CAPSULES
» Definition : “capsules are unit solid dosage form in which drug is enclosed within soluble shell
of gelatin or similar material intended to be swallowed whole.”
According to B.P, “Capsules are solid preparations with hard or soft shells of various shapes &
capacities, usually containing a single dose of active ingredients.”
» ADVANTAGES : ( over tablet )
Tasteless and odourless , so used to mask unpleasant taste and odour of drugs
Attractive appearance
Easy to administer
Economical
Easy to handle and carry
Protect drug from damage due to humidity & light
Liquid substances can be filled
» DISADVANTAGES :
Not suitable for hygroscopic and deliquescent substances as they absorb moisture present
in shell and shell become brittle.
less stable as compare to tablet
some of the tablets are divided into halves and quarters by drawing lines during
manufacturing to facilitate breakage whenever a fractional dose is req.
The incompatibility of medicaments and their deterioration due to environmental factors
are less in tablet.
» CLASSIFICATION :
CAPSULES
Non-gelatin
Gelatin capsules capsules
(veg.capsules)
Hard gelatin Soft gelatin
capsule capsule
“ Hard gelatin capsules → for filling of solid material”
“ Soft gelatin capsules → for filling of liquid and semisolid material”
hard gelatin capsules :
The hard gelatin capsule consists of 2 pieces in the form of cylinder closed at one end.
The shorter piece is called the cap.
This cap fits over the open end of longer piece called body.
HGC is also known as dry-filled capsules or two piece capsules.
Formulation of gelatin capsule:
Gelatin :
It is the major component of the capsule.
Gelatin is a heterogeneous product derived by irreversible hydrolytic extraction of
treated animal collagen.
Types of gelatin :
Type – A Type – B
(PHARMAGEL-A) (PHARMAGEL-B)
Source Pork skin Bone
Processing Acid processed Base processed
Isoelectric point 9 4.7
Methods of manufacturing of empty gelatin capsule shells :
There are 2 methods :
1. Centrifugal casting method
2. Dip pin method ( commonly used )
Steps of dip pin method : https://youtu.be/NVqN-Dinh48
No. steps description
Temp. of pins = 22º & time req.= 12 secs
1 Dipping
Temp. of gelatin soln. = 50º
Pins are rotated to distribute the gelatin uniformly around the
2 Spinning
pins.
3 Drying By use of dry air and dehumidification.
4 Stripping By bronze knives.
5 Trimming By stationary knives.
6 Joining Cap and body are joined.
7 polishing Polishing by polymer.
Properties of gelatin :
property Ideal range Equipment
Bloom strength 150-250 gm By bloom gelometer
viscosity 25-45 millipoise By capillary pipette
Plasticizers :
Amount of plasticizer affect flexibility of the shell.
Amount of plasticizer → SGC > HGC
Ex. = sorbitol Glycerol PEG
Composition of gelatin & plasticizer decides the hardness of shell:
Hardness of shell Gelatin : plasticizer
Hard 1:0.4
Medium 1:0.6
soft 1:0.8
Dyes / pigments :
Approved by D&C act.
Ex. Of dyes (Soluble) : Erythrosine Indigo caramine
Ex. Of pigments (Insoluble) : TiO2 ( for white )
Oxides of Iron ( for black, yellow & red )
preservatives : ( 0.2% )
Methyl paraben : propyl paraben → 4:1
1% fumaric acid : to ↑se acid solubility & ↓se aldehyde tanning of gelatin.
0.15% SO2 : prevent decomposition of gelatin.
Opacifiers :
Gives opaque appearance to shell.
Also provides protection against light.
Ex. : 0.2% - 1.2% TiO2.
Flavours :
Imparts pleasant taste & odour.
Ex.: Ethyl vanillin ( 0.1% )
2% essential oil
5% sugar solution → for chewable capsules.
Other excipients : includes…..
Diluents
Absorbents
Glidants
Anti-dusting compounds
Stabilizers
METHODS OF CAPSULE FILLING :
[ YouTube link = https://youtu.be/Huq7SeTVFhk ]
Capsule filling involves several steps:
(1) feeding : empty shells of gelatin are fed into hopper & it‟s direction is adjusted
automatically such as body positioned downwards.
(2) separation : body and cap is separated by means of vacuum suction.
(3) filling : now, determined quantity of dose is filled into body.
(4) locking ( or Recombining ) : after filling medicaments cap is again placed on
body and locked.
(5) Ejection : finished capsules are ejected by means of punch.
Ex. Of capsule filling machines :
fully automatic → (1) Zanasi (2) Farmatic (3) Macofer
semi-automatic → (1) Eli-Lilly [ Park davis ]
(2) Hofliger & karg
(3) Osaka
specialized → (1) Rotofill = for filling of pellets.
(2) Vericap-1200 = capsule weighing machine.
(3) Quali-seal = for filling of liq.
(4) Erweka KEA = dusting and polishing machine
PROBLEMS AND REMEDIES :
There are many problems occurred during production of hard gelatin capsule.
Here, we are focusing on problems arises during filling of capsules.
Deliquescent / Hygroscopic powders :
“These are the substances which absorbs moisture from surrounding.”
When deliquescent or hygroscopic material is filled in capsule,
It absorbs moisture from shell (surrounding) & make it brittle.
And may leads to hydrolysis of API.
Remedy : addition of adsorbent like MgCO3 & MgO.
Adsorbents will adsorb moisture itself and hence prevent products‟ hydrolysis.
Eutectic mixture :
“It‟s mixture of substances having a melting point lower than that of any of its‟
components.”
When such components are filled in capsule, they melt within the capsule.
This may alter stability and desirability of capsule.
Remedy : use of adsorbent like Kaolin, MgCO3 may solve this problem.
Small dose of drug :
This problem arises with potent drugs.
Because it requires very less quantity of API.
This might not be sufficient to be filled.
Remedy : addition of inert powder → „Diluents‟ or
Use small size of capsule shell (for instance 5 )
Incompatibilities of materials :
When two or more APIs or excipients are incompatible with each other
They may leads to any physical or chemical incompatibility
And leads to therapeutic failure and poor patient compliance.
Remedy : microencapsulate those APIs with inert coating.
particle shape :
The shape of the particle influences all the stages of powder handling.
For capsule filling , most critical particle shape is the needle or rod shape.
Remedy : granulation of such material is the only successful approach to overcome
this problem.
Sometimes , addition of excipients with roundish shape of similar particle size also
proven useful.
IP Capsules :
Cephalexin capsules IP :
Usual strength : 250 mg , 500 mg.
Storage : in tightly closed container in cool place.
Labeling : the label states that strength in terms of the equivalent amount of anhydrous
cephalexin.
Standards : cephalexin capsule contain NLT 90.0% and NMT 110.0% of stated amount
of anhydrous cephalexin, C16H17N3O4S.
Identification :
Shake the contents of the capsule equivalent to 0.5 gm of anhydrous cephalexin
Add 1 ml of water & 1.4 ml of 1M HCl
Filter and wash with 1 ml of water
Add saturated soln. of sodium acetate into filtrate until ppts. Occurs.
Dissolution :
Dissolution apparatus : USP dissolution apparatus – 2 ( paddle apparatus )
Dissolution media : 900 ml water
Speed of paddle : 100 rpm
Time : 45 mins
Detection : measure absorbance in UV-Visible spectroscopy at 261nm
wavelength.
Standards : NLT 75% of the stated amount of anhydrous cephalexin.
Water : NMT 10.0% W/W, determined on 0.3gm of the contents of the capsule.
SOFT GELATIN CAPSULES :
“A softgel or soft gelatin capsule is a solid capsule (outer shell) surrounding a liquid
or semi-solid center (inner fill)”.
Formulation of soft gelatin capsules :
Same as described in hard gelatin capsules earlier.
Manufacturing of SGC ( filling of SGC ) :
Mainly done by 4 methods : (1) Plate process
(2) Rotary die process
(3) Reciprocating die process
(4) Accogel technology
Rotary die process : https://www.youtube.com/watch?v=pu9bvGlCxVc
» PROCESS :
This is continuous and automatic capsule filling process.
Two continuous sheets of gelatin are supplied to the two die rolls.
Both die rolls are having matching numbers of dies.
And both die rolls rotates at same speed in opposite direction.
Medicament tank : which stores the blend of ingredients which are about to fill.
Metering device : controls the rate of filling as well as dose of API.
As the gelatin sheets come in between the rollers
The material to be filled in is injected through the metering device
The pressure exerted by the material forces the gelatin sheet to go in the cavities of die
Which forms two halves of the capsules and fill them.
Operating speed : 25,000 to 30,000 capsules per hour.
FIGURE : ( of rotary die process )
The following should be monitored/controlled:
1. Gelatin temperature
2. Fill temperature
3. Ribbon thickness
4. Seal or seam width
5. Fill quantity
QUALITY CONTROL TESTS FOR CAPSULES :
Whether capsules are produced on a small scale or large scale all of them are required
to pass through certain tests i.e., quality control tests to ensure the quality of the
finished product.
[1] PHYSICAL TESTS OF CAPSULES :
Soft gelatin capsules are tested for physical integrity (absence of leakage) by visual
inspection. Similarly, hard gelatin capsules are tested for any breach of physical
integrity (breakage or opened cap and body).
Capsule diameter sorter : it allows to pass next uniform capsule within suitable range
of diameter.
Capsule colour : any capsule whose colour does not conform to the reference colour
standard for that particular product is discarded others passes the test.
[2] WEIGHT VARIATION :
For HGC;
Take 20 intact capsules & Weigh all intact capsules
Then, remove all content of each capsule with help of small brush
Weight the empty shells individually
Net wt. of drug = wt.of intact capsule – wt. of empty shell
Capsules can be weigh accurately with the help of Rotoweigh & vericap-1200.
For SGC;
Take 20 capsules and weigh them
Cut each capsule, open and contents are removed by washing with suitable solvents
Dissolved content is allowed to dry by evaporating the solvent
Remained dried weight is considered as net wt.
Ideal range : NMT 2 capsules should deviate from following range;
Avg. wt. of capsule %deviation
<300 mg 10%
>300 mg 7.5%
[3] Content uniformity:
Take 30 capsules and select 10 capsules randomly among them and analyze
9 of 10 capsules should be in the range of ±15% (85-115%)
If not, then remaining 20 capsules are analyzed
Test passes if all 30 capsules are within ±25% ( 75-125% )
And NLT 27 of the 30 are within 85-115%
[4] Disintegration test :
The disintegration test determines that whether capsules disintegrate within
prescribed time when placed in a liquid medium under the prescribed integral
conditions .
introduce one capsule in each tube and suspend the apparatus in a beaker
containing 60ml water at 37º C,
Capsule passes the test if, no residue remains on the screen after prescribed time;
Ideal range : For HGC → 15 – 30 mins
For SGC → 60 mins
[5] Dissolution test :
The dissolution test is carried out using the dissolution apparatus official in both
the U.S.P and I.P. ( mostly conducted using basket apparatus)
The capsule is placed in a basket and then basket is immersed in the dissolution
medium and rotated at a specified speed . ( 100 RPM )
The dissolution medium is held in a covered 1000ml glass vessel and maintained
at 37ºC±0.5ºC by means of a constant temperature suitable water bath .
The stirrer speed and type of dissolution medium are specified in the individual
monograph .
Dissolution acceptance criteria : ( as per I.P )
Stage No. of capsules tested Acceptance criteria
S1 6 No cap. is less than Q+5%
Avg. of 12 cap. is equal to or NMT Q% & no cap. is less than
S2 6 ( total 12 )
Q-15%
Avg. of 24 cap. is equal to greater than Q% and NMT 2 cap. are
S3 12 ( total 24 )
less than Q-15% and no cap. is less than Q-25%
[6] Stability :
By accelerated stability study ,
Temp. → 40º C
Humidity → 80% RH
[7] Moisture content :
By „toluene distillation method’.
Collect the distillate & remove the water by heating.
For HGC→ 12-16%
For SGC→ 6-10%
[8] Other :
Seal thickness determination
Capsule rupture test
Determination of freezing and high temperature effect.
CLIMATIC CONTROL IN CAPSULE DEPARTMENT:
Capsules should be dispensed in tightly closed glass or plastic containers to protect from
dust and extremes of humidity and temperature.
The capsules should be stored under controlled conditions of temperature and humidity.
The storage area preferably should have a….. temp.→ 15-30ºC
Humidity → less than 70% RH
Under condition of low humidity : capsules become brittle
Under condition of high humidity : capsules become soft and shapeless.
If capsule is very hygroscopic in nature , packet of desiccant like silica gel or anhydrous
calcium chloride may be placed to prevent the absorption of excessive moisture by the
capsules.
Multi-laminated aluminum foil , which are heat sealed , are required in severe climatic
conditions or where the warehousing facilities can‟t be maintained at uniform temp.
In some locations, windows set into roof through which sunshine could shine on carton
causing high local temperature.
Sometimes, other heat sources such as overhead space heaters that could cause a similar
problem.
Temp. alteration during storage may leads to produce deleterious effects on product and
also reduce shelf life of capsule.
So, capsules should be stored at a temperature not exceeding 30º C.
If both temp. and humidity is maintained, the only cause of capsule damage could be
sudden heat changes that result in localized moisture transfer effects within the container.
Even if the temperature in the warehouse is well controlled , care must be taken if the
temperature in the production filing area is significantly different.
For example: in winter, the temp. in the warehouse could be lower than in the production
area.
If this is the case, time should be allowed for the boxes of capsules to come to
equilibrium with their new surrounding before they are opened.
This will allow time for the humidity inside the cartons to change and come to
equilibrium ,thus avoiding any dimensional changes in the capsule shells.
difference between sgc & hgc :
Sgc hgc
Comprises of two parts : (1) body
Comprises of only body.
(2) cap
So many shapes are available like oval,
Mostly formulated in cylindrical form
spherical, cylindrical, tube etc.
Medicaments filled are mostly in liquid or Medicaments filled are in solid form like:
semisolid form. Pellets, beads, powder, granules
There is no specific size available.
Shells are available in only specific standard
Size of SGC can be adjusted depending upon
range of size i.e. 000 to 5.
dose of medicaments.
Gelatin is used in it‟s molten form. Gelatin is used in hard form.
Shell of SGC should be flexible so they Shell of HGC should be rigid so they require
require more amount of plasticizers. less amount of plasticizers.
Gelatin: plasticizer→ 1:0.8 Gelatin: plasticizer→ 1:0.4
Low bloom gelatin is used. High bloom gelatin is used.
Moisture content→ 6-10% Moisture content→ 12-16%
Capsule filling and sealing both goes
Capsules are sealed after filling of capsules.
simultaneously.
Closure : inherently sealed by heat and Closure: by traditional friction, interlocking or
pressure. liquid sealing.
It requires 60 minutes to disintegrate. It disintegrates within 15 to 30 minutes.
Ex: omeprazole enteric coated capsules Ex: isotretinoin 10 mg SGC
microencapsulation
Definition : “ Microencapsulation is a process of applying thin coating to small particles
of solid or droplets of liquids”
Microspheres: “ microspheres are free flowing powders consisting of spherical
particles of size ideally less than 125 microns.”
Each microsphere is basically a matrix of drug dispersed in a polymer form.
( matrix system )
Microcapsules : “microcapsules are polymeric particles ranging in size from 1-1000
micron”
In microcapsule, drug ( core material ) is enclosed within the polymeric embryonic
membrane. ( Reservoir system )
Core material : defined as a material to be coated.
It can be solid or liquid in nature.
Solid core can be a mixture of actives, stabilizers, diluents, release retardants etc.
Coating material : defined as a material which is used to coat core material.
Include lengthy list of polymeric substances.
Purpose of microencapsulation :
Provide environmental protection to drug.
Bitter taste masking.
Enable single layer tablet to contain chemically incompatible ingredients.
Reduce gastric irritation and volatility of medicaments.
Provide controlled release : sustained release
prolong release
METHODOLOGY:
Various methods for microencapsulation are listed below:
Sr.no Microencapsulation method Core material
1 Air suspension method
Only solid
2 Pan coating
3 Multi-orifice centrifugal process
4 Coacervation phase separation
Solid & liquid both
5 Solvent evaporation
6 Spray drying & spray congealing
Other least applicable methods are…………
7) Complex emulsion method
8) Polymerization method
9) Vaccum deposition method
10) Thermal gelation etc…
Air suspension method
This technique was invented by Professor Dale.E.Wurster.
So, this technique is widely known as “Wurster process”.
» Principle: It consists of the dispersing of the solid ( core material ) in a supporting air
stream and the spray coating of air suspended particles.
» Procedure:
Core material is loaded in equipment and start the air stream
Particles will be suspended on an upward moving air stream
When particles travels through the coating zone, they are coated by
the coating material ( usually the polymer solution )
so, coating material is spray applied when particles are air suspended
or in fluidized state, that‟s why it is also known as “fluidized bed coating”.
During each pass through the coating zone, the core material receives
an increment of coating material
This cyclic process is repeated for several times depending upon the purpose of
microencapsulation and the coating thickness desired.
» Figure :
The supporting stream also serves to dry the product while being encapsulated.
Drying rate of product ∝ temp. of supporting air stream.
» Factors :
1. Density, surface area, MP, solubility, friability, volatility, crystallinity, and
flowability of the core material.
2. Concentration of coating material.
3. Viscosity of coating material
4. Application rate of coating material
5. Amount of coating material required.
6. Volume of air required.
7. Temp. of air.
» Advantages :
Simple process
Easy to use
Variety of coating materials can be used ( ex. In solution , emulsion , dispersion )
Applicable for both microencapsulation and macroencapsulation.
» Disadvantages:
Only used when core material is solid.
Only applicable when coating material forms adhesive bond with core material.
» Youtube links: https://youtu.be/snLEMu1NAdM
https://youtu.be/IcIsC3rvdss
COACERVATION PHASE SEPARATION
Dense coacervate
Coacervation : separation of solution into two immiscible liquid phases
Dilute vehicle
3 steps process…..
(1) Formation
(2) Deposition (3) Rigidization
of 3 immiscible
of the coating of the coating
chemical phase
» Procedure:
Step – 1 : Formation of 3 immiscible chemical phase :
3 immiscible phases are…… (1) core material
(2) coating material
(3) liquid vehicle
Firstly, the core material is dispersed in a solution of the coating polymer
Then add this dispersion into a liquid vehicle
Now, form coacervates by using one of the following methods…….
(A) By temp. change
(B) Non-solvent addition
(C) Salt addition
(D) Incompatible polymer addition
(E) Polymer-polymer interactions
Note = This step is shown in figure as (a) and (b)
» Figure :
Step – 2 : Deposition of the coating :
In this step, coacervates of polymer is coated upon the core material.
Prerequisite for effective coating : Adsorption of coacervates at the interface
formed between the core material and liquid vehicle.
Shown in figure as (c) .
Step – 3 : Rigidization of the coating :
It involves rigidization of the coating, usually by…….
(a) Thermal
(b) Desolvation techniques
(c) By adding cross-linking agents [ ex. Formaldehyde ]
Shown in figure as (d).
Coacervation by temp. change :
Purpose : of any coacervation technique is to reduce the solubility of polymer anyhow so it can
be separated out as coacervate phase ( give two phase dispersion ) .
Given graph represents phase diagram when coacervation is induced thermally.
Temp. → polymer conc. is plotted.
It gives binodal curve ( FEG ) or phase-boundary .
Above this curve , system exists as a single-phase ( homogenous solution ).
As the temp. of the system is decreased from point A.→ point E.
Phase boundary is crossed & system enter into two-phase region.
Hence, phase separation of the dissolved polymer occurs in the form of immiscible
liq. droplets.
Under proper polymer concentration, temp. and agitation ……
the liq. polymer droplets coalesce around the dispersed core material, thus forming
the embryonic microcapsules.
The phase boundary curve indicates that with ↓es in temp…….
»One phase become polymer poor ( means only vehicle phase)
»And second phase become polymer rich ( coating material phase).
Point-B→ pure vehicle
Point-C→ coexisting phase
Point-D→ concentrated polymer phase.
Example:
Liquid vehicle Cyclohexane
Coating material Ethylcellulose
Core material PCM
Youtube links : https://youtu.be/XnxitFTYoTc
APPLICATIONS OF POLYMERS :
There are mainly 2 type of polymers :
Polymers
Non-
Biodegradable
biodegradable
Natural Synthetic
BIODEGRADABLE POLYMERS :
“ Polymers that undergoes chemical or enzyme catalyse hydrolysis.”
Biodegradable property of polymer make possible to implant them into body without
need of removal by surgical operations.
It have been applied as carrier for control delivery of low molecular weight drugs as
well as bioactive proteins.
There are two types of it :
1. Natural
2. Synthetic
» [1] Natural :
They are attractive.
Readily modified by simple chemistry.
Various biochemical applications.
Various modified drug delivery systems
Ex. : gelatin, albumin, polysaccharides (like starch, dextran, chitosan)
» [2] Synthetic :
They are mainly synthesized by using various chemical approaches.
Various examples are as follows……….
[1] Polyester : contains Ester bonds.
Degraded by hydrolytic cleavage of ester bonds.
Acts as drug carrier due to their biocompatibility.
Use : in sutures, artificial heart valve, internal patches.
[2] poly-orthoesters : (POE)
Degraded by surface erosion mechanism because of hydrophobicity &
water impermeability.
It possess 4 families :
1. POE-I
2. POE-II
3. POE-III
4. POE-IV
Use: to formulate SR dosage form.
[3] Polyanhydrates : contains anhydride bond.
Used for short term delivery of bioactives.
Because it shows rapid degradation in-vivo.
They possess hydrophobic properties.
Hydrolytically labile anhydride bond.
[4] Polyphosphazene : contains phosphorus & nitrogen atom.
Made up by reaction of phosphorus & chlorine bond with
polydichlorophosphazene.
Non-biodegradable polymers :
[1] Polyethylene : 3 types of polyethylene, i.e;
1. Linear high density polyethylene (HDPE)
2. Branched low density polyethylene (LDPE)
3. Ultrahigh molecular weight polyethylene (UHMWPE)
HDPE & UHMWPE are frequently used as biomaterials.
[2] Polycarbonates : carbonate linkage in chain.
It is a tough and transparent plastic commercially available.
Polycarbonate is used to make components for oxygenator for open heart
surgery, venous reservoir and arterial filter.
It is in use due to its sterilizability , ease of processing, biocompatibility
and clarity.
[3] poly amides : ( Nylons )
They have amide linkage in their chain.
The 1st polyamide synthesized was Nylon-66.
It was synthesized through the polycondensation of hexaethylenediamine
and adipic acid.
used as surgical sutures.
[4] Poly ether ether ketone : ( PEEK )
Crystalline polymer
Thermally stable
Resistant to many chemicals
Very tough
Specifically applicable for pipes in oil refineries and chemical plants.
Useful to make parts of scientific instruments, aerospace and biomedical
devices where high price is not a limitation.
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