Transcript Controlled Release Caps

Compounding
Capsules
Dr. Muslim Suardi, MSi., Apt.
Faculty of Pharmacy University of Andalas
Capsules
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“Capsules are gelatin shells filled with
the ingredients that make up an
individual dose”
Dry powders, semi-solids, & liquids
that do not dissolve gelatin may be
encapsulated.
±20% of all prescriptions dispensed in
capsules
Advantages
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May be used to mask the unpleasant
tastes, aromas, or appearance of a
drug.
Allow powders to be dispensed in an
uncompressed form, thus allowing for
quicker dissolution & absorption of the
drug following oral dosing (as
compared with tablets).
Advantages
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Administration routes: oral, inhalation,
rectal, or to be diluted for vaginal,
rectal, oral or topical use.
Easier than tablets for some people to
swallow.
Can be make to alter the release rate
of the drug.
Disadvantages
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Easily tampered with (although
techniques exist for preventing this).
They are subject to the effects of RH
& to microbial contamination.
Difficult for some people to swallow.
More expensive (commercially).
Hard Gelatin Capsules
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Consists of a base or body & a shorter
cap, which fits firmly over the base of
the capsule.
For human use, eight sizes of capsules
are available. The capacity of each
size varies according to the
combination of drugs and their
apparent densities.
Hard Gelatin Capsules
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Available as clear gelatin capsules or in
a variety of colors.
Different colored capsules to
distinguish 2 capsule formulations for
the same patient, or to encapsulate
unattractive ingredients.
A dye can be added to the powder
before filling a clear capsule to impart
a color for identification or esthetics.
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Some types of hard gelatin capsules
have a locking cap, which makes it
more difficult to reopen the capsule
Relative Sizes &
Capacities of Capsules
Capsule
Size
Volume (ml)
Lactose (mg)
Acetosal (mg)
000
1.37
1340
1000
00
0.95
929
600
0
0.68
665
500
1
0.50
489
300
2
0.37
362
250
3
0.30
293
200
4
0.20
195
125
5
0.13
127
60
"Punch" Method of
Compounding Capsules
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Punch method to hand fill capsules at
the prescription counter
The ingredients are triturated to the
same particle size & then mixed by
geometric dilution.
The powder is placed on a powder
paper or ointment slab & smoothed
with a spatula to a height
approximately half the length of the
Punch Method
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The base of the capsule is held
vertically & the open end is repeatedly
pushed or "punched" into the powder
until the capsule is filled; the cap is
then replaced to close the capsule.
Each filled capsule is weighed using an
empty capsule as a counterweight.
Punch Method
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Powder is added or removed until the
correct weight has been placed in the
capsule.
The filled capsule is tapped so that no
air spaces are visible within the
contents.
Capsule Machines
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Available for filling 50, 100, & 300 cap
at a time.
Each manufacturer's machine is
slightly different in its operation, but
the series of operations is the same.
Cap are first loaded into the machine.
Most machines come with a capsule
loader which correctly aligns all of the
capsules in the machine base.
Capsule Machines
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There are plates on the machine base
that can be adjusted.
First, the plates are adjusted to hold
the capsule bodies in place while the
caps are removed all at one time.
The caps remain in place in the top of
the machine for later use.
Capsule Machines
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Then the plates are adjusted again so
that the capsule bodies will "drop" into
place so that the tops are flush with
the working surface of the plate
There are plates on the machine base
that can be adjusted. First, the plates
are adjusted to hold the capsule
bodies in place while the caps are
removed all at one time.
Capsule Machines
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The caps remain in place in the top of
the machine for later use. Then the
plates are adjusted again so that the
capsule bodies will "drop" into place so
that the tops are flush with the
working surface of the plate
Capsule Machines
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The formulation powder is poured
onto the plate and special spreaders
and combs are used to fill the
individual capsules. Some
manufacturer's have special shakers
that will also help spread the powder
and fill the capsules. The powder is
spread evenly over the plate, and the
comb is used to tamp and pack the
powder into the capsules.
Capsule Machines
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These two processes are repeated
over and over again until the capsule
bodies are filled with the powder. All
of the caps are then simultaneously
returned to the capsule bodies, and
the closed capsules are removed from
the machine.
Capsule Machines
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The machine has the advantage of
filling many capsules in a timely
manner. However, there is a tendency
to pack the capsules in the middle of
the plate with more powder than the
capsules along the periphery. It takes
practice to ensure that each capsule
has the same amount of drug. A
quality control procedure should be
executed with each batch of capsules
Final Processing
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Once the capsules have been
compounded and the capsule closed,
the pharmacist may want to "seal" the
capsule.
The best way is to use "locking"
capsules, where the body and cap lock
together, making it very difficult to
open the capsule again.
Final Processing
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If using locking capsules, during the
filling process the cap is not
completely closed onto the body in the
weighing procedure to determine the
weight of powder in the capsule. The
locking is done only one time and that
is after the capsule is correctly filled
Final Processing
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If locking capsules are not used, a
seal can be made by touching the
outer edge of the body with a moist
towel to soften the gelatin.
Alternatively, a cotton swab dipped in
warm water can be rubbed around the
inner edge of the cap. When the cap is
closed on the body, it is slightly
twisted to form the seal
Final Processing
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When compounding and sealing are
complete, the capsules may need
cleaning to remove fingerprints, traces
of body oils, or loss powder from the
capsule. Fingerprints and oils cannot
be effectively cleaned from capsules
so the best way to prevent these
problems is to wear gloves during the
compounding process. Any clinging
powder can be removed by rolling the
Final Processing
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Another proposed cleaning method is
to put the capsules in a container filled
with sodium bicarbonate, sugar, or
sodium chloride, and gently roll the
container. Then the container contents
can be poured into a ten-mesh sieve
where the "cleaning salt" will pass
through the sieve.
Final Processing
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Capsules should be visually inspected
and checked for:
Uniformity - check capsules for
uniformity in appearance and color.
extent of fill - check capsules for
uniformity of extent of fill to ensure
that all capsules have been filled.
locked - check capsules to ensure that
they have all been tightly closed and
Quality Control
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USP requires that the capsule, "shall
not be less than 90% & not more than
110% of the theoretically calculated
weight of each unit.
It is possible to have capsules that
pass the weight variation requirement
but not have content uniformity.
Quality Control
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Content uniformity test: measures the
variability in the amount of active drug
contained in each capsule.
It is possible to have capsules that
pass the weight variation requirement
but not have content uniformity. This
can occur if the material put into the
capsules is not a homogenous mixture
of all the ingredients
Quality Control
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Some caps would then have more
active drug than other caps.
Appropriate mixing: geometric dilution
of all caps ingredients into a homogenous mixture before filling the caps.
The weight variation data will be
sufficient to ensure the quality of the
caps.
Additional Considerations
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Caps are made of gelatin, sugar, &
water & contain ±10-15% moisture.
Gelatin can absorb up to 10x its
weight in water.
So if gelatin caps are placed in areas
of high humidity, they will become
malformed or misshapened as they
absorb moisture.
Additional Considerations
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If caps are placed in low RH, they
become dry & brittle & may crack.
To protect caps from the extremes of
RH, they should be dispensed in
plastic or glass vials & stored in a cool,
drug place.
It appears that a storage RH of 3045% is best.
Cotton can be placed in the top of the
Additional Considerations
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If powders that are being mixed
before encapsulation are very light
and fluffy and "difficult to manage,"
add a few drops of alcohol, water, or
mineral oil. As an alternative, mix
these powders in a plastic bag. If the
powders seem to have a "static
charge," use about 1% sodium lauryl
sulfate.
Additional Considerations
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Mg stearate <1% can be added to
powders to increase their "flowability"
which makes filling caps easier.
Mg stearate is a hydrophobic
compound & may interfere with the
dissolution of the powders
Controlled Release Caps
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HPMC, or Methocel, is a cellulose
derivative polymer that is used as a
hydrophilic matrix material.
When Methocel hydrates, it forms a
gel of such consistency that drug
diffusion through the gel can be
controlled.
Controlled Release Caps
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A hydrophilic matrix controlled release
system is a dynamic system composed
of polymer wetting, polymer
hydration, & polymer dissolution.
At the same time, other soluble
excipients or drugs will also wet,
dissolve, & diffuse out of the matrix
while insoluble materials will be held in
place until the surrounding polymer
Controlled Release Caps
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Initially, the surface becomes wet &
Methocel polymer starts to partially
hydrate forming a gel layer on the
surface of the capsule.
As water continues to permeate into
the caps, the gel layer becomes
thicker, & soluble drug will diffuse out
through the gel layer.
Controlled Release Caps
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Ultimately, water will dissolve the caps
shell & continue to penetrate into the
drug core. So release is controlled by
the dissolution of soluble drug into the
penetrating water & diffusion across
the gel layer
Controlled Release Caps
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To formulate a successful hydrophilic
matrix system, the polymer substance
must wet & hydrate to form a gel layer
fast enough to protect the interior of
the caps from dissolving &
disintegrating during the initial wetting
& hydration phase. If the polymer is
too slow to hydrate, gastric fluids may
penetrate to the caps core, dissolve
the drug substance, & allow the drug
Controlled Release Caps
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Even among the family of HPMC
products (Methocel E, F, & K), there
are significant differences in the rate
at which the polymers will hydrate.
This is due to the varying proportions
of the 2 chemical substituents
attached to the cellulose backbone,
HPC & methoxyl substitution
Controlled Release Caps
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Even among the family of HPMC
products (Methocel E, F, & K), there
are significant differences in the rate
at which the polymers will hydrate.
This is due to the varying proportions
of the 2 chemical substituents
attached to the cellulose backbone,
hydroxypropoxyl and methoxyl
substitution
Controlled Release Caps
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The methoxyl substituent is a
relatively hydrophobic component &
not contribute as greatly to the
hydrophilic nature of the polymer &
the rate at which it will hydrate.
The hydroxpropoxyl group does
contribute greatly to the rate of
polymer hydration.
Controlled Release Caps
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As a result, Methocel K products are
the fastest to hydrate because they
have the lower amount of the
hydrophobic methoxyl substitution & a
higher amount of the hydrophilic
hydroxypropoxyl substitution.
The range of chemical substitution in
Methocel products is shown below.
Chemical Substitution in
Methocel
Products
% Methoxyl
% Hydroxypropoxyl
Relative Rate of Hydration
Methocel K
19-24
7-12
Fastest
Methocel E
28-30
7-12
Next Fastest
Methocel F
27-30
4-7.5
Slow
Methocel A
27.5-31.5
0
Slowest
Controlled Release Caps
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Increasing the conc of the polymer in a
matrix system increases the viscosity of the
gel that forms on the caps surface.
An increase in the conc of the polymer used
will generally yield a decrease in drug
diffusion & drug release.
An increase in the conc of polymer also
tends to put more polymer on the caps
surface. Wetting is more readily achieved so
gel formation is accelerated
Measuring Drug Release
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This sample experiment was
conducted in water & showed that
after 2.5h, release was still continuing
from the controlled release caps
Rate of Release
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Determined by plotting the Cumulative
Amount Released vs some function of
time.
For matrix diffusion controlled release,
adaptations of the Higuchi eq are used;
time is expressed as the square root of
time & has units of min1/2. A linear
trendline is fit through the points that
occur after a lag time or before any
asymptotic values are reached.
Rate of Release
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Release of salicylic acid in 0.01N HCl is
shown in the plot below.
Conventional caps apparently released
all of its contents by 30min, since after
that time the amount released
remained constant.
Release rate was 1.55 mg/min1/2
which is almost 3x as fast as seen with
the controlled release caps
Rate of Release
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But more importantly, the controlled
release caps continuously releases
drug for hours, where the
conventional capsule released all the
drug within 30min