C H A P T E R
27
Capsules Dosage Form: Formulation and
Manufacturing Considerations
S.W. Hoag
University of Maryland, Baltimore, MD, United States
27.1 INTRODUCTION—CAPSULES AS A
DOSAGE FORM
Capsules are a unique dosage form with a long his-
tory of use in pharmacy. The original patent was issued
in 1834 to a Parisian pharmacist, Joseph Gérard Dublanc,
and pharmacy student, François Achille Barnabé
Mothès, for the invention and manufacture of gelatin
capsules.1 The basic idea of a capsule is to enclose the
drug or active pharmaceutical ingredient (API) in an
odorless, tasteless, elegant, easy-to-swallow, and easy-to-
fill shell. Today there are two main types of capsules: the
hard gelatin capsule and the soft gelatin capsule, often
called softshells. This chapter will focus on hard gelatin
capsules. The hard gelatin capsule can be used for dry
fills such as powder, liquids, and semisolids, while the
softshell is exclusively used for liquids and semisolids.
The typically capsule shell is made of gelatin, but in
recent years, there have been a variety of gelatin alterna-
tives introduced to the market. The vast majority of cap-
sule applications are for oral delivery of an API;
however, there are specialty applications such as cap-
sules that can be loaded into dry-powdered inhalers,
add reagents as part of a diagnostic kit, and occasionally
as a suppository base with glycerin.2 The majority of
capsules are filled with a dry powder; however, semiso-
lids, nonaqueous liquids, and other dosage forms such
as beads, mini tablets, and even mini capsules can be
filled into a capsule shell. These applications will be dis-
cussed. In terms of production, capsules are one of the
most flexible forms. They can be made one a time in a
compounding pharmacy, in small-scale production for
clinical studies, and all the way up to commercial pro-
duction with machines that can make hundreds of
Developing Solid Oral Dosage Forms
DOI: http://dx.doi.org/10.1016/B978-0-12-802447-8.00027-3
thousands of capsules per hour. Given the importance
capsules have in the pharmaceutical industry, the objec-
tive of this chapter is to give a broad overview of cap-
sules, gelatin, capsule manufacture, capsule filling, and
capsule formulation.
From the patient perspective, capsules have many
advantages, making them among the most popular dos-
age forms on the market. Generally speaking, most
patients consider capsule shells to be smooth, slippery,
and easier to swallow than tablets.3 In addition, cap-
sules eliminate all contact between the drug and the
mouth, which makes them tasteless and odorless, as
most drugs have a bitter taste with an unpleasant after-
taste. This greatly improves patient compliance and
consequently therapeutic outcomes. In addition, cap-
sules can be made with a clear, high-gloss film that can
be attractively colored and printed on, and they can
have an elegant appearance, which also enhances
patient acceptance. For patients who have trouble swal-
lowing, the capsule can be opened up, and the contents
sprinkled on a food such as applesauce, which is
advantageous for pediatric and geriatric patients.
From a drug delivery point of view, capsules have
many advantages. For immediate-release (IR) dosage
forms, a key step is the breakdown of the capsule shell,
which is analogous to disintegration in a tablet. For cap-
sules, this occurs readily; see the discussion of gelatin
cross-link in Section 27.2.2. Thus, capsules are ideally
suited for IR delivery. In addition, capsules can be used
for other types of release profiles as well. In addition to
dry powder fills, multiparticulate beads can be filled
into capsules, as shown in Fig. 27.1. For example, mor-
phine sulfate has a short half-life, and with an IR deliv-
ery system, it requires dosing every 8 hours, but with a
723 © 2017 Elsevier Inc. All rights reserved.
724 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
FIGURE 27.1 The different types of fills that can be put into
hard gelatin capsule shells. Source: http://www.epmmagazine.com/news/
empty-hard-capsules-and-barrier-packaging-films/.
Plasma concentration (ng/mL)
18
16
14
12
10
8 health care worker such as with parenteral products.
6 Nonself-administration products that are big sellers
4
2
0 as diabetes where the patient must regularly give him-
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (h)
AVINZA once-daily Morphine solution 6-times daily
FIGURE 27.2 Multiparticulate dosing of morphine sulfate with
Avinza, from the official FDA label.
controlled-release dosage such as Avinza or Kadian, it
can be dosed once a day, as seen in Fig. 27.2, which is a
big advantage in terms of compliance. For patients in
an institutional environment, it has greater convenience
for the nursing staff. In addition, with multiparticulate
beads, you can have a mixture of beads with different
release rates. If you look at the initial phase of the
plasma concentration versus time pharmacokinetic pro-
file in Fig. 27.2, you can see the initial onset is the same
as the oral solution. This is because the coated beads
are mixed with uncoated beads for rapid onset of pain
relief. In addition to putting multiparticulate beads in a
capsule, with modern filling equipment, you can also
fill capsules with other dosage forms such as mini
tablets and all possible combination of beads, tablets,
capsules, powders, and even liquids, as shown in
Fig. 27.1.4
From the company perspective, capsules can be
used throughout the entire drug development process
from preclinical studies in rodents to first-in-human
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
studies all the way through the commercial
manufacturing of a marketed product. While capsules
are not as cost effective as tablets to manufacture, cap-
sules are still relatively inexpensive to manufacture,
and being a solid dosage form with a dry powder fill,
capsule formulations promote good stability compared
to other delivery systems such as liquid formulations.
Another advantage of capsules is the relative ease of
formulation. For initial formulations, the formulation
requirements are minimal; however, as the speed of
production goes up, the formulation requirements also
go up. For capsules, the formulation requirements are
that a consistent plug with a consistent weight is
formed. For tablets, the formulation must flow well
and be very compressible, which is a more stringent
requirement than forming a plug with a consistent
weight. The relative simplicity of capsule formulations
can speed up the development process, especially for
high-dose, poorly compressible drugs. This formula-
tion simplicity makes capsules popular for clinical
trials where speed is critical. Perhaps one of the big-
gest advantages of capsules is that they can be self-
administrated, which is required for a drug to be a top
seller, because of the high cost of administration by a
are typically only used for life-threating diseases such
self or herself an injection.
One big advantage of capsules from the marketing
and patient perspective is the wide range of colors,
sizes, and printings that are available for capsules
shells (see Fig. 27.3). Having unique colors or printings
of a logo can help companies establish the brand ID of
a product for marketing purposes. A good example of
this is Nexium (esomeprazole magnesium), which is
an over-the-counter proton-pump inhibitor for gastro-
esophageal reflux. The unique “purple pill” has been
successfully used to establish a recognizable product
brand, and this could not be done without the unique
purple color of the capsule shell and the printing of
the gold bands and name on the capsule shell (see
Fig. 27.3). Also, color is the most remembered trait of a
medication and important for patient acceptance. For
example, you wouldn’t want to make an antidepres-
sant capsule black or a sleep aid sunrise yellow and
red. This is one area that capsules can easily accommo-
date a wide range of consumer tastes and preference
requirements to produce an elegant dosage form that
is appealing to patients.
Despite many advantages, capsules also have some
important disadvantages. In common with all oral
delivery systems, the capsule exposes the drug to the
gastrointestinal (GI) tract and the GI tract to the drug.
For example, some drugs when exposed to the GI tract
 27.2 GELATIN AND CAPSULE SHELL COMPOSITION
FIGURE 27.3 Diversity of capsule shell showing printing and colors.
can cause nausea, vomiting, and diarrhea. Other drugs
such as iron in prenatal supplements and fish oil cap-
sules have an unpleasant “burp back” effect, which
reduces patient compliance. In addition, some drugs
that are readily degraded in the GI tract, either due to
stomach acids or enzymatic degradation in the stom-
ach and small intestine, don’t make good candidates
for capsules. Also, for controlled-release dosage forms,
the maximum duration of action is limited to the GI
transit time.
Some disadvantages unique to capsules include inter-
actions between the drug, the excipients, and the cap-
sule shell. Hydroscopic materials may dry out the
capsule shell and cause it to become brittle. A typical
capsule shell has between 12% and 16% water, and if
the water content drops much lower, the shell can crack
during normal handling. Conversely, the capsule shells
can absorb water from the environment and develop
problems with drug stability due to too much water,
and the capsule shell can become tacky. Another disad-
vantage of gelatin capsule shells is you have to make
sure the shells are made from a bovine spongiform
encephalopathy (BSE)
free source. In addition, capsule
plugs are made with a lot less force than tablets, so for
high-dose bulky materials such as botanical supple-
ments, the dosage form size will be much bigger, and
patients prefer smaller dosage forms. Tablets are less
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
725
expensive to manufacture because you don’t have to
buy the capsule shells, and tablets have higher rates of
production, which reduces capital expenditures. In my
experience, capsule-filling machines are more complex
than a tablet press and take a longer time to setup up,
break down, and do cleaning validation due to all the
moving parts. When doing a change over from one cap-
sule size to another, you need to replace the dosing disk,
the tamping pins or dosator, and all the bushings
involved with separating the capsule shell. The change
over from one size to another can take many hours to
complete.
27.2 GELATIN AND CAPSULE SHELL
COMPOSITION
Today, gelatin is the most commonly used material
to make hard capsule shells; however, as gelatin alter-
natives gain in popularity, this may change in the
future. Since the first patent in 1834, gelatin has been
used to make capsule shells, and it has a long history
of use in pharmaceutical capsules and as a food addi-
tive. Gelatin is cost effective and nontoxic with an
excellent safety profile; the issue of BSE is discussed in
Section 27.2.4. In addition, gelatin has many excellent
mechanical properties such as the ability to form films
726 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
with precise dimensions and mechanical properties
that can withstand the rigors of high-speed processing
on commercial-scale production equipment. With gela-
tin, the film formation and gelling properties occur
over a narrow temperature range.5 The tribology sur-
face properties and shell clarity are also critical for
patient acceptance of a capsule shell. Also, gelatin has
many excellent delivery properties. It is readily soluble
in water and softens at body temperatures for rapid
release; the issue of gelatin cross-linking is discussed
in Section 27.2.2.6 Gelatin is recognized in all the major
pharmacopeias throughout the world. For these rea-
sons, gelatin is the most popular material used to
make two-piece hard capsule shells.
Gelatin is made up of proteins derived from the
skin and the bones of cattle and pigs and is a byprod-
uct of the meat industry, which helps make it cost
effective. Gelatin is made up of primarily collagen,
which is one of the main proteins in connective tissue.
For example, 46% of pig skin and 29.4% of bovine
hides are made of collagen.6 Gelatin undergoes revers-
ible thermal gelation at 35 C. This temperature and a
narrow transition range are critical because capsules
are made by a dipping process in a gelatin solution
and when cooled must rapidly form a thin, uniform
film on the dipping pin.7 In addition, gelatin is readily
soluble in water and softens at 30 C. These properties
make it an excellent ingredient from a manufacturing
and drug delivery point of view.6
There are different types of collagen found in
different parts of the body. For example, skin is
mainly made up of type I collagen and to a lesser
extent type III collagen.6 Collagen is composed of three
chains that form a triple-helix structure. The chains
have a high percentage of the amino acids glycine, pro-
line, and hydroxyproline in a repetitive sequence.6
When the three chains are linked together, they form a
very stable triple helix that is stabilized by intrachain
and interchain hydrogen bonds (see Fig. 27.4). Upon
heat treatment, the triple helix can denature (other fac-
tors can lead to denaturation, but they are not relevant
for this discussion), and depending upon temperature
and water content, the chains can exist in different
states with different degrees of cross-linking via the
formation of a triple helix (see Fig. 27.5). Once dena-
tured, they can form gels, and the extent of gel forma-
tion depends upon the temperature, moisture content,
and how fast the gel solution was dried.6,8,9 It is these
changes in state with different degrees of cross-linking/
triple-helix formation that contribute to the gelling
behavior of gelatin and give gelatin its unique proper-
ties for forming capsules and drug release.
Gelatin is made by either acid or alkaline processing
of cow bones or cow and pig hides. The process has
many steps and requires a long time to complete.
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
FIGURE 27.4 Structure of collagen. Source: Wikipedia collagen.
Fig. 27.6 shows the basic steps.10 The gelatin made
from pork skin via acid treatment is called Type A gel-
atin, and the gelatin made from bones and animal skin
by alkaline processing is called Type B gelatin. Each
gelatin type has its own properties (see Table 27.1).
Type A gelatin has a higher degree of plasticity and
clarity, and Type B gelatin forms tougher films and is
a little hazier. A capsule shell is made from the mix-
ture of the two gelatins, so the capsule shell has the
right clarity and mechanical strength properties to run
well on a filling machine.
The first step in the gelatin-making process is to
pretreat the bones and hides (see Fig. 27.6). For bones,
this means crushing, degreasing, and demineralization
of the bones to remove all the calcium phosphate,
Ca3(PO4)2, using diluted hydrochloric acid (HCl) to
solubilize the tricalcium phosphate, which can then be
removed by washing. The spongy organic material left
after the demineralization of the bones is called
ossein.11 The goal of the pretreatments is to produce a
relatively purified collagen than can be converted into
gelatin. After pretreatment, the gel can either be limed
(alkaline treatment) or acid treated. The goal of liming
is to condition the collagen so it produces gelatin with
the desired physical properties and to do so with good
yields.10 The liming process causes both chemical and
physical changes in the collagen. For example, during
liming, deamination of the collagen amino acids such
as glutamine and asparagine occurs with the evolution
of ammonia, and the alkali labile cross-links between
the chains are broken. For acid treatment, the gelatin
has a higher isoelectric point (see Table 27.1) because
the glutamine and asparagine residues remain in the
amide form and are not converted to carbocyclic acid
form as with the alkali treatment. As with liming, the
 27.2 GELATIN AND CAPSULE SHELL COMPOSITION 727

FIGURE 27.5 Changes in collagen structure that influence gelling properties. Duconseille A, et al. Gelatin structure and composition linked to
hard capsule dissolution: a review. Food Hydrocol 2015;43:360
76.

acid treatment breaks up the collagen chains. The acid
treatment is faster (on the order of 24 hours) than lim-
ing (8
12 weeks), but it has poor yields for many col-
lagen sources such as bones and cattle hides.
After alkali or acid treatment, the collagen must be
extracted from the liquor. The pH, time, temperature,
and number of extractions (typically 3
6) vary with
the product. The goal of extraction is to heat up the
liquor under carefully controlled conditions to the
point where the gelatin solubilizes; typically this is
between 50 C and 60 C for the first extraction. The sol-
uble materials are then filtered and or washed to
remove the insoluble components. The soluble material
is deionized, typically by ion exchange. The cleanup
process is repeated several times until the material is
very pure (Fig. 27.6). Then the soluble gelatin is concen-
trated and cooled until it gels and can be processed
into a powder for shipping (Fig. 27.6).10,11 The gelatin
produced by the first extraction typically has a higher
molecular weight, higher viscosity, higher gel strength,
and lighter color, which is preferred for making cap-
sules as compared to later extractions.
27.2.1 Capsule storage
A key component of gelatin is water. Newly made
capsules will have a water content between 13% and
16%. If the amount changes, the capsule can become
brittle and fracture when running on a commercial
machine. Also, in our experience, if the water content
changes, the dimensions can slightly change, leading to
problems of capsule separation, rejoining, and solvent
sealing. For example, when sealing fish oil hard-shell
capsules, if the dimension change so the gap between
the cap and the body increases, oil can leak into this
space. This prevents the tight sealing of the cap to the
body because the sealing solvent can’t get into this
space. Thus, capsule shells must be carefully stored. At
a minimum, they should be stored in a tightly sealed
box, and ideally, they should be stored in a temperature-
and humidity-controlled room. For example, the
Capsugel company recommends that for Coni-Snap cap-
sules, the ideal storage conditions in the original corru-
gated box and tightly sealed polyethylene bag are 50%
RH at 21 C. However, if the facilities are maintained

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

728 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
Bone
Degreasing
Grading
Demineralization
Liming
Deliming
FIGURE 27.6 Gelatin manufacturing process. Adapted from Jones.
with a relative humidity in the range of 35
65% RH
and temperatures in the range of 15
25 C, you should
be able to keep them for the full 5-year shelf-life.
27.2.2 Gelatin cross-linking during storage
As discussed, gelatin undergoes a reversible thermal
gelation due to the physical interactions such as hydro-
gen bonding between the protein chains (Fig. 27.4), and
it is this gelation process that is in part responsible for
the rapid drug release from a capsule. However, there
are a whole host of irreversible chemical reactions that
can occur between the gelatin protein chains that can
cross-link the protein chains together.12 When the
extent of cross-linking becomes great enough, the gela-
tin becomes insoluble, and the capsule shell forms an
insoluble film around the API. This swollen, rubbery,
water-insoluble membrane is called a pellicle, and
when it forms during dissolution testing, the drug
release is greatly slowed, and the capsule fails to meet
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
Hide
Washing
Acidification
Extraction
Clarification
Filtration
Deionization
Concentration
Filtration
Sterilization
Chilling
Drying
Grinding
Grading
Blending
its dissolution specification. Common causes of gelatin
cross-linking include aldehydes (in the active or excipi-
ents), peroxide impurities, storage in high heat and
humidity, and rayon coilers.12
15 When testing a mod-
erately cross-linked gelatin capsule, it will fail dissolu-
tion due to pellicle formation; however, when tested
in vivo, it may still have good bioequivalence com-
pared to a noncross-linked capsule due to proteolytic
enzymes in the gut.12,16 These results indicate that the
in vitro capsule dissolution test may not be predictive
of what happens in vivo due to the digestive enzymes.
Thus, the United States Pharmacopeia (USP) came up
with a two-tier dissolution test, and if the capsules fail
in the regular dissolution medium, they can be retested
in medium containing proteolytic enzymes.
27.2.3 Capsule shell additives
Besides a structural polymer gelatin or hydroxypro-
pyl methylcellulose (HPMC), there are other additives
 27.3 CAPSULE SHELL MANUFACTURING
in the capsule shell. Coloring agents are often added to
gelatin because pure gelatin is clear, which allows light
to contact the API and the patient to see the powder
inside of the capsule. The most popular dyes added to
capsule shells are synthetic water-soluble dyes (eg,
azo, indigoid, quinophthalone, triarylmethane, and
xanthene), pigments such as titanium dioxide and iron
oxides, and natural dyes such as carotenoids.17 When
adding a coloring agent, one can either add a dye or a
lake to the capsule shell.18 In general, dyes impart a
transparent or translucent color to the capsule shell,
and the patient can still see though the shell, albeit a
colored view. In contrast, pigments block the light and
opaquely color the capsule shell, blocking light from
reaching the inside of the capsule. Titanium dioxide
(TiO2) is the most commonly used opacifying agent. It
has a white color and is mostly inert. TiO2 can help the
dye better opacify the shell; thus, they are often added
together.
Printing inks are not really part of the gelatin, but
they are materials applied to the capsule shell and
could affect the product. Capsule printing is often done
to meet Food and Drug Administration (FDA) product
identification requirements, and the printing ink color-
ants must meet the same regulatory requirements as
those for the capsule shell.1 Generally, inks are made
up of insoluble colorants dispersed in a volatile solvent
and a film former.19 The colorants must be insoluble, or
when the solvent evaporates, it will bleed, making the
printing look blurry. The coloring agents can either be
added as a pigment like the iron oxides, which are
insoluble but limited in colors, or as lakes. Lakes are
made by precipitating a dye onto an aluminum hydrox-
ide or titanium dioxide carrier, thus, making them
insoluble.18 Lakes have the advantage of coming in a
wide range of colors and are insoluble. A common ink
film former is shellac, which has broad acceptance in
the major pharmacopeias and adheres well to gelatin.
Typical solvents used in the capsule printing inks
include ethyl alcohol, isopropyl alcohol, n-butyl alco-
hol, and water. Obviously, one has to be sure that the
residual solvent levels don’t exceed regulatory limits.
Fortunately, the amount of ink applied is small, so this
is typically not a problem if dried properly.
A warm gelatin solution can support rapid micro-
bial growth, so care must be taken to keep the total
microcount low when working with these solutions.
A properly stored capsule will have a water content in
the 13
16% range, which is low enough to not support
microbial growth. Thus, preservatives are not used in
gelatin capsules manufactured in Europe and in the
United States. However, in older products, preserva-
tives such as methyl and propyl parabens and sodium
metabisulfite were added to gelatin solutions to control
microbial levels during production.7
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
729
Sometimes processing aids can be in a capsule shell.
For example, sometimes a surfactant such as sodium
lauryl sulfate can be used in capsule shell manufactur-
ing. Also, there can be proprietary pin-release agents
used to help the capsule shell be stripped from the pin
after dipping. Also, things such as silicon dioxide have
been used in gelatin manufacturing. Some additives
are allowed in the USP, while others are disclosed
with a confidentially agreement with the capsule shell
manufacturer. If there are stability problems, gelatin
additives should be considered when trying to solve
the problem.
27.2.4 Mad cow disease
In the 1980s and 1990s, BSE (also known as mad cow
disease) was found in cattle in Europe, and in the
United Kingdom people were actually infected, most
likely from eating animal products containing
brain or spinal cord parts. While the process of produc-
ing gelatin is very harsh with either an acid or
alkaline treatment and reduced the infectivity to
undetectable levels, there is still a very slight possibility
that the prion that causes BSE could survive the process.6
Given that prions are difficult to detect, suppliers of gela-
tin must have preventative measures in place so their
products do not contain prions. These measures include
obtaining gelatin from certified BSE-free production
areas. Only healthy slaughtered animals can be used, and
the gelatin must not contain animal parts exposed to
neurological tissues such as the skull and backbone verte-
brae. The regulations for certifying that gelatin is BSE-
free varies from country to country. For example, Japan
and Argentina require only hide gelatin. Thus, make sure
that suppliers can supply a BSE-free certificate, as this
will be needed for release. Typically manufacturers have
these on their websites for download, and the certificate
should be kept as part of the batch records for clinical
studies and product release to the market.
27.3 CAPSULE SHELL MANUFACTURING
The first step in making a hard-shell capsule is to
produce a well-mixed dipping solution; the history of
capsule making is discussed by Jones et al.7 In addition
to gelling polymers, gelatin, or HPMC, the solution
could contain other additives such as coloring agents.7
The key quality attributes of the gel solution include
viscosity and gelation temperature. To achieve the nec-
essary attributes, the gelatin solution is made from a
combination of Type A and B gelatin for the best com-
bination of shell strength and clarity.
730 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
Capsule shells are made by dipping pairs (body and
cap) of room-temperature stainless-steel pins into a
heated gelatin solution. Because the pins are below the
gelling temperature, the gelatin begins to form a thin
gelatin layer or film on the pins (Fig. 27.7).20 After a
short time in the gel solution, the pins are removed
and rotated several times to evenly distribute the gel
over the pin. Once the gel is evenly distributed on the
pin, a blast of cool air is used to set the gelatin on the
pin. At this point, the gelatin is dried, and the pins are
sent through a long series of continuous ovens until
the moisture content is at the desired level (Fig. 27.8).
The drying is primarily done using dry, slightly
warmed air to avoid softening or melting the gelatin in
the drying oven; recall the gelling temperature of gela-
tin is about 30 C. After the gelatin is dried, the capsule
is striped off the pin and trimmed to the proper length.
Once trimmed, the two halves are put back together in
Dipping Process for Making Hard
Gelatin Capsules
Manufacturers in N.
Amer.
Shionogi Qualicaps
Capsugel div.Pfizer
Pharmaphil (Canada)
FIGURE 27.7 Dipping pins in a gel solution.
Making Capsules Cont.
HCM
GFT BORSOR
MELT
PRINTING
SHIPPING LABELING
FIGURE 27.8 The hard gelatin capsule manufacturing process.
Source: Dennis Murachanian, Capsulgel.
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
the prefit position. At this point, printing is done if
needed before packing in cartons for shipping.
27.4 ALTERNATIVES TO GELATIN
Issues with BSE, religious dietary restrictions with
pork-based products, consumer preferences for healthy
veggie products, and animal rights concerns have led
to the demand for nonanimal-based capsule shells.
Given the exacting processing requirements where
capsule shells have to run smoothly on the same com-
mercial filling machines as the gelatin capsules and the
drug delivery requirements of capsule shells, it has
been hard to find cost-effective alternatives to gelatin
capsule shells. Despite these difficulties, there are now
a range of gelatin alternatives readily available on the
market, but these products were not easy to develop.
The most common alternative to gelatin is hypromel-
lose in USP official nomenclature, also known as HPMC.
All major suppliers of capsules now produce HPMC cap-
sules. HPMC is a cellulose ether of vegetable origin,
which eliminates concerns with religious restrictions and
dietary preferences against animal products. Like gelatin,
HPMC has a long-use history in the pharmaceutical
industry for things such as a wet granulation binder,
layering binder, controlled-release matrix former, film
coating material, and suspending agent. It has an excel-
lent safety profile, is considered GRAS (generally
regarded as safe), and is listed in all the major pharmaco-
poeias.5 HPMC has lower water content, on the order of
4
7% compared to gelatin, which is in the range of
13
16%. This reduces problems with brittleness due to
loss of water because water does not plasticize HPMC as
much as it does gelatin, and a lower water activity level
generally is good for moisture-sensitive drug stability.1
There are also differences in water and oxygen perme-
ability, which is important for drug stability.1,21
HPMC capsules are made by the same dipping pro-
cess as gelatin. To form an HPMC capsule, the HPMC
solution must rapidly form a film on the dipping pin.
Currently, this film can be formed either by thermal
gelation or gelling via a gelling system. Unlike gelatin,
HPMC undergoes reverse thermal gelation; in other
words, HPMC forms a gel at higher temperatures,
whereas gelatin forms a gel at lower temperatures.22
For cellulose-based polymers such as HPMC, it is not
unusual for them to be more soluble at lower tempera-
tures, because at higher temperatures, the hydrophobic
interactions predominate more than the hydrophilic
interactions, and the hydrophobic interactions lead to
aggregation between the polymer chains. As the num-
ber of aggregates goes up, the gelation occurs. This
transition temperature can also be affected by environ-
mental factors such as ionic strength.23 Silva has shown
 27.5 HARD SHELL
that the sol-gel transition temperature occurs at about
55 C; however, this transition temperature is affected
by environmental factors and differences in the HPMC
polymers such as the molecular weight and the degree
of substitution.22,23 Thus, to make HPMC capsules on
the same dipping pin system, the HPMC solution is
kept cool at room temperature, and the pins are heated
to above the gelation temperature.5 The hot pins are
dipped into the cool HPMC solution, removed from
the solution, spun on the pins to form a uniform film,
and then dried, much like the gelatin capsule-making
process.
The disadvantage of thermal gelation using a cold
HPMC solution and hot pins to make the capsules is
that very expensive capsule-making equipment must be
modified or developed to accommodate these differ-
ences in processing. Another approach is to add gelling
agents to the HPMC solution, and these gelling agents
have the property of being a solution at cold tempera-
tures and a gel at higher temperatures. This allows the
use of the same cold solution/warm pin equipment
when making HPMC capsules.5 Currently there are two
commercial polymer gelling agents: kappa-carrageenan
and gellan gum. Kappa-carrageenan is a structural
polymer obtained from red seaweed. It is a sulfonated
polysaccharide that is widely used in the food industry
as a gelling and thickening agent, and it has an excel-
lent safety profile. Kappa-carrageenan has the unique
feature that it forms helical structures at room tempera-
ture, and the gelation occurs via interactions between
the helixes. Being a sulfonated polymer, the sulfate
group is unionized at the typical working pHs of
κ-carrageenan, which makes the polymer very sensitive
to ions, and small changes in ionic strength can affect
the gelling behavior of κ-carrageenan.24,25 This sensitiv-
ity is used to control the gelling temperature of
κ-carrageenan, so it can be processed on commercially
available dipping machines.
The other polymer used commercially as a gelling
agent for capsule manufacturing is gellan gum. Relative
to κ-carrageenan, gellan gum is new polymer that was
only discovered in the late 1970s. It is produced by the
bacterium Sphingomonas elodea. Gellan gum is a linear
anionic polysaccharide that has one carboxyl side group
and one 0-acetyl substituent per chemical repeat unit.26
The carboxylic group, which can ionize at the typical
working pH of the polymer, makes the gelation temper-
ature sensitive to environmental factors such as ionic
strength. Like κ-carrageenan, the ionic strength and the
pH of the gelling solution can be controlled so that gel-
lan gum gels at a good temperature for making cap-
sules on commercially available dipping machines.
Examples of commercially available HPMC capsules
made by thermal gelation include Vcaps Plus, also
called tg-HPMC. Commercial capsules made with
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
731
κ-carrageenan include QualiV, also called c-HPMC,
and commercial capsules made with gellan gum
include Vcaps, also called g-HPMC.5 A critical issue
with capsule performance is how these three types of
capsules compare to each other and with gelatin. The
key properties such as water uptake, mechanical
strength, color-hiding power, stability, esophageal
transit time, in vitro dissolution, and in vivo bioequiv-
alence of these different types of capsules have been
extensively studied.5,27
29
These studies and others are hard to summarize
because the results depend upon the type of drug and
the test conditions used, but in general, they found that
the performance was similar, but there were important
differences between the different types of capsules
shells. Thus, without some type of evaluation, one can-
not assume that the capsule shells types are inter-
changeable because there could be conditions where the
differences could affect in vivo performance and patient
outcomes. A purchasing agent should not make the
decision to switch from one type of capsule shell to
another, as this should be done within the confines of a
company’s change control procedures.
Currently, HPMC capsule shells have been devel-
oped to the point of being commercially available from
all the major suppliers; however, in the future, there
will be many new developments in capsules shells.
Some of these new technologies include pollen capsule
shells, starch hydrolysate capsule shells, HPMC soft-
gel shells, and capsule shells that are designed for
modified release; for example, there are enteric capsule
shells and controlled-release capsule shells for colonic
delivery. Because these new innovations are not as
widely available as HPMC, they will not be discussed
further, but they have been reviewed by Stegemann.5
27.5 HARD SHELL
The most commonly available capsule shells are the
hard gelatin capsule shell. This shell comes in two
parts: the body and the cap (Fig. 27.9). These capsule
shells are made of a hard gelatin or HPMC, which is
ridged and can be handled and run though processing
equipment. This is in contrast to soft gelatin shells,
which have to be formed and are typically used for
liquids and semisolids. Originally, the cap and the
body just fit together without a locking mechanism,
but this lead to problems, as sometimes the cap and
the body separate during handling and shipping; thus,
most capsule shells today come with a locking mecha-
nism that keeps the cap and the body from separating.
The Coni-Snap capsule shell is one such example, as
you can see in Fig. 27.10. There is a locking ring that,
once engaged, holds the cap and the body together.
732 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS

FIGURE 27.9 Capsule shells showing features.

FIGURE 27.10 Capsule shells.

As shown in Fig. 27.10, the shells come from the man-
ufacture in the prefit position, and after filling, they
are pushed together to lock. Note that in this context
locked is not the same as sealed.
Modern capsule-filling equipment can fill up to
200,000 capsules per hour. For a capsule shell to run on
such a high-speed machine, it places a lot of perfor-
mance requirements on the capsule shell. Things such
as the mechanical strength of the gelatin film, dimen-
sional accuracy of the shell, the ability to vent air during
high-speed closure, closure-locking mechanism, prefit
locking strength, the ability to align for rectification, and

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

 27.5 HARD SHELL
closure are all essential qualities that are needed to run
on a high-speed machine. How these features are engi-
neered into a capsule shell is part of a company’s patent
portfolio and used as special features to sell capsule
shells.1 Traditionally, three of the biggest manufacturers
of capsules were Capsugel, who made the Snap-Fit and
Coni-Snap capsule shells; Pharmaphil (now part of
Qualicaps), who made the Lox-it capsule shells; and
Shionogi Qualicaps (now called Qualicaps), who made
the Posilok capsules. This is not a complete list of all
manufacturers current or past. During the past decade,
a lot of companies in China, India, and other parts of the
world have started to manufacture capsule shells; they
are too numerous and transitory to review here.
27.5.1 Capsule sizes
Capsules come in standard sizes (Fig. 27.11). These
sizes range from 000 to 5, which have volumes from
733
1.36 to 0.13 mL, respectively. To estimate the fill
weight of these capsules, one can use the basic bulk or
tapped density if you compress during filling. The
bulk density will give you an approximate fill weight,
which can then be adjusted by trial and error. A more
quantitative method for determining the fill weight is
to use the method developed by Khawam.30,31
27.5.2 Use in preclinical and clinical studies
For clinical research, when one wants a blinded pla-
cebo or to make a comparison to a particular formula-
tion or existing product, it can be very difficult because
making an exact look-alike copy of a product can be
very difficult and time consuming. Thus, capsule man-
ufacturers have developed special-sized capsules with
a wide body specifically designed to make it easier
to be directly filled with an intact tablet (Fig. 27.12).

Capsule Sizes

000
00
0
1
2
3
4
5

Volume 1.36 0.95 0.67 0.48 0.37 0.27 0.20 0.13 mL

Starch fill* 1110 775 530 365 300 200 160 100 mg

*Density of 0.8 gm/mL

FIGURE 27.11 Standard capsule sizes. Source: Dennis Murachanian, Capsulgel.

FIGURE 27.12 Double-blinded capsules for clinical studies.

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

734 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
There are eight different sizes of double-blind (DB)
capsules: AAA, AAel, AA, A, B, C, D, and E; see the
Capsugel website for size details. These capsules can
be filled by a compounding pharmacist. This can avoid
the expense of good manufacturing practice (GMP);
however, many compounding pharmacists lack the
capacity to support even small clinical studies. The
double-blinded capsules have some unique features
that make it hard to break the blind. For example, the
body is extended, and the cap fits into the body, mak-
ing it very difficult to pull them apart without destroy-
ing the capsule, which makes it almost impossible for
the patient and curious nurses or physicians to break
the blind without obvious signs of damage, which can
alert researchers to this possibility. Obviously this is
not a foolproof method of blinding, but it will at least
stop the casual patient or health care worker from
breaking the blind.32
27.5.3 Animal testing
Administration of an API to an animal is one of the
important initial steps in preclinical research. If you are
administering the drug to an animal such as a dog, pig
or primate, you can use human dosage forms, but if you
need to administer an API to a rodent, then human dos-
age forms are too large. For preclinical research, the API
is typically administered as a solution, emulsion, or sus-
pension via gavage; however, some APIs may have
poor stability, and a liquid preparation would not have
the needed shelf life for testing. Some APIs may be very
difficult to formulate as a liquid predations, and if the
study questions have to do with the API in the solid
state, then a liquid preparation will not answer your
questions. For these situations, capsules have been spe-
cifically developed and designed to be delivered to
mice, hamsters, rats, and guinea pigs (Fig. 27.13). In
addition, they have developed specially filling appara-
tus and tools for capsule administration, also shown in
FIGURE 27.13 Capsule used for administration to rodents.
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
Fig. 27.13. These capsules are hand-filled one a time (see
Section 27.6.1 for a discussion of hand-filling), so their
use is limited to preclinical studies. Also, these capsules
can be filled without excipients, which is an advantage
when compactability and stability are a concern. On the
other end of the spectrum are large specialty capsules
for livestock. For example, there are capsules that can
deliver gram quantiles of medication orally, rectally,
and vaginally to cattle.
27.6 CAPSULE FILLING
As mentioned previously, capsules are shipped with
the cap and the body prefit together. Thus, to fill a cap-
sule, the basic steps are: separate the cap from the body,
fill the formulation into the body, put the cap back onto
the body, and lock the cap and the body together. One
of the beauties of capsule filling is that it is very flexible
in terms of scale. Capsules can be hand-filled one at a
time, as done in a compounding pharmacy, or they can
be hand-filled using a jig, a semiautomated capsule-
filling machine, or filled on commercial-scale machines
making over 150,000 capsules per hour.
The primary differences between small-scale filling
and commercial production is in how the powder is
transferred into the capsule body. Small-scale produc-
tion is done by directly filling the powder into the cap-
sule shell and relying on the bulk/tapped density of
the powder to get the correct dose for the volume of
the capsule shell used. Capsules can also be made by
direct weighing of the API into the capsule body. For
commercial production, the capsule is filled in a pro-
cess called indirect filling, which is done by forming a
plug that is transferred into the capsule shell. Forming
a plug has several advantages over direct filling.
The plug is made by compressing the powder into a
cohesive mass, which holds together during the trans-
fer to the capsule body. This can be done by multiple
 27.6 CAPSULE FILLING
tamping on a dosing-disk machine or by compression
in a dosator. The advantage of forming a plug is that
the powder can be compressed to higher density,
which allows for higher capsule fill weights, which
given the patient preference for swallowing smaller
capsules can be important. This is very important for
botanical products that typically have very low bulk
densities and if not compressed can lead to the patient
having to swallow very large capsules. In addition, the
machine operating parameters of the dosing-disk or
dosator machine can be adjusted to accommodate the
natural variation of the formulation components to
product more consistent fill weight, thus, improved
dose uniformity.
27.6.1 Hand-filling capsules
Hand-filling is the easiest and the slowest method.
It has the least formulation requirements and can
accommodate just about any API that is compatible
with the capsule shell materials, but this method is not
scalable to faster modes of production. Hand-filling is
typically done to prepare a small number of capsules
for toxicity and bioavailability studies in animals and
humans. Using a capsule-filling jig, one can produce
enough capsules to support a phase I study or clinical
research studies. Hand-filling can either be done one
capsule at a time or by using a capsule-filling jig.
Hand-filling one capsule at time is what is com-
monly done in a compounding pharmacy, where you
form a little pile of powder on a pill tile and then push
the inverted capsule body into the powder blend until
the capsule body is filled up and has the desired
weight. Alternatively, you can weigh the API directly
into the capsule body, but this is very slow process. In
recent years, an automated weight system has been
developed for direct filling of the API into a capsule
shell; the system is called the Xcelodose system, which
is described in Section 27.6.3. The capacity of hand-
filling is about 5
20 capsules per hour depending
upon the material being filled and operator skill.
To increase manual production rates from that of a
pill tile, one can use a capsule-filing jig, also called a
hand-filling capsule machine (Fig. 27.14), such as those
sold by CroPharm Inc., Torpac Inc., and Capsugel Inc.
Typically, these jigs can make from 100 to 500 capsules
per fill (Fig. 27.14). The basic steps are to (1) rectify
the capsules, (2) separate the cap from the body, (3) fill
the powder, (4) join the cap and the body together,
and (5) eject the filled capsules from the jig. These
steps are shown in Fig. 27.14. Because the cap and the
body have slightly different dimensions, the basic idea
of the hand-filling jig is to use a series of plates with
different sized holes to independently manipulate the
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
735
cap and the body for all the filling steps. To rectify the
capsules, they are randomly poured onto a tray that
has a series of slots, one slot for each capsule. The mid-
dle of the slot is bigger than the ends, so the capsules
fall into a hole body first. At the bottom of the hole are
four plates with a hole for each capsule. The top plate
has a hole that allows the body to pass through but
not the cap. Below the top plate are three plates
(Fig. 27.14). The middle plate is on an eccentric cam,
which moves the middle plate relative to the other two
plates in order to lock the capsule body in the three
plates. Once the capsule bodies are locked in place, the
top plate is removed along with the caps, resulting in
the separation of the cap from the body. The capsule
bodies can be pushed flush with the top of the three
lower plates so when a powder mass is poured onto
the jig plate, it can be evenly distributed to each cap-
sule. Often during the filling of the capsules a tamper
is used to slightly compress the powder. This increases
the bulk density of the fill and helps distribute the
powder into each capsule. Once the capsules are full,
they are rejoined by putting the top plate back on and
squeezing the stand so the capsule bodies are pushed
up through the three middle plates and into the top
plate where the caps are held. Then the top plate is
removed, the capsules are manually pushed into the
locked position, and they are dumped into a tray for
packaging or further processing.
27.6.2 Liquid filling two-piece capsules
For some drugs, a liquid fill can be better than a dry
powder; for example, for drugs with low solubility, the
delivery can be enhanced with a self-emulsifying drug
delivery system.33 Also, with highly potent, for exam-
ple, hormones, or cytotoxic drugs where worker expo-
sure to dust is a problem, a liquid fill can provide
better containment, and with low-dose drugs, content
uniformity can sometimes be easier to maintain in a liq-
uid formulation rather than a hard-to-mix powder.34
Typically, liquids are filled in soft-shell capsules, but
with special modification of traditional filling equip-
ment, liquids and semisolids can be filled in two-piece
capsules. Liquids can also be hand-filled into two-piece
capsules for feasibility studies and clinical studies.
For liquid fills, all the steps are the same as with the
powder fills, but instead of filling a powder into the
capsules, a pipet or liquid manifold is used to fill each
capsule with a liquid (Fig. 27.15). For liquids, the cap
and the body must be sealed to prevent leaking. This
is very important for oils such as omega-3 fatty acids
that turn brown when oxidized, which is a very obvi-
ous defect on the surface of a capsule shell. Thus, once
the capsules have been filled, it is important to quickly
736 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS

(a) (b)

(c) (d)

(e) (f)

FIGURE 27.14 Steps for using a hand-filling jig: (a) rectification of capsules, (b) capsule separation, (c) separated capsules ready to fill,
(d) using plastic scraper to distribute powder in capsule shells, (e) closing capsule shells, and (f) emptying filled capsule shells.

seal them. Capsules can be sealed either by banding
with heated gelatin or a hydroalcoholic solution fusion
process.35 In addition to liquid filling for over-the-
counter product, capsules should be banded so as to
be tamper evident.36
To seal a two-piece capsule using a hydroalcoholic
solution, the solution is either sprayed onto the capsule
shells in a pan coater or, if hand-sealing, via a swab.
When the liquid comes in contact with the gap between
the cap and the body, the liquid surface tension wicks
the solution into the gap, and then gentle heat is
applied, typically between 40 C and 50 C, for a minute.
Typically a 50:50 water-ethanol solution is used. The
water in the alcohol solution softens the partially dissol-
ving the gelatin, and when heated, the two pieces fuse
together. Then the water evaporates, and the gelatin
returns to its dry state, but the two halves are bonded
together. If pure water is used, too much softening
occurs. The capsule may develop ripple defects, and
sometimes the gelatin bubbles when heated. If too
much water is applied, this can lead to twinning (when
two capsule shells stick together), and at the point
where the shells are conjoined, there is typically a spot
defect in the gelatin. To band a capsule requires special

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

 27.6 CAPSULE FILLING
FIGURE 27.15 Liquid filling of hard gelatin capsules.
equipment that heats up the gelatin and then applies a
thin band around the joint between the body and the
cap.34,35 When liquid filling two-piece capsules, it is
best to use capsule shells specifically designed for
liquid filling. These capsules have features such as no
vents and are designed for improved sealing of the
liquid or semisolid. Liquid filling can also be done on
a commercial scale, but this is beyond what will be
covered here, and the interested see reader can see
Cole et al.34 and Niederquell.37
27.6.3 Powder in capsule automated filling
It is well known that only a small fraction of the
compounds synthesized make it to the market. Given
the extreme risk of developing new compounds, the
goal of most companies is to make a go-no-go decision
as soon as possible for any compound in development.
A pivotal point in the development process is the first
studies in humans, and to conduct these studies, one
needs a formulation to administer to the patient. One
way to develop a formulation rapidly is to directly
weigh only the API into the capsule, which is called
the powder-in-capsule (PIC) method. With only the
powder in a capsule, you don’t have to worry about
adding an excipient to make the capsules. For exam-
ple, you don’t have to worry about lubricants and flow
aids in the formulation, and consequently, you don’t
worry about excipient compatibility and how much to
add to make the process run well.
To meet this need for rapid PIC formulation manu-
facture, companies such as Capsugel Inc. have devel-
oped an automating weighting system that can fill
between 100 μg to 100 mg per capsule, and according
to the company, it can do this with a 2% RSD. The
trade name for this system is Xcelodose. The system
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
737
accommodates up to a size 00 capsule, and the auto-
mated version of Xcelodose can fill up to 600 capsules
per h. As discussed, hand-filling via direct weighing is
very slow, and without an automated system, hand-
weighing would not be practical for a phase I study. A
more detailed description of the Xcelodose system and
its operation for filling capsules to put in a dry powder
inhaler can found in the review by Edwards.2
27.6.4 Semiautomatic
The next level of filling is a semiautomatic capsule-
filling machine, shown in Fig. 27.16. Conceptually, this
is the same as the hand-filling jig, that is, with no plug
formation. The only differences are that a few more
steps are automated and scaled up, and the powder is
fed into the capsule shells using an auger rather than by
manual feeding (Fig. 27.16). Some semiautomatic-style
systems use vibration to fill the powder into the cap-
sules, but to the best of the author’s knowledge, these
systems are not that popular and won’t be discussed
further. In the old days, semiautomatic machines were
commonly used for commercial production, but over
the years, the plug-forming indirect-filling machines
have largely replaced the semiautomatic machines for
commercial production, and today these machines are
typically used for small-scale, flexible manufacturing of
batches for feasibility studies and early-phase clinical
trials.
With a semiautomatic capsule-filling machine, the
process of capsule rectification is automated (Fig. 27.16).
With these systems, the capsules are randomly fed into
a slot, and then a finger pushes in the middle of the
prefit capsule. Because the body is smaller, it moves
first, which orientates the capsules so they are all facing
in the same direction (Fig. 27.17). Once the capsules are
all aligned, they are pushed into the dosing rings. As
with the capsule-filling jig, when the rings are manually
separated, the cap is separated from the body. After
separation, the body ring (Fig. 27.16) is placed under
an auger-driven hopper and rotated on a turntable.
To fill the capsules, the body ring is rotated, and
the hopper auger is turned on so the powder is
fed from the hopper at a fixed rate as the body ring
rotates. The fill weight is determined by a combination
of the turntable speed and the auger speed. The faster
the turntable rotates, the lower the fill rate. As there is
less time under the auger, which dispenses powder at a
fixed rate, the faster the auger rotates, the higher the fill
weight, as a faster auger speed pushes the powder out
faster into the capsule bodies. Once all the capsule have
been filled, the rings are pushed back together to rejoin
the cap and the body, and finally the capsules are
ejected from the rings (see Fig. 27.16).
738 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS

FIGURE 27.16 Semiautomated capsule-filling machine (eg, Colton Type 8).

FIGURE 27.17 Capsule rectification.

Typically these machines can produce up to 27.6.5 Commercial production methods

10,000
15,000 capsules per hour, depending upon the
ease of formulation handling and operator skill. The
formulation requirements are essentially the same as
hand-filling, but the powder has to flow out of the
hopper with the aid of an auger, so the formulation
can’t segregate, and it needs to be relatively free flow-
ing. Lubricants and flow aids may be necessary if dis-
charge from the hopper is problematic. If the material
is known to be sticky, that is, adhere to metal, then for-
mulation changes must be made for the formulation to
run well. Formulation strategies for API sticking to
capsule-filling machine parts are similar to those for
dealing with sticking and picking in tablets.38
The indirect method of capsule filling involves form-
ing a plug and then ejecting the plug into the capsule
body. This method of capsule filling is used in the vast
majority of commercial filling operations. There are
two principal methods for making a plug, the dosing
disks and the dosator methods, and these commercially
available capsule-filling machines can make 150,000 or
more capsules per h. To reliability fill at high speeds
requires a very good formulation. It is a misnomer to
say there are no formulation requirements for a capsule
because all you have to do is get the drug into the cap-
sule shell. While this may be true for hand-filling or

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

 27.6 CAPSULE FILLING
slow filling on a semiautomatic capsule-filling
machine, for high-speed production, this is not the
case. In the next sections, we will discuss in general
terms the steps of capsule filling for the dosing-disk
and dosator method of filling followed by a discussion
of capsule formulation. For a history of capsule filling
and a detailed discussion of capsule-filling machines,
see Lightfoot.39
27.6.5.1 Dosing disk
The dosing-disk method of filling uses a disk with
holes and tamping pins to form a plug (Fig. 27.18). This
type of machine is exemplified by the Bosch (formerly
Hofliger Karg) GKF models and the Harro Hofliger
(H&H) KFM models. The dosing-disk setup, shown in
Fig. 27.18, has the powder bed above the dosing disk,
and it uses tamping pins to push the powder into holes
in the dosing disk. A typical dosing disk has from 12 to
100 holes drilled in the dosing disk. To simplify the dis-
cussion and match the discussion to the illustrations, I
will refer to the H&H machine, which has a dosing
disk with 12 holes. This discussion can be easily
extended to other machines such as the Bosch GKF
machine, which has 72 holes, so the same things are
happening, but instead of 12 holes, there are 72 holes in
six groups, and the dosing disk rotates 60 instead of
90 like the H&H machine. The matching tamping pin
assembly has a tamping pin to match each hole. These
are mounted onto a single assembly, with all tamping
pins going up and down simultaneously. Typically, the
tamping pin assembly tamps, that is, goes up and
Capsule filling – dosing disc principle
FIGURE 27.18 Schematic of Bosch dosing-disk capsule-filling machine.
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
739
down, 2
5 times for each hole to form a plug. Then the
disk rotates to the next set of tamping pins and com-
presses the plug three to five times more. With each
tamp, the capsule plug become taller and denser. After
three sets of tamps, the dosing disk rotates to the final
hole, which is open on the bottom so that the capsule
plug is unsupported. The capsule body is below the
final position of the dosing disk, and when tamping pin
comes down, it ejects the plug into the capsule body.
The tamping pins are spring loaded to prevent over-
loading the capsules, which are not designed to take
large forces. Typical tamping forces range from 20 to
200 N (see Fig. 27.19). For a more detailed description
of this process and the monitoring of plug formation,
see Shah and Augsburger.40 To have a consistent fill
weight, it is essential to keep the powder bed at a con-
stant bulk density. Thus, there are typically moving baf-
fles in the powder bed that sweep across the dosing
disk to keep the bed a uniform density. The primary
factors controlling the fill weight are the thickness of
the dosing disk, the thickness of the powder bed, and
the tamping pressure.
27.6.5.2 Dosator
A dosator, shown in Fig. 27.20, is made up of a dos-
ing tube and a piston that slides up and down in the
dosing tube. Typical dosator machines include Zanasi,
MG2, Dott. Bonapace, and Macolar machines. To make
a plug, the dosing tube is inserted into a powder bed,
and the piston compresses the powder to form a plug.
Then the dosing tube is withdrawn from the powder
Bosch GKF
740 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS

(a) (b)

FIGURE 27.19 (a) Spring-loaded tamping pin with strain gauge instrumentation and two different dosing disks showing size differences.
(b) Spring-loaded tamping pin with strain gauge instrumentation and two different dosing disks showing size differences.

(a) (b)

FIGURE 27.20 (a) Close up of a dosator and (b) Dosing tube and piston.

bed and positioned over an open capsule body, and the
piston ejects the plug into the capsule body,
(Fig. 27.21). The first step to forming a plug is to insert
the dosing tube into the powder bed of a set height.
This height is usually greater than the height of the pis-
ton, that is, the powder bed height is greater than the
height of the open length of the tube. By inserting the
dosator into a powder bed, the powder is precom-
pressed in a manner analogous to the precompression
during tablet compression in a die (Fig. 27.20).
Following precompression, the powder is compressed
by the piston to form a plug. Then the dosator is with-
drawn from the powder bed and positioned over the
empty capsule body, and the piston ejects the plug into
the capsule body (Fig. 27.20). For a more detailed
description of the process and the monitoring of plug
formation, see Small and Augsburger.41 Like the
dosing-disk method, to have a consistent capsule fill, it
is essential that the powder bed be kept at a constant
bulk density. Thus, in the powder bed, there are typi-
cally moving baffles that move through the powder
bed to keep the density and the height of the bed con-
stant. This is important because the dosator is always
inserted in the same location of the powder bed. The
primary factor controlling fill weight is the height of
the piston in the dosing tube (ie, the volume of open
space in the dosing tube), and the second-most-
important factor is the height of the powder bed.
27.7 CAPSULE FORMULATION
REQUIREMENTS
As mentioned previously, to reliably produce
capsules on a high-speed filling machine, you need at a
minimum a formulation that (1) flows well, (2) consoli-
dates to form a plug, (3) has sufficient lubricity to be
efficiently ejected into the capsule body, and (4) when
the capsule shell dissolves, the formulation must disin-
tegrate for drug release. Obviously there are other
criteria such as stability, but these are drug specific and
beyond the scope of this chapter. In the following

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

 27.7 CAPSULE FORMULATION REQUIREMENTS
Capsule Filling – Dosator Method
MG2 Futura
FIGURE 27.21 Dosator filling principles.
sections, we will discuss these fundamental properties
that every formulation must have and the typical exci-
pients used to create a robust formulation.
27.7.1 Flowability
For both the dosing-disk and the dosator-filling
methods, a uniform powder bed density is essential to
getting a consent capsule fill weight on a high-speed
machine. Because for each capsule the volume of pow-
der is repeatedly removed from the same location in
the powder bed, the powder bed must reform, or the
fill weight will drop and vary. Replenishing the pow-
der bed is accomplished via the intrinsic flow proper-
ties of the powder and with the aid of baffles or
agitators that move in the powder bed to redistribute
the powder to the locations where the powder was
removed. With all this movement of the powder bed,
another formulation requirement is that the formula-
tion does not segregate. The problem of segregation is
formulation specific and beyond the scope of this
chapter, but the interested reader can see Xie et al.42 In
addition, for the dosing-disk machine, fluidity is
important because as the powder flows into the tamp-
ing pin holes at faster speeds, the less time the powder
has to flow into the tamping pin hole, which is why
sometimes with poorly flowing formulations when the
speed goes up, the fill weight decreases.
As discussed by Hardy et al., flow is a critical factor
affecting fill weight uniformity for dosing-disk
machines.43 Thus, when developing a formulation, the
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
741
ability to measure flow in the laboratory before doing
full-scale experiments on a high-speed machine will
save a lot of time and resources. Much research has
been done on flow measurements. One problem with
most of the current flow measurements is they do not
measure the fundamental physical properties, so the
flow measurement can’t be directly related to the perfor-
mance in a capsule-filling machine. Another issue is that
different flow methods look at slightly different powder
flow properties. For example, in static versus dynamic
flow and flow at low-bulk versus high-bulk density, the
different methods won’t always have the same rank cor-
relation. Thus, one must look at several flow parameters
to gain a thorough understanding of a formulation’s flu-
idity; see Ramachandruni and Hoag for a more com-
plete discussion of these issues.44 Thus, with these
empirical methods, experience is needed to apply them
to the formulation development.
For capsule filling, some of the most commonly
used methods to measure flow are the angle of repose,
Carr index, Hausner ratio, funnel flow rate, FT4, and a
minimum orifice diameter.45,46 Other methods such as
a shear cell are more fundamental measurements of
powder flow from which flow predictions can be
made, but these methods require specialized and often
expansive equipment.
Two of the most commonly used methods of charac-
terizing flow are the Carr compressibility index and
the Hausner ratio. The Carr index is defined as
ρt 2 ρb
CI 5 3 100 ð27:1Þ
ρt
742 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
where ρt is the tapped bulk density, and ρb is the loose
bulk density. The Hausner ratio is defined as
ρ needed to understand the relationship between weight
H5 t ð27:2Þ
ρb
Both of these methods are based upon a change in
density when the powder bed is subjected to force by
tapping. The principle of these methods is that when
the powder is loosely packed cohesive powder will
form many bridges due to the cohesive bonds between
the particle at the point of contact between the parti-
cles, and when the powder bed is tapped, these cohe-
sive bonds are broken. The powder bed collapses to a
smaller volume and hence a higher density, whereas
less cohesive powders won’t undergo as much change
in bulk density, as they do not form the bridging cohe-
sive bonds.48 Thus, small changes in density as a result
of tapping are indicative of a good flowing powder as
they don’t form cohesive bonds or large changes in
bulk density. From empirical experience, typical values
of the Carr index and Hausner ratio for powders are
given in Table 27.1. One reason these methods are so
popular is that they are easy to measure, and because
bulk density is important for the choice of mixer and
the capsule shell size, they are often measured as part
of formulation development. Because these methods
are empirical, the next question is how does this corre-
late to fill weigh and fill weight variation, which has
been the subject of much research.
Nair et al. studied the relationship between the Carr
index, the flow rate index, and the minimum orifice
diameter in relation to machine settings such as tamp-
ing pin height, fill weight, and fill weight variation.49
They found that the flow is critical to the fill weight
and the fill weight variation. In general, they found
that pin height setting and the bed height could be set
to minimize weight variation, and flow measurements
were helpful in making such decisions. In another
TABLE 27.1 Empirical Relationship Between the Carr Index
and Hausner Ratio
Observed flowability Carr index
Excellent 5
10
Good 11
15
Fair 16
20
Passable 21
25
Poor 26
31
Very poor 32
37
Exceedingly poor 38
45
Adapted from Carr RL. Evaluating flow properties of solids. Chem Eng 1965;
72:415
9; Wassgren C, Pedersen H. Particle and powder flow characterization; 2010.
http://pharmahub.org/resources/362.47
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
study, Osorio and Muzzio found results consistent
with Nair et al., in which several flow parameters are
variation and content uniformity.50 Heda et al. com-
pared the filling requirements of formulations run on
the Zanasi LZ64 dosator and the Hofliger-Karg (H&K)
GKF 70.51 They found that poor flow measured by the
Carr index was correlated by poor weight uniformity,
and a Carr index in the range from 20 to 30 was ideal
for weight variation.
To improve the flow of capsule formulation, glidants
such as colloidal silica, cornstarch, talc, and magnesium
stearate can be added to the formulation; of all these
materials, colloidal silica is the most commonly used gli-
dant. It should be noted that magnesium stearate has
some effect on powder flow, but its principal effect is as
a lubricant. Glidants typically have very small particle
sizes and work by disrupting the cohesive forces
between the particles.52 There are many theories on how
glidants function, but the mechanism by which they
work is not well understood; see Armstrong for a discus-
sion.53 It is generally believed that to reduce cohesion
between the particles, glidants coat the particles.52 Thus,
there is an optimum level for best flow, which is gener-
ally less than 1% and typically 0.1
0.25%, and empirical
observation by the author has found that if the concen-
tration of colloidal silica exceeds that needed to coat the
powder surfaces, the excess colloidal silica will not
improve flow and can actually reduce flowability, so the
optimal glidant concentration is a critical parameter that
needs to be determined.
27.7.2 Compressibility and compactability
of capsule plugs
With the indirect method of capsule filling, a plug is
formed and then ejected into the capsule body. The typi-
cal capsule plug can be handled but will easily crumble
when squeezed between your fingers. There are many
similarities and important differences between capsule
plug formation and tablet compaction.43,54 Both capsule
plugs and tablets are formed by the compression of a
Hausner ratio powder in a confined space. Generally, capsule plugs
1.05
1.11 are compressed at forces under 200 N, while tablets are
made by compression forces that range from 10 to
1.12
1.18
15 kN. A typical capsule plug has a much higher poros-
1.19
1.25 ity, typically greater than 30%, with typical values rang-
1.27
1.33 ing from 40% to 60%. In contrast, tablets have porosities
less than 20%, and typical values are from 5% to 15%. In
1.35
1.45
diametric compression, the typical breaking force for a
1.47
1.59 capsule plug is under 1 N, and for tablets, the range is
1.16
1.82 from 100 to 300 N. Another difference is the height-to-
diameter ratio. For capsules, this is typically from 3:1 to
4:1 depending upon capsule size, and for tablets it is
typically less than one, with a 0.3:1 ratio being typical.
 27.7 CAPSULE FORMULATION REQUIREMENTS
Plug integrity is critical to the filling performance
and in particular weight variation, because during the
transfer from the powder bed to the capsule body, any
powder that falls from the plug will result in a capsule
weight variation. For dosing-disk machines, this can
occur just before ejection when the dosing disk is
moved over an open space where the capsule plug is
unsupported to the position the plug over the capsule
body. For dosator machines, this can occur when the
dosing tube is withdrawn from the powder bed and
moved over the capsule body.55,56 In addition, during
plug formation, differences in consolation can also
lead to a plug weight variation and consequently dose
uniformity problems. Thus, the ability of the plug to
be transferred to the capsule body without a loss of
powder is a critical quality attribute that must be con-
trolled if a formulation is to be run successfully on a
high-speed capsule-filling machine. Another key issue
with plug compressibility for high-dose drugs and
botanical products in particular is that you want to
minimize the capsule size; thus, increasing the bulk
density is important to optimizing the fill weight that
can be put in the smallest size capsule possible. Note
this requirement of forming a cohesive plug is at odds
with the requirement of a free-flowing powder, so
when developing a capsule formulation, one must bal-
ance the need for a free-flowing powder with the need
to form a cohesive plug.
One way of assessing the propensity of a capsule
plug to lose mass during transfer to the capsule body is
to measure the mechanical strength of the plug and, in
particular, plug compactability. In this chapter, I will
110M
DCL11
FIGURE 27.22 Diametric compress of a capsule plug; see Moolchandani et al.
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
743
use the notation commonly adopted by many authors
such as Leuenberger: The term “compressibility” is
defined as the ability of a powder to decrease in vol-
ume under pressure, and the term “compactibility” is
defined as the ability of the powdered material to be
compressed into a tablet of specified strength (ie, radial
tensile strength or deformation hardness).57 One of the
most common ways to measure plug strength is by
measuring the diametric crushing force or strength.
This test is similar to measuring tablet-crushing force
using diametric compression (Fig. 27.22). This method
has been studied for capsule plugs.51,55,56,58 In general,
increasing the compression force increases the plug
hardness and the bulk density. However, there is a
point where more force, in the range of typical capsule
forces, does not increase the plug-crushing force and
can actually adversely affect the weight variation. The
compressibility of a formulation is very dependent on
the ingredients in the formulation and the compactabil-
ity of the API, and each formulation must be optimized
for optimal filling.
27.7.3 Lubricity
As mentioned previously, capsule plugs are typi-
cally made using compression forces less than 200 N,
but forces as 300 N have been reported. While these
forces are much lower than those used to make tablets,
there is still a need for lubricants in a capsule formula-
tion that is to be run on high-speed filling machines.
Like tablets, traditional lubricants have been shown to
significantly reduce the ejection force and improve
AL
DCL15
744 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS

capsule filling.41,55,56 In addition, like tablets, there is
an optimal lubricant level. Too little lubricant will cre-
ate problems with ejection, and too much lubricant will
create problems with weight uniformity and dissolu-
tion. The optimal level of lubricant depends upon the
nature of the formulation. As a general rule, for plastic
materials such as microcrystalline cellulose and starch,
concentrations from 0.25% w/w to 0.5% w/w works
best, and for brittle materials such as dibasic calcium
phosphate and intermediate materials such as lactose,
higher concentrations around 1.0% w/w may be
needed.
27.8 CAPSULE FORMULATIONS
27.8.1 Filler binders
The nature or requirements of the capsule formula-
tion is very dependent upon the filling method
(Table 27.2). As discussed previously, for slow-speed
direct-filling methods, the excipients requirements are
minimal, and for PIC filling, there are no excipients in
the capsule. When hand-filling using a jig, one needs a
filler binder to bulk up the API volume such that the
powder fill volume matches the capsule shell volume.
Thus, the only excipient requirements are for a consis-
tent bulk density, compatibility with the API, and no
interference with the drug release. When filling cap-
sules using the semiautomatic or auger principle, one
needs a better flowing formulation that can undergo
uniform mass flow out of a hopper without rat holing
in addition to having the correct bulk density and not
interfering with the drug release. When filling by the
indirect methods, one needs a formulation that can
form a plug, and the plug must be ejected into a cap-
sule shell, be compatible with API, and not inhibit the
drug release. To achieve these objectives, one must
come up with the right combination of excipients that
meets these requirements.
A typical capsule formulation for each of filling
methods discussed in this chapter is shown in
Table 27.2. The first thing to consider when developing
a formulation is the nature of the API. The formulation
must be built around the nature of the API. This discus-
sion applies to a typical API. For very low-dose drugs
of less than a couple of milligrams, special formulation
and blending techniques must be applied to ensure
content uniformity; see Garcia and Prescott.59 Also, if
the drug has other constraints such as low solubility,
special techniques must be applied, which are beyond
the scope of this chapter. If we consider the API to be
one part, then the first thing to be added is the filler
binder; typically the filler binder is added in two to
three parts of the formulation. For example, if the dose
is 50 mg, then the filler binder would typically be
added in an amount of 100
150 mg as a starting point
and then optimized from there.
Commonly used filler binder types include lactose,
starch, dibasic calcium phosphate, and the cellulosics
such as microcrystalline cellulose (MCC). Each of these
excipient types comes in a variety of grades, and as a
general rule for capsule filling, the direct compression
grades are preferred for capsule formulation as they
tend to have the best combination of flowability and
compactability. When selecting the filler binder for a
drug with poor solubility, it is best to choose water-
soluble binders such as lactose. One should avoid high

TABLE 27.2 Typical Excipient Amounts Used in Capsule Formulations

Direct filling methods Indirect filling methods

Ingredient PIC Hand-filling Auger-filling Dosing disk Dosator

API 1 part 1 part 1 part 1 part 1 part

Filler-binder NA 2
3 parts 2
3 parts 2
3 parts 2
3 parts
Disintegrants
• Traditional NA 10%
20% wt; 10%
20% wt; 10%
20% wt; 10%
20% wt;
• Super 4%
8% wt 4%
8% wt 4%
8% wt 4%
8% wt
Lubricants 0
• Hydrophobic NA NA 0.5%
1.0% wt 0.5%
1.0% wt 0.5%
1.0% wt
• Water soluble 2%
4% wt 2%
4% wt 2%
4% wt
Flow aids
• Silicas NA NA 0.25%
0.5% wt 0.25%
0.5% wt 0.25%
0.5% wt
• Starches 2%
4% wt 2%
4% wt 2%
4% wt
Surfactants NA 0.5%
2% wt 0.5%
2% wt 0.5%
2% wt 0.5%
2% wt

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

 27.8 CAPSULE FORMULATIONS
concentrations of excipients that are known to gel;
for example, HPMC would not be a good filler binder
for low-dose drugs with poor solubility. Also, in high
concentrations (ie, for low-dose drugs), MCC can form
a gellike structure that can inhibit release. Thus, for a
low-dose formulation, is it good to add some lactose
or starch in with the MCC.
Minimizing API segregation when selecting a filler
binder is a critical factor for content uniformity. As a
general rule, the most important thing affecting the seg-
regation tendency of a formulation is particle size dif-
ferences between the filler binder and the API; that is,
big differences in particle size should be avoided. In
the author’s personal experience with free-flowing non-
cohesive powders, ideally, I like to keep the API filler
binder-to-particle size ratio somewhere between 1:3 or
3:1, with a target of 1:1. Of note, this range is the ideal
range; however, in the real world, this might not be
practical. Formulations with particle size ratios outside
of this range may work perfectly well, but a formulator
should verify the segregation tendency of the forma-
tion.42 This also applies to free-flowing noncohesive
powder systems. For cohesive powder systems, such as
a micronized powder of less than 20 μm, the problem is
typically not segregation but deaggregation of the
micronized powder during mixing.59
The issue of ingredient compatibility with each
other and the capsule shell is complex and very API
dependent, so it won’t be covered further.60 However,
the Maillard reaction between reducing sugars such as
lactose glucose, galactose, maltose, and maltodextrines
and drugs with primary and secondary amino groups
such as peptides and proteins is a common reaction
and should be considered when developing a formula-
tion. From a practical point of view, when the reaction
occurs, yellow and brown spots are formed, and as the
reaction proceeds, the reactants turn black; the reaction
is promoted by high temperatures and alkaline pHs.14
Also, the Maillard reaction requires some free water,
and only a small amount may be required for the reac-
tion to occur. Thus, the hygroscopicity of the overall
formulation and the type of lactose used must be con-
sidered to maintain good stability. From a moisture
point of view, lactose is either in an anhydrous or a
monohydrate form. The differences between them are
that the monohydrate forms have a low propensity for
water, while the anhydrous forms readily absorb
water. In addition, the water in the monohydrate form
is crystalline water and thus does not significantly
react.61,62 In summary, the capsules can be filled with
lactose and have good stability for long-term storage
as long as sufficient care is taken to ensure that the
free water content is kept low. This requires a tight
container closure system and a formulation that does
not promote water absorption.63
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS
745
27.8.2 Disintegrants
Disintegrants are added to a formulation to promote
the drug release. They do this by increased water wick-
ing into the plug, and they promote deaggregation of
the plug particles. For IR tablets disintegrants are essen-
tial, but for capsules, they are less important because the
plug is less of a barrier to the drug release than a com-
pressed tablet. (See the discussion in Section 27.7.2 about
the differences between a capsule plug and a tablet.)
Adding a disintegrant to a capsule formulation does
facilitate the drug release, which makes the formulation
more rugged to the inevitable variation in excipient
properties and processing conditions that occur during
production over the manufacturing life of a product.
There are two classes of disintegrants: traditional
disintegrants, such as starch, and super disintegrants,
which include croscarmellose sodium, crospovidone,
and sodium starch glycolate. Currently, these three sup-
per disintegrants are the most popular disintegrants. In
capsule formulations, super disintegrants are typically
used at levels from 4% to 8% (Table 27.2), which is about
twice that used in a typical tablet formulation.64,65 The
reason for this is that when a disintegrate breaks apart
the plug, it does so by swelling, and this expansion of
the disintegrant particles pushes the adjacent particles
apart, but because plugs have a much higher porosity
and the particles are not packed as close together, a
given amount of expansion does not push the particle
apart as much as in a tablet where the particles are
much closer together. Sodium starch glycolate is known
to swell more than other super disintegrants, which
makes it a popular choice for capsule formulations.
27.8.3 Lubricants and flow aids
The requirements for formulation lubricity and
flowability have been discussed, and in this section,
the lubricants and flow aids for capsule formulation
will be discussed. In common usage, the terms lubri-
cant and flow aid are sometimes used synonymously,
but for this discussion, we will use the term lubricant
or true lubricant to describe an excipient that reduces
the friction between the capsule plug and the metal
surface of the dosing tube or the dosing disk. A glidant
is something that improves the flowability of the pow-
der. In addition, sometimes lubricants are added to
reduce powder adhesion to metal surfaces. For some
drugs, such as amlodipine, adherence to metal surfaces
can be a significant problem; if the powder builds up,
it can adversely affect content uniformity.
Lubricants can be broken into hydrophobic and
water soluble. Of the hydrophobic lubricants, the
most popular and efficient lubricant is magnesium
stearate. In this context, efficiency refers to the ability
746 27. CAPSULES DOSAGE FORM: FORMULATION AND MANUFACTURING CONSIDERATIONS
of a lubricant to reduce powder metal friction.
Hydrophobic lubricants include the metallic stearates
such as calcium stearate and stearic acid. Magnesium
stearate typically uses about 0.5% wt, while the metal-
lic stearates are included at between 0.5% and 1.0% wt,
and stearic acid in the range of 1
5% wt is commonly
used. For some capsule formulations, it is important
that all the ingredients be soluble; for example, cap-
sules used in a diagnostic kit need to be completely
soluble. For these formulations, lubricants such as
polyethylene glycol (PEG) can be used. These lubri-
cants are not as efficient as magnesium stearate and
must be used at a higher concentration; in the range of
5
15% wt is typical. To improve flow, the most com-
mon glidant is colloidal silica, but also starch and talc
can be used to improve flow in a capsule formulation;
the typical amounts used are given in Table 27.2.
27.8.4 Surfactants
For some drugs with low bioavailability, surfactants
can be added to increase the wetting of powder mass.
By improving API wetting, this can increase the rate of
water uptake, which can improve the dissolution and
the bioavailability of the formulation. Two commonly
used surfactants are sodium docusate (SDS) and
sodium lauryl sulfate (SLS). Typical use levels for SDS
are in the range of 0.1
0.5% wt, and for SLS, they are
in the range of 1
2% wt (Table 27.2).
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