Introduction

 Softgels consist of a liquid or semisolid matrix inside a one-piece outer

gelatin shell
 The active ingredient may be either in solution or in suspension in the
capsule-fill matrix
Introduction
 Characteristics of the fill matrix:
 Hydrophilic (for example polyethylene glycols)
 Lipophilic (such as triglyceride vegetable oils)
 Both hydrophilic and lipophilic ingredients
 Microemulsions and nanoemulsions
Introduction
 The softgel capsule shell consists of :
 Gelatin
 Water
 Plasticizer
 Can be transparent or opaque, and can be colored and flavored
 Preservatives are not required owing to the low water activity in the
finished product
Introduction
Introduction
 The softgel can be coated with enteric-resistant or delayed-release
material
 Although softgels can be made in any shape, oval or oblong shapes are
usually selected for oral administration
Routes of administration
 Softgels can be formulated and manufactured in different drug
delivery systems:
 Orally administered soft gels:
 Easy to swallow and convenient unit dose form

 Contain solutions or suspensions

 Chewable softgels:
 Highly flavored shell that is chewed to release the drug liquid fill matrix

 The drug(s) may be present in both the shell and the fill matrix
Routes of administration
Routes of administration
 Suckable softgels:
 Consist of a gelatin shell containing the flavored medicament to be sucked
and a liquid matrix or just air (empty) inside the capsule
 Twist-off softgels:
 Contain a tag to be twisted or snipped off, thereby allowing access to the fill
material
 Can be very useful for unit dosing of topical medication, inhalations or oral
dosing of a pediatric product
 Meltable softgels:
 Designed for use as “patient friendly” pessaries or suppositories
Routes of administration
Advantages
 Rationale for the selection of softgels as a dosage form:
 Improved drug absorption (rate and extent)
 Patient compliance and consumer preference
 Safety for potent and cytotoxic drugs
 Oils and low melting-point drugs
 Dose uniformity for low-dose drugs
 Product stability
Advantages
 Increased rate of absorption:
 By using a drug-solution matrix in a soft gel formulation, the drug arrives the
GIT in the form of a solution
 The shell ruptures within minutes to release the drug solution which is
usually in a hydrophilic or highly dispersing vehicle
 Useful for some drugs:
 For therapeutic reasons, such as the treatment of migraine or acute pain
 For drugs with a limited absorption windows in the GIT
Advantages
Advantages
 Increased bioavailability:
 Self-emulsifying system:
 Certain drugs may be solubilized in a vehicle that is capable of spontaneously
dispersing into an emulsion on contact with GI fluid
 Certain drugs may be solubilized in an oil/surfactant vehicle that produces a
microemulsion or a nanoemulsion on contact with GI fluid
Advantages
 Increased bioavailability:
 Example: a nanoemulsion of progesterone has been developed:
 The solubility of the drug is maintained as long as possible, delivering solubilized
drug directly to the enterocytes (intestinal absorptive cells) membrane
 Increased bioavailability
Advantages
Advantages
Advantages
 Decreased variability in plasma concentration:
 High variation of drug concentration in plasma is a common characteristic of
drugs with limited bioavailability
 By dosing drug in solution, variability in plasma drug concentration can be
significantly reduced
 Example: the cyclic polypeptide drug cyclosporine (Neoral, Sandimmune®)
benefits from such an approach by using a microemulsion preconcentrate in a
softgel
Advantages
 Safety for potent and cytotoxic drugs
 Avoiding processes used in preparing tablets and hard-shell capsules can
generate a significant quantity of dust: mixing, granulation and
filling/compression processes
 Formulation as a softgel can have a safety advantage for operator and
environmental protection
Advantages
 Oils and low melting-point drugs:
 When the pharmaceutical active ingredient is an oily liquid or has a melting
point less than 75 °C
 If the drug is an oily liquid, it can be encapsulated directly into a softgel without
adding a further diluent
 Low melting point drugs may be formulated with a diluent oil in order to ensure
satisfactory liquid flow and dosing into softgels
Advantages
 Dose uniformity of low-dose drugs:
 Liquid dosing avoids the difficulties of poor powder flow and therefore poor
content uniformity
 An important benefit for formulations containing drug doses in the
micrograms
 Improved homogeneity is achieved by dissolving the drug in a liquid and
then encapsulating the liquid matrix in a softgel
Advantages
 Patient compliance and consumer preference
 Consumers preference for softgels could be because:
 Ease of swallowing
 Absence of taste
 Convenience
 Improved compliance due to:
 Enhancement of the bioavailability
 Reduction in the dose administered
 Reduction in the capsule size
Advantages
 Product stability against:
 Oxidation: the liquid is prepared and encapsulated under a protective
nitrogen atmosphere, subsequently dried shell has very low oxygen
permeability
 Moisture: by formulating in a lipophilic vehicle and packaging in well
designed blister packs using materials of low moisture transmission
Formulation: shell
 Gelatin shell formulation
 Typical softgel shells are made up of:
 Gelatin
 Plasticizer
 Colorants and/or opacifiers
 Flavors (sometimes)
Gelatin
 Most commonly the gelatin is alkali- processed (Type B)
 Normally constitutes 40% of the wet molten gel mass
 Type A acid-processed gelatin can also be used
Plasticizers
 They usually account for 20-30% of the wet gel formulation
 The most common used in softgels is:
 Glycerol
 Sorbitol and propylene glycol are also frequently used, often in combination
with glycerol
Plasticizers
 The plasticizer is chosen based on:
 Ease of processing
 Its compatibility with the fill formulation
 The desired final properties of the softgel (hardness, appearance, handling
characteristics and physical stability)
Plasticizers
 One of the important aspects of softgel formulation is to ensure that there
is minimum interaction or migration between the liquid fill matrix and
the softgel shell
 The choice of plasticizer type and concentration is important in ensuring
the compatibility of the shell with the liquid fill matrix
Plasticizers
 The amount and choice of the plasticizer contribute to the hardness of the
final product and may even affect its:
 Dissolution
 Disintegration
 Physical and chemical stability
Water
 Usually accounts for 30-40% of the wet gel formulation
 Ensures proper processing during gel preparation and softgel
encapsulation
 Following encapsulation, excess water is removed from the softgels
through controlled drying
 In dry softgels the equilibrium water content is typically in the range
5 – 8% w/w, which represents the proportion of water that is bound
to the gelatin in the softgel shell
Water
 Water is important for good physical stability, because in harsh storage
conditions softgels will become either too soft and fuse together, or too
hard and embrittled
Colorants and opacifiers
 Colorants (soluble dyes, or insoluble pigments or lakes) and opacifiers are
typically used at low concentrations in the wet gel formulation
 Colorants can be either synthetic or natural, and are used to impart the
desired shell color for product identification
Colorants and opacifiers
 An opacifier, usually titanium dioxide, may be added to produce an
opaque shell when the fill formulation is a suspension, or to prevent
photodegradation of light-sensitive fill ingredients
 Titanium dioxide can either be used alone to produce a white opaque shell
or in combination with pigments to produce a colored opaque shell
Manufacture of softgels
 Sealing of two sheets of gelatin film (ribbons) between a pair of
matching flat brass dies
 Each die contained pockets into which the gelatin sheet is pressed
and into which the medication is filled
 The pressure between the two plates enables individual capsules to
be cut out from the die mold, and these capsules are subsequently
dried
Manufacture of softgels

http://www.youtube.com/watch?v=C0_DeuBmsDY
Properties of soft gelatin shells
 Oxygen permeability
 The gelatin shell of a softgel capsule provides a good barrier against
the diffusion of oxygen into its contents
 q is the quantity of oxygen that passes through the gelatin
 A is the area
 h is thickness of the shell
 (p1 - p2) is pressure difference
 t is time of diffusion
 P is the permeability coefficient
Properties of soft gelatin shells
 P is affected by the formulation
of the gelatin shell
 For maximum protection
against the ingress of O2, the
gelatin shell should be dry and
formulated to contain ≈ 30-40%
of glycerol
Properties of soft gelatin shells
 Residual water content:
 The minimum water values are found at glycerol levels in the shell of between
30 and 40%
 Such a formulation dried at 31% RH has a water content in the shell of about
7%
Properties of soft gelatin shells
Formulation of fill material
 Softgel can be considered as a biphasic dosage form:
 A solid-phase capsule shell
 A liquid-phase fill matrix
 Although it is possible to incorporate a drug in the shell of a softgel, the
overwhelming majority of products have the active ingredient within the
fill matrix
Formulation of fill material
 The choice of components is made according to the following criteria:
 Capacity to dissolve the drug
 Compatibility with the softgel shell
 Rate of dispersion in the GIT after the softgel shell ruptures and releases the
fill matrix
 Capacity to retain the drug in solution in the GI fluid
 Ability to optimize the rate, extent and consistency of drug absorbed
Types of softgel fill matrices
 Lipophilic liquids/oils
 Hydrophilic liquids
 Self-emulsifying oils
 Microemulsion and nanoemulsion systems
 Suspensions
Lipophilic liquids/oils
 Triglyceride oils, such as soya bean oil
 Some active ingredients can be formulated into simple oily solutions for
encapsulation in softgels
 Examples:
 Hydroxycholecalciferol
 Vitamin D
 Estradiol
Hydrophilic liquids
 Polyethylene glycol (PEG) is the most frequently used
 Example
 PEG 400 (molecular weight  400 Da)
 Smaller hydrophilic molecules such as ethanol or water can be incorporated
in the softgel fill matrix in very low levels, typically below 10% w/w
Self-emulsifying oils
 A combination of a pharmaceutical oil and a non-ionic surfactant such as
polyoxyethylene sorbitan monooleate (an oily formulation which
disperses rapidly in the GI fluid)
 The resulting oil/surfactant droplets allows for rapid transfer of the drug
to the absorbing mucosa and subsequent drug absorption
Microemulsion and nanoemulsion systems
 Drug may be dissolved in an oil/ surfactant
 Microemulsion and nanoemulsion systems have the advantage of:
 Have a high capacity to solubilize drug compounds
 Retain the drug in solution even after dilution in gastrointestinal fluids
Microemulsion and nanoemulsion systems
 To produce a microemulsion or nanoemulsion in the GIT a
“preconcentrate” is formulated in the softgel fill matrix
 The preconcentrate fill matrix contains a lipid component and one or
more surfactants
 This spontaneously form a microemulsion or a nanoemulsion on
dilution in an aqueous environment
 The resulting microemulsion or nanoemulsion is often stable for
prolonged periods
Types of softgel fill matrices
 Video: curcumin self microemulsifying drug delivery system
 https://www.youtube.com/watch?v=xdhLHi9Haww
Suspensions
 Drugs that are insoluble in softgel fill matrices are formulated as
suspensions
 The continuous phase may be any of the vehicles described before
 Suspension formulations provide significant advantages for certain low-
solubility drugs which are very poorly absorbed after oral administration
Lipolysis systems
 Lipolysis is the breakdown of lipids (hydrolysis of triglycerides into
glycerol and free fatty acids)
 Lipid formulations can promote the solubility of drug compounds
and facilitate dissolution
 Lipid components of a softgel fill matrix (composed of triglycerides
or a partial mono/di- glycerides) are often subject to intestinal fat
digestion or lipolysis
Lipolysis systems
 Lipolytic products interact with bile salts to form small droplets or vesicles
(micelles)
 These vesicles are broken down into smaller and smaller vesicles resulting
in the formation of mixed micelles that are approximately 3 – 10 nm in size
(similar fashion to a nanoemulsion)
 http://www.bioavailability.com/Drug_For_Tech.html
Lipolysis systems
 If a drug possesses higher solubility in lipolytic products than in
triglyceride oils, it is advantageous for lipolysis to occur in the intestinal
lumen
 In this way, the process of lipolysis promotes the formation of an excellent
dissolution medium for the drug
Lipolysis systems
 On the other hand, the absorption of a drug may be adversely affected by
the presence of bile salt, and in such a case it may be advantageous for
lipolysis to be reduced or blocked completely
 Certain hydrophilic and lipophilic surfactants have the ability to block or
promote lipolysis
Lipolysis systems
 Mixed intestinal micelles comprising bile salts and lipolytic products
can enhance the bioavailability of hydrophobic drugs whose
absorption is normally dissolution-rate limited
 Mixed intestinal micelles can be very potent solubilizing agents for a
wide range of hydrophobic drugs
 The surface of the micelles remains hydrophilic and this facilitates
rapid micellar diffusion across the aqueous boundary layer to the
intestinal membrane that separates the absorptive membrane from
the intestinal lumen
Lipolysis systems
 A lipolyzing microemulsion preconcentrate into a softgel results in:
 Rapid gastric dispersion due to self-emulsifying properties
 Maintain drug in solution using a solvent system which prevents
precipitation
 Digestible lipid composition to facilitate transfer of solubilized drug via
mixed micelles
 High drug concentration at the site of absorption
Case study: progesterone
 Physiochemical properties:
 High molecular weight (314.5 g/mole)
 Hydrophobic drug
 Poor solubility in aqueous GI fluids (< 0.1 mg/mL in water)
 Pharmacokinetic properties:
 Poorly absorbed
 Rapidly metabolized by the liver
 Slow dissolution and absorption from oral suspension provides steady flow of
drug to liver where it is extensively metabolized
Case study: progesterone

Solubility of progesterone in predigested triglycerides and

lipolyzed formulation
Case study: cinnarizine
 Cinnarizine: hydrophobic drug whose absorption is normally dissolution-
rate limited
 Formulation A was prepared as a lipolysing formulation
 Formulation B as a non-lipolysing formulation
 Pp 471 Aulton and 608
Case study: cinnarizine
 Formulation A was composed of:
 Digestible triglyceride oil
 Hydrophilic surfactant: block
 Lipophilic surfactant: promote
 In vitro this formulation exhibited 79% lipolysis after 60 minutes, compared
to the digestible oil alone
 Formaulation B:
 Lipophilic surfactant that did not overcome the effects of the hydrophilic
surfactant on the lipolysis of the triglyceride oil and was shown to lipolyse to
an extent of only 3%
Case study: cinnarizine
Product quality considerations
 Ingredient specifications:
 All of the ingredients of a softgel are controlled and tested to ensure
compliance with pharmacopeial specifications
Product quality considerations
 Aldehydes and peroxide test:
 Trace impurities present in polyethylene glycol (limited levels are allowed)
 High levels of these impurities can result to cross-linking of the gelatin
polymer, leading to polymerization and poor solubility
 On prolonged storage this can lead to slow dissolution of the capsule shell
and subsequent reduction in the rate of drug release
Product quality considerations
 Ingredient specifications:
 The ingredient requiring the most careful control is gelatin itself
 Once a particular grade of gelatin is used in a softgel formulation the quality
is controlled using parameters such as:
 The viscosity of a hot solution and
 The Bloom strength of the gel
Product quality considerations
 Bloom is a test to measure the strength of a gel or gelatin
 The test was originally developed and patented in 1925 by Oscar T. Bloom
 The test determines the weight in grams needed by a specified plunger
(normally with a diameter of 0.5 inch) to depress the surface of the gel by 4
mm without breaking it at a specified temperature
Product quality considerations
 Gel and film texture measurement and analysis
 Youtube!: https://www.youtube.com/watch?v=qXx8GeesSYk
Product quality considerations
 Measure texture: Bloom strength, elasticity, rupture force and gel strength
 Youtube!: https://www.youtube.com/watch?v=-Q-Rr3WvXfA
In-process testing
 The four most important tests are:
 The gel ribbon thickness
 Softgel seal thickness at the time of encapsulation
 Fill matrix weight and capsule shell weight
 Softgel shell moisture level and softgel hardness at the end of the drying
stage
Finished product testing
 Finished softgels are subjected to the following compendial tests for unit
dose capsule products:
 Appearance
 Active ingredient assay
 Related substances assay
 Fill weight
 Content uniformity
 Microbiological testing