Introduction

 Capsule (Capsula in Latin) means a small box

 The capsule is a package made from gelatin or other suitable material
which is filled with medicines to produce a unit dosage, mainly for
oral use
 A solid preparations intended for oral administration made with a
hard or soft shell
 Can use powder (HGC) and liquid (SGC) ingredients
 Could also be used for inhalation, rectal and vaginal administration
Introduction
Advantages
 Easy to swallow (shape)
 Mask unpleasant taste, color and odor using tasteless shell
 Capsule shell is physiologically inert and dissolves easily and is
quickly digested in the GIT (gelatin is a protein)
 Capsule shells can be opacified or colored to give protection from
light
 Produced in large quantities: economic, attractive and available in
wide range of colors
 Easy to store and transport
Disadvantages
 They are not suitable containers for water or liquids that dissolve gelatin
 Very soluble salts, such as bromides or iodides should not be dispensed in
capsules. Why?
 Because the rapid release of such materials may cause gastric irritation
 Formaldehyde can delay the release
Disadvantages
 Deliquescent powders can not be used in the capsule shells because they
may dry the capsule shell and it can become brittle
 Deliquescent powders: are materials which have a strong affinity for
moisture and will absorb relatively large amount of water from the
atmosphere if exposed to it, forming a liquid solution (e.g., calcium
chloride)
Disadvantages
 Efflorescent materials on the other hand can not be used because they
tend to make the capsule shell soft
 Efflorescence: is the loss of water of crystallization from a hydrated form
to the atmosphere
Types of capsules
 Two types:
 Hard gelatin capsule:
 Two pieces: cap and body
 Can be clear, colorless, and essentially tasteless
 Can be colored with various dyes and made opaque by adding agents such as titanium
dioxide
 Soft gelatin capsule
 One piece
Shell: raw materials
 The raw materials used in the manufacture of both types of capsule
are similar
 Both contain:
 Gelatin or hydroxypropyl methylcellulose (HPMC) to produce a shell with a
low moisture content
 Water
 Colorants
 Optional materials such as process aids and preservatives
 Soft gelatin capsules contain various plasticizers
Gelatin
 A natural substance obtained by the partial hydrolysis of collagen
obtained from the skin and bones of animals
 In commerce, it is available in the form of a fine powder, a coarse powder,
shreds, flakes, or sheets
Gelatin
 There are two main types of gelatin:
 Type A: produced by acid hydrolysis of animal skins
 Type B: produced by alkaline hydrolysis of bovine bones
 Gelatin is the major component of the capsule shell
Gelatin
 Properties:
 Non-toxic, widely used in food stuffs, and acceptable for use worldwide
 Readily soluble in biological fluids at body temperature
 Good film-forming material, producing a strong flexible film (the wall
thickness of a hard gelatin capsule is about 0.1 mm)
 Solutions of high concentration (40% w/v) are mobile at 50 °C
 Undergoes a reversible change from a sol to a gel at temperatures only a few
degrees above ambient conditions
Colorants
 Water-soluble dyes
 Insoluble pigments
Colorants
 Water-soluble dyes:
 The dyes used are mostly synthetic in origin
 Azo dyes ( -N=N-)
 Non-azo dyes which come from a variety of chemical classes
 Most commonly used are of non-azo class
 Examples are:
 Erythrosine (E127)
 Indigo carmine (E132)
 Quinoline yellow (E104)
Colorants
 Insoluble pigments
 Iron oxides (E172)
 Titanium dioxide which is white and used to make the capsule opaque
 To make a range of colors, dyes and pigments are mixed together as
solutions or suspensions
Process aids and preservatives
 Process aids: materials used to aid in the manufacture of capsule
shells
 0.15% sodium lauryl sulfate
 A wetting agent, to ensure that the lubricated metal molds are uniformly covered when
dipped into gelatin solution
 Preservatives
 Manufacturers operating their plants to GMP guidelines no longer use them
 In finished capsules, moisture levels are within the range 13 – 16% w/v
 These levels will not support bacterial growth because water is strongly
bonded to gelatin molecules
Manufacture of empty capsules
 Summary:
 Metal molds at room temperature are dipped into a hot gelatin solution
which gels to form a film
 The resulting film is dried, cut to length, removed from the molds and the
two capsule parts are joined together
 A fully automated and continuous process
Manufacture of empty capsules
 https://www.youtube.com/watch?v=0EwaIQ-U6QQ
 https://www.youtube.com/watch?v=83IKH9DW47c
 https://www.youtube.com/watch?v=lkUb2hWAbiU
 Please watch on Youtube!
Manufacture of empty capsules
 Preparation of the raw materials:
 A concentrated solution of gelatin (35 – 40%) is prepared using demineralized
hot water (60 – 70 °C) in jacketed pressure vessels
 The mixture is stirred until the gelatin has dissolved and then vacuum is
applied to remove any entrapped air bubbles
 Pigments and dyes are added and viscosity is adjusted
Manufacture of empty capsules
 Preparation of the raw materials:
 Viscosity is the parameter used to control the thickness of the shells (the
higher the viscosity, the thicker the shell wall produced)
 The prepared mixture is then transferred to a heated holding hopper on the
manufacturing machine
Manufacture of empty capsules
 The manufacturing machine:
 The manufacturing machine is approximately 10 m long, 2 m wide and 3 m
high
 Consists of two parts which are mirror images of each other: on one half the
capsule caps are made and on the other the capsule bodies are made
 The machine is also divided into two levels, an upper and a lower level
Manufacture of empty capsules
 The manufacturing machine:
• Molds, commonly referred to as pins, made of stainless steel are mounted in
sets on metal strips, called bars
• Approximately 50000 mold pins per machine
• The machine is housed in a large room where the humidity and temperature
are closely controlled
Manufacture of empty capsules
Manufacture of empty capsules
 Capsules are formed by dipping sets of molds ( which are at room
temperature (22 °C)) into the molten gelatin solution
 The molds are slowly withdrawn from the solution and then rotated
during their transfer to the upper level of the machine, to form a film
of uniform thickness
 Groups of “pin bars” are then passed through a series of drying kilns
(ovens), in which large volumes of controlled humidity air are blown
over them
Manufacture of empty capsules
 When they reach the back end of the machine the bars are
transferred back to the lower level and pass through further drying
kilns until they reach the front of the machine
 The dried films are removed from molds, cut to the correct length,
the two capsule parts are joined together and the complete capsule
delivered out of the machine
 The pins are then cleaned and lubricated for the start of the next
cycle
Manufacture of empty capsules
 Capsule shells pass through a series of sorting and checking processes,
which can be either manual, mechanical or electronic, to remove as many
defective pieces as possible
 Capsule shells are finally packed for shipment in moisture-proof liners,
preferably heat-sealed aluminum foil bags, in cardboard containers
Manufacture of empty capsules

http://www.youtube.com/watch?v=0EwaIQ-U6QQ
Properties of empty shells
 Flexibility:
 Important as it allows the shell to absorb mechanical handling without any
adverse effect
 Related to the moisture content of the gelatin shell which acts as a plasticizer
Properties of empty capsule
 Moisture content:
 The standard moisture content specification for hard gelatin capsules is
between 13% and 16% w/w
 This value can vary depending upon the conditions to which they are
exposed:
 At low % RH: they will lose moisture and become brittle
 At high % RH: they will gain moisture and soften
 Moisture content can be maintained by controlling the storage conditions in
sealed containers at an even temperature
Properties of empty capsule
 Solubility and disintegration:
 Capsules are readily soluble in water at 37 °C. When the temperature falls
below this temperature, the rate of dissolution decreases
 Below 30°C, capsules are insoluble and simply absorb water, swell and distort
 Temperature is an important factor to take into account during disintegration
and dissolution testing
 The pharmacopeia has set a limit of 37 ±1 °C for the media for carrying out
these tests
 Capsules made from HPMC have a different solubility profile, being soluble at
temperature as low as 10 °C
Capsule sizes
 Hard gelatin capsules are made in a range of fixed sizes; the standard
industrial sizes in use today for human use are from 0 to 4
 Estimation of fill weight:
 For a powder:
 The simplest way to estimate the fill weight is to multiply body volume by its bulk density

 For liquids:
 The fill weight is calculated by multiplying the specific gravity of the liquid  the capsule
body volume  0.8
Capsule sizes
 Sizes (contd)
 Elongated sizes:
 To accommodate special needs, some intermediate sizes are produced – they have an
extra 10% of fill volume over the standard sizes
 Example: for 500 mg doses of antibiotics (relatively large) elongated size 0 capsules
are commonly used
Capsule sizes
Capsule no: 000 00 0 1 2 3 4 5V
Content (mg): 950 650 450 300 250 200 150 100
Capsule sizes
Self-locking capsules
 Introduced when automatic filling and packaging machines were
introduced
 Filled capsules are subjected to strong vibration during this process,
causing some to come apart and lose their contents
 What to do in order to overcome this?
 Modern capsule shells have a series of indentations on the inside of the cap
and on the external surface of the body
Self-locking capsules

Traditional capsule open and closed, Snap-fit capsule open and locked
with and without sealing band Coni-Snap capsule open and locked
Capsule filling
 Hard gelatin capsules can be filled with a large variety of materials of
different physicochemical properties
 Types of material for filling into hard gelatin capsules:
 Dry solids: powders, pellets, granules, tablets
 Semisolids: thermo-softening mixtures, thixotropic mixture, pastes
 Liquids: non-aqueous liquids
Capsule filling
Capsule filling
 Gelatin is a relatively inert material
 The substances to avoid are:
 Those which cause cross-linking reactions that make the capsule shell
insoluble (formaldehyde)
 Those that interfere with the integrity of the shell, e.g., substances containing
free water, which can be absorbed by gelatin causing it to soften and distort
Capsule filling
 Limitations of the properties of materials for filling into capsules:
 Should not react with gelatin
 Should not contain a high level of free moisture
 The volume of the unit dose should not exceed the sizes of capsule available
Capsule filling machines

https://www.youtube.com/watch?v=x
wGPielvFFE

Manual filling
Capsule filling machines
 Industrial scale
 In your future industrial pharmacy course
 https://www.youtube.com/watch?v=R9-wIoHvZrM
Formulation
 All formulations for filling into capsules have to meet the same basic
requirements:
 Should be capable of being uniformly filled to give a stable product
 Should release their active ingredients contents in a predictable manner
 Should comply with the requirements of the pharmacopeia and regulatory
authorities, e.g., dissolution tests
Formulation

Active
Excipients
Ingredient

The majority of products for filling into capsules

are formulated as powders
Formulation
 The selection of the excipients depends on:
 The properties of the active ingredient
 The dose of the drug, its solubility, particle size and shape
 The size of capsule to be used: free space inside the capsule that is available to
be used
Formulation
 Size of the dose:
 Active ingredients that are easy to formulate are low dose potent drug (they
occupy only a small percentage of total volume < 20%) and the properties of
the mixture will be governed by the excipients
 High unit dose drugs (e.g., 500 mg antibiotics) leave little free space within
the capsule: excipients must be chosen that exert their effect at low
concentration (< 5%), the properties of the mixture will be governed by the
active ingredient
Formulation
 Types of excipient used in powder-filled capsules:
 Diluents: which give plug-forming properties
 Lubricants: which reduce powder to metal adhesion
 Glidants: which improve powder flow
 Wetting agents: which improve water penetration
 Disintegrants: which produce disruption of the powder mass
 Stabilizer: which improve product stability
Formulation
 Formulation for fill material:
 There are three main factors in powder formulation:
 Good flow (using free flowing diluent and glidant)
 No adhesion (using lubricant)
 Cohesion (plug-forming diluent)
Formulation
 Formulation for fill material:
 The factor that contributes most to the uniform filling of capsules is good
powder flow
 This is because the powder bed, from which the dose is measured, needs to
be homogeneous and packed reproducibly in order to achieve uniform fill
weights
Formulation
 Formulation for fill material:
 Low dose active ingredients can be made to flow well by mixing them with
free-flowing diluents (e.g., lactose)
 The diluent is also chosen for its plug-forming properties: the most
frequently used ones are lactose, maize starch and microcrystalline cellulose
Formulation
 When space is limited (i.e., you cannot add enough diluent), you can add:
 Glidants (colloidal anhydrous silica): are materials that reduce
interparticulate friction
 Lubricants (magnesium stearate): are material that reduce powder to metal
adhesion
 Both exert their effect by coating the surfaces of other ingredients
improving their flow
Formulation: factors affecting drug release
 Disintegration of the capsule shell:
 The first stage in active ingredient release is disintegration of the capsule
shell
 When capsules are placed in a suitable liquid at body temperature (37 °C),
gelatin starts to dissolve and within 1 minute the shell will split, usually
beginning at capsule ends
 The contents will start to empty out before all the gelatin has dissolved
Formulation: factors affecting drug release
 The limiting factors in drug release is the formulation of the contents,
which ideally should be hydrophilic and dispersible
Formulation factors: particle size
Formulation factors: particle size
 The smaller the particle, the greater the relative surface area (area of the
active available to the dissolution fluid)
 Negative effect: small particles tend to aggregate together and the effect is
lost
Formulation factors: diluents
 Inert materials added to a mixture intended:
 Increase its bulk to a more manageable quantity
 Produce the proper capsule fill volume
 Provide cohesion to the powders, which is beneficial in the transfer of the
powder blend into capsule shells
 Although they are relatively inert chemically, they do play a role in
release
 The diluent used should be chosen relative to the solubility of the
active ingredient
Formulation factors: diluents
 If a soluble diluent (i.e., lactose) is added to a poorly or insoluble
compound, it will make the powder mass more hydrophilic, enabling
it to break up (dissolve) more readily
 Readily soluble active ingredients are best mixed with insoluble
diluents (e.g., starch or microcrystalline cellulose). Why?
 Because they help the powder mass to break up without interfering with their
solubility in the medium
Formulation factors: lubricants and glidants
 Tend to make the formulation more hydrophobic
 The most commonly used lubricant for both encapsulation and tableting
is magnesium stearate
Formulation factors: lubricants and glidants
Formulation factors: lubricants and glidants
 However, hydrophobic additives are not always deleterious because they
reduce the cohesiveness of the powder mass
Formulation factors: lubricants and glidants
Formulation factors: increasing dissolution
 The addition of surfactants can be used to increase dissolution of the
capsule content
 A disintegrant (in a capsule formulation) may facilitate the breakup and
distribution of the capsule’s contents (the capsule plug)
Formulation factors: increasing dissolution
 Surfactants:
 Na lauryl sulfate
 Used as a wetting agent
 Best results are achieved when used:
 For poorly soluble drugs
 In a combination with a soluble diluent in a level of 1%
Formulation factors: disintegrants
 Usually are not added or used in a much lower level than used in
tablets to capsule formulations
 This is because the powder plug is much less compacted (more
porous) than a tablet
 Recently, super-disintegrants have been introduced:
 Swell many fold on absorbing water (e.g., sodium starch glycollate)
 Act as wicks, attracting water into the plug (e.g., crospovidone)
Formulation optimization
 The formulator has to produce a product that complies with the
three formulation goals:
 Uniform filling
 Drug release
 Meeting pharmacopeial requirements
 Sometimes these goals are contradictory
 For example, extra hydrophobic lubricant is required for filling
machine performance, but may interfere with drug release
 Formulation optimization is required
Formulation optimization
 To summarize, the main factors in powder formulation release for
capsules are:
 Active ingredient, optimum particle size
 Hydrophilic mass, relating solubility of active to excipients
 Dissolution aids, wetting agent, superdisintegrant
 Optimum formulation for filling and release
Modified release
 Many products are formulated to release their contents in the stomach
 Sometimes, there is a need to modify the position of product release
 Capsule formulation can be manipulated to release their contents at
various positions along the gastrointestinal tract
Modified release
 Floating capsule
 Enteric-coated capsule
Modified release: floating capsule
 For some compounds, it has been suggested that the best way to
improve their absorption is for the dosage form to be retained in the
stomach so that it will dissolve slowly, releasing a continuous flow of
solution into the intestines
 Floating capsules contain various hydrophilic polymers, such as
methylcellulose
 Methylcellulose swells on contact with water and forms a mass that
can float on the gastric liquids
Modified release: EC capsules
 Some compounds are destroyed at acidic pH of the stomach
 An enteric product can be made by:
 Coating the filled capsule with an enteric film in a similar manner to a tablet
 Formulating the contents as pellets and coating them with an enteric polymer
Swallowing issues
 A common problem with oral dosage forms is making them easy to
swallow
 Some people have swallowing difficulty because the process is not a reflex
and is controlled by the central nervous system
 The capsule is a good shape for swallowing because the tongue will
automatically align it with its long axis pointing towards the throat
Swallowing issues
 Patients who have difficulty swallowing should be instructed to do it either
standing or sitting, in order to make full use of gravity, and to take a drink of
water to lubricate the throat
 They should drink a little water and hold it in the mouth
 The capsule should be placed in the mouth and the head tilted forward
 The capsule will now float on the water towards the back of the mouth and
when the head is lifted the bolus of water and the capsule will go straight down
the throat to the stomach
 In the stomach the release of the active ingredient can be modified in a number
of ways