SHELL
FORMULATION
DEVELOPMENT
FOR SOFT
CAPSULES
www.softcaps.science
TABLE OF
CONTENTS
1. INTRODUCTION 3
2. RAW MATERIALS
SELECTION
4
2.1 GELATIN 4
2.2 PLACTICIZERS
5
3. SHELL FORMULATION
SCREENING 6
4. COMMON
COMPATIBILITY ISSUES 7
4.1 CROSS-LINKING 7
4.2 MIGRATION 8
4.3 CRYSTALLIZATION
9
5. CONCLUSION 10
ABOUT US 12
1. INTRODUCTION
The capsule shell, often simplistically regarded as mere packaging material for the
encapsulated content, plays a critical role in ensuring product stability and efficacy.
Far from being an inert container, the capsule shell can significantly impact the
quality, performance, and shelf life of the final product. Therefore, a comprehensive
and meticulous approach to capsule shell development is essential to guarantee the
desired outcomes.
Our e-book was written to give an overview of raw material selection, critical aspects,
and common quality issues during capsule shell development. It covers the essential
considerations for developing robust and compatible soft capsule shells, including the
selection of appropriate gelatin types and plasticizers, formulation screening
approaches, and strategies for addressing common compatibility issues such as
crosslinking and migration.
3
2. RAW MATERIALS
SELECTION
The shell of a soft gelatin capsule consists of the gelling agent gelatin, a plasticizer,
water, and optionally colorants.
2.1 GELATIN
Gelatin is derived by hydrolyzation of animal collagen, typically bovine bones, bovine
hides, or pig skin. Fish and chicken bones gelatin do not have any commercial
significance for pharmaceutical products.
The animal material is processed in an acidic (type A) or alkaline (type B) process,
which leads to a breakdown of the collagen triple helices to fractions of peptides and
protein chains of various molecular weight (MW). A portion of microgel with high
MW, i.e. above 400 000 g/mol, also may remain in the gelatin.
The manufacturing process impacts the characteristics of gelatin with regard to e.g.
amino acid composition, isoelectric point, length of protein chains and resulting
molecular weight distribution. These parameters in turn impact aspects crucial
processability, e.g. gel strength and viscosity, as well as its compatibility with the
capsule fill.
WANT MORE EXPERT INSIGHTS ON SOFT CAPSULES?
VISIT OUR RESOURCES SECTION ON WWW.SOFTCAPS.SCIENCE AND LEARN MORE
ABOUT:
Selecting a CDMO for Capsule shell Latest updates of USP
your softgel
development
development <1094>
4
For example, type A gelatins derived However, once water is removed, the
from pig skin typically display a broad capsule shell becomes brittle.
molecular weight distribution (MWD) Therefore, addition of other,
and contain alpha, beta, and gamma nonvolatile plasticizers is required to
chains and low molecular peptides. ensure sufficient plasticity and
They are commercially available in physical stability of the capsules over
higher bloom number grades (e.g. 170- the shelf life.
220) and exhibit comparably lower
viscosity. In contrast, type B bovine Low molecular glycols and sugar
bone gelatin, broadly used by softgel alcohols are widely used as plasticizers
capsule manufacturers, contains a for soft capsule shells. Propylene
high portion of alpha chains and has a glycol, due to its small size and
bloom number of 150-160. The MWD hydrophilicity, has very good
and amino acid composition can plasticizing properties, but is not
furthermore impact the tendency to suitable to be used as the only
crosslinking, a common and critical plasticizer in capsule shells due to its
quality issue observed in soft capsules. volatility, among other things. Like
water, part of it may evaporate during
storage, leading to brittleness of the
Some gelatin manufacturers have
capsule shell.
therefore recently been developing
specific gelatin grades to address this
Glycerol, on the other hand, has low
issue, by e.g. increasing the portion of
volatility and displays excellent
low MW fractions in the material.
compatibility with gelatin in a wide
concentration range. However, while it
2.2 PLASTICIZERS is the widest used plasticizer, it may
not be suitable for use as the only
The use of external plasticizers is
plasticiser for hydrophilic fill
essential to ensure the elasticity and
formulations. Due to their small size,
physical stability of the dried capsules.
glycerol molecules may migrate into
By increasing the space between
the capsule fill, thus leading to a
protein chains and therefore their
partial loss of plasticizing effect in the
mobility, plasticizers reduce the glass
shell and increased brittleness of the
transition temperature of the gelatin
capsules during storage.
solution and allow processing during
encapsulation.
Therefore, for such fill formulations,
larger molecules with lower tendency
Water has excellent plasticizing
to migrate to the capsule fill such as
properties and is added to the gelatin
noncrystallizing sorbitol solution or
mass to allow processing. Excess sorbitol anhydrides can be applied.
water has then to be removed from
the newly formed capsules to increase
their physical stability.
5
3. SHELL FORMULATION
SCREENING
The main objective during shell Impurity profile and potential for
development is the definition of interaction of fill formulation
gelatin type and plasticizer type and excipients with the capsule shell.
the amount that is appropriate for the
fill formulation. Moreover, Taking these considerations into
processability aspects should be account, several gelatin types and
addressed; these typically include the plasticizer combinations should be
amount of water required for tested during initial formulation
processing and efficient drying. While screening for evaluation of
this is a crucial aspect, soft gel capsule compatibility and stability. Ideally,
manufacturers typically propose encapsulation trials should be
processable quantitative compositions performed rather than laboratory
based on their experience. compatibility trials on raw materials,
since they seldomly can detect the
The following aspects of the drug variety of possible interactions and
substance and fill formulation should incompatibilities between capsule fill
therefore be considered in an initial and shell. In some cases though, using
shell formulation risk analysis: appropriate study design, preliminary
compatibility trials the fill with isolated
Properties of the drug substance, shell material may indicate some
e.g. aqueous solubility, sensitivity to incompatibility issues.
oxygen or hydrolytic degradation
Critical molecular structures of the The prototypes should be evaluated
drug substance or impurities that for pre-defined, potentially critical
may induce crosslinking, e.g. quality attributes of the capsule shell,
aldehyde groups such as rupture/disintegration time,
Characteristics of the fill water content and capsule hardness
formulation, e.g. lipophilicity, water along with the remaining drug
content product CQAs.
Potential of fill components for
migration into the hydrophilic
capsule shell—especially in case of
small, hydrophilic molecules such
as ethanol or propylene glycol
6
4. COMMON
COMPATIBILITY ISSUES
With the increasing complexity of fill e.g. oxidative degradation of drug
formulations, interactions between the substance or excipients. Unfortunately,
capsule fill and capsule shell are it is typically observed only in the
frequently encountered in soft course of stability testing. Early
capsules. While chemical indication for crosslinking can be
incompatibilities between drug detected at accelerated storage
substance and shell materials conditions, though sometimes they are
sometimes occur, by far the most overdiscriminating and not fully
common are crosslinking and representable for the behavior at
migration phenomena. ambient conditions.
When caused by the interaction with
the capsule fill, crosslinking manifests
4.1 CROSS-LINKING as the formation of a thin, insoluble
layer around the capsule fill (“pellicle
Crosslinking is likely the most common formation”).
quality and compatibility issue with
soft capsules. It is characterized by a
gradual decrease in dissolution
accompanied by an increase in
variability. Crosslinking of gelatin
occurs when protein chains are
connected by covalent bonds, thus
becoming insoluble in water.
There are two types of crosslinking.
Internal crosslinking may occur as a
result of heat and humidity exposure
over time. When internal crossliniking
occurs, the entire capsule shell
becomes insoluble.
External crosslinking is commonly
caused by the presence of aldehyde
groups in the formulation, which may
either originate from the used raw
Pellicles observed during disintegration
materials, e.g. as synthesis impurities,
testing of soft capsules
or may be formed during storage by
7
While often the focus of development
4.2 MIGRATION
activities for crosslinked soft capsules is
placed on analytical method Initially, the softgel capsules were
development, crosslinking can be mostly used to encapsulate lipophilic
addressed and, in many cases, liquids, which practically limits the
significantly reduced, applying a interaction with the hydrophilic
systematic approach to shell capsule shell. In the past 20 years,
development. however, many PEG-based hydrophilic
or other amphiphilic fill formulations
The following factors can positively containing surfactants, e.g.
impact crosslinking: SEDDS/SMEDDS, were developed to
address low aqueous solubility of new
Gelatin type: a broad screening drug substances.
should consider various sources
and even mixtures of gelatins As such fill formulations are typically
Type of plasticizer: likely due to miscible with water, glycerol and
their molecular structure and size, propylene glycol, these components, if
some plasticizers may contribute to present in the capsule shell, also tend
improved solubility of capsule shells to migrate to the capsule fill until
if the product is prone to equilibrium concentrations are
crosslinking. In some cases, a reached. On the other side, hydrophilic
combination of two or more fill components such as ethanol and
plasticizers may lead to additional propylene glycol – both often used as
improvement. co-solvents in SEDDS/SMEDDS
Amount of plasticizer: likewise, the formulations – also migrate to the
plasticizer amount can impact capsule shell. Migration phenomena
crosslinking lead mostly to physical instabilities,
Process variables: adjustment of e.g. softening or brittleness of the
storage and processing durations capsule shell, but may also cause
can be beneficial for some precipitation of drug substances in the
formulations fill, thus decreasing its solubility and
Further aspects related to the capsule potentially bioavailability.
fill formulation can contribute for
alleviation of crosslinking, e.g. selection Migration can be limited significantly –
of purified raw material grades for all although not always completely – by
excipients, addition of antioxidants, considerate shell formulation
specific storage conditions of raw development.
materials.
8
For this purpose, the type and amount
of plasticizers may be adjusted, for
IS ADDITION OF
example, by formulating a shell using PRESERVATIVES TO
sugar alcohols as plasticizers rather THE CAPSULE SHELL
than only glycerol, or a combination
thereof.
REQUIRED?
4.3 PRECIPITAITON Bacterial growth occurs at water
activity values above 0.80. Dried soft
The migration of water into the gel capsules typically have a water
hydrophilic capsule fill can cause other activity of the capsule shell below 0.50.
challenges, with one of the most The microbial growth is therefore
concerning being the precipitation of limited by design. Moreover, the raw
poorly soluble drug substances. When materials are commonly controlled for
water permeates the fill matrix, it can microbial contamination and
alter the solubility of the drug, leading processing of the gelatin mass takes
to its precipitation. It often occurs in fill place at elevated temperatures.
formulations which contain PEG as Therefore, although sometimes
the only solvent for the drug practiced, the addition of preservatives
substance. to the capsule shell is regarded as
superfluous and is generally not
Precipitation can jeopardize the recommended.
bioavailability of the active ingredient
and can affect the overall stability and
appearance of the capsule. It is
therefore crucial to understand the
precise solubility parameters of the
drug during fill formulation studies, e.g.
by addition of representative amounts
of water to the formulation. The
migration of water into the capsule fill
can be also be improved by selecting a
gelatin type which requires less water
for processing.
9
5. CONCLUSION
In the end, the development of a robust and compatible capsule shell is a critical
aspect of soft capsule formulation development. It begins with a thorough
understanding of the raw materials, including gelatin types and plasticizers: this step
is essential for designing a shell that ensures product stability and performance. The
selection of appropriate shell components should be based on a comprehensive risk
assessment, taking into account the characteristics of the drug substance, the fill
formulation, and potential interactions between the shell and the fill.
Formulation screening, ideally through encapsulation trials, is crucial for evaluating
the compatibility and stability of different gelatin types and plasticizer combinations.
Common compatibility issues, such as crosslinking and migration, can be addressed
by optimizing the shell formulation, adjusting plasticizer types and amounts, and
considering process variables.
While the capsule shell is often overlooked as a mere packaging material, its impact
on product stability and performance cannot be understated. By adopting a
systematic approach to shell formulation development, considering the complex
interplay between the shell and the fill, formulators can develop robust and
compatible soft capsule products that meet the desired quality attributes and
ensure patient safety and efficacy.
10
THIS IS HOW CAN WE
SUPPORT YOUR SOFTGEL
PROJECT:
We prepare risk-based formulation development concepts in
consideration of the entire capsule.
We utilize the appropriate shell excipient palette for the
capsule fill right from the start of development.
In complex softgel development projects, we take lead
formulation roles within the development team and manage
CMO activities.
We bring specialized analytical expertise for the
characterization of common quality issues in soft capsules.
We help you bring the right partners for analytical,
manufacturing, and regulatory activities for a successful
softgel development.
We help prepare the CMC sections of IND/NDA/MAA files for
softgel products in CTD format.
We support troubleshooting activities.
INTERESTED?
Contact us [email protected] and tell us about your project.
© Trias Pharma GmbH, 2024 11
ABOUT US
THE AUTHOR
A pharmacist with 15 years of
experience in the development
of soft capsules, Yanitsa is expert
in formulation and process
development. She has managed
a variety of R&D, transfer and
troubleshooting projects and
has successfully supported
numerous clients solve complex
YANITSA MITEVA challenges all around soft
Founder and softgel expert capsules.
THE COMPANY
We are independent experts in
soft capsules.
Focusing on a systematic
approach and backed by
decades of experience in the
development and manufacture
of soft capsules, we help
companies understand the
critical factors and develop
robust softgel capsules.
12
