Technology & Services
Advances in Liquid Fill Capsule Technology
a report by
William Bowtle
Technical Director, Encap Drug Delivery Ltd
The commercial pharmaceutical and nutriceutical
markets have driven the development of alternative
forming materials for the traditional capsule shell
material gelatin. The on-going establishment and
further development of the manufacturing
technology for liquid fill capsules have provided an
enabling base for certain new applications for oral
drug delivery, especially for lipid-based systems. This
report comments on costs and describes some recent
product applications for two-piece capsule liquid fill
systems including DuoCap™, ChewCaps™ and
Organic Sachet™. It also refers to alternative sources
for gelatin.
Costs
A common question in early consideration of liquid-
filled capsules is their cost in relation to other oral
dosage forms, for example powder capsules, coated
tablets and, for controlled release products, pellet-filled
capsules. Cost components include those for
development, plant and raw materials. For
development and manufacturing purposes, it is widely
recognised that liquid fill capsules are significantly less
demanding of environmental and Good
Manufacturing Practice (GMP) compliance
requirements for potent or cytotoxic drugs than
standard capsule or tablet formats, due to their not
generating dust. This has major impact in reducing
costs associated with dedicated rooms, buildings and
air handling and in simplifying handling procedures.
Scale-up costs are minimised since the filling/sealing
processes are achievable on the same full-scale
equipment from batch sizes of 3,000 capsules upwards.
Approximate capital costs for full-scale equipment
are in the order coated tablet – liquid-fill or pellet-fill
capsule – powder-fill capsule. Current full-scale
running costs are also likely to decrease with the
current development of larger-capacity filling
machines (for example Bosch) and of integrated
filling/sealing machines (Shionogi).
New Capsule Applications
The development of systems for processing of
hydroxypropyl methylcellulose (HPMC) liquid-filled
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capsules at Encap Drug Delivery has shown that the
format is also suited to novel capsule applications.
Chewcaps™
Encap Drug Delivery has explored various
formulations for ‘chewable’ capsules containing a
range of flavours. The mouthfeel is agreeable as the
capsule body is crushed and folded into the flavoured William Bowtle is Technical Director
matrix by chewing. Gelatin capsules simply fracture, of Encap Drug Delivery Ltd, UK. His
main current responsibilities are in
creating a very uncomfortable sensation. Several new product development for client
other issues arise during formulation work: companies. Mr Bowtle has extensive
experience in formulation and
processing in a wide range of liquid
• the suitability of the matrix for the mechanics of fill applications, including
chewing (hardness/brittleness/chewability); improvement of bioavailability,
controlled release formulations and
cytotoxic products. He was
• the duration of residence in the mouth; responsible for the development of
the first commercial thermosoftening
capsule product using two-piece liquid
• the ability to mask taste; and fill capsule technology. Mr Bowtle
later established the independent
company specialising in the contract
• the taste of the shell. development and manufacture of
liquid-filled two-piece capsules.
Here, the permeability of the HPMC product is an
advantage. Typically, gelatin capsules do not transmit
odour. For a chewable, where taste is significant to
user acceptability, the perceived flavour may be
enhanced by perception of the product odour on
opening the (bulk) pack.
Organic Sachet™
Larger-volume (3–5ml) HPMC capsules are now
also becoming available commercially. Although not
currently being aimed at use in humans, they may
have other applications, for example as a disposable
container for, say, single-use toothpaste. Their
physical size would preclude them from being used
for consumption and this, in itself, opens up other
possibilities. They have the advantage that they are
cold water-soluble and are therefore suitable for
simple (domestic) disposal. The appearance of empty
uncoloured capsules is amber, cf. bright colourless.
This is unlikely to be an issue where the shell is being
used as a non-consumed container. The capsules
may, of course, be coloured and printed.
One remaining issue for HPMC capsules is their 1
 Technology & Services
Figure 1a: In Vitro Release from Duocap™ Capsules
Figure 1b: DuoCap Capsules
suitability for particular markets. All are suitable for
nutriceutical markets but some may have restricted
pharmaceutical application due to specific technical
issues, for example solubility characteristics at low
pH. One supplier (Shionogi) has declared
compliance of its materials with pharmacopoeiae in
the US, Europe and Japan.
DuoCaps™
Multiphase Delivery in Gelatin or
HPMC
Commonly, a multiphase oral format is required to
meet clinical needs for specific plasma time course
profiles of compounds with biological half-lives in
the order of one to six hours, for example to produce
1. C O’Driscoll, “Drug delivery to the intestinal lymphatic system’’, The Drug Delivery Companies Report, Spring
2 2002, pp. 32–38.
an initial elevation of plasma level and then provide
for appropriate prolonged elevated plasma level. The
format may also be useful in avoidance of site-specific
degradation in the gastrointestinal tract,
improvement of patient compliance and avoidance
of compatibility issues for multicomponent products.
Commercially, they are also important in meeting
marketing needs for line extensions.
Their preparation is often complex at bench level
and proportionately difficult at manufacturing scale.
Using its liquid fill technology for hard capsules,
Encap Drug Delivery has developed a practicable and
convenient formulation system that is well suited to
such multiphase products (DuoCap™). It has also
designed and built machine modules that enable full-
scale manufacturing on Bosch-based equipment. It
enables a capsule (wide range of formats, including
coated) to be filled into a larger liquid-filled capsule,
which may, in turn, be coated. The approach is well
suited to formulating and filling formulations with
various functions:
• specific in vitro release requirements (pulsatile or
bimodal);
• avoidance of site-specific degradation in the
gastrointestinal tract;
• improvement of patient compliance;
• compatibility issues for multicomponent products;
and
• marketing needs for line extensions.
Examples of in vitro data are shown in Figures 1 and 2
for nicotinamide/caffeine gelatin capsule formats,
with and without enteric coating on the inner
capsule, to demonstrate flexibility of the DuoCap™.
Targeted Lymphatic Delivery
Drug delivery to the intestinal lymphatic system has
been highlighted for commercial development.1 The
area has been the subject of extensive academic work
but little commercial exploitation. It aims to improve
the absorption of low-solubility/lipophilic compounds
through lymphatic absorption. Systems include
microemulsions and self-emulsifying systems and are
well suited to liquid fill capsule-based dosage units.
Microemulsions are important for low-solubility
compounds. They are homogeneous, clear fluid
systems comprising an aqueous phase, an oily
phase, a surfactant and a co-surfactant. They are
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 Advances in Liquid Fill Capsule Technology

formed spontaneously on gentle mixing, are Figure 2a: In Vitro Release from Duocap™ Capsules,
thermodynamically stable and of low viscosity. Enteric-coated Inner
These properties make them potentially suitable for
drug formulation, for example cyclosporin. Their
transparency is due to the small droplet size
(100–600nm) formed by the oil, water and
amphiphile. Their use had previously been
restricted due to the toxicity of the various
surfactants but is now well established. Typical
components are non-ionic surfactants, derivatives
of propylene glycol or polyglycerols (present as co-
surfactants) and vegetable oils or fatty acid esters
(present as the oily component).

The proportions of the components are established

using pseudo-ternary phase diagrams to map out the
microemulsion domain. The proportions in which
the fluid remains clear define the range of mix
proportions that are potentially viable. It is important
as a next step to ensure that these mixes are
compatible with hard capsules since excessive levels Figure 2b: Fish Oil Capsules Coated with Acryleze and Opadry
of particular components may cause shell
embrittlement and failure.

Such groups as Gattefosse have developed self-

emulsifying drug delivery systems. They generally
contain an oil or lipid-related material, a surfactant
and may contain a co-surfactant. They are
applicable for substances with low water solubility.
For example, combinations of acetylated
monoglycerides and various high and low
hydrophilic/lipophilic balance carriers can be used
to give a self-emulsifying system for certain low-
solubility materials. There are many examples in the
literature. Such systems have been used and widely
studied for specific high-cost compounds, for
example cyclosporin. They could, however, be
used for more common drugs such as flurbiprofen.

Capsule Materials
Bovine Gelatin
Animal gelatin, derived from the collagen of bone
and skin, is the historical major material for two-
piece capsules. It presents a number of issues in
manufacture and use, including technical, regulatory,
commercial and consumer acceptability aspects.
Major companies routinely consider transmissible
spongiform encephalopathy issues for potential
components during product development. The
industry has well-established procedures to ensure
the safety and suitability of pharmaceutical gelatin.
Nevertheless, the commercial availability of suitable
alternatives has been considered a major requirement
for both pharmaceuticals and nutriceuticals. Their
availability and potential use have been reviewed.2
Fish Gelatin
Capsules made from fish gelatin have become
available recently on a commercial scale. Roxlor
(France) has started manufacture of these products,
using gelatin derived from fish skin. The gelatin used
here is derived from warm-water (cf. cold-water)
species since the levels of originating proline and
hydroxyproline (significant to gelling characteristics)
in their collagen more closely resemble the levels in
mammalian collagen. The specified chemical and
physical characteristics of these capsules match those
for gelatin products from other manufacturers,
enabling them to be run on standard machines for
two-piece capsules. Importantly, their so-called
acceptable quality level attributes for incidence of
defects match those for products from other capsule

2. W Bowtle, ‘’Options in materials for liquid-filled capsules’’, Pharm. Manuf. Pack. Source, 2002 (2), pp. 78–81. 3

BUSINESS BRIEFING: PHARMATECH 2003

 Technology & Services
suppliers, ensuring similar product quality.
Experience in this company indicates that they are
well suited to the liquid fill format.
Human Gelatin
Longer term, availability of ‘human’ gelatin,
produced from recombinant human collagen, may
provide a suitable low-cost gelatin for shell
manufacture. FibroGen, Inc. (San Francisco) has
developed transgenic plant expression technology that
can produce gelatin precursor collagen. Their current
aims are for cGMP manufacturing of ‘human’ gelatin,
with consistent high quality and no potential
contaminants. Commercial exploitation will depend
on the development of systems for large-volume,
high-quality product. To this end, FibroGen and
Prodigene have announced collaborative work on
production of such recombinant gelatin in maize for
high-volume/low-cost bulk material.
HPMC
HPMC represents the current major alternative
material for two-piece capsule shells. Their
commercial manufacture differs from that for gelatin
shells, with the producers (Capsugel, Shionogi
Qualicaps and Su Heung) using differing techniques
to solve specific issues, for example use of differing
additives and mechanical processing techniques. The
products compare closely in principal physical
properties (detailed dimensions, etc.) to gelatin
capsules and may be filled on standard capsule-filling
equipment. They do differ in detailed structure, with
there also being differences in specific quality
characteristics. Their use for liquid fill products is
commercially attractive but has been restricted until
recently due to technical issues in their sealing. Encap
Drug Delivery has developed formulation and
manufacturing systems that provide for robust high-
speed liquid fill processing, matching the quality
standards of gelatin capsule products.
The Future
It is important for capsule technology development
to offer flexibility of materials and delivery systems to
meet scientific and fast-moving commercial markets.
Formulation approaches such as microemulsions can
be expected to be used for novel low-solubility
compounds and for extending patent lives of older
compounds. Other means of targeted delivery and
new carrier systems also offer potential wide
application. For example, colonic delivery may be
feasible for capsule formats using amylose/
ethylcellulose coating systems. Solid lipid
nanoparticles, derived from warm oil-in-water
microemulsions and with drug loading up to 25%,
offer the interesting possibility of using a new
delivery vehicle that targets lymph and is likely to be
compatible with liquid capsule technology.
The two-piece liquid fill capsule format is well suited
to such approaches and offers the flexibility of design
application and manufacturing technology to meet
the industry’s needs. ■
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