DEVELOPING THE

FORMULATION
18 LACAP, DIXIE MAE N.

What is
the GOAL?

To prepare a capsule with:

> Accurate dosage
> Good bioavailability
> Ease of filling &
production stability
> Elegance

DRY FORMULATIONS

active and inactive components must be blended

thoroughly to ensure a uniform powder mix for the fill.
-

! LOW-DOSE
!
!

DRUGS

Care in blending
Lack of homogeneity in blending may result in
significant therapeutic consequences.

! PRE-FORMULATION
!

STUDIES

To determine:

if all the formulations bulk powders may be

effectively blended together.

!
!

require reduction of particle size

any other processing to achieve homogeneity

DILUENT/FILLER

! added to

the
formulation to
produce the proper
capsule fill
volume

! provides

bulk and
cohesion to the
powder

! beneficial

in
transferring
powder blends into
capsule shells

DISINTEGRANTS

> Assist the breakup and distribution of the

capsules content in the stomach

HOW TO ACHIEVE UNIFORM DRUG

DISTRIBUTION?

*Density and particle of the drug and nondrug components

must be similar

! Particle

size
may be reduced
by:

! MILLING
! MICRONIZATION

MILLED POWDER
! Milling

process

! particles

ranging from
50 to 1000 micrometer

! blended

effectively for
uniform distribution
throughout a powder mix

! ONLY

IF the DRUG DOSAGE

is 10 mg or GREATER

MICRONIZED
POWDER
! Micronization Process
! DRUG DOSAGE:less than 10 mg
! P ARTICLE SIZE:1-20 um(mcm)
! f or lower dose or smaller
particles

HIGH SPEED AUTOMATED

EQUIPMENT

LUBRICANT/GLIDANT
! enhances
mix

! aids

flow properties of powder

in high-speed automated
equipment (industrial scale
production)

Magnesium Stearate
! (lubricant)

for its waterproofing

characteristics

! cant

be penetrated by the
gastrointestinal fluids

! delays

drug dissolution & absorption

useful for modified release capsule

SODIUM LAURYL
SULFATE
! surface
agent

active

! facilitates

wetting by the GI
fluids

! is

added to aid
drug dissolution
and absorption
delay

DISINTEGRATION
AGENTS
microcrystalline cellulose

! facilitates

breakup and
distribution of the
capsules content

! aids

GI fluids to
displace the air around
the powder for the
penetration to occur
and drug dispersion and
dissolution to start

Why do we INSERT CAPSULES/

TABLETS inside capsules?
! to

separate chemically
incompatible agents

! to

add pre-measured
amounts of potent drug
subs.
rather than weighing a potent
drug

COATED PELLETS
! (industrial

scale)

! designed

for
modified release
drug delivery

! commonly

placed in
capsule shells
DICLOMAX
diclofenac
SLOW RELEASE

GELATIN CAPSULES
! unsustainable

for
aqueous liquids

! water

softens
gelatin, causing
leakage

GELATIN CAPSULES
! FIXED

OR VOLATILE OIL

! do

not interfere with gelatin shell

ex POLYETHER
stability

! LOCKING

GELATIN CAPSULES/ Capsule

sealed with a THIN COAT OF GELATIN

! WET

MASS/PASTE

! fixed/volatile
! placed

oil with INERT POWDER

in caps. in usual manner

EUTECTIC MIXTURES
! mixtures

of agents that have a propensity

to liquefy when admixed

! mixed

with a DILUENT/ADSORBENT to
separate interacting agent & to absorb
any liquefied material that may form

LARGE SCALE CAPSULE

PRODUCTION
! liquids

are placed in SOFT GELATIN

CAPSULES that are sealed during filling &
manufacturing

IND. VS COMMUN.
! slight

loss in fill material during

preparation & capsule filling will not
materially affect an industrial sized
batch

! slight

loss of powder could result in an

inadequate quantity to fill the last
capsule
CP can calculate in excess of 1 or two capsules more than what is
required to fill the capsule EXCEPT when dealing with capsules
containing controlled subs!
amount of drug used & called for must STRICTLY COINCIDE

SELECTING THE
CAPSULE SIZE
18 LACAP, DIXIE MAE N.
DURING PRODUCT
DEVELOPMENT

FORMULATION
REQUIREMENTS
! dose of
! density

the active ingredient

and compaction
characteristics

Diluents are added when dose of the

drug is inadequate to fill the volume
of the capsule body

GUIDE IN SELECTING
CAPSULE SIZE
! density

& compaction characteristics

of a capsules active & inactive
components

! comparison to other
! prior experiences

similar materials

HARD GELATIN
CAPSULES
! encapsulates
! SMALLEST
!

65 mg- 1g

CAPSULE(#5)

65 mg or more

SELECTING THE
CAPSULE SIZE
! (extemporaneous)

best capsule size

determined by TRIAL

! SMALLEST PROPERLY FILLED capsule

! body filled with the drug mixture,
not the cap

Easy Method to Select

the Proper Capsule Size
! weigh

ing. for the REQUIRED # if caps

OFis to big
CAPSULES
caps size(ml) x #caps = FINAL
VOLUME

! place

then just add diluent to attain

powder in GRADUATED
the final volume
CYLINDER(take note of volume)

! divide volume by the

! compare the vol with

# of capsules

the approx. on
the table and select the caps. size
that will accommodate the powder

TETRACYCLINE CAPSULES
! ACTIVE

ING: Tetracycline
HCl (250 mg)

! FILLER:

Lactose

! LUBRICANT:
Stearate

Magnesium

! CAPS

COLORANT: FD&C
YELLOW#6

! CAPS

OPAQUANT:Titanium
dioxide

FILLING HARD CAPSULE

SHELLS
18 LACAP, DIXIE MAE N.

PUNCH METHOD

such weighing protects

against uneven filling of
capsules and premature
exhaustion or underuse of
powder

! amount

of powder packed into the

capsule depends on the degree of
compression

! should

punch each capsule in the same

manner and weigh the product after
capping

NONPOTENT drug - 1st filled capsule

is weighed

POTENT drug - EACH CAPS is weighed

PUNCH METHOD

24-300 caps per machine

HAND-OPERATED FILLING
MACHINE

200-2000 caps per hour

MACHINE DEVELOPED
FOR INDUSTRIAL USE
! automatically

separate
th caps from the empty
capsules
165000 caps per hour

! fills

the bodies
ACCURACY OF DRUG DOSGE IS
VERIFIED THROUGH

! scrapes

AYTOMATED
IN PROCESS
off the
excess

! replace

the caps

powder

! seals
! cleans

SAMPLING & ANALYSIS

the capsiles
the outside caps

CAPSULE SEALING
18 LACAP, DIXIE MAE N.

TAMPER EVIDENT CAPSULES

! KAPSEALS,
DAVIS

PARKE-

! seals

with a colored
band of gelatin

! if

removed, the band

cannot be restored
without expert
releasing with gelatin

TAMPER EVIDENT CAPSULES

!
!

HEAT-WELDING
PROCESS

! THERMAL

uses

COUPLING

a liquid
fuses cap to the wetting agent that
body through the
lowers the melting
double wall
point in the contact
thickness at their
areas of the cap and
juncture
body, and then
distinctive ring thermally bonds the
around the capsule two parts using low
where heat welded temp (40C-45C)

CAPSULE SEALING
! INDUSTRIAL CAPSULE SEALING MACHINES
! 60000 to 150000 gelatin banded, heat
welded or thermally coupled capsules
PER HOUR

! EXTEMPORANEOUSLY
! seal by lightly coating

the inner
surface of the cap with a warm
gelatin soln then immediately pour to
placement on the filled capsule body.

CLEANING AND
POLISHING CAPSULES
18 LACAP, DIXIE MAE N.

CLEANING & POLISHING CAPSULE

MACHINE