Solid Dosage Forms

Tablets and Hard Gelatin

Capsules – the two most
common oral dosage types
Capsules and tablets
 Preferred for oral administration
 Convenient – easily carried, identified
and taken (patient compliance)
 No separate measuring devices
(spoons etc) as needed for liquid
dosage forms
 Efficient (and economical) to
manufacture, package and ship
 Fairly stable with relatively long shelf
lives
Tablets and Capsules
The first thing a consumer (patient) notices
when they obtain/take their medication is the
appearance , namely what?

This is a key factor in producing and marketing

medications, since it is how patients identify
and subsequently dose themselves
i.e. What to take and when to take it

It also has patent and copyright implications

Why?
Tablets and Capsules
 Physical features – tablet,capsule
descriptions
 Are they:
 Round, oblong, thick, thin, large or small in
diameter (tabs), capsule size?
 Flat or convex (tabs)
 Unscored or scored (tabs -halves, quarters)
 Engraved (tabs) or imprinted (tabs , caps)
(name or dose)
 Coated or uncoated (tabs ,caps)
 Coloured (tabs, caps)
 Single or multilayered (tabs)
Quality standards - testing
Both in-house and compendial (USP) testing
requirements including:
 Tablet, capsule weight (individual)
 Weight variation (why care?)
 Content uniformity (uniformity of what?)
 Potency ( strength of dosage vs label claim)
 Purity (of what?)
 Tablet thickness
 Tablet hardness
 Disintegration
 Dissolution
Quality standards
 Both in-house and USP requirements must be met
 Laboratory testing Includes: both tabs and caps
a) Description (both)
b) Dosage weight (both - capsule fill weight)
c) Weight variation (both - cap fill wt)
d) Content uniformity (both)
e) Thickness (tabs only)
f) Hardness (tabs only)
g) Disintegration (both)
h) Dissolution (both)
i) Assay (potency) (both)
j) Purity (Impurities) (both)
Quality standards - Tablets
 Tablet production process must be
controlled and the finished product is tested
throughout ( in process tests)
 Tests done to control the process itself and
to ensure the tablet complies with the
regulations
 In process tests – size, hardness,
Disintegration, friability (mostly physical
tests to see if the process is producing the
correct physical product (chemical tests are
added later in the QC lab)
Tablet weight and USP weight
variation

 Quantity of fill placed in the die in the tablet

press determines the weight of the resultant
tablet
 Volume of fill can be adjusted to make
tablets of desired weight and content
 Can calculate – if tablet contains 20 mg of
active, need 2 kg of API for every 100,000
tablets
 For a total tablet weight (including
excipients) of 200 mg, 20 kg of the
formulation must be used
Tablet weight and weight variation

 Depth of fill would then have to be

adjusted so that each die contains 200
mg (in this case) of the formulation

 During production, tablets are

periodically removed and inspected
(both visually and by weight checks
and other tests)
Weight variation

 Important
 Don’t want some tablets to weigh 150
mg and others to weigh 250 mg even
though they average out to 200 mg
 WHY?
 Obviously want to have a uniform dose
per tablet
 USP sets limits to weight variation for
different products
Dosage Uniformity
1 - Weight variation
For uncoated tablets:

 Weigh 10 tablets accurately

(individually)
 Calculate average weight
 Then based on assay, calculate the
API contained per tablet (ie label
claim)
 Check to see if falls within specs
Dosage Uniformity
2 - Content uniformity

 10 individual dosage units are assayed for

their content according to the monograph
 The requirements are met for Dosage
uniformity if the amount of active in each
tablet is between 85 and 115% of the label
claim (with a relative standard deviation
(rsd) of less than 6%
 If not, do more tests to check for statistical
validity
 If still doesn’t pass- then reject
Physical Quality Tests

Thickness
Hardness
Friability
Disintegration (also a performance test)
Dissolution (also performance test as
well as a chemical quality test –
strength, amount per time )
Tablet thickness

 Thickness depends on:

 Diameter of die
 Amount of fill
 Compactibility of fill
 Force or pressure applied during
compression

 Need uniform conditions of fill, die and

pressure
Tablet thickness

 Pressure will also affect tablet

hardness
 Tablet hardness in turn will affect
disintegration and dissolution – why
important?

 Thickness easily measured with a

hand gauge during production
Tablet hardness and friability
 Tablet press can exert pressures between
3000 and 40,000 pounds of force
 Generally greater pressure produces harder
tablets
 Also affected by the compactibility of the
formulation itself
 Tablets should be hard enough to resist
breaking during normal handling (during
production and shipping - friability)
 Still soft enough to disintegrate after
swallowing
Tablet hardness and friability

 Special testers used to determine

degree of force needed to break a
tablet
 Measured in kg or other units
 All tablets of the same production
batch should have the same hardness
values (within a range)
Friability

 Friabilator
 Determines tablets tendency to
crumble
 Picks up and drops tablet a defined
number of times (set speed and
duration of test)
 Weigh tablets initially
 Weigh after tumbling
 Determine amount lost as powder
Tablet disintegration

 Tablet must first disintegrate in order

to fully release its API (it is the first
stage of what process?)
 Active will then be available to be
dissolved and absorbed into the
bloodstream
 All USP tablets must pass a
disintegration test
Disintegration

 Tablets placed in a basket

 Basket raised and lowered in a suitable fluid
(water or a buffer) 29-32 cycles per minute
 Complete disintegration is defined as when
“any residue (except fragments of coatings)
remaining on the screen is a soft mass with
no firm core”
 Must disintegrate within a defined time
specified by the USP (eg 30 or 45 minutes)
Disintegration

 If one or more tablets do not

disintegrate further testing is called for
(defined by USP)

 Enteric coated tablets can also be

tested BUT difference is that they
should NOT disintegrate in simulated
gastric fluid but subsequently should
disintegrate in simulated intestinal fluid
Tablet dissolution

 Important for the following reasons:

 Guides formulation and product
development process
 Can monitor the initial manufacturing
process – variability can indicate a
problem
 If consistent dissolution results
obtained – assures bioavailability from
batch to batch
 A requirement for regulatory approval
Dissolution

 Go into any pharmaceutical lab – will

see all sorts of dissolution testing and
apparatus
 Starts at formulation steps all the way
through to finished product testing
 Really important also for generic
manufacturers – demonstrate that their
product is bioequivalent to the branded
drug
Dissolution

 Purpose is to provide a possible

indication of the drugs potential
bioavailability
 How much of the API present in the
product is likely to be available to the
body to absorb and utilize
Dissolution
 A number of formulations and
manufacturing factors can affect dissolution
and disintegration
 Eg
 Particle size of the drug substance in the
formulation
 Solubility and hygroscopicity of the
formulation
 Type and concentration of disintegrant,
binder, lubricant
 Manufacturing method
 Fairly complex relationships and factors
Dissolution

Arguably the most important

pharmaceutical test that we can
perform on an oral dosage form.

Why?

More on this later (prior to exam)

Assay and Purity

Assay – a confirmation of a dosage forms label

claim (ie 325mg acetaminophen tab must
contain about 325mg for each tab)
Result expressed as actual mgs/tab and as a
percentage of the label claim

Purity – a check of the API’s “cleanliness”. Is it

pure or does the dosage form contain
unwanted substances derived from the API
– ie has it degraded?
Capsules and tablets
 Preferred for oral administration
 Convenient – easily carried, identified
and taken (patient compliance)
 No separate measuring devices
(spoons etc) as needed for liquid
dosage forms
 Efficient to manufacture, package and
ship
 Fairly stable with relatively long shelf
lives
Capsules

 Fairly simple dosage type

 Medicinal agents enclosed in a small shell
of gelatin
 Gelatin shell may be hard or soft –
depending on contents
 Intended to be taken whole (not opened)
 Used to make most commercial medicated
capsules
Hard gelatin capsules

 Also used frequently in preliminary

clinical trials
 Empty capsule made from mix of
gelatin, sugar and water
 Clear colourless and tasteless
 May be coloured using dyes or made
opaque (by adding TiO2)
 If stored in high humidity – may distort
Gelatin
 If stored in extreme dryness – become
brittle
 Partial hydrolysis of collagen obtained
from the skin, white connective tissue
and the bones of animals
 Available in a fine powder, shreds,
flakes or sheets
 Stable in air
 Prone to microbial contamination when
moist
Gelatin
 Cross-linking – chemical change to the
gelatin, caused by aging of capsules, which
causes the capsule to become elastic when
wetted and dissolution is retarded
 Usually packed with a packet of dessicant
 Shells soluble in gastric fluid and digested
by digestive enzymes (dissolve best at 37 C,
poorly at 30 C and below)
 Moisture levels are 13-16% but generally do
not support bacterial growth since moisture
is too strongly bound to the gelatin molecule
Manufacture of hard gelatin
capsule shells
Preparation of hard filled gelatin
capsules

 1/ developing formulation and

selecting capsule size
 2/ filling capsule shells
 3/ sealing capsules
 4/ cleaning and polishing filled
capsules – excess powder vacuumed
off and capsules polished
Formulation
Hard Gelatin Capsules (HGC) are usually filled
with powder, however they can be filled with
smaller tablets, pellets, other capsules,
pastes and powder plugs.

Pellets are a very common capsule fill. Why?

Pellets can be purchased or made to contain
coating layers which can serve different
purposes (delayed drug release, enteric
coatings, immediate release, etc)
Formulation
For Powders:
 Actives and inactives blended thoroughly
 Uniform powder mix (especially important
for low dosages – why?)
 Verify mixing process – how?
 Diluent or filler used to produce proper
capsule fill volume
 Disintegrants may be added
 Powder must be free-flowing – add lubricant
or glidant
 “plugs” of powder can develop over time
and change capsule performance – how?
Formulation
 Each capsule typically holds between 65 mg
and 1 g of powder
 Encapsulating machines – purpose is
simple – to fill and seal the capsules
 Capsules may be filled by hand (Feton
apparatus) for small R&D batches or by
Pharmacists
 Each hard gel capsule consists of a body
and a cap that fit together to hold contents
inside
Formulation

 The capsule body is larger and the cap

is shorter. The cap fits snuggly over
the capsule body and usually “snaps”
into place with the help of small
grooves or indentations along the
capsule
 Why do we want to lock the two
together?
Formulation

 Hard Gelatin capsules come in

standard sizes for human use and are
identified by numbers
 000 is the largest HGC (1.4ml volume)
while 5 is the smallest (0.13ml)
 From largest to smallest

- 000,00,0,1,2,3,4,5
Formulation

 The choice of which capsule size to

use for the formulation will depend on
the amount of powder fill needed to be
encapsulated and how the powder
compresses once filled.
Capsules

 Hard Gelatin capsules are unsuitable

for encapsulating aqueous liquid
dosage forms – they are softened by
water and other liquids

 Liquids are more typically placed into

soft gelatin capsules
Soft gelatin capsules

 Made of gelatin BUT add glycerin or a

polyalcohol to make it more elastic or
plastic-like
 Contains more moisture – must add a
preservative
 Used to seal and encapsulate liquids,
suspensions, pastes, dry powders etc
Soft gel capsules

 Can be manufactured to produce

different drug delivery systems:
 Orally administered softgels releasing
their contents in the stomach
 Chewable softgels
 Twist off softgels designed with a tag
to be twisted or snipped off – useful for
unit dosing of topical medication,
inhalations
 Meltable softgels – re suppositories
Key features and advantages of
softgels

 Improved drug absorption (esp for poorly

water soluble drugs)- why improved?
 Patient compliance and consumer
preference
 Safety (for potent and cytotoxic drugs) –
avoids dust, handling problems during
manufacture and after marketing
 Good for oils and low mp drugs (hard to
prepare tablets, hard shell capsules)
 Dose uniformity for low dose drugs (liquid
flow control easier than powder flow control)
 Product stability – protected against
oxidation etc
Soft capsules

 Produced, filled and sealed in a

continuous process
 Most prepared by a rotary die process
 Two ribbons of gelatin brought
together between rotating dies
 Material is injected into the pockets
formed between the ribbons
 Pockets then sealed by pressure
Soft capsules

 Filled, sealed and cut all in one

process
 Then dropped into a refridgerated tank
to prevent sticking to one another
In process testing

 Gel ribbon thickness

 Softgel seal thickness during
encapsulation
 Fill matrix weight and capsule shell
weight
 Moisture levels
 Finished product tested as per
capsules and tablets
Softgel capsules

 Biphasic dosage form – solid phase capsule

shell and a liquid phase fill matrix
 Triglyceride oils (eg soya bean oil)
commonly used as a solvent or vehicle for
the active water-insoluble drug (eg vitamin
E, steroids, etc)
 Hydrophilic liquids – PEG (polyethylene
glycol) – can dissolve polar actives
 Self emulsifying oils (oil plus surfactant)
 microemulsions
Soft capsules

 Encapsulated liquids:

 Water-immiscible liquids – oils, etc

 Eg vitamin E
 Water miscible liquids – alcohols etc

 Liquids that easily migrate through the

capsules cannot be used
Tests on capsules

 Compendial test methods and / or “in

house” methods are used to certify
these products, as with tablets. Test
requirements for capsules are
basically the same as for tablets
although soft gel caps may contain
preservatives which need to be tested
for.
Tests on capsules
 Disintegration – same equipment as tablets
 Dissolution – same equipment as for tablets
 Weight variation – contents (weight)
corrected for Assay result
 Content uniformity – Individual Assays done
– if one piece capsule, how can we assay?
 Stability testing – on contents and capsules
(by observation, disintegration, etc)
 Moisture permeation
 Most of these are in common with tests
done on tablets
Tests on capsules
HGC’s can become subject to a
phenomenon called “cross-linking” in
which the gelatin molecules cross link
due to some chemical reaction which
usually takes place over time.
This causes the HGC to become very
elastic-like in the presence of liquids
Why would this be such a concern?
How would we show that cross linking
has not occurred?
Tests on capsules
 Disintegration (not as common as for tabs)
 Dissolution
 Content uniformity – usually by individual
assay
 Potency ( Assay -strength of dosage vs
label claim)
 Purity (of contents as well as capsule itself)
 Stability testing – monitor potency and purity
 Moisture permeation – why important?

Most of these are in common with tests done

on tablets
Assay and Purity
Assay – a confirmation of a dosage forms label
claim (ie 325mg acetaminophen capsule
must contain about 325mg for each
capsule)
Result expressed as actual mgs/cap and as a
percentage of the label claim

Purity – a check of the API’s “cleanliness”. Is it

pure or does the dosage form contain
unwanted substances derived from the API
– ie has it degraded?
Capsules and Tablets

All (most) drug dosage forms (solid, oral,

liquid) must be tested in order to
demonstrate essential characterisitcs:
1. Purity
2. Identity RECALL??
3. Strength
4. Quality
“PISQ” – what tests will indicate these ?
Compressed tablets

Purity – test sample for levels of

impurities. Impuritites are compounds
contained in the dosage form that are
not API and are not excipients.
They are usually by products formed due
to API degradation and are often toxic
rather than therapeutic
This is known as “Impurity” testing
Compressed tablets

Identity – test sample to show( prove) that the

dosage form contains the active ingredient
that it says it contains.
Can compare to a standard (pure API) using
some analytical method in order to do this
Record and report the physical description as
well. (Why?)
This together is known as “Identification”
Compressed tablets

Strength – test sample to show (prove)

that the dosage form contains the
amount of active ingredient that it says
it contains (label claim)
This is known as “Assay” or “Potency” or
“Content Uniformity” since content
uniformity is really an assay
Compressed tablets

Quality – test sample to show that the

dosage form will maintain its integrity
and will perform as expected
These are the physical tests such as
hardness, friability, disintegration and
perhaps most important of all,
Dissolution
Disintegration

Conventional capsules do not undergo

the same disintegration process that
tablets do
(why not)

Usually, the only limiting step to

disintegration is the capsule shell itself.
Disintegration

This means that if the capsule shell does

not disintegrate readily, content
exposure and subsequent dissolution
will be delayed or may not happen at
all

Once the capsule contents are exposed,

dissolution can begin
Disintegration

For non-conventional capsules, capsule

contents may require a different
disintegration and / or dissolution
process
Conventional caps – contain free flowing
powder
Non conventional caps – may contain
“plugs”, beads, pellets, small tablets
Disintegration

For HG capsules – disintegration and

subsequent dissolution of the capsule
shell begins at the shoulder of the
capsule