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Section 8
Hard Shell Capsules
By Larry L. Augsburger, Ph.D., University of Maryland, School of Pharmacy, Baltimore, Maryland
Table of Contents
Hard Shell Capsules
Table of Contents.......................................................................................................................1
Types of Capsules......................................................................................................................... 2
Why Capsules? ............................................................................................................................. 2
What Are the Down-Sides? .......................................................................................................... 3
Filling Hard Shell Capsules ........................................................................................................... 4
Semi-Automatic Machines........................................................................................................ 4
Fully Automatic Machines......................................................................................................... 4
Dosing-Disc Machines.......................................................................................................... 5
Dosator Machines................................................................................................................. 6
SUPAC Equipment Guidance ....................................................................................................... 7
Instrumented Filling Machines and Filling Machine Simulators ................................................... 7
Design of Direct-Fill Formulations ................................................................................................ 7
Selection of Excipients ............................................................................................................. 7
Fillers..................................................................................................................................... 7
Glidants................................................................................................................................. 8
Lubricants ............................................................................................................................. 9
Disintegrants ....................................................................................................................... 10
Surfactants.......................................................................................................................... 10
Hydrophilization ...................................................................................................................... 10
Granulation.............................................................................................................................. 10
Direct-Fill Formulation Strategy and Capsule Size..................................................................... 11
Statistical Methods in Formulation Development....................................................................... 11
Expert Systems for Formulation Support ................................................................................... 11
General References..................................................................................................................... 12
Literature Cited ........................................................................................................................... 12
1
Hard Shell Capsules
hard gelatin capsules remain the heavily predominant type of hard shell capsule.
Types of Capsules
Capsules are “container” dosage forms in which
the formulation is contained in shells usually
comprised of gelatin. Gelatin capsules are classified as soft or hard, depending on the nature of
the shell and its contents. The original gelatin
capsule is the soft gelatin capsule. In this case,
the shell is plasticized with glycerin, sorbitol or
other polyhydric alcohols that impart a degree
of flexibility to the shell material. Typically, these
capsules are considered “one-piece” capsules.
They are formed, filled and sealed in a single,
continuous process, usually in a rotary die
machine. Generally, soft gelatin capsules are
filled with a pumpable liquid phase (solution,
suspension, etc.): in most cases, these formulations are developed and filled for the industry
by specialty soft gelatin capsule contractors.
This discussion will focus on the formulation and
filling of hard shell capsules.
Why
WhyCapsules?
Capsules?
Among solid dosage forms, the capsule is second only to the compressed tablet in frequency
of utilization for drug delivery. Given the unique
advantages of this dosage form, the popularity
of the capsule should not be surprising. For
instance, because the medication is contained
within the capsule shell, the capsule provides a
tasteless, odorless delivery system without the
need for a secondary coating step. And many
patients perceive that swallowing capsules is
easier than swallowing tablets. Easy swallowing
may derive from the tendency for the shell to
hydrate rapidly and become slippery in the
mouth, the tendency for the capsule to float
when taken with a fluid and, because of its
oblong shape, a tendency to assume an
orientation that favors passage down the
throat. Indeed, surveys have consistently
supported a generally favorable attitude of
consumers toward capsules(1,2).
The two-piece hard gelatin capsule consists of
a cap-piece that slips over the open end of a
body-piece. The shells are fabricated and
supplied empty to the pharmaceutical industry
by shell suppliers. The contents are formulated
and filled into the hard gelatin capsules by the
pharmaceutical manufacturer without resort to
a specialty contractor. Sealing is most often
accomplished by a separate process that applies
a band of gelatin around the midsection of the
filled capsule where the cap overlaps the body.
Generally, the fill materials will be dry solids, e.g.,
powders, granules, beads, or tablets. Pumpable
liquid phases also may be filled into hard gelatin
capsules; however, effective sealing is required
to assure no leakage. In other cases, a warm
liquid phase may be filled into the capsule that
sets to a semi-solid matrix upon cooling.
From the formulator’s point of view, hard
shell capsules provide unique capabilities and
options for dosage form design and formulation.
Because the contents are contained within the
shell, there is no need to form a compact that
must stand up to handling in the same sense as
a compressed tablet. This means that with an
appropriate choice of excipients, it may be
possible to direct-fill into capsules many larger
dose actives that could not be tableted without
a granulation step. In addition, modern capsule
filling machines make possible the multiple
filling of beads, granules, tablets, powders
and pumpable liquids into hard shells, and this
provides the formulator with numerous options
to design unique delivery systems or simply to
separate incompatible substances within the
same capsule. Because tablets may be filled
Although hard shell capsules are traditionally
made from gelatin, capsules fabricated from
hydroxypropyl methylcellulose or a starch
hydrolysate have appeared on the market in
recent years. Such alternatives to gelatin will
be of interest to those who, for religious, cultural
or other reasons wish to avoid capsules made
from animal derived components. However,
2
available which are capable of filling as many
as 100,000 or more capsules per hour.
into capsules (“super-encapsulation” or “overencapsulation”), capsules are frequently used
to double-blind clinical studies. Finally, most
Phase I development studies are carried out
with capsule formulations because of the
relative simplicity of formulation and manufacture, even though the final formulation may be
slated to be a compressed tablet. In certain
instances, it may be possible to design a
formulation that will run on a capsule filling
machine or a tablet press with equal facility.
Gelatin capsules may not be appropriate for
certain, strongly hygroscopic substances. The
physical stability of gelatin capsules is dependent upon maintaining an equilibrium moisture
content in the shell of about 13-16%. If the
moisture content drops much below this range,
the shells tend to become brittle. At moisture
contents much above this range, the shells tend
to become soft and sticky at the extreme. Since
most of the moisture associated with hard gelatin capsules is free water, it can move into or
out of the shell fairly easily, and the direction
will depend on the relative hygroscopicity of
the contents and the nature of the surrounding
atmosphere.
The ability of automatic filling machines to fill
pumpable liquids into hard shell capsules also
provides flexibility for the formulator. Liquid filled
capsules may offer special advantages for formulating poorly soluble drugs, since they could
be solubilized or dispersed (in micronized form)
in the liquid vehicle. At the same time, the utilization of liquid filling may enhance the chances of
attaining desired content uniformity of very low
dose drugs owing to the accuracy of liquid
pumping mechanisms and the avoidance of
dry-solids mixing problems, through dissolution
or dispersion of the drug in micronized form
in the liquid vehicle.
Gelatin capsules are also subject to cross-linking
on exposure to traces of aldehydes, or upon
storage for sufficiently long periods of time at
extremes of temperature or humidity. This
cross-linking leads to loss of aqueous solubility
of the shell. Moderately stressed capsules may
fail to meet USP dissolution standards in media
without enzymes, but bioavailablity may not
necessarily be compromised in such cases
owing to the presence of proteolytic enzymes
in gastrointestinal fluids that can metabolize the
cross-linked gelatin. An FDA/Industry Working
Group has recommended a two-tiered dissolution test(3): if the capsules fail the dissolution test
[vehicle not containing enzymes], “conduct the
second tier in the same medium and under the
same conditions as the first tier, with the exception that enzyme will be added to the medium.”
If the gelatin capsule passes the second tier
test, its performance is considered to be
acceptable.
Finally, hard shell capsules provide ideal vehicles
for dispensing modified-release beads or granules, since these may be filled into the capsules
without the need for a compression step that
could rupture or otherwise damage controlledrelease coatings and thus, undermine the
designed-in drug release profile.
What
thethe
Down-Sides?
WhatAre
Are
Down-Sides?
The size capsule selected will be governed by
the powder bulk. Low bulk density, bulky substances may require granulation prior to capsule
filling. In general, capsule sizes should be as
small as practical. This not only facilitates
swallowing but also reduces packaging and
shipping costs. Although larger capsules are
sometimes employed, most consumers can
manage capsule sizes up to #0.
The hydroxypropyl methylcellulose-based
capsules now commercially available may avoid
both the cross-linking and moisture sensitivity
concerns; however, there currently is limited
literature on the properties and performance
of these capsules compared to gelatin(4,5).
Capsule filling machines are not as fast as tablet
presses; however, fully automatic machines are
3
body ring on another turntable that rotates
beneath the foot of the powder hopper. An
auger in the hopper rotates to encourage a
more or less constant downward flow of the
formulation while the filling ring rotates. The
amount of formulation delivered to the capsule
bodies depends primarily on the dwell time of
the bodies under the foot of the hopper, i.e., the
speed of rotation of the filling ring. Fill weight
uniformity depends primarily on uniformity of
flow from the hopper, and formulations should
be designed accordingly. Maintaining a more
or less uniform bed height in the hopper is also
important to the maintenance of a uniform
powder feed rate. However, any overrun of
already filled capsules under the hopper can
cause an increase in the fill weight of those
capsules. Some fill weight variation also can
result because of differences in the angular
velocity of capsule bodies in the filling ring at
different radial distances from the center of
rotation. Examples of these “ring machines”
are Capsugel Cap 8 and Qualifill 8S machines.
Filling Hard Shell Capsules
Regardless of their mechanical design, all hard
shell capsule filling machines have the same
operational steps in common: rectification,
capsule separation, filling, closure of the
capsule, and ejection of the filled and closed
capsule from the machine. Rectification is a
mechanical process that causes the empty
capsules to be lined up all in the same direction,
i.e., body-end downward, as they are introduced
into the filling mechanism. For capsule separation, the rectified capsules are introduced into
a split bushing, or its equivalent. The bushing
consists of an upper part and a lower part. A
vacuum is applied from the bottom piece to
cause the body to be drawn into the lower
section of the bushing. The cap remains in
the upper bushing piece because its diameter
is too large to permit it to follow the body piece.
The two bushing pieces are then separated to
expose the body piece for filling. In the filling
step, one of several possible mechanisms is
utilized to fill the body. In capsule closure, the
cap and body bushings are brought back together and the cap and body pieces are rejoined via
push pins. In most cases, ejection of the filled
and closed capsules from the bushing is caused
by push pins; in some cases, compressed air
may be utilized for this purpose.
Reier, et al.(6) and Ito, et al. (7) have contributed
excellent discussions of the factors affecting
encapsulation of powders on such machines.
Fully Automatic Machines
Most modern automatic filling machines employ
pistons or tamping pins that lightly compress
the powder into plugs (sometimes referred to
as “slugs”), and eject the plugs into the empty
capsule bodies. The compression forces are low,
often in the range of 50–150N, up to about 100fold less than that employed in typical tablet
compression. Often, the plugs will be very soft
compacts and not able to be recovered intact
from filled capsules. There are two main types
of these fillers: dosator machines and dosingdisc machines. In a recent survey of the pharmaceutical industry, it was reported that dosator
machines were used slightly more frequently
among the firms responding; however, about
18% of the firms indicated that they use both
types of filling machines(8).
Semi-Automatic Machines
Semi-automatic machines, which require an
operator to be in attendance at all times, were
once the workhorses of the capsule filling industry. Today, they are more likely to be employed
when smaller batch sizes are required, such
as production of early phase clinical supplies.
Quoted production capacities for powder filing
range from 6000-8000 capsules/hour up to as
high as 15,000 capsules/hour, depending on
the capsule size. The rectified capsules are
delivered into holes in a split ring (equivalent
to the split bushings above). As the ring rotates
on a turntable, vacuum pulls the capsule bodies
into the lower ring, leaving the caps behind in
the upper ring. After capsule separation, the
operator separates the rings and places the
4
lation, size of tooling and powder depth over
the disc, the fill weight achieved is determined
primarily by the thickness of the dosing disc and
the piston penetration setting (or tamping force).
Dosing-Disc Machines: This filling principle has
been described in numerous places (9-10). The
basic operation is illustrated in Figure 1. The
dosing-disc forms the base of the dosing or
filling chamber. The dosing-disc is provided with
holes that are closed off by a solid brass “stop”
plate that slides along the bottom of the disc to
form the dosing cavities. In most machines, the
cavities are indexed under tamping pins at each
of five tamping stations (Fig. 1). The formulation
is maintained at a somewhat constant level
over the dosing-disc. A capacitance probe
senses the powder level and activates an auger
feed mechanism when the powder depth falls
below a preset level. As the disc rotates (indexes), the formulation is distributed over the disc
by centrifugation with the assistance of baffles
mounted to the disc. Powder falls into the
dosing cavities as they move from one tamping
station to the next. Additional powder is pushed
into the dosing cavities by the descending
tamping pins at each tamping station. Each
plug is thus tamped five times. Excess powder
over the disc is scraped off as the dosing-disc
indexes the plugs to the ejection station where
they are positioned over empty capsule bodies
and ejected by transfer pins. For a given formu-
Kurihara and Ichikawa(11) found a minimum in the
relationship between the angle of repose of the
powder and the coefficient of variation of fill
weight in a dosing-disc machine. This observation suggests that a certain flow criterion may
be required for maximum fill weight uniformity.
At higher angles of repose, powders may not
have sufficient mobility to distribute well over
the dosing disc. At lower angles of repose, the
powder may be too fluid to maintain a uniform
bed. A different situation can be expected for
machines fitted with agitators to facilitate distribution of the powder over the dosing disc.
Formulations for these machines should be
adequately lubricated to prevent filming on
pins, to reduce friction between any sliding
components that the formulation comes into
contact with, and to facilitate plug ejection.
Some degree of formulation compactibility is
desirable for clean, efficient plug transfer at
ejection.
Figure 1: Diagrammatic representation of the dosing disc filling principle.
Five tamping stations (1–5) and plug ejection are illustrated.
Powder Bed
1
Scrape-off
Mechanism
2
3
4
5
Ejection
Dosing
Disc
Plug
“Stop” Plate
Capsule Body
in Bushing
5
Dosator Machines: Figure 2 illustrates the
dosator principle, which has been previously
described(12, 13). The dosator consists of a moveable piston inserted in a cylindrical tube. The
position of the piston is preset to a height that
defines a volume that would contain the desired
dose of the formulation (Fig. 2, A). During the
filling process, the open end of the dosator is
first pushed down into a powder bed the depth
of which has been pre-set and is maintained at
that level by agitators and scrapers. Powder thus
enters the open end of the dosing tube where it
is slightly compressed against the piston (Fig. 2,
B). Before the dosator is lifted from the powder
bed, the piston may be used to deliver a tamping blow that further compresses the forming
plug (Fig. 2, C). The dosator bearing the plug
is then lifted from the powder bed (Fig. 2, D)
and positioned over an empty capsule body
where the piston is thrust downward to eject
the plug (Fig. 2, E). In certain machines, the
empty capsule body is moved into position
under the raised dosator to receive the ejected
plug. For a given size of tooling, the fill weight
attained for a given formulation is determined
primarily by the initial height of the piston in
the dosing tube, and secondarily by the height
of the powder bed.
Figure 2: Diagrammatic representation of the dosator filling principle.
Lower end of piston
Ejection
Dosing tube
Compression
A
Piston
Height
Setting
Powder
Bed
Height
D
Plug
B
C
Key: A – Initial piston height setting;
B – Modest plug compression as dosator dips into powder bed;
C – Active piston compression of the plug;
D – Plug transport to ejection station;
E – Ejection of plug into capsule body.
6
E
SUPAC Equipment Guidance
Design of Direct-Fill Formulations
Although hard shell capsules may be filled
with modified release beads, liquids or semisolid matrices, this discussion will focus on
the use and selection of excipients for direct-fill
formulation.
The manufacturing equipment addendum to the
SUPAC-IR/MR guidances place the dosator and
dosing-disc types of capsule filling machines in
different subclasses of the same class of
machines. If machines fall within the same class
and subclass, they are considered to have the
same design and operating principle. A postapproval change of manufacturing equipment
between subclasses within the same class of
equipment likely would not require a preapproval supplement, provided certain other
conditions are met. But, changes in equipment
that are in the same class, but different subclasses, as would be case for a change between
a dosator machine and a dosing-disc machine,
should be carefully considered and evaluated
on a case-by-case basis. The guidance places
the burden on the applicant to provide the data
and rationale at the time of change to determine
whether or not a preapproval supplement is
justified. The reader should refer to “Guidance
for Industry, SUPAC-IR/MR – Manufacturing
Equipment Addendum,” FDA, CDER, January
1999 for a full discussion.
Selection of Excipients
As a general rule, all excipients used in a formulation should be screened for compatibility with
the drug substance.
Fillers: Depending on the dose of the drug,
fillers may be required to increase bulk. Starch
and lactose are the most common capsule fillers;
certain inorganic salts such as magnesium and
calcium carbonate and calcium phosphate are
also sometimes used in this role. Using fillers
whose flowability and compactibility have been
enhanced through physical modification (i.e.,
filler-binders for direct compression tableting)
is particularly advantageous in the development
of direct-fill formulations for automatic capsule
filling machines. These include, for example,
pregelatinized starch (Starch 1500®), spray
processed lactose (Fast-Flo® Lactose) and
unmilled dicalcium phosphate dihydrate (Ditab®;
Emcompress®), and microcrystalline cellulose
(Avicel®). Formulations for dosator machines in
particular may benefit from the greater compactibility of such fillers, particularly when drug
dosage is large, since it is essential to prevent
powder loss from the end of the cylinder during
the transfer from the powder bed to ejection into
the capsule body. The compactibility of such
fillers should contribute to the formation of a
stable arch at the dosator open orifice(23) and
the formation of mechanically strong plugs. The
failure to have a cohesive plug may also cause
a “blow off” of powder as the plug is ejected
into the shell. The high compactibility of microcrystalline cellulose that is well recognized in
direct compression tableting may be of
particular benefit in direct-fill capsule formulations. Numerous studies reporting the use of
microcrystalline cellulose in direct-fill capsule
formulations filled on dosator or dosing disc
Instrumented Filling Machines
and Filling Machine Simulators
Both dosator(13-15) and dosing-disc machines(16-18)
have been instrumented to permit measurement
of the tamping or compression forces developed
in plug formation and plug ejections forces.
These developments have enabled systematic
study of the relationship of formulation and
process variables to manufacturability and drug
dissolution from capsules. More recently, that
research has been extended by the use of
simulators that can mimic certain filling
machines (19-21) or certain aspects of machine
filling(22) under controlled laboratory conditions
with small quantities of material.
7
machines or simulators have been reported(8, 10, 13,
15-18, 22)
. Patel and Podczeck(24) studied several
microcrystalline celluloses in a dosator machine
(Zanasi AZ5) and concluded that medium and
coarse particle size grades can be considered
good excipients for capsules. In a more recent
study, silicified microcrystalline cellulose and
microcrystalline cellulose were found to be good
plug formers when tested in a compaction simulator at tamping forces and piston speeds similar
to those found in some filling machines(25). The
materials were tested neat using a prelubricated
die. Several grades of silicified microcrystalline
cellulose and a control grade of microcrystalline
cellulose (typical particle size of 90 µm) produced plugs having higher maximum breaking
force than anhydrous lactose and Starch 1500
under similar compression conditions.
2. Caution may need to be observed when
large amounts of soluble fillers are used in
combination with soluble drugs, as the
dissolution of the filler may interfere with
the dissolution of the drug.
For example, it was reported(29) that the
inclusion of 80% lactose in a capsule
formulation severely slowed the dissolution
of water-soluble chloramphenicol, and there
was little or no effect on dissolution when
adding up to 50% lactose.
3. Formulators may need to consider the
potential impact of the pH-dependence of
the filler on the population to be served by
the product.
The intrinsic dissolution rates of dicalcium
phosphate dihydrate, anhydrous dicalcium
phosphate, and calcium sulfate dihydrate
have been reported(28). The dramatically
reduced intrinsic dissolution rates exhibited
by these fillers under less acidic conditions
suggested that they should be used with
caution in formulations intended for populations that may exhibit achlorhydria, such as
the elderly. The presence of high levels in
the formulation may substantially delay
disintegration and dissolution.
Although the choice of the filler can impact
on running characteristics, formulators must
also consider any potential impact on drug
dissolution. The solubility characteristics of
both the drug and the filler should be considered. Following are some considerations that
may be helpful to formulators:
1. Generally, soluble fillers should be selected
for poorly soluble drugs.
In one commonly cited example(26) the dissolution of poorly soluble ethinamate from
capsules improved greatly upon increasing
the concentration of lactose in the formulation to 50%. In another example(27), lactose
at a concentration of 50% was found to
enhance the dissolution of phenobarbital
from capsules, but had no effect on the
dissolution of the water soluble sodium
phenobarbital.
Glidants: Glidants in the form of finely divided
dry powders may be added to formulations in
small quantities to improve their flow properties.
Usually, there is a concentration for best flow.
For the colloidal silicas (e.g., Cab-O-Sil®,
Aerosil®) this concentration is often less than l%.
This optimum concentration varies with the
glidant and may be a function of the amount
needed to just coat the bulk powder particles(30,
31)
. Higher concentrations often will result in either
no further improvement in flow or a worsening
of flow. In addition to the colloidal silicas, cornstarch, talc, and magnesium stearate may exhibit
glidant activity in a formulation. York(32) compared
glidants and reported their order of effectiveness
for two powder systems as follows: fine silica >
magnesium stearate > purified talc.
The intrinsic dissolution rates of some fillers
have been reported(28). Anhydrous lactose
(predominantly the more soluble b-lactose)
was found to exhibit almost twice the
intrinsic dissolution rate of a-lactose
monohydrate.
8
machine for 30 minutes when the magnesium stearate level was 1%. Reducing the
level of magnesium stearate to 0.25% was
found to provide adequate lubrication and
dissolution was satisfactory over a 30
minute run. Satisfactory dissolution was
also reported when the magnesium stearate
was replaced with the more hydrophilic
Stear-O-Wet® (magnesium stearate
coprocessed with sodium lauryl sulfate)
and sodium stearyl fumarate.
Lubricants: Like tablet formulations, capsule
formulation usually requires lubrication. The
same lubricants and concentrations in formulations that are used in tablet formulations are
used in capsule formulations, and they provide
essentially the same functionality. Lubricants
can facilitate plug ejection and reduce filming
on piston or tamping pin faces. They can reduce
adhesion of powder to metal surfaces and
friction between sliding surfaces in contact with
the formulation. Hydrophobic substances such
as magnesium stearate, calcium stearate and
stearic acid are generally the most effective
lubricants. Of these, magnesium stearate is
used the most widely. The proper use of these
excipients involves several considerations:
Ullah, et al.(35) reported a similar problem
when scaling up a cefadroxil monohydrate
formulation containing 1% magnesium
stearate that was initially developed on a
Zanasi LZ-64 dosator machine. When scaled
up to a GKF 1500 dosing disc production
machine, dissolution was significantly slower
compared to the development batch. It was
suggested that shearing of magnesium
stearate during the tamping step may
increase the coating of the drug particles
with the hydrophobic lubricant. Based on
laboratory experiments with a small scale
mixer/grinder aimed at simulating the shearing action of the filling machine, they selected a level of 0.3% magnesium stearate for
scale up to 570 kg and 1100 kg (full production) size batches. Dissolution from both
scale up batches was found satisfactory.
1. Excessive concentrations of hydrophobic
lubricants such as magnesium stearate are
likely to retard drug release by making
formulations more hydrophobic.
2. Laminar lubricants (magnesium stearate,
calcium stearate) are “shear sensitive.”
During mixing the particles delaminate, i.e.,
shear, to form a film on the surfaces of the
bulk powder. If blended for a sufficient
length of time, even a low concentration of
a laminar lubricant can slow drug dissolution(33). In practice, it is best to add the
appropriate level of lubricant last and blend
for a minimum amount of time, typically 2-5
minutes.
4. In certain cases, an optimum level of
magnesium stearate has been reported
for best dissolution.
3. Mixing and delamination doesn’t necessarily
end after a blender is stopped: the powder
feed mechanism and/or the filling principle
of the filling machine can cause additional
mixing and shearing. It may be necessary to
reduce the level of the laminar lubricant or
consider other lubricant options to compensate for such effects.
Stewart et al.(36) studied the effect of magnesium stearate concentration on the dissolution of a model low dose drug, riboflavin
from capsules. They found that the effect
of the lubricant level was dependent on the
type of filler. Soluble fillers exhibited prolonged dissolution times with increasing
lubricant levels, but less predictable trends
were found with insoluble fillers. In certain
instances, insoluble fillers were only slightly
affected by the magnesium stearate; whereas, with microcrystalline cellulose, there
appeared to be an intermediate concentra-
Overmixing of magnesium stearate in the
hopper of an MG2 dosator machine in which
the powder in the hopper is continuously
mixed with a rotating blade was reported by
Desai, et al.(34). Dissolution of three drugs
was markedly reduced after running the
9
tion at which the dissolution rate was
fastest.
employed in capsule formulations include
sodium lauryl sulfate and sodium docusate(26, 43).
Generally, levels of 0.l-0.5% are sufficient. For
best results, surfactants should be finely divided,
especially if they have a low solubility and
dissolution rate.
Mehta and Augsburger(37) reported an
intermediate level of magnesium stearate at
which the dissolution rate of hydrochlorothiazide from capsules was best. Microcrystalline cellulose was the filler making up
more than 90% of the formulation. Based on
measurements of plug breaking strength it
was suggested that as the magnesium
stearate level was increased, any initial
increase in hydrophobicity of the formulation
may be more than offset by reduced plug
cohesiveness which probably promotes plug
dispersion and dissolution. At higher magnesium stearate levels, the hydrophobic effect
may be overwhelming, since dissolution was
observed to slow down. This possible dual
effect of magnesium stearate has also been
suggested by others(38) who found that the
dissolution rate of rifampicin from capsules
increased with lubricant blending time.
Hydrophilization
The wetability of poorly soluble drugs can be
enhanced by applying a hydrophilic polymer to
the drug surfaces(44). In this process, a solution
of the hydrophilic polymer, e.g., methyl cellulose,
is distributed onto the drug in a high-shear
mixer. The resultant mixture is dried and
screened.
Granulation
Often employed to increase the bulk of powders
for encapsulation, granulation also improves
flowability and can reduce the tendency of fine
particles to agglomerate or adhere to metal surfaces. Wet granulation provides for the addition
of a liquid phase in which a low dose drug may
be dissolved to promote its uniform dispersion
throughout the mass. Once locked into granules,
any subsequent segregation of the low dose
active is prevented. Since binders typically are
hydrophilic polymers, the wet granulation
process effectively accomplishes the
hydrophilization process described above.
When actives are sensitive to exposure to heat
and/or aqueous binder solution, formulations
may be dry granulated by slugging or roller
compaction, although the dry process does not
provide for the addition of the drug in solution.
The liquid addition of a low dose drug to fillers
may also be accomplished by dissolving the
drug in a non-aqueous solvent, spraying the
solution onto the filler, and evaporating the
solvent.
5. The metallic stearates are alkaline and
should not be used if the drug substance
is subject to alkaline hydrolysis or other
untoward reaction.
Disintegrants: Disintegrants can facilitate liquid
uptake and the dispersion of capsule plugs in
dissolution fluids. The newer classes of disintegrants, which have been called “super disintegrants,” have strong liquid uptake and swelling
potential, should be considered for inclusion in
direct-fill formulations for tamping or dosator
machines(39-41). These include croscarmellose
sodium (Ac-Di-Sol®), sodium starch glycolate
(Primojel®, Explotab®) and crospovidone
(Polyplasdone® XL). For capsules, the required
level of addition is often double that required for
tablets, and may be 4–8% or more, depending
on the formulation.
Surfactants: Surfactants can enhance drug
dissolution by increasing the wetting of the
powder mass, and at concentrations exceeding
the critical micelle concentration, they can
increase drug solubility(42). Common surfactants
10
be judged from their breaking force(16, 25), and
the ejectability of the plugs from the device
can be related to lubrication requirements.
Direct-Fill Formulation Strategy
and Capsule Size
The required dose and tapped bulk density of
the drug substance provide an initial estimate
of the minimum size of capsule that will contain
the medication. The actual size capsule formulated will depend on any excipient requirements
and/or marketing or patient acceptability considerations. Although larger sizes are sometimes
used, generally the largest size capsule that can
be easily managed by patients is a #0. The
difference between the tapped volume of the
desired drug dose and the volume of capsule
selected provides an initial estimate of the
volume available for excipients.
Statistical Methods in Formulation
Development
Increasingly, statistical techniques are being
used in the development of pharmaceutical
formulations or at least to clarify the critical
formulation and process variables and their
interactions. Recent examples of the application
of such techniques to hard gelatin capsule
formulations include the response surface
analysis of Piscitelli et al.(46) and the multivariate
analysis of Hogan et al.(47).
Expert Systems for Formulation
Support
A comparison of the loose (poured) bulk density
to the tapped density also gives an indication
of the flowability of the drug substance through
calculation of Carr’s compressibility index, CI,
as follows(45):
Cl =
Expert Systems are computer programs that
attempt to capture the expertise of experts in
a given field. Based on rules or decision trees,
these programs can facilitate the development
of a formulation by suggesting excipient and
levels and procedures after certain facts about
the drug are input (e.g., dose, solubility, flowability and others). Several expert systems for capsule formulation support have been described
in the literature(48-50).
(r1 - rb)
x 100
rt
Where rt is the tapped density and rb is the
loose bulk density. Powders with CI values less
than 15% are considered to have excellent flow;
those with values greater than 40% have very
poor flowability(45). As discussed, excipients may
be chosen to enhance both flowability and plug
formation. Powders having CI values in the range
of about 20-25 or lower should be acceptable in
many cases. Limitations owing to the bulk of the
drug may require the formulator to consider
granulation.
During development, formulations may be
evaluated in a simulator or other laboratory
plug forming device, such as a dosator mounted
to a physical testing machine (e.g., Instron) or
a plug tester such as that supplied by Bosch.
Plugs should be compressed with forces in the
operating range of the filling machine, often
50–100N. The required capsule size can be
related to the length of plugs so formed. Further,
the plug forming ability of the formulation can
11
machine-method,” Chem. Pharm. Bull. 1969,
17: 1138-1145.
General References
V. Hostetler, and J.Q. Bellard. “Capsules I. Hard
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8. P. Heda, “A comparative study of the formulation requirements of dosator and dosing
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