeter than sucrose but has an unpleasant after taste.
- Aspartame is 180 times sweeter than sucrose but is unstable in presence of moisture and
heat.
Colorants
• Used for Identification and to enhance patient compliance
• Coloring is often accomplished during coating, but a colorant can be included
in the formulation prior compaction (WG). The colorant can be added as a soluble
dye (wet granulation process) or insoluble powder (lakes) (direct compression).
• The coloring agent must be:
1- Safe (FDA approved)
2- It’s percentage must not exceed 0.05%
• FDA classifies the colorants into:
1- Food, drug and cosmetic type (FD&C Type)
2- Drug and Cosmetics type (D & C Type)
3- External Drug and cosmetic type (external D&C type)
These colors may be: Dyes, Natural Colors, Lakes, nondegradable, non-
absorbable polymers
Surface-active agents
• Surface active agents may be incorporated into tablets to
improve the wetting properties of hydrophobic tablets and
hence increase the rate of tablet disintegration.
• Besides that, surface active agents can lead to increase the
aqueous solubility of poorly water-soluble drugs in the GIT.
• Sodium lauryl sulfate is the classical example of surface
active agents.
INFLUENCE OF FORMULATION PARAMETERS ON TABLET
QUALITY ATTRIBUTES

•Physicochemical properties of drug and filler.


• Water soluble drug + water soluble filler will decrease
the disintegration time

• Water soluble drug + water insoluble filler will


increase the disintegration time
Other variables affecting tablet quality
attributes:-
• Binder level within the formulation (too much binder
will enhance the granules strength and hence will
retard the disintegration and decrease the
dissolution)
• Disintegrant level within the formulation (next
slides)
• Lubricant nature and blending time with final
granulation (blending time should be minimized as
much as possible) (next slides)
Disintegrant level within formulation, particle
size and its positioning. ?????
• Basically increasing the disintegration level will shorten the
disintegration time
• The positioning of disintegrants within intragranular and
extragranular portions of granulated formulations can affect their
efficacy. Placing the disintegrant in the extragranular portion results
in rapid disintegration to granular particles, while the disintegrant
present in the intragranular portion will promote further
disintegration to the primary particles thus aiding dissolution.
• The small particle size of disintegrant will maximize the surface area,
and thus increase the water uptake leading to short disintegration
time.
Lubricant nature and Blending time

• Hydrophobic lubricants like magnesium stearate will form hydrophobic film on


the drug and excipients particles. Consequently, decreases the rate of
disintegration and dissolution of tablets
• Hydrophilic lubricants like sodium lauryl sulfate, polyethylene glycol 4000 and
6000 avoid the dissolution rate deleterious effect of magnesium stearate. But,
the effective lubricants are hydrophobic lubricants like magnesium stearate.
So, combined lubricant mixture between them will be suitable regarding to
efficiency and biopharmaceutical behavior.
• Increase the blending time will retard the dissolution, therefore always reduce
the blending time of lubricant with tablet powder or granules (2-5 minutes).
• Also, avoid mixing disintegrant with lubricant, since the lubricant will make a
film on the surface of the disintegrant and decrease its wettability leading to
decreased disintegration. Therefore the lubricant is always the last to add
Manufacturing of Tablets
Compressed tablet formation
1. Direct way
2. Indirect way (wet granulation or dry granulation)

•Or
1. Dry method (direct compression or dry granulation)
2. Wet method (wet granulation)
Granulation
Granulation is the process in which powder particles
are made to adhere to form larger particles called
granules. Pharmaceutical granules typically have a size
range between 0.2 and 4.0 mm
Reasons for granulations:
1. To prevent segregation of the constituents in the
powder mix
2. To improve the flow properties of the mix
3. To improve the compression characteristics of the
mix (charge vs size reduction)
Granulations
4. The granulation of toxic materials will reduce the
hazard of the generation of toxic dust which may
arise when handling powders

5. Materials which are slightly hygroscopic may


adhere and form a cake if stored as a powder.
Granulation may reduce this hazard as the granules
will be able to absorb some moisture and yet retain
their flow ability because of their size. (surface area
reduction)
Methods of Granulation

Wet
granulation

Dry
granulation

Granulation
Dry granulation
• The primary powder particles are aggregated under high
pressure. There are two main processes.
Either a large flat tablet (1 inch = 2.5 cm) (known as a 'slug')
is produced in a heavy-duty tableting press (a process known
as 'slugging') or
the powder is squeezed between two rollers to produce a
sheet of material ('roller compaction').
• In both cases these intermediate products are broken using a
suitable milling technique to produce granular material,
which is usually sieved to separate the desired size fraction.
The unused fine material may be reworked to avoid waste.
This dry method may be used for drugs that do not compress
well after wet granulation, or those which are sensitive to
moisture and heat.
Dry Granulators
• Dry granulation converts primary powder particles
into granules using the application of pressure
without the intermediate use of a liquid.
• It therefore avoids heat-temperature combinations
that might cause degradation of the product. What
about disintegration ability of the produced tablets
compared to those prepared with wet granulation?
• Two pieces of equipment are necessary for dry
granulation:
1. a machine for compressing the dry powders into
compacts or flakes, and
2. a mill for breaking up these intermediate products
into granules (hammer mill)
Dry Granulators
• Equipment:
A. Slugger (or heavy duty rotary press)
B. Roller compaction
Wet granulation
• It involves the massing of a mix of dry primary powder
particles using a granulating fluid followed by drying
• The fluid contains a solvent which must be volatile so
that it can be removed by drying, and be non-toxic.
• Typical liquids include water, ethanol either alone or in
combination. Therefore, wet granulation method is not
suitable for drugs which are unstable with heat or
moisture
• The granulation liquid may be used alone or, more
usually, as a solvent containing a dissolved adhesive
(also referred to as a binder or binding agent} which is
used to ensure particle adhesion once the granule is
dry.
Wet granulation
• Water:
Adv:
1. Commonly used for economical end ecological
reasons.
2. Inflammable
Disadv:
1. adversely affect drug stability, causing hydrolysis of
susceptible products, and
2. it needs a longer drying time than do organic
solvents.
Organic Solvent:
water-sensitive drugs are processed, or when a
rapid drying time is required.
Initial mixing

Wet massing then


Binder solution granulation

Screening of wet
mass

Tray drying: overnight

Dry screening

Blending, remember disintegrant ,


lubricant: last step
• The mixed powders are fed into the
bowl of the planetary mixer and
granulating liquid is added as the
paddle of the mixer agitates the
powders.
• The moist mass has then to be
transferred to a granulator, such as
an oscillating granulator.

• The rotor bars of the granulator


oscillate and force the moist mass
through the sieve screen, the size
of which determines the granule
size.
• The mass should be sufficiently moist to
form separate granules when sieved. If
excess liquid is added, strings of material
will be formed and if the mix is too dry
the mass will be sieved to powder and
granules will not be formed.
• The granules can be collected on trays
then transferred to a drying oven.
Granules may aggregate leads to bridge
formation which needs additional step of
sieving
Fluid bed granulator •Heated and filtered air is blown or
sucked through the bed of unmixed
powder to fluidize the particles and
mix the powder.
•Granulating fluid is pumped from a
reservoir through a spray nozzle
positioned over the bed of particles.
•The fluid causes the primary particles
to adhere when the droplets and
powders collide
•Escape of material from the
granulation chamber is prevented by
exhaust filters,
•Sufficient liquid is sprayed to produce
granules of required size. The spray is
turned off but the fluidizing air
Advantage: continue to dry the granules.
One unit to perform
“three in one”:
Mixing, granulating &
drying
What is the direct compression (DC)?
• DC is tabletting of a blend of ingredients i.e., the compression mixture
without granulation or aggregation process
• The compression mixture contains the active pharmaceutical
ingredients (API) blended with one or more excipients.
• The excipients may includes;
• dry binder
• Filler/diluent: directly compressible excipients e.g. spray dried lactose
• Lubricant: e.g. ,magnesium stearate
• Disintegrant: e.g. starch
• Glidant: e.g. silicone dioxides
• Flavouring agent
Advantages of Direct Compression over
Granulation

• More economical (less time, space, fewer steps)


• Avoids heat and moisture of wet granulation
• Chemical stability

Disintegration Primary particles

Disintegration Deaggregation To Granules

Primary particles
Direct Compression
Disadvantages
• due to difference in particle size and bulk density
between the drug and diluent may lead to stratification
within the powder which may then result in poor
content uniformity of the drug in the compressed
tablets (granulation?).
• Most materials cause relatively weak intermolecular
action that tend to hinder compaction (powder
relaxation).
• Because of the dry nature of direct compression, static
charge build up during mixing may prevent good
compaction (granulation?)
Steps in the different methods of Tablet Manufacture

Wet granulation Dry granulation Direct compression

1. Milling of drugs and excipients 1. Milling of drugs and 1. Milling of drugs and
2. Mixing of milled powders excipients excipients
3. Preparation of binder solution 2. Mixing of milled 2. Mixing of
powders ingredients
4. Mixing of binder solution with 3. Compression into 3. Tablet compression
powder mixture to form wet mass slugs
5. Coarse screening of wet mass 4. Screening of slugs,
using mesh screen then milling to get
6. drying of moist granules granules
7. Screening of dry granules 5. Mixing with half
through mesh screen disintegrant
8. Mixing of screened granules Mixing with lubricant
with half disintegrant then
Mixing with lubricant 6. Tablet compression
9. Tablet compression
Single punch tablet press
1. Die Filling
• This is normally accomplished by gravitational flow of the powder
from a hopper into the die

• The die is closed at its lower end by the lower punch.


The Compaction Process
(Single station Tablet Press)

Filling Compression Ejection Repeat Filling


2. Tablet formation (compaction)
• The upper punch descends and enters the die and the powder is
compressed against the lower punch until a tablet is formed.

• After maximum applied force is reached, the upper punch leaves the
powder, i.e. the decompression phase.
3. Tablet Ejection
• During this phase the lower punch rises and the tablet is
subsequently removed from the die and die table by a punching
device.
Single-Station Press
Can produce up to 200 tablets per minute
Small scale production/formulation development
The powder is fed by gravity from the hopper shoe.
https://www.youtube.com/watch?v=owN3kEhw-nk

Upper punch
Hopper shoe

Die
Lower punch

Ejection regulating screw

Capacity regulating screw


Multi-Station (Rotary) Press
Up to 60 dies & punches produce tablets on a larger scale (> 10 000 min-1).
Dies mounted on a rotating turret with punches above and below, rotating at
the same speed. Powder is force fed into the die by a paddle device within a
feed frame. Punches pass between rollers to compress the powder in the die
https://www.youtube.com/watch?v=4xggZRckfTE

Filling Compression Ejection


Some Common tablet problems (defects)
1- Capping

• The upper or lower segment of the tablet separates


horizontally, from the main body and comes off as a
cap, during ejection from the tablet press, or during
subsequent handling.
• Caused by low amount of binder, use of incorrect
binder, the presence of large amount of fine powders,
air entrapment, non-clean machine, no time for
compression, aging, or improper storage
2- Lamination
• Separation of a tablet into two or more distinct
horizontal layers.
• Caused by low amount of binder, use of incorrect
binder or the presence of large amount of fine powders
3- Chipping
• Breaking of tablet edges, while the tablet
leaves the press or during subsequent
handling and coating operations.
• Reason:
Incorrect machine settings or insufficient
lubrication, or sticking on punches faces due to
improper drying of granules
4- Cracking
• Small, fine cracks observed on the upper and lower
central surface of tablets, or very rarely on the
sidewall are referred to as ‘Cracks’.
•Caused as a result of rapid expansion
of tablets, and too dry granules, and can
be solved by using proper binder at
proper concentration
5- Sticking
• Tablet material adhering to the die wall.
• Reason:
Improperly dried or improperly lubricated
granules.
6- Picking
• Small amount of material from a
tablet is sticking to the tablet-
surface by a punch face.
• The problem is more prevalent
on the upper punch faces than on
the lower ones. Picking is of
particular concern when punch
tips have engraving or embossing
letters, or is not flat (concave)
• Can be solved by proper
antiadherent Tablet Picking
7- Mottling
• It is an unequal colour distribution on the tablet face.
• Causes:
• Different colour of the drug and excipients
• Migration of dye during drying of granules
• Treatment
• Use a dye to mask both the drug and excipients
• Change the solvent system to allow homogenous distribution of color
in the tablet
Tablet coating

Dr. Maha Nasr


Definition:
Tablet coating is the application of coating material to the exterior of a
tablet with the intention of conferring benefits and properties to a
dosage form over the uncoated variety.”
Tablet covered with one or more layers of
mixture of various substances

Why coating?
Therapeutic

Technology Marketing
Aspects of tablet coating????
I- Therapy
1- Avoid irritation of esophagus and stomach
2- Avoid inactivation of drug in GIT
3- Improve drug effectiveness
4- Prolong dosing interval e.g., SR preparations
5- Improve patient compliance with easy of swallowing due to the
lubricant action
II- Technology
1- Reduce influence of moisture
2- Avoid dust formation from tablet core
3- Improve drug stability and separate incompatible materials
III- Marketing
1- Avoid bad taste
2- Distinguished product identity
3- Improve product appearance and acceptability
Types of tablet coating:-
1- Sugar coating
2- Film coating
3- Functionalized coating
3.1- Enteric coating
3.2- Controlled release coating
3.3- Specialized coating e.g., press
coating (time programmed release)
Sugar Coating
• Traditionally the sugar coating form the bulk of tablet
coating therefore, the film coating are the most modern
technology in tablet coating

• Description of tablets:
• Smooth, rounded and polished to a high gloss
• Process: Multistage process involving 6 separate operations:
• First of all we have to do de-dusting to avoid rough tablets
• 1- waterproofing or Seal tablet core
• 2- Sub-coating (largest layer)
• 3- Smoothing
• 4- Coloring
• 5- Polishing
• 6- Printing

https://www.youtube.com/watch?v=PVg8z4TnwxU
1- Sealing tablet core:
Application of a water impermeable polymer such as shellac, cellulose
acetate phthalate and polyvinyl acetate phthalate <Dissolved in
waterproofing solvent (alcohol)> which protect the core from
moisture and increase the shelf life.
2- Sub-coating: Main step
3-5 sub-coats of a sugar based syrup are applied. (rounding the tablet
and provide bonding between sugar coating)
The sugar and water syrup also contain agents such as acacia, PVP or
gelatin to enhance coating.
When the tablets are partially dried, they are sprinkled with a
dusting powder, usually a mixture of powdered sugar and starch,
but some times talc, acacia or chalk (Ca-carbonate).
3- Smoothing process: (Inside a clean pan)
Remove rough layers formed in step 2 with the application of thick sucrose
syrup (5-10 additional coatings) to get a smooth and rounded surfaces.
Between each addition we may prevent the sticking by adding dusting
powder
4- Finishing and <Coloring (optional)>: (Inside a clean pan)
Titanium based pigments are included in thin (low viscosity syrup) syrup
Between each addition we may prevent the sticking by complete drying
5- Polishing: to give a characteristic shine commonly using bees wax,
carnauba wax.
6- Printing: edible ink for characterization
Disadvantage of Sugar Coating?
• Tedious, time consuming (1 to3 days)
• Mottling and spotting of finished tablets
• Increase in tablet weight by 30 to 50%
• Batch to batch variation
• May affect tablet disintegration time
• Scored or grooved tablet
Film Coating??
• Modern approach to coating tablets, capsules or pellets by surrounding them with
a thin skin tight coating of polymeric material (increase the wt by only 3%). Good
for grooved tablets
(enteric coating is part of this type)
• Process:
• Single step process, which involving spraying a coating solution containing the
following;
- Polymer: 7-18%
- Solvent (aq. Or non aq)
- Plasticizer: dense, impermeable film, high gloss and mechanical strength
- Colorant
The solution is sprayed onto tablets followed by drying which facilitate the removal of
the solvent leaving behind the deposition of thin film of coating material around
each tablet.
Advantage of Film Coating?
1- One stage procedure, less time consuming (1-
3 hours)
2- Tablet weight increased by only 2 – 4%
3-More economic
4- It does not affect disintegration time of
tablets
5- Can be adapted for CR, SR or enteric coat.
Disadvantage:-
• There are environmental and safety implications of
using organic solvent
• financial expenses
1- Polymer
Film coating
Immediate Release Modified Release

PVA/PEG Cellulose Extended Enteric coating


graft derivatives e.g.,
Release coating polymer e.g.,
polymer HPMC polymers e.g., - Methacrylic acid
Water soluble
cellulose co-polymers
Form film with derivatives e.g., -Phthalate ester
good mechanical Ethyl cellulose CAP (cellulose
properties (water in- acetate
soluble) phthalate”
2- Solvent or vehicles
Used to be organic solvents and now being replaced by
aqueous system.
• Disadvantages of organic solvents:
1 -Environmental pollution
2 -Safety; flammable and explosive
3- Not Economic
4 -Residual solvent causes toxicity
3- Plasticizers
a) Modify the physical and mechanical properties of the polymer,
Making it more flexible to adhere will to the tablet.
b) Make the film to resist attritional effects and decrease film
brittleness.
Examples:
Water soluble: e.g. PEG 400, Propylene glycol, glycerin and these
can be used in aqueous based spray system.
Water insoluble: e.g. triacetin, castor oil. (2%)
4- Colorants
• The water insoluble pigments have certain advantages over
water soluble dyes; more chemically stable, give better
opacity and covering power.
• They also optimize impermeability of the film to water vapor.
• Examples: FD&C, D&C lakes, Titanium dioxide, iron oxide
Problems Encountered in Film Coating
• Picking: break of small portion of the film from the
tablet and sticking to another tablet.
• Sticking: tablets stick to one another due to increased
rate of addition of coating solution.
• Peeling: large fragment of the film is removed due to
tablet attrition with each other.
• Mottling: non uniform distribution of the color.
Functional coating (Type of film coating)
• Enteric Coating using phthalate acid esters or pH dependent
polymers modified acrylic polymers (Eudragits). (drug protection,
stomach protection, Intentional drug release inside intestine).
• (Transit time <shellac>) vs. pH dependent?)
• Controlled-Release:)
Use a restricted water solubility or low permeability polymers as film
coating solutions, such as EC, modified acrylic polymers (Eudragit ( .
• Coating of a multi particulate systems to different coat thickness, so
as to release the drug at different rates. These particles are either
compressed into tablets or filled into hard gelatin capsules.
Coating Pans:
Fluidized bed (coater) or Air suspension coating device
Tablet quality control tests
QUALITY CONTROL TEST :

QC refers to produce (or) a set of steps taken during manufacturing of a


product to ensure that it meets requirements

QC is the monitoring process through which manufacturer measures


actual quality performance compares it with standards & finds out the
causes of deviation from standard to ensure quality product not once but
every time .

2
UNOFFICIAL TESTS :
Appearance
Size and shape
Hardness (resistance to fracture)

OFFICIAL TESTS
Friability (resistance to attrition)

Weight variation test

Content uniformity tests

Dissolution test

Disintegration test
3
These factors must be
controlled during production
(in-process controls) and
verified after the production
of each batch to ensure that
established product quality
standards are met.

FIGURE : Quality control in the manufacturing


of tablets
UNOFFICIAL TESTS
Appearance :

It should be free from cracks ,depression, pinholes etc.

Colour & polish of the tablet should be uniform on whole surface

There should be no signs of coating

Surface should be smooth

6
Dimensions :
The thickness or diameter of a tablet is determined by the diameter of the die, the amount
of fill permitted to enter the die, the compaction characteristics of the fill material, and
the force or pressure applied during compression.
The dimensions of the tablets, thickness & diameter are measured by using digital vernier
calipers, screw guage or automated equipment (resistance to crushing machine)

7
HARDNESS : (mechanical strength test= resistance to fracture)

It is defined as the fracture/crushing strength of the tablet or force required


to break a tablet across the diameter

Hardness of the tablet is the indication of strength

Why do we do hardness test for tablets ?


tablet should be stable to mechanical stress & transportation
Degree of hardness varies with different manufacturers & different tablets
In general, tablets should be sufficiently hard to resist breaking during
normal handling and yet soft enough to disintegrate properly after
swallowing.

8
It is a valuable test ,which influence the tablet dissolution & disintegration

Depending upon the type & concentration of the binding agent the hardness varies

Binding agents (eg) ; acacia mucilage ,starch paste , sugar syrup , methyl cellulose
dispersion etc.

9
• The greater the pressure applied during compression, the harder the
tablets.

• Certain tablets, such as lozenges and buccal tablets, that are intended
to dissolve slowly are intentionally made hard; other tablets, such as
those for immediate drug release, are made soft.

• Special dedicated hardness testers or multifunctional systems are


used to measure the degree of force (in kilograms, pounds, or in
newtons) required to break a tablet.
• A force of about 4 kg (40 newton) is considered the minimum
requirement for a satisfactory tablet (4-20 Kg).
• https://www.youtube.com/watch?v=sMUaxCwJjEk

Resistant to crushing machine


OFFICIAL TESTS
Weight variation test for tablets
USP – OFFICIAL LIMITS
Tablet weight limit

130mg or less ±10 %

130 – 324 mg ±7.5 %

> 324 mg ±5 %

BP - OFFICIAL LIMITS
Tablet weight limit
80mg or less ±10 %
80mg – 250 mg ±7.5 %
> 250mg ±5%
13
Test procedure :

20 tablets were randomly selected for the test, every tablet in each batch should have uniform weight .

20 tablets are weighed individually. Average weight is calculated from individual weight of all tablets

Individual weight is compared with average weight.

The percentage difference in the weight variation should be with in the permissible limits.

The percentage deviation is calculated by using the formula:

% weight variation = individual weight – average weight


---------------------------------------------×100
individual weight

14
Result :

Not more than two of the individual weights deviates from the average
weight by more than the percentage given in the pharmacopea and none
deviates by more than twice that percentage

15
FIGURE: Automatic weight, hardness,
thickness, and tablet diameter test
instrument for quality control. Using a
microprocessor and monitor for
visualization, the instrument
can test up to 20 samples at a time.
https://www.youtube.com/watch?time_continue=267&v=aGw4SMK9wO4
Content uniformity test :

This test is applied to assure uniform potency for tablets of low dose drugs

The test is applicable to tablets that contain 10mg / < 10mg (or) < 10%w/w of active
ingredients

procedure :
Select 30 tablets randomly from the batch

At least 10 of them are assayed individually

Out of 10 tablets 9 tablets must contain not less than 85% not more than 115% of
labelled drug content

10 th tablet may not contain < 75% or > 125 % of labelled drug content.
17
Result :

Batch passes the test

If there is any deviation then perform the assays individually for 20 tablets

Out of 30 tablets none may fall outside of the 85% to 115% range for the batch
to be accepted.

Various factors are responsible for the variable content uniformity in tablets.
This may include: Tablet weight variation, Uneven distribution of the drug in
the powder or granules, Segregation of the powder mixture during formulation
processes and poor flow, improper analysis.

18
Friability test: (mechanical strength test = resistance to attrition)

It is used to measure the strength of the tablet

It is used to measure tablet to withstand mechanical shock & abrasion without


crumbling during the handling of manufacturing ,packaging, shipping , and consumer
use.

The friability of tablets is indicated by chipping , capping (or) breaking

Friability is strictly adhered to coated tablets

Friability problem is encountered with thin tablets ,large diameter tablets ,granules
(excessively dried or excessive fine granules )

19
The extent of friability is measured by using Roche Friabilator

It rotates at a rate of 25 rpm .10 tablets are weighed collectively & placed in
the chamber of friabilator.in the friabilator the tablets are exposed to rolling
resulting from free fall of the tablets within the chamber of friabilator
20
After 100 revolutions (4 min ) the tablets were taken out from the friabilator and intake
tablets were again weighed collectively.

% friability is calculated by using the formula :

W1 – W2
friability = --------------- × 100
W1

W1 = Weight of the tablet before test


W2 = Weight of the tablet after test

A maximum weight loss of not more than 1% generally is considered acceptable


for most products.
https://www.youtube.com/watch?v=K6eBtVzNA8s
21
Disintegration test (D T) :

For the medicinal agent in a tablet to become fully available for absorption, the tablet
must first disintegrate and discharge the drug to the body fluids for dissolution.

There is no correlation between dissolution & disintegration. Disintegration is a pre-


requisite for the dissolution .

Tablet disintegration also is important for tablets containing medicinal agents (such as
antacids and anti-diarrheals) that are not intended to be absorbed but rather to act
locally within the gastrointestinal tract. In these instances, tablet disintegration
provides drug particles with an increased surface area for activity within the
gastrointestinal tract.

22
• 6 tablets are taken, If 1 or 2 tablets fail to disintegrate completely,
repeat the test on 12 additional tablets.
• The requirement is met if not less than 16 of the total 18 units are
disintegrated.
• The apparatus consists of a basket and rack assembly containing six open-
ended transparent tubes of USP-specified dimensions, held vertically
upon a 10-mesh stainless steel wire screen.
• During testing, a tablet is placed in each of the six tubes of the basket, and
through the use of a mechanical device, the basket is raised and lowered
in the immersion fluid at 29 to 32 cycles per minute, the wire screen
always below the level of the fluid.
• For uncoated tablets, buccal tablets, and sublingual tablets, water at
about 37°C ± 2 serves as the immersion fluid unless another fluid is
specified in the individual monograph (such as simulated gastric or
intestinal fluid).
• For most normal release tablets, the max time permitted is 15 minutes.
(different limits exist for different types of tablets ex: fast disintegrating
tablets)
• Tablets are said to have disintegrated if no fragments (other than
fragments of coating) remains on the screen. Chewable tablets are not
required to comply with the test.
TABLET TYPE DISINTEGRATION TIME

Uncoated 15 minutes
Plain coated tablet 60 minutes
Enteric coated tablet 3 hours
Dispersible tablet 3minutes
Effervescent tablet ˂ 3 minutes
Sublingual tablet 4 hours
Buccal tablet 4 hours
Vaginal tablet 60minutes
chewable tablet not required
26
DISSOLUTION TEST :

This test measures the amount of time required for a given percentage of the drug
substance in a tablet to go into solution under a specified set of conditions.

Rate of drug absorption for drugs is often determined by rate of drug dissolution from
the tablet. It is intended to evaluate the physiological availability of the drug substances,
and ensures bioequivalence from batch to batch. (ININC)

27
• The dissolution medium for each drug is different, could be water or acidic medium
(0.1 M hydrochloric acid) or alkaline medium (alkaline buffers 6.8 ±0.05).
• Dissolution rate test is performed at 37 oC ± 0.5. Samples are removed from the
dissolution chamber at periodic intervals and analyzed for drug content using a UV
spectrophotometer or HPLC. Dissolution samples removed for assay should be
filtered.
• Most commonly, the results of dissolution tests are expressed in terms of the time
versus percent released of drug
• For tablet dosage form design purposes, and for critical product comparison,
however, the time required for substantially complete 80 to 90% release or amount
released versus time profiles are the most desired approach.
• 6 vessels are used according to the USP while 3 vessels are used according to the BP
• https://www.youtube.com/watch?v=FpkU123LVTc
Basket method Paddle method
Limits :

Dissolution testing & interpretation can be done by 3 stages (S1,S2,S3)

In stage 1 : 6 tablets were tested & are acceptable if all of the tablets are not less than
Q + 5%

In stage 2 : additional 6 tablets were tested .if all average of 12 tablets is greater than
or equal to Q & no unit is less than Q – 15%

If the tablets fails the test

In stage 3 : all the average of 24 tablets is greater than or equal to Q & if not more
than 2 tablets are less than Q - 15 % and no tablet is less than Q - 25 %

31
Factors affecting dissolution of drug
1. Physiochemical properties of the drug
• Polymorphic form: A metastable form of a solid has higher solubility
and dissolution compared to its stable counterpart.
• Particle size: The smaller the particle size of a solid, the larger the
particle surface area and the higher the dissolution.
• Salt form: A salt form of a drug has a higher aqueous solubility
compared to its conjugate acid or base, as well as higher dissolution.
• Hydrates versus anhydrates: The anhydrous form shows higher
dissolution than hydrates due to their solubility differences.
2. Factors related to tablet manufacturing
• The amount and type of binder can affect the hardness, disintegration, and dissolution of
tablets.
• The method of granulation, granule size, and size distribution can affect tablet dissolution.
• The concentration and type of disintegrants used, as well as the method of their addition, can
affect disintegration and dissolution.
• Compression force applied to tablet
3. Factors related to method of dissolution study
• Composition of the dissolution medium, pH, ionic strength, viscosity.
• Type of dissolution equipment.
• Temperature of the medium
• Volume of dissolution medium
• Intensity of agitation
• Sink or non-sink conditions (under a sink condition, the concentration of the drug should not
exceed 10 % of its maximum solubility in the dissolution medium in use)
Conclusion :

quality control tests are used for evaluating the quality of tablets

Inorder to maintain quality very batch of formulation should be tested according to


compendial standards

35
Capsules

19:11 1
What are capsules?
• Capsules are solid dosage forms in which drugs & inert
substances are enclosed in a soft or hard shell of
gelatin

Hard gelatin capsules Soft gelatin capsules


2
What are capsules?
• Gelatin capsule shells may be hard or soft
• Most filled capsules are intended to be swallowed whole
• On occasions, capsules can be opened to mix with food
or drink (under supervision of a pharmacist)

3
Why use capsules?
• Capsules are conveniently carried
• Easily identified (Shape, colour, and manufacturer’s name)
• Easily taken
• There is no need for spoons or other measuring devices
• Are tasteless when swallowed
• Are more stable and have a longer shelf-life than their liquid
counterparts
• Pharmacists can use empty hard gelatin capsules for extemporaneous
compounding

4
Hard gelatin capsules
• Empty capsule shells are made of gelatin, sugar, and water
(for flexibility)
• They are clear, colourless, and essentially tasteless
• They may be coloured with various FD&C and D&C dyes
• Made opaque by adding agents such as titanium dioxide
• Many with caps and bodies of different colours
• Hard gelatin capsule shells are used in most commercial
medicated capsules

5
Hard gelatin capsules
Why was gelatin chosen to prepare capsules?
• Gelatin is non-toxic
• Soluble in biological fluids
• Excellent mechanical properties

6
The gelatin

• Collagen (from skin, white connective tissue, and bones


of animals) Partial hydrolysis Gelatin (a protein)
• Type A: Acid hydrolysis
• Type B: Alkaline hydrolysis
What about individuals refusing to take gelatin (of
animal origin) or worried about bovine diseases (Bovine
spongiform encephalopathy)?
• Other polymers (e.g. Hydroxypropylmethylcellulose or
starch) are investigated to prepare capsules
7
Vegicaps® capsules

• Formulated mainly from modified starch and


carrageenan
• Accepted by those with cultural and religious
restrictions to animal-based products
• Easy to swallow
• Free from sugar, gluten, and animal products

8
The gelatin
• Hard gelatin capsules contain 13% to 16% of moisture
(low level which doesn’t support bacterial growth)
• If stored in high humidity moisture is absorbed
distorted and lose their rigid shape
• If stored in extreme dryness moisture is lost
brittle and crumble when handled
• Thus: maintain hard gelatin capsules in an
environment free from excessive humidity or dryness

9
The gelatin
Thus: maintain hard gelatin capsules in an
environment free from excessive humidity or dryness

HOW?

Capsules are packaged along with a small packet of a


desiccant material (silica gel and activated charcoal)

10
The gelatin
• Gelatin is insoluble but softens in cold water
• Gelatin can absorb water up to 10 times its weight
• Gelatin is soluble in hot water and in warm gastric
fluid (where gelatin capsules rapidly dissolve and
release its contents)
• Gelatin (being a protein) is digested by proteolytic
enzymes and absorbed in the GIT

11
Manufacturing hard gelatin
capsules
• Hard gelatin capsule shells = the capsule body + a
shorter cap
• The two parts overlap when joined

Body Cap Capsule

19:11 12
What Shape?

19:11 13
Sealing and self-locking
closures:
 Hard gelatin capsules are made self-locking by
forming indentations or grooves on the inside of the
cap and body portions. When fully engaged, a positive
interlock is created between the cap and body
portions. This keeps the empty capsules joined during
shipping and handling.

 Examples include Coni-Snap and Coni-Snap Supro


capsule which is similar to Coni-Snap relative to
locking mechanism, but differs in that it is short and
the cap overlaps the body to a greater degree.
Capsule sizes

000 00 0 1 2 3 4 5

19:11 15
Filling hard gelatin capsules
General steps for large-scale or small-scale preparation:

• Preparing the formulation


• Selecting the capsule size
• Filling the capsule bodies
• Capping capsule bodies
• Capsule sealing (optional)
• Cleaning and polishing the filled capsules
19:11 16
The powder mix
• A diluent or filler → achieve the proper capsule fill
volume and facilitate the transfer of the powder blend
into capsule shells
• Fillers: Lactose, microcrystalline cellulose, and starch
• Disintegrants: assist the breakup and distribution of
the capsule's contents in the stomach
• Disintegrants: pregelatinized starch, croscarmellose,
and sodium starch glycolate

19:11 17
The powder mix
• Lubricants or glidants enhances flow properties
(important for high-speed automated filling)
• Lubricants/glidants: SiO2, Mg stearate, stearic acid, or
talc (0.25% - 1%)
• Mg stearate ↑ waterproofing → retard penetration by
GIT fluids → delay drug dissolution and absorption
• Surface-active agents (e.g. sodium lauryl sulfate)
facilitate wetting by the gastrointestinal fluids

19:11 18
e.g. Tetracycline capsules

19:11 19
The fill material

19:11 20
Other capsule fillings
• Tablets, small capsules, coated pellets, granules →
separate chemically incompatible agents/premeasured
amounts of potent drugs /modified release
• No aqueous liquids → water softens gelatin → leakage
• Fixed or volatile oils (which do not affect the stability
of the gelatin shells) can be placed in hard gelatin
capsules
• The liquid may be mixed with an inert powder to make
a wet mass or paste which may then be placed in
capsules . Alternatively, put liquids in soft gelatin
19:11 21
Filling the capsules (manual)

Hand-operated filling machine for manual filling of


large-numbers of capsules
https://www.youtube.com/watch?v=FLXmiUmcQog
19:11 22
Capsule sealing
• Tamper-evident capsules are prepared by sealing the
joint between the two capsule parts

Sealed capsules

19:11 23
Capsule sealing
Sealing can be achieved by:
• Kapseals (Parke-Davis): using a colored gelatin band
• Sealing through heat-welding of cap & body at the
double wall at their juncture
• Sealing by a liquid wetting agent (water/ethanol)
• Extemporaneously: sealing by lightly coating the cap
inner surface with a warm gelatin solution
immediately prior to placement of the capsule body

19:11 24
Cleaning and polishing capsules
• The powder mix may be bitter or unpalatable → remove
powder before packaging or dispensing
• On a small scale: capsules are cleaned individually or in
small numbers with clean gauze
• On a large scale: capsule-filling machines have a
cleaning vacuum that removes any excess material from
the capsules surface

• 19:11 25
Soft gelatine capsules

26
Soft gelatin capsules
• Capsules consist of one piece hermetically-
sealed soft shells
•Made of gelatin to which glycerin or sorbitol
(polyhydric alcohol) is added as a plasticizer
• Need a preservative to retard microbial growth
• Preservatives → methylparaben and/or
propylparaben

27
Soft gelatin capsules
•Are mostly used to encapsulate and
hermetically seal: liquids, suspensions, and pasty
materials
•Are pharmaceutically elegant and are easily
swallowed
•Are able to hold a larger amount of liquid-based
formulations compared to tablets and hard
gelatin capsules
28
Soft gelatin capsules -
components
• Gelatin
•Plasticizing agents
•Water
•Miscellaneous excipients

29
Plasticizers
• Plasticizers are additives that increase the
plasticity of a material
• The mechanical properties of soft gelatin
capsules are controlled by the inclusion and
concentration of plasticizers
• Plasticizers: polyhydric alcohols (glycerol or
sorbitol) or their mixtures
• Plasticizer concentration is generally 20–30%
w/w 30
Plasticizers
• This concentration range determines the
mechanical properties of the soft gelatin
capsule
• Plasticizer concentrations > 30% w/w →
capsule is too flexible and tacky (sticky)
• Plasticizer concentrations < 20% w/w →
capsule is too brittle

31
Water
• Water is required during the manufacturing
process and in the finished product
• During manufacture of the soft gelatin
capsules: water concentration is 30 - 40% w/w
• In the finished/dried capsule: the water
concentration is 5–8% w/w
• Water ensures capsule flexibility
• Over-drying of capsules result a brittle product32
Miscellaneous excipients
• Colorants
• Opacifiers (TiO2): protect light-sensitive API’s
• Preservatives (methylparaben and/or
propylparaben)

33
Formulation of the fill
• The fill material is primarily liquid-based
• The therapeutic agent may be dissolved or
dispersed within the fill material
• There are several categories of fill material:
(1) lipophilic liquids
(2) self-emulsifying systems
(3) water-miscible liquids
34
Lipophilic liquids
• Include vegetable oils (volatile and non-
volatile) (e.g. soyabean oil), and fatty acid esters
• A limited number of drugs are soluble in these
materials → inclusion of co-solvents in
formulation . Alternatively, the drug fill may be
formulated as a suspension (requiring the
inclusion of viscosity-modifying agents)

35
Self-emulsifying systems
• Self-emulsifying systems are lipophilic liquids
that contain a non-ionic emulsifying agent (e.g.
Tween)
• Following release into the gastrointestinal tract,
the fill material rapidly emulsifies into small
droplets (with high surface area) → enhances
drug dissolution and absorption

36
Water or water-miscible
liquids
• High-molecular-weight alcohols, e.g. PEG 400, PEG
600
• Small concentrations of ethanol and water (< 5%) can
be used
• The drug can be dissolved or dispersed within the
solvent
• Liquids that can easily migrate through the capsule
shell are not suitable for soft gelatin capsules e.g.
Water or alcohols > 5%
37
Soft gelatin Capsule filling
 https://www.youtube.com/watch?v=vkwoqyh5fL8

19:11 38
I. Kapseals (Parke-Davis) is:

I. What are the advantages (2 Advantages) of using gelation


as shell components
1.
2.

I. Vegicaps is formulated mainly from…………………………. As


shell components

I. Hard gelatin capsules contains…………………….of moistures

19:11 39
Pulmonary drug delivery
Introduction
• Inhaled drug delivery is used for the treatment or prophylaxis of
airways diseases, such as bronchial asthma, chronic obstructive
pulmonary disease (COPD) and cystic fibrosis in order to deliver the
drug directly.
• The administration of a drug at its site of action can result in a rapid
onset of activity.
• Smaller doses can be administered locally and reducing the potential
incidence of adverse systemic effects and reducing drug costs.
Introduction
• The pulmonary route is also useful where
a drug is poorly absorbed orally, e.g.
sodium cromoglicate (anti-inflammatory
used for asthma treatment), or where it is
rapidly metabolized orally, e.g.
isoprenaline (Adrenaline agonist).
• The avoidance of first-pass metabolism.
• The lungs also used as a route for
delivering drugs having systemic activity,
because of its large surface area, the
abundance of capillaries and the thinness
of the air–blood barrier
Inhalation aerosols
• An aerosol (by atomization) is defined as a two phase system of solid
particles or liquid droplets dispersed in air or other gaseous phase,
having sufficiently small size to display considerable stability as a
suspension.
• The deposition of a drug/ aerosol in the airways is dependent on four
factors:
1. The physicochemical properties of the drug
2. The formulation
3. The delivery/ liberating device.
4. The patient (breathing patterns and clinical status).
Inhalation aerosols
• The most important physical property of an aerosol for inhalation is
its size.
Formulating and delivering therapeutic
inhalation aerosols
54 22-Apr-
12
1. Pressurized metered-dose inhalers (metered-dose inhalers (MDIs)
• In pMDIs, drug is either dissolved or suspended in liquid propellant(s)
together with other excipients, including surfactants, and presented
in a pressurized canister fitted with a metering valve.
• A predetermined dose is released as a spray on actuation of the
metering valve.
• The high-speed gas flow helps to break up the liquid into a fine spray
of droplets.
Containers
• Pharmaceutical aerosols may be packaged in tinplated steel, plastic-
coated glass or aluminium containers.
Propellants
• The propellants used in pMDI formulations are liquefied gases,
traditionally chlorofluorocarbons (CFCs) which are now largely
replaced by hydrofluoroalkanes (HFAs).
• At room temperature and pressure, these are gases but they are
liquefied by decreasing temperature or increasing pressure.
• The head space of the aerosol canister is filled with propellant vapour,
producing the saturation vapour pressure at that temperature.
• On spraying, drug and propellant are expelled and the head volume
increases.
• To re-establish the equilibrium, more propellant evaporates and so a
constant pressure system with consistent spray characteristics is
Advantages of pressurized metered-dose
inhalers
• Portability
• Low cost and disposability.
• Many doses (up to 200) are stored in the small canister and dose
delivery is reproducible.
• The inert conditions created by the propellant vapour, together with
the sealed container, protect drugs from oxidative degradation and
microbiological contamination.
Disadvantages of pressurized metered-dose
inhalers
• Difficult to deliver high doses.
• There is no information about the number of doses left in the MDI.
• Accurate co-ordination between actuation of a dose and inhalation
is essential.
Spacers -actuated metered-dose inhalers
• Some of the disadvantages of pMDIs (inhalation/ actuation
coordination and the premature deposition of large droplets high in
the airways) can be overcome by using extension devices or ‘spacers’
positioned between the pMDI and the patient
• Frequently employed with a pMDI, for administering aerosol
medications to young children.
Dry powder inhalers
• In dry powder inhaler (DPI) systems, drug is inhaled as
a cloud of fine particles.

• The drug is either preloaded in an inhalation device or


filled into hard gelatin capsules or foil blister discs
which are loaded into a device prior to use.
48 Dry Powder inhalers
Advantages DPIs over pMDIs
• DPI formulations are propellant-free
• Do not contain any excipient other than a carrier
which is usually lactose.
• They are breath-actuated, avoiding the problems of
inhalation/actuation coordination
• DPIs can also deliver larger drug doses than pMDIs
Disadvantages of DPI
• Liberation of powders from the device is limited by
the patient’s ability to inhale.
• DPIs are exposed to ambient atmospheric conditions,
which may reduce formulation stability.
• DPIs are less efficient at drug delivery than pMDIs,
such that twice the dose is often required for delivery
from a DPI compared to the equivalent pMDI.
Formulating dry powder inhalers
• Drug powders for use in inhalation systems are usually micronized.
• Alternatives are spray drying, spray freeze drying and supercritical
fluid technology.
• The high-energy powders produced by micronization have poor flow
properties because of their static, cohesive and adhesive nature.
• The flowability of a powder is affected by physical properties,
including particle size and shape, density, surface roughness,
hardness, moisture content and bulk density.
Formulating dry powder inhalers
• To improve their flow properties, drug particles are mixed with larger
‘carrier’ particles (median size usually 30–150 μm) of an inert
excipient, usually lactose (α-lactose monohydrate).
• Drug and carrier particles are mixed to produce an ordered mix in
which the small drug particles attach to the surface of the larger
carrier particles.
• This improves liberation of the drug from the inhalation device by
improving powder flow and improves the uniformity of capsule or
device filling.
Formulating dry powder inhalers
• Once liberated from the device, the turbulent air flow generated
within the inhalation device should be sufficient for the de-
aggregation of the drug/ carrier aggregates.
• The larger carrier particles impact in the throat, whereas smaller drug
particles are carried in the inhaled air deeper into the respiratory
tract.
Unit-dose devices with drug in hard
gelatin capsules
• Each dose, contained in a hard gelatin capsule, was
placed individually into the device, in a loose- fitting
rotor.
• The capsule was pierced by two metal needles on
either side of the capsule, and inhaled air flow though
the device caused a turbo vibratory air pattern as the
rotor rotated rapidly, resulting in the powder being
dispersed to the capsule walls and out through the
perforations into the inspired air. e.g. the HandiHaler®
and the Aerolizer/ Cyclohaler®
Multi-dose devices with drug
in foil blisters
• In this system, drug is mixed with a coarse lactose carrier and filled
into an aluminium foil blister disc which is loaded, by the patient, into
the device on a support wheel.
• Each disc contains four or eight doses of drug and the blisters are
pierced with a needle as a result of mechanical leverage of the lid.
• Air flow through the blister causes the powder to disperse as the
patient inhales through the mouthpiece.
• The foil blisters are numbered, so that the patient knows the number
of doses remaining.
Nebulizers
Nebulizers deliver large volumes of drug solutions and suspensions and
are frequently used for drugs that cannot be conveniently formulated
into pMDIs or DPIs, or where the therapeutic dose is too large for
delivery with these alternative systems.
Advantages of Nebulizers
The drug inhaled during normal tidal breathing through a mouthpiece
or facemask, and thus they are useful for patients such as children, the
elderly and patients with arthritis, who experience difficulties with
pMDIs.
Types of Nebulizers
1. Jet nebulizers:
• Jet nebulizers use compressed gas (air or oxygen) from a compressed
gas cylinder to convert a liquid (usually an aqueous solution) into a
spray.
• The jet of high-velocity gas is passed through a narrow Venturi nozzle.
• An area of negative pressure, where the air jet emerges, causes liquid
to be drawn up a feed tube from a fluid reservoir.
• Liquid emerges as fine mist, which collapse into droplets as a result of
surface tension.
Types of Nebulizers
2. Ultrasonic nebulizers
• In ultrasonic nebulizers the energy necessary to atomize liquids
comes from a piezoelectric crystal vibrating at high frequency.
• At sufficiently high ultrasonic intensities, a fountain of liquid is formed
in the nebulizer chamber.
• Large droplets are emitted from the apex and a ‘fog’ of small droplets
is emitted from the lower part

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