11 Chap 11 (bc/d) - Pharmaceutical Press

208 Chapter 11 • Formulation and physical properties of soft capsules
in such a way as to reduce the tendency of propylene
glycol to migrate, during production and on
storage, by using it as a plasticizer component in
the shell and adjusting the manufacturing conditions
at the drums to reduce tackiness of the
ribbons (Brox et al., 1993; Woo, 1997). An
additional benefit of this approach is, that the
amount of water required for dissolving and
melting the gelatin may be reduced owing to the
lower viscosity of propylene glycol compared to
glycerol and sorbitol solutions, thus reducing the
overall water exchange between shell and fill.
The problems associated with the use of a
volatile solvent such as ethanol are more difficult
to solve. To prevent volatilisation of ethanol, the
finished capsules have to be enclosed in a solventtight
packaging material such as an aluminium
blister. Moreover, replacement of glycerol by
higher polyols such as xylitol, sorbitol, sorbitol/
sorbitan blends and/or hydrogenated starch
hydrolysates has been reported as an effective
means of reducing the rate and extent of ethanol
diffusion into the shell (Reich, 1996; Moreton and
Armstrong, 1998). In certain cases, however, both
approaches may not be sufficient to prevent fill
deterioration, since ethanol diffusion cannot be
fully prevented. Thus, for a microemulsion preconcentrate
formulation that is very sensitive to
the co-solvent concentration, the only way to
overcome the problem at present, is the use of a
co-solvent other than ethanol, that is not volatile
and does not show any diffusion into the capsule
shell. For ciclosporin microemulsion preconcentrate
soft capsules, such approaches have been
filed in two patents, namely a European Patent
Application (Woo, 1995) describing the use of
dimethylisosorbide and a US Patent Application
(Shin et al., 2000) that describes the use of a
microemulsion preconcentrate containing a
lipophilic instead of a hydrophilic co-solvent.
Post-treatments and coatings
Soft gelatin capsules may be post-treated after production
or coated to improve product stability, to
modify the dissolution rate and to enable enteric
capsules to be produced. Several patents have
been filed describing the use of protective coatings
to overcome the stability problems of soft
capsules arising from the hygroscopic nature and
heat sensitivity of the soft capsule shell. However,
most of these attempts have failed in practice,
since coating of soft capsules is not an easy task.
The low surface roughness of soft capsule shells
and the intrinsic insolubility of the shell components
in organic solvents means that coatings
applied as an organic solution usually do not
adhere properly to the capsules, resulting in
onion-like coatings of layers peeling off immediately
after drying or on storage. Aqueous coatings,
on the other hand, may result in capsule swelling,
softening and/or sticking together, since water is
acting as a plasticizer for the gelatin capsule shells.
To balance the two extremes, emulsion-based
formulations or solutions in a mixture of water
and alcohol have been recommended (Osterwald
et al., 1982). The technological approach of choice
for soft capsules to be coated is using the fluidisedbed
air-suspension technique.
Capsules with modified dissolution characteristics,
such as gastroresistant enteric soft gelatin
capsules, have been described in the scientific
and patent literature and can be achieved by
adding gastroresistant, enteric-soluble polymers
to the gelatin mass prior to capsule formation, or
by aldehyde post-treatment or enteric coating of
the dried capsules. All three attempts have their
specific difficulties. For soft gelatin capsules produced
by the rotary die process, the last two
approaches are in practical use.
Aldehyde post-treatment of soft gelatin capsules
has been known for many years as a popular
means to reduce their dissolution rate, i.e. the
capsules take a long time to dissolve and have left
the stomach before this occurs. Formaldehyde
has been described to cross-link effectively soft
capsules to render them gastroresistant. Since
safety questions have been raised about the
presence of trace amounts of formaldehyde in
foods and pharmaceuticals, the use of aldehydes
without health concerns such as aldoses have
been claimed in a patent (Fischer, 1986) and are
actually used. The major disadvantage of any
aldehyde treatment of soft gelatin capsules is that
cross-linking can continue on storage. Alternatively,
soft gelatin capsules may be coated with a
gastroresistant, enteric-soluble polymer. Owing
to the aforementioned difficulties associated with
organic and aqueous soft capsule coating, a