THE PHARMACEUTICAL
INDUSTRY
Manufacturing Processes
The Pharmaceutical Industry
Takes the active ingredients of drugs and
converts them into a form that can easily
be given to a patient.
Involves mixing the active ingredient/s
with various other ingredients with
appropriate chemical properties, then
either compressing the mixture into
tablet, filling a gelatin capsule with it or
dissolving it in an appropriate solvent.
Advantages of Industrial
Production
Low prime cost (including innovations)
Large scale production
Unified package (good for transportation)
Quality control processes (standard
technical documentation)
Standard Technical Documentation
safe,
Necessary to provide us with
effective and qualitative
medicines
Pharmacopoeia
Technology and technical regulations
State standards
Producer Pharmacopoeia articles
SOPs
CGMPs
Basis of most technological
processes – dosage form of drug
Solid dosage forms (tablets, capsules,
powders, granules, dragee, …)
Liquid dosage forms (solutions,
suspension, emulsion)
Soft dosage forms (ointments, liniments,
capsules, patches, gels…)
Gaseous dosage forms (gases, aerosols)
Definitions
Medicine is defined in the Medicines Act
1981 as “any substance or article other
than a medical device that is
manufactured, imported, sold or supplied
wholly or principally for administering to
one or more human beings for a
therapeutic purpose
Where a therapeutic purpose is defined
as treating, preventing, or diagnosing
disease.”
Tablet
Solid dosage form that is prepared by
compressing or molding of the drug into
various sizes and shapes.
The most common means of
administering a medicine. Tablets are
compressed powder, formulated so as not
to break up or chip before being taken,
but to disintegrate in the digestive tract
and release the drug in a consistent and
predictable manner.
Tablet
Dissolution is the rate-limiting step in the
delivery of drug from a tablet to the
systemic circulation.
This requirement, and the requirement
that the drugs be of suitable size to be
taken, means that there is more involved
in the tablet making than simply taking a
powder and compressing it.
Advantages
Production aspect
Large scale production at
lowest cost
Easiest and cheapest to
package and ship
High stability
User aspect (doctor,
pharmacist, patient)
Easy handling
Lightest and most compact
Greatest dose precision &
least content variability
Disadvantages
Some drugs resist
compression into dense
compacts
Drugs with poor wetting,
slow dissolution,
intermediate to large
dosages may be difficult or
impossible to formulate and
manufacture as a tablet that
provide adequate or full
drug bioavailability
Bitter taste drugs, drugs
with an objectionable odor,
or sensitive to oxygen or
moisture may require
encapsulation or
entrapment prior to
compression or the tablets
may require coating
Tablets for Oral Administration
Film coated tablets
Enteric coated tablets
Effervescent tablets
Sublingual tablets
Buccal tablets
Troches
Chewable tablets
Controlled release tablets - slow release tablets
(SR) and modified release tablets (MR)
TABLETING
Tableting Process
Step 1: Dispensing
Sufficient active ingredient to make up a
batch is weighed out, and at the same
time the first of the excipients to be used
is added to the mixture.
The excipients used as this stage are
fillers (to dilute the active) and binders:
either lactose or polyvinyl pyrrolidine
(both of which act as both fillers and
binders).
.....Step 1
The quantity of excipient required in any
tablet can vary considerably depending
upon the active ingredient, the tablet size
required and the dose.
For example: aspirin tablets are only
approximately 10% excipient, while other
tablets are more than 99% excipient.
Step 2: Granulation
The stage in which the tablet ingredients
are thoroughly mixed, and prepared for
compressing. Two different methods are
used, with the choice of method based on
particle size and shape.
a) Dry granulation
b) Wet granulation
Dry Granulation
The simpler of the two methods, and is
suitable for tablets where the particle size
of both the active and the excipients are
the same.
The active ingredient and the excipients
are sieved through a fine mesh and
thoroughly mixed.
If the particle size differs, desegregation
can occur in the tablet hopper during the
compression stage leading to non-
uniform dispersion of the active in
tablets.
Wet Granulation
More complicated, but is more commonly
used. It is necessary for tablets in which
the active ingredient and excipients have
different particle sizes.
It also helps tablets with very spherical
particles to bind together, by making
them more lumpy in shape.
....Wet Granulation
The dry mixed ingredients from the
dispensing stage are mixed with liquid –
usually a paste made of maize starch and
water, sometimes water or alcohol.
These are mixed to form a dough, cut into
very small pieces, and are dried below
60OC either in a hot air oven or a fluid bed
drier until they are < 2% moisture.
The dried pieces are milled into very small
granules and blended with a salt of a fatty
acid or talc.
....Wet Granulation
This powder coats the granules of the
other ingredients, and acts a lubricant to
reduce friction during the compression
and ejection of the tablets.
But, lubricants also reduce the rate at
which tablets disintegrate and dissolve in
the digestive tract.
The classification of manufacturing
methods
wet granulation: suitable for drugs that are stable to
granulation moisture and heat
dry granulation: suitable for drugs that are
sensitive to moisture and heat
powder compression : suitable for drugs that
direct
are sensitive to moisture and heat, fill material
compression
possessing, good flowability and compressibility
crystal compression ： suitable for drugs
with proper crystal form and good
flowability
Step 3: Compression
Tablets are compressed on machines that
can usually produce 16, 32, or 64 tablets
per rotation.
The weight and strength of the tablet is
controlled by adjustment of the volume of
the die into which the powder for each
individual tablet is fed immediately prior
to compression.
The main components of single-punch
tablet presses: die; lower punch; upper
punch
The main components of single-punch
tablet presses
t a b l e t
h o p p e r
Core h a r d n e s s
components: a d j u s t o r
die f e e d
s h o e
lower punch d i e
u p p e r
c a v i t y
upper punch p u n c h
d i e
l o w e r
p u n c h
t a b l e t e j e c t o r
a d j u s t o r
t a b l e t w e i g h t
....compression
The compression machine is loaded with
dies that either simply compress the
powder into a tablet of suitable size and
shape, or that also emboss them with
various identification marks or put a
groove in them so that they can be
broken in half.
Tablet production may be finished at this
stage or if required, they can proceed on
to being coated.
Classes of Tablet Presses
Tablet presses:
a. single-punch presses
b. multi-station rotary presses
The compression cycle of a rotary tablet press
Wet Granulation
Compressed Tablets
Contains:
Medicinal agent
Diluents or filler
Binders or
adhesives
Disintergrants
Lubricants
Miscellaneous
adjuncts
Colorants and
flavorants
Diluents
Diluents increase the volume to a
formulation to prepare tablets of the
desired size.
Widely used fillers are lactose, dextrin,
microcrystalline cellulose starch, pre-
gelatinized starch, powdered sucrose,
and calcium phosphate.
Binders
Binders promote the adhesion of particles
of the formulation. Such adhesion
enables preparation of granules and
maintains the integrity of the final tablet.
Commonly used binding agents include:
water, ethanol, starch, gelatin and sugars
(sucrose, glucose, dextrose, and lactose).
Disintegrants
The breakup of the tablets to smaller
particles is important for dissolution of the
drug and subsequent bioavailability.
Disintegrators promote such breakup. To
rupture or breakup of tablets,
disintegrating agents must swell or expand
on exposure to aqueous solution.
Thus, the most effective disintegrating
agents in most tablet systems are those
with the highest water uptake property.
In general, the more hydrophilic, the better
disintegrating agents are therefore highly
hydrophilic.
Lubricants
A substance capable of reducing or preventing
friction, heat, and wear when introduced as a film
between solid surfaces. It works by coating on the
surface of particles, and thus preventing adhesion
of the tablet material to the dies and punches.
Lubricants play more than one role in the
preparation of tablets.
Commonly used lubricants include: talc,
magnesium stearate, calcium stearate ,stearic
acid, hydrogenated vegetable oils and PEG.
Step 4: Tablet Coating
Tablets may be coated to:
improve the stability
Improve appearance and acceptability
Mask an unpleasant taste
Protect the tablet from the acid in the
stomach
Avoid irritation of stomach
For easy identification
Reduce influence of moisture
Tablet Coating
The general methods involved in coating
tablets are as follows
1) sugarcoating tablets
2) film-coating tablets
3) fluid-bed or air suspension coating
4) compression coating
5) Enteric coating
....Tablet Coating
Sugar coating – most common type of
coating used; but requires application of
up to 27 coats of different sugar, sealing
and polishing coats.
Film coating is nowadays used.
The polymer used (hydroxypropyl
methylcellulose, methylcellulose,
hydroxypropylcellulose or
carboxymethylcellulose sodium – cellulose
polymers with different functional
groups in place of some or all of the – OH
groups) is simply mixed with water or
another appropriate solvent.
....film coating
This solution is sprayed onto the tablets
as they are turned in a large rotating
bowl, the solvent evaporates off, and a
layer of film remains on each tablet.
Film coatings have the advantage that
they can be applied to embossed tablets
without the embossing being filled up
with coating solution.
STEP 5: PACKAGING
Quality Standards and Compendial
Requirements
The apparent physical features of compressed
tablets:
1) shape: round, oblong, unique
2) thickness: thick or thin
3) diameter: large or small
4) flat or convex
5) unscored or scored in halves, thirds and
quadrants
6) engraved or imprinted with an identifying
symbol and/or code number
7) coated or uncoated
8)colored or uncolored
9) number of layers.
Other physical specifications and quality
tablet weight weight variation
content uniformity tablet thickness
tablet hardness tablet
disintegration
drug dissolution
in-process controls
verification after the production
Tablet Hardness
1)The greater the pressure applied, the
harder the tablets.
2) The hardness required by different
tablets
a) lozenges and buccal tablets: hard
(dissolve slowly)
b) the tablets for immediate drug
release: soft
3) Measurement
a) special dedicated hardness testers
b) multifunctional equipment
Friability
1) It is used to determine a tablet’s
durability
2) Method: allowing the tablets to roll and
fall within the rotating apparatus
(friabilator); determine the loss in weight;
3) requirement: weight loss ≤1%
Tablet Dissolution
1) The importance of in vitro dissolution test
a) to guide the formulation and product
development process toward product optimization
b) to monitor the performance of
manufacturing process
c) to assure bioequivalence from batch
to batch
d) as a requirement for regulatory
approval for product marketing for products
registered with the FDA and regulatory
agencies of other countries.
2) The goal of in vitro dissolution is to
provide a reasonable prediction of the
product’s in vivo bioavailability.
Basis: The combinations of a drug’s
solubility and its intestinal permeability
are supposed as a basis for predicting the
likelihood of achieving a successful in
vivo – in vitro correlation (IVIVC).
3) The formulation and manufacturing factors
affecting the dissolution of a tablet
a) the particle size of the drug substance
b) the solubility and hygroscopicity of the
formulation
c) the type and concentration of the
disintegrant, binder, and lubricant used
d) the manufacturing method, particularly, the
compactness of the granulation and the
compression force
e) the in-process variables
Some Special Areas of Drug
Production
drugs Galenical (extraction of medicinal
plants: tinctures, extracts …)
biotech pharmaceuticals
children's medicines
ophthalmic formulations
geriatric medicines
....Galenicals
• Nomenclature: owing to Galen who
discovered it
• Menstrum: solvent used for extraction (ex.
Water, alcohol, ether)
• Marc: the inert fibrous and other insoluble
materials remaining after extraction
• Types: Infusions
Decoctions
fluid extracts
semi-solid extracts
dry extracts
tinctures
medical oils
Drugs: Galenicals
The process of extraction refers to the
mass-transfer processes and flows
through the diffusion laws
The main factors are:
1)nature and characteristics of medicinal
herbs
2)Properties of the extracting agent (water,
ethanol, ethyl ether, chloroform, acetone,
liquefied gases )
Main stages of production
Main stages of production:
Raw material preparation
Extraction process
Purification (settling, filtration,
centrifugation)
Concentration or drying
Filling and packing
Galenicals
Galenicals: Quality Control
Organoleptic characteristics (transparency,
chromaticity, taste, flavor)
Ethanol content and density (in tinctures)
Dry residue
Heavy metals
Capsules
Process is similar to that of tablets
The major difference is that after mixing
of the formulation ingredients, instead of
being compressed, the mixture is filled
into gelatin capsules that may be either
hard or soft in texture.
Liquids/Syrups
Three main categories:
1. Liquid for oral administration
2. Liquids for injections
3. Liquids applied topically
(creams and ointments)
Liquids for Oral Administration
Usually the simplest formulations
available, as the ingredients are simply
mixed in a suitable sized tank
The most important aspect of
manufacture is to ensure all ingredients
are fully dissolved and well mixed before
packing and that the formulations contain
suitable effective preservatives.
Liquids for Oral Administration
Where the liquid is a suspension, mixing
of the bulk must be continued during
packing to ensure even dispersion of the
active at all times.
These liquids, generally include, in
addition to the active ingredient/s and
the solvent, antimicrobial agents to
prevent the growth of molds and yeasts,
and often include sweeteners such as
sucrose, sorbitol, aspartame, glycerin.
Other substances are added to alter
solubility, flavour, viscosity.
Liquids for Intravenous
Administration
Manufacture must occur
under aseptic conditions
using methods that ensure
the finished injection is
sterile.
Injections are usually
rendered sterile by
autoclaving; however, some
medicines cannot be
autoclaved and so must be
sterilized by filtration during
the manufacturing process.
Injections may also be prepared in
powder form, either freeze dried or as
pure powder, for reconstitution
immediately prior to use.
Injections may be prepared for
intramuscular or subcutaneous
administration often using oils as the
vehicle rather than water.
Injected liquids also contain small
amounts of additives (NaCl) – used in
aqueous solutions to make the injected
solution isotonic.
Liquids for Topical Applications
• Prepared as either ointments or
creams
• Ointments – are dispersions of
water in oils; creams are the
opposite.
• Manufacture for both involves
preparation of separated oil and
water phases containing the
required ingredients, heating each
phase to between 60 – 70OC,
mixing then cooling with
continuous stirring until the cream
or ointment is formed.
• The bases used are
hydrocarbons such as
lanolin.
• Depending on the base
used, the cream/ointment
may wash off or easily be
absorb into the skin, or it
may remain on the surface,
and thus protect the skin
underneath.
LIQUIDS AS SYRUPS
