CAPSULESCAPSULES

Are solid dosage forms in which one or more medicinal and or inert substances are enclosed within a small shell or container generally prepared from a suitable form of gelatin. Depending upon their formulation, the gelatin capsule shells may be hard or soft.

Characteristics:Characteristics:1. May be swallowed whole by the patient

2. May be inserted into the rectum for drug release and absorption from the site

3. The contents may be removed from the gelatin shell and employed as a pre measured medicinal powder, the capsule shell being use to contain a dose of the medicinal substance.

Example: Theo-dur Sprinkle

Characteristics:Characteristics:4. Elegance

5. Ease of use

6. Portability

7. Tasteless shell to mask the unpleasant taste/odor of the drug

8. Permits physician to prescribe the exact medication needed by the patient

Characteristics:

9. conveniently carried

10. readily identified

11. easily taken

12. tasteless when swallowed

13. commonly embossed or imprinted on their

surface the manufacturer’s name and product code readily identified

14. available in variety of dosage strength

15. provide flexibility to the prescriber and accurate

individualized dosage for the patient

16. packaged and shipped by manufacturers at lower cost less breakage than liquid forms

17. more stable and longer shelf life

Characteristics:

Components Of CapsulesComponents Of Capsules1. Gelatin

2. FD & C and D & C colorant

3. Sugar

4. Water - 12 to 16 % but may vary depending on the storage condition

5. Sulfur dioxide (.15%) - prevent decomposition during manufacture

6. Opaquants/Opacifying agent - titanium dioxide

HARD GELATIN HARD GELATIN CAPSULESCAPSULES

Also referred to as “DFC” Dry Filled Capsule. Manufactured into two sections, the capsule body and a shorter cap.

A recent innovation in capsule shell design is the Snap-Fit, Coni-Snap, and Coni Snap Supro hard gelatin capsules.

Capsule size

For human use, empty capsules ranging in size from 000 the largest to 5 the smallest. Generally, hard gelatin capsule are used to encapsulate between 65 mg to 1 gram.

HARD GELATIN CAPSULES

usually use in the extemporaneous compounding of Rx.

made of gelatin, sugar, and water

clear, colorless and essentially tasteless

colored with various FD & C and D & C dyes and made opaque by adding agents such as titanium dioxide

combination of colorants and opaquants to make them distinctive, many with caps and bodies of different colors

GELATIN is obtained by the partial hydrolysis of

collagen obtained from skin, white connective tissue and bones of

animals

available in the form of a fine powder, a coarse powder, shreds, flakes, or sheets

Stable in air when dry but when become moist - subject to microbial decomposition

HGC contain 13 to 16 % of moisture

extreme dryness- capsules may become brittle and crumble

capsules absorbed moisture - a small packet of a dessicant material - to protect against moisture

dessicant use = dried silica, gel, clay, activated charcoal

prolong exposure to high humidity can affect in vitro capsules dissolution - changes have been observed in capsules containing tetracycline, chloramphenicol, nitrofurantoin

gelatin is insoluble in cold water and soluble in hot water and in warm gastric fluid

gelatin being a protein, is digested by proteolytic enzymes and absorbed

Drug absorption depends on a number of FACTORS

1. Solubility of the drug

2. Type of product formulation ( immediate release, modified, enteric)

3. Gastrointestinal contents

4. Physiologic character and response

Production of empty HGC

• Elililly• Warner lamberts• R.P. Scherer corporationDippingSpinningDryingStrippingTrimmingJoining

Manufacture of Hard Gelatin Capsule

@ manufactured into 2 sections, the capsule body and the shorter cap

@ the 2 parts overlap when joined, with the cap fitting snugly over the open end of the

capsule body

@ shells are produced by chemical dipping of pins or pegs of the desired shape and diameter into a temperature-controlled reservoir of melted gelatin mixture

@ the pegs made of manganese bronze, are affixed to plates, each capable of holding up to about 500 pegs

Manufacture of Hard Gelatin Capsule

@ each plate is mechanically lowered to the gelatin bath, the peg submerge to the desired depth and maintained for the desired period to achieve the proper length and thickness of coating

@ the plate and the pegs are slowly lifted from the bath and the gelatin dried by a

gentle flow of temperature-and humidity-controlled air.

@ when dried, each capsule part is trimmed mechanically to the proper length and removed from the pegs, the capsule bodies and caps are joined together

MANUFACTURING OF HARD GEL CAPSULES

1. Once raw materials have been received and released by Quality Control, the gelatin and hot demineralized water are mixed under vacuum in Stainless Steel Gelatin Melting System.

MANUFACTURING OF HARD GEL CAPSULES

2. After aging in stainless steel receiving tanks, the gelatin solution is transferred to stainless steel feed tanks.

MANUFACTURING OF HARD GEL CAPSULES

3. Dyes, opacifants, and any needed water are added to the gelatin in the feed tanks to complete the gelatin preparation procedure. The feed tanks are then used to gravity-feed gelatin into the Capsule Machine.

MANUFACTURING OF HARD GEL CAPSULES

4. From the feed tank, the gelatin is gravity fed to Dipper section. Here, the capsules are molded onto stainless steel Pin Bars which are dipped into the gelatin solution.

MANUFACTURING OF HARD GEL CAPSULES

5. Once dipped, the Pin Bars rise to the upper deck allowing the cap and body to set on the Pins.

MANUFACTURING OF HARD GEL CAPSULES

6. The Pin Bars pass through the upper and lower kilns of Capsule Machine Drying System. Here gently moving air which is precisely controlled for volume, temperature, and humidity, removes the exact amount of moisture from the capsule halves.

MANUFACTURING OF HARD GEL CAPSULES

7. Once drying is complete, the Pin Bars enter the Table section which positions the capsule halves for stripping from the Pins in the Automatic section.

11. Finished capsules are pushed onto a conveyer belt which carries them out to a container.

MANUFACTURING OF HARD GEL CAPSULES

12. Capsule quality is monitored throughout the production process including size, moisture content, single wall thickness, and color.

Empty capsule property

Empty capsule contain a significant amount of water that acts as plasticizer for the gelatin film and is essential for their function.

The standard moisture content specification of HGC is between 13% to 16% w/w.

Advantages Of Coni-Snap

1. The tapered rim avoid telescoping

2. The indentations prevent premature opening

3. The grooves lock the two capsule parts together

after the capsule has been filled.

1. Tapered rim

2. Grooves

3. Indentations

Developing the Formulation and Selection of Capsule Size

@ the goal is to prepare a capsule with accurate dosage, good bioavailability, ease of filling and production, stability and elegance

@ The active and inactive components must be blended thoroughly to ensure a uniform powder mix for the fill

@ Preformulation studies are performed to determine whether all of the formulation’s bulk powders may be effectively blended together.

@ diluent or filler may be added to produce the proper capsule fill volume - ex. Lactose, microcrystalline cellulose and starch

Developing the Formulation and Selection of Capsule Size

@ disintegrants are frequently included in a capsule formulation - to assist the breakup and distribution of the capsule’s contents in the stomach - ex. Pregelatinized starch, croscarmellose, sodium starch glycolate

@ when necessary particle size may be reduced by milling to produce particles ranging

from 50 to 1000 um

@ drugs of lower dose or smaller particles are required, micronization is employed - 1 to 20 um particle size

Selection of capsule size• Dose of drug• Density and compaction characteristics of

drug

• Weigh the ingredients for reqd. no. of capsules to be prepared

• Place in a measuring cylinder—obtain volume• Divide the vol by no.of capsules– we get voulme

that will be occupied by the powder for each capsule

• See table select nearest size• If larger multiply the capsule size in volume by the

no.of capsules to be prepared---so we get final volume of powder to be prepared

• Add additional diluent in measuring cylinder containing the other powders to the mark indicted for total vol of powder

• Total powder blend(weight)-initial quantities =Quantity of additional diluent that was added

Industrial Scale@ the powder mix must be free-flowing to

allow steady passage of the capsule fill from hopper and into the capsule shell

@ addition of lubricant or glidant - fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid or talc (about 0.25-1%) to the powder mix

enhances flow properties

@ Magnesium stearate as lubricant, the water proofing characteristics of this water-insoluble material can retard penetration by the gastrointestinal fluids and delay drug dissolution and absorption

Industrial Scale@ a surface active agent - sodium lauryl sulfate, is used to facilitate wetting by the Gastrointestinal fluids to overcome the problem

@ inserting tablets or small capsules into capsules are possible

Examples:

1. Powder or granulate in capsule

2. Pellet mixture in capsule

3. Paste in capsule

4. Capsule in capsule

5. Tablet in capsule

1. Powder or granules 4. Capsule

2. Pellet mixture 5. Tablet

3. Paste

Filling of Capsules

POWDERS w/ capseal GRANULES

BEADS TABLETS

Filling of Capsules

CAPLETS PASTES

LIQUIDS w/ capseal

Developing the Formulation and Selection of Capsule Size

@ gelatin capsules are unsuitable for aqueous liquids because water softens gelatin and distorts the capsules, resulting leakage of the content

@ some liquids or volatile oil do not interfere with the stability of the gelatin shells - may be placed in locking gelatin capsules to ensure retention of the liquid

@ Eutectic mixtures of drugs - tends to liquefy may be mix with a diluent or absorbent such as magnesium carbonate, kaolin or light magnesium oxide to separate the interacting agents and to absorb any liquefied material that may form.

Developing the Formulation and Selection of Capsule Size

@ liquids are placed in soft gelatin capsules that are sealed during filling and manufacturing

@ selection of capsule size is done during product development

@ the choice is determined by requirements of formulation, including the dose of

the active ingredient and the density and compaction characteristics of the drugs.

@ hard gelatin capsules are used to encapsulate about 65 mg to 1 g of powdered material

Tetracycline CapsulesActive Ingredient Tetracycline hydrochloride 250 mg

Filler Lactose

Lubricant/glidant Magnesium stearate

Capsule colorantsFD & C Yellow No.6, D & C Yellow no.10, D & C

Red No.28, FD & C Blue No.1

Capsule opaquant Titanium dioxide

Acetaminophen With Codeine CapsulesActive ingredients Acetaminophen 325 mg, Codeine phosphate 30 mg

Disintegrant Sodium starch glycolate

Lubricant/glidants Magnesium stearate, stearic acid

Capsule colorantsD & C Yellow No. 10, edible Ink, FD & C Blue No.1 (FD & C Green No.3 and FD & C Red No. 40)

Diphenhydramine Hydrochloride Capsules

Active ingredient Diphenhydramine HCl 25 mg

Filler Confectioner’s sugar

Lubricants/glidants Talc, colloidal silicon dioxide

Wetting agent Sodium lauryl sulfate

Capsule opaquant Titanium dioxide

Sequence of Events

Filling Hard Capsules Shells

1. Use Punch Method

@ powder is placed on a sheet of a clean paper or porcelain plate

@ using spatula - formed into a cake having a depth of approximately one-fourth to one-third

the length of the capsule body

@ then empty capsule body is held between the thumb and forefinger and punched vertically into the

powder cake repeatedly until filled

Filling Hard Capsules Shells

2. Feton capsule filling

@ with empty capsule in the loader tray, the tray placed on top of the filler unit

@ the loader inserts the capsules into the filling unit and is removed, and the top plate is lifted to

separate the caps from the bodies

@ the powder is placed on the unit and the capsule bodies filled

@ the top plate is returned to the unit and the caps placed on filled capsule bodies

ProFill 100 - The ProFill 100 Capsule Filling Machine utilizes an advanced design for fool-proof manual filling of two-piece capsules. With the ProFill 100 machine, there is no need for expensive capsule filling equipment and electrical/vacuum connections.

Manually Operated Bench-top Equipment

• Capsule caps and bodies are rejoined and the capsules are closed.

Industrial scale Filling

• operations involved– rectification of empty capsules– separation of caps from bodies– filling capsule bodies– replacing caps and ejecting filled capsules

Dosing systems• Dependent: that use the capsule body directly

to measure the powder. Uniformity of fill weight can only be achieved if the capsule is completely filled

• Independent: the powder is measured independently of the body in a special measuring device. Weight uniformity is not completely dependent on filling the body completely. With this system capsule can be part filled

• 3 basic methods for powder filling– auger or screw– dosator– dosing disc

Capsule Filling

– auger• semi-automatic operation• filling based on volume• need good powder flow properties

Auger-Filling Principle

• Powder or granules are contained in mass flow hoppers with rotating augers

• Powder is fed continuously out of the hopper outlet due to the rotation of the auger.

• Amount of powder fed into the body depends on the time capsule body spends underneath the hopper outlet and auger speed

- slower rotation increases the fill weight

Auger- Filling Principle

Independent dosing systems

• Use dosing mechanisms that form a plug• Soft compact formed at low compaction

forces(10N to 100N)• Two types of plug forming machines

Dosator

• Weight of the powder filled can be adjusted by altering the position of the piston inside the tube :increasing or decreasing the volume, and by changing the depth of the powder

tamping finger & dosing discfilled based on weight continuous operation

Dosing disc

• Powder fillweight can be varied by the amount of insertion of the fingers into the disc and by adjusting the amount of powder in the hopper

Vibration-Assisted Filling(Osaka filling machine)

• Capsules are placed under the powder bowl• Powders or granules pass through the bowl’s

mesh flow with help of vibration• Bodies are filled to maximum plus more on top• Spring-loaded plunger compresses the powder

inside the capsule body to make a firm plug• A scraper removes the powder outside the turn

table bores• Capsule bodies are pushed upwards to be

closed

Vibration-assisted Filling

Filling

Filling of Pellets

• Double Slide Method• Vacuum-assisted Method

Double Slide Method

• Pellets flow from pellet machine to dosing chambers

• Dosing slide is closed to separate dosing chamber and pellet magazine

• Outlet slides open

Double Slide Method

Vacuum-assisted Method

• Dosing tube enters pellet bed• With the help of vacuum, the pellets are

sucked into the dosing tube• Excess pellet are scraped off the end of

the dosing tube• Dosing tube is lowered and pellets

released into capsule body

Vacuum-assisted Method

Filling of Tablets• Dosing slide which can accommodate exactly

1 tablet moves underneath tablet feeder• Slider moves over the capsule body where

tablet simply drops into it• If properly filled, the pin dropped into the

capsule body will have limited movements, the horizontal bar connected to the pin touches the sensor

• If not properly filled, horizontal bar will switch the sensor indicating incorrect filling. Empty capsules can be detected and eliminated from the product.

Filling of Tablet

Basic requirements for filling

• All formulations must be capable of being filled uniformly & give a stable product

• Must release active contents in a form that is available for absorption by the patient

• Must comply with pharmacopeial requirements

FORMULATION FOR FILLING PROPERTIES• Good flow properties• No adhesion (use lubricant)• Cohesion(plug forming diluent)• Excipents:• Diluents• Lubricants(reduce powder to metal

adhesion)• Glidants (improve powder flow, ↓interparticulate

friction)

• Wetting agents’(improve water penetration)• Disintegrants (aid disruption of powder mass)• Stabilizers(improve stability)

Problems in capsule filling

• After the powder ingredients have been homogenously bended by any suitable technique , the flow of the resultant mixture must be adequate to ensure delivery of sufficient powder to the capsules at thetime of filling. Demixing must not occur during the powder handling in the filling equipment itself.

• Physical incompatibilites between active ingredients , between diluent or between active ingredients and/or diluents & the capsule shell may create problems

• Elevated temperatures and humidity must be studied

• Powder mix must provide type of flow characteristics required by the equipment

• If slug is desired Use Micro crystalline cellulose: directly compressible excipient, can also use mineral oil as a binder or even alcohol

• If filling powder such as acetyl salicylic acid Also use Lubricants eg. corn starch

• Use current FDA approved excipients• GRAS • Oils for cohesiveness or for control of

dusting FDA approved

Finishing

• Dusting And/or polishing operation

• Pan polishing :polyurethane or cheese cloth liner is place in the pan ,liner used o trap the removed dust as well as to impart gloss to the capsules

• Cloth dusting: rubbing with a cloth that may or may not be impregnated with oil

• Brushing: Capsules are fed under rotating soft brushes which serve to remove the dust from the capsule shell.Vaccuming for dust removal

Cleaning and Polishing

On a small scale, capsules maybe cleaned individually or in small numbers by rubbing them with a clean gauze or cloth.

On a large scale, many capsule-filling machines are affixed with a cleaning vacuum that removes any extraneous material from the capsules as they exit the equipment. Or using Accela-Cota apparatus.

Capsule Sealing1. Tamper evident capsules by sealing the joint between the 2 capsule parts

2. Distinctive looking capsules by sealing them with colored band of gelatin (Kapseals). If removed, the band cannot be restored without expert sealing with gelatin

3. Through a heat welding process that fuses the capsule cap to the body through the

double wall thickness at their juncture - distinctive ring around the capsule

where heat welded

Example: Weld’s gelatin seal

Capsule Sealing

4. Liquid wetting agent that lowers the melting point in the contact areas

of the capsule’s cap and the body using low temperatures (40-450C)

5. Extemporaneously prepared then Lightly coating the inner surface of the

cap with a warm gelatin solution immediately prior to placement on

the filled capsule body.

Weld’s Gelatin seal fuses the two capsules halves to create one piece capsule that is tamper-evident

Capsule Sealing

The capsule sealing process of banding ( Kapseals, Quali-caps) has been utilized for a number of years. In this process, two capsule parts are sealed with gelatin or polymer band at the seam of the cap and body.

Recently, a tamper resistant seal on hard gelatin capsules was developed in which the contact areas of the cap and body are wetted with a mixture of water and ethanol and then thermally bonded at 1040 to 1130F.

• ROTOSORT is a filled capsule-sorting machine by Eli lily150,000 capsules per hr

• It is a mechanicalsorting device that removes losse powder,unfilled joined capsules,filled or unfilled bodies and loose caps

• Erweka KEAdedusting & polishing machine

Milling /Sieving of all Ingredients

Blending

Powder Blender / Empty Capsules

. Capsule Filler

Capsule cleaner/deduster

Capsule injection screen

Capsule check-weighing system/reject

Finished capsules

8. Packaging

Preparation Of Filled Hard Gelatin Capsules

1. Developing and preparing the formulation and selecting the

size of capsule

2. Filling the capsule shell

3. Cleaning and polishing the filled capsules

MANUFACTURING OF SOFT

GELATIN CAPSULES

Soft gelatin capsules (Softgels)

• Soft gelatin capsules are made of gelatin, glycerin (or a polyhydric alcohol such as sorbitol) and water etc. to hermetically seal and encapsulate liquids, suspensions, pasty materials, dry powders and even preformed granules, pellets, tablets. They may be manufactured to be oblong, oval or round in shape.

• Similar to hard gelatin shell, except plasticizer is incorporated (sorbitol, propylene glycol, glycerin)

• Usually filled with liquids or suspensions (dry solids are possible, including compressed tablets (“Geltabs”).

• Advantages of Soft Gelatin Capsules• High Accuracy/precision possible liquid

flow more precise than powder flow.• Hermetically sealed (inherently)• bioavailability advantages for poorly

water soluble drugs, increased rate of absorption

• Reduced dustiness; lack of compression stage in manufacture

• pharmaceutically elegant,easily swallowed by the patient

• Oil & low melting drugs• Specialty packages available• Safety: potent & cytotoxic drugs

Example of Soft Gelatin Capsule

Examples of Soft Gelatin

Disadvantages of Soft Gelatin Capsules

• Generally, product is contracted out to a limited number of specialty houses,e.g. Scherer, Banner.

• more costly to produce than tablets or hard shell capsules

• Stability concerns with highly water soluble compounds, and compounds susceptible to hydrolysis

• Not adaptable to incorporation of more than one kind of fill into the same capsule (compared with hard shell capsules)

• Requires special manufacturing equipment • Limited choices of excipients/carriers compatible with

the gelatin

The pharmaceutical applications of soft gelatin capsules are

1) as an oral dosage form 2) as a suppository dosage form 3) as a specialty package in tube form, for human

and veterinary single dose application of topical, ophthalmic, and otic preparations, and rectal ointments.

The nature of soft gelatin capsule shell

The gelatin is pharmacopoeial grade with additional specifications required by the capsule manufacturer.

a) Bloom strength: b) viscosity: Generally, 25 to 45 millipoise is

acceptable.c) iron: ≤15ppm

• The components of soft gelatin capsules• gelatin• glycerin or polyhydric alcohol• water/moisture• preservative• colorant• markings• opaquants• Flavors may be added and up to 5%

sucrose may be included for its sweetness and to produce a chewable shell.

Properties of gelatin Bloom Strength or gel strength

• : measure of the cohesive strength of the crosslinking that occurs between gelatin molecules

• reflects the average molecular weight of its constituents..

• The name is from Oscar T. Bloom, inventor of the Bloom gelometer.

• The gel strength of gelatin is a measure of the rigidity of a gel formed from a 6.67%

solution held at 10 0C for 17 hrs. Bloom is a measure of force (weight) required

to move a plastic plunger that is 0.5 inches in diameter 4 mm into the surface of this gel

Bloom range:150-250 gm The higher the Bloom number ,the stiffer the

gelatin , more physically stable the resulting capsule shell and more expensive.

Viscosity of gelatin• It is determined on a 6.67%conc of gelatin

in water at 600C is a measure of the molecular chain length & determines the manufacturing characteristics of the gelatin film

• Viscosity of gelatin : 25 - 45 millipoise

• Low –viscosity (25-32 millipoise) high bloom(180-250 gm) used for capsulation of hygroscopic vehicles or solids

• Standard gelatin formulas can be modified so as to require upto 50% less water for satisfactory operation on the capsulation machine.

Iron

• Iron is always present in raw gelatin and its concentration usually depends on iron content of large quantities of water used in its manufacture

• NOT MORE THAN 15ppm• (because of its effect on dyes &possible

color reactions with organic compds

The fill material of soft gelatin capsules

LIQUIDS• Water-miscible, volatile liquids

CANNOT be included • Water & alcohol cannot exceed 5%

of contents as cosolvent • Gelatin plasticizers cannot be

included as major constituent • pH 2.5-7.5(acidic: hydrolysis, alkali: tanning)• Aldehydes, in general, must be

excluded (Cause cross-linking)• Contents must flow under gravity

at RT

What can be added in Softgel • Water immiscible non-volatile liquids

• vegetable oils, mineral oils, fish oil(solvent or suspending agent for some other A.I eg. Vitamins

• Low molecular weight PEG's

• Nonionic surfactants such as polysorbate 80

• Aromatic and aliphatic hydrocarbons

• High MW alcohols, esters & organic acids

• All liquids ,solutions, suspensions should be homogeneous & air free

Capsulation of water immiscible liquids is most simple

• There are four primary types of inner fill materials:

1) Neat Substance, especially oily liquids eg. Cod liver oil capsules 2) Solution Fills: Active dissolved in a carrier Oils such as soybean oil and Miglyol 812

(neutral oil, triglycerides of medium chain fatty acids)

Polyethylene Glycols: especially PEG 400 -600

Other solvents: Any other solvent, which doesnot degrade or solubilize the gelatin shell, i.e., dimethyl isosorbide, surfactants, diethylene glycol monoethly ether.

• Optional Ingredients for solution fills: • 1. Water or alcohol: up to 5% w/w (if needed for

solubility). • 2. Polyvinylpyrrolidone: Up to 10% w/w used in

combination with PEG (can increase drug solubility, and also improve stability by inhibiting drug recrystallization).

Minimum fill volume

• Minimum fill calculated from specific gravity of the liquid

• Vitamin A palmitate(1,000,000 units A/g) has fill vol;0.45 minims

• Fish oil as a source of Vitamin Ahas fill volume :8.8 minims

• 3) Suspension Fills: Active dispersed in a carrier.

• Suspensions can accommodate about 30% solids before viscosity and filling become a problem

• Suspensions can be heated up to 35ºC to decrease viscosity during the filling process

• Suspended solids must be smaller than 80 mesh -- mill or homogenize before filling to prevent needles from clogging during filling.

• 4)Solids that are not sufficiently soluble in liquids or in combinations of liquids are capsulated as suspensions.

• Most organic and inorganic solids or compounds may be capsulated.

• Such materials must be 80 mesh or finer in particle size

• The capsulation of suspensions is the basis for the existence of a large group of products.

• Again, the design of suspension type formulations and the choice of the suspending medium are directed toward producing the smallest size capsule having the characteristics previously described

• AIM: Maximum production capacity consistent with maximum physical and ingredient stability and therapeutic efficacy.

Base adsorption

• base adsorption is expressed as the number of grams of liquid base required to produce a capsulatable mixture when mixed with one gram of solid(s).

Factors influencing the base adsorption of a solid

• the solids particle size and shape• its physical state (fibrous, amorphous, or

crystalline) • density• moisture content• its oleophilic or hydrophilic nature.

• the solid(s) must be completely wetted by the liquid base.

• For glycol and nonionic type bases, the no wetting agent required

• but for vegetable oil bases complete wetting of the solid(s) not achieved without an additive.

• Soy lecithin, at a conc of 2 to 3 % by weight of the oil, serves excellently for this purpose

• Weigh a define amount of the solid (40g is convenient) into a 150 ml tared beaker.

• In a separate 150 ml tared beaker, place about 100 g of the solid base.

• Add small increments of the liquid base to the solid, and using a spatula, stir the base into the solid after each addition until the solid is thoroughly wetted and uniformly coated with the base.

• This should produce a mixture that has a soft ointment like consistency.

• Continue to add liquid and stir until the mixture flows steadily from the spatula blade when held at a 45-degree angle above the mixture

• Weight of the base/ Weight of the solid = Base Adsorption

• The base adsorption is used to determine the “minim per gram” factor (M/g) of the solid(s). The minim per gram factor is the volume in minims that is occupied by one gram (S) of the solid plus the weight of the liquid base (BA) required to make a capsulatable mixture.

• The minim per gram factor is calculated by dividing the weight of the base plus the gram of solid base (BA+ S) by the weight of the mixture (W) per cubic centimeter or 16.23 minims (V).

A convenient formula is- • (BA + S) x V = M/g W

• Thus lower the base adsorption of the solid (s) and higher the density of the mixture, the smaller the capsule will be.

• This also indicates the importance of establishing specifications for the control of those physical properties of a solid mentioned previously that can affect its base adsorption.

• The final formulation of a suspension invariably requires a suspending agent to prevent the settling of the solids and to maintain homogeneity prior to, during, and after capsulation.

Example of suspension fills include drug suspended in the following carriers

Oily mixtures: • a) Soybean Oil with beeswax (4-10% w/w) and

lecithin (2-4% w/w). The lecithin improves material flow, and imparts some lubrication during filling. Add enough beeswax to get a good suspension, but avoid creating a non-dispersible plug.

• b) Gelified Oil (e.g. Geloil® SC), a ready to use system composed of soybean oil, a suspending agent, and a wetting agent.

• 2. Polyethylene glycol • • PEG 800 -1000 for semi-solid fills • • PEG 10,000 -100,000 for solid fills • • Or mixtures of the above. (Heat up to 35ºC to

make fluid enough for filling)

Manufacturing process :

• Plate process :• The process involves

• Placing the upper half of a warm plasticized gelatin sheet over a die plate containing numerous die pockets,

• Application of vacuum to draw the sheet in to the die pockets,

• Filling the pockets with liquor or paste,• Folding the lower half of gelatin sheet back over the filled

pockets, and• Inserting the “ sandwich” under a die press where the

capsules are formed and cut out.

Today, this equipment can no longer be purchased.

Soft capsules manufacture

• Original Rotary Die Process (R.P. Scherer: 1933)

• Reciprocating die process Norton Company 1949

• Accogel Process (Stern Machine) - Lederle: 1949 Only equipment for filling powders, granules into soft gelatin capsules

Rotary die process

• A self-contained unit capable of continuously and automatically producing finished capsules from a supply of gelatin mass and filling material which may be any liquid, semi- liquid, or paste that will not dissolve gelatin

This machine has two, side-by-side cylinders in each of which half-moulds are cut.

These cylinders, like the rollers of a mangle, rotate in contrary direction

And as they are mirror images the moulds come together precisely during rotation

Gelatin preparation deptt

Dissolve gelatin in water at 80 ℃, under vacuum , add plasticiser,colors, opacifiers, preservatives, flavours

This process is specific to eachproduct. Milling or Homogenising

Deaeration

QC Testing

Preparation of the fill material

Hot gel mass supplied to encapsulation machine through heat transfer pipes by a casting method that forms separate gelatin ribbons each with a width of approx 150 mm.

• Two ribbons of gelatin are fed between the rollers( veg oil used as a lubricant)

• Each ribbon provides one half of the softgel• And, just before the opposing rollers meet,

jets of medicament press the gelatin ribbon into the moulds, filling each half..

The moment of pressure follows, immediately sealing the two halves together to form a capsule.

These rotary machines are capable of producing between 25000 and 30000 capsules an hour with an accuracy of dosage of approximately ± 1 percent.

Control parameters

• Temperature• Timing• Pressure

• Immediately after manufacture ,the capsules are conveyed through a naphtha wash unit to remove the mineral oil lubricant

• Washed capsules subjected to drying

Drying

The first stage – a tumble drier –removes a significant portion of the water present in the shell. The semi-dried capsules are spread onto trays and kept under controlled temperature and humidity to complete the drying activity in a tunnel dryer(20% RH).

Capsules at equilibrium with 20 to 30% RH at 21-24 ℃ are considered dry & the shell of the capsule contains 6 to 10% water

• Maybe sent to finishing department for heat• Branding or ink printing for purpose of

identification

Inspection & Sorting

The dried capsules are inspectedand packed into bulk containers in order to prevent further drying and for storage.Further they are sorted to ensure uniformity in weight, size and shape.

Inspecting, Counting, Packaging, and Storing Capsules

@ should have a uniform in appearance

@ defective capsules should be rejected

@ capsules may be counted manually or automated equipment

@ containers are then mechanically capped, inspected visually or electronically, labeled, and inspected once more.

@ packaged in glass or in plastic containers

Inspection of Capsules

ABBOT Counting Tray

Typical shell hardness ratios Hardness Ratio Dry glycerin

to dry gelatin Usage

Hard 0.4:1 Oral,oil-base or shell softening pdts & those for hot humid areas

Medium 0.6:1 oral, tube, vaginal oil-based, water miscible based, temperate areas

Soft 0.8:1 For cold dry areas

Questions (Pune University)• Write a Note on gelatin in capsule

manufactureElaborate the process of capsule shell manufacture of HGC with importance of each step

• Write a note on manufacture of gelatin & HGC

• Properties of gelatin with special reference to pH, moisture& microbial aspects

• Significance of weight variation test of a filled HGC containing Vitamin B-complex

• Draw Schematic diagram for production of HGC

• What are the standards for gelatin &HGC• Discuss formulation to be filled in HGC• Explain rotary die process for manufacture

of softgels• In process Quality control parameters of

soft gelatin capsules• Working and construction of hand

operated HGC

Packaging

• Blister Packaging

Packaging & Storage

• packed in a well-closed glass or plastic containers and stored in a cool place.

• that they are more convenient to handle and transport and protect the capsules from moisture and dust. To prevent the capsules from rattling a tuft of cotton is placed over and under the capsules in the vials.

• Empty gelatin capsules should be stored at room temperature at 30 -45% humidity.

• High humidity may cause softening of the capsules and low humidity may cause drying and cracking of the capsules.

• Storage of capsules in glass containers will provide protection not only from extreme humidity but also from dust.

• In vials containing very hygroscopic capsules a packet-containing desiccant like silica gel or anhydrous calcium chloride may be placed to prevent the absorption of excessive moisture by the capsules.

• Now a days capsules are strip packaged which provide sanitary handling of medicines, ease in counting and identification.

• Storage of filled capsules is dependent on the characteristics of the drugs they contain.

• Semisolid filled hard gelatin capsules should be stored away from excessive heat, which may cause a softening or melting of the contents.

PRODUCT QUALITY CONSIDERATIONS

Ingredient specifications All ingredients of a soft gel are controlled and tested to ensure compliance with

pharmacopoeial specifications.

Impurities such as aldehydes & peroxides which may be present in polyethylene glycols. Presence of high levels of these impurities gives rise to cross-linking of the gelatin polymer, leading to insolubilization through further polymerization.

In process Quality Control

• Fill weight & capsule shell weight • Gel ribbon thickness• Measurement of thickness of seal of total

capsule shell(Seam thickness)• Fill moisture content (determines drying

end point for each lot)

• Specifications for all above tests are based on Softgelsize, amount & type of fill

Check-weighing Based on Gravity Flow• The capsules are fed

from the hopper by means of a drive mechanism and size-dependent guiding plate onto the weighing cell.

• After check weighing, the capsules are classified into correctly and incorrectly filled ones.

Automatic Capsule weighing apparatus (Vericap1800A Checkweigher)

Quality Control of Capsules

Standards for Empty hard gelatin capsule shell

• Shape and Size• Dimensions of cap & body• Thickness of Capsule shell• Moisture (13-16%)• Color

Official Quality Control Tests• Disintegration Test :• Use guiding disc if capsule floats on top of

water• One capsule is suspended in each tube (3

inch long), then suspended in the beakers to move up and down for 30 mins. unless otherwise stated in monograph.

• 28-32 cycles per min ,37±2 ○ SC• Capsules pass the test if no residue of drug

or other fragments of shell remain on no.10 mesh screen of the tubes.

Weight variation Test

• 20 capsules are taken at random and weighed. • Their average weight is calculated,• Each capsule is weighed individually and

their weight noted.

• The capsule passes the test if the weight of individual capsule falls with in 90-110% of the average weight.

• If this requirement is not met,• then the weight of the contents for each

individual capsule is determined and compared with the average weight of the contents.

• The contents from the shells can be removed just by emptying or with the help of small brush.

• From soft gelatin capsules the contents are removed by squeezing the shells which has been carefully cut.

• The remainder contents are removed by washing with a suitable solvent.

• After drying the shells, they are weighed and the content weights of the individual capsules are calculated.

• The requirements are met if• (1) not more than 2 of the differences are

greater than 10 % of the average net content and

• (2) in no case the difference is greater than 25 %.

Content uniformity test

• This test is applicable to all capsules which are meant for oral administration.

• For this test a sample of the contents is assayed as described in individual monographs and the values calculated which must comply with the prescribed standards.

Content Labeling Requirement

• All official capsules must be labeled to express the quality of each active ingredient in each dosage unit

Stability Testing

• Control capsule : A capsule that contains mineral oil, with a gelatin shell having a dry glycerin to dry gelatin ratio of about 0.5 to 1 and a water to dry gelatin ratio of 1 to 1,

It is dried to equilibrium with 20 - 30 % RH at 21 to 24 ○ C

• Control capsule should have satisfactory physical stability (with help of proper packaging) at temperature ranging from just above freezing to as high as 60○ C.

• For the unprotected control capsule, low humidities (less than 20 % RH), low temperature (less than 2○ C) and high temperatures (greater than 38○ C) or combinations of these conditions have only transient effects.

• Capsule returns to normal when returned to optimal storage conditions

• The capsule returns to normal when returned to optimum storage conditions. As the humidity is increased, with in a reasonable temperature range, the shell of the unprotected control capsule should pick up moisture in proportion to its glycerin and gelatin content.

Effect of Temperature and Humidity on Capsule shell

Temperature Humidity Effect on Capsule shell

21-24°C >60% Capsules become softer, tackier and bloated

> 24°C >45% More rapid and pronounced effects – unprotected capsules melt and fuse together

Test conditions for accelerated physical stability tests for capsule dosage forms

TEST CONDITION OBSERVATION 80 % RH at room temperature in an open container.

Capsules are observed periodically for 2 weeks, both gross and subtle effects of the storage conditions are noted and recorded. The control capsule should not be affected except at 80% RH

40○ C in an open container.

40○ C in closed container.

Moisture Permeation Test

It is determined by packaging the dosage unit together with a color-revealing dessicant pellet, exposing the packaged unit to known relative humidity over a specified time, observing the dessicant pellet for color change ( indicating absorption of moisture) and comparing the pretest and post test weight of the package unit

Dissolution studies

Dissolution is principally useful as a QC test. It can be predictive of in vivo

behaviour, but this must be demonstrated by an in-vivo in-vitro correlation study

(IVIVC).

Apparatus 1 Basket

Apparatus 2

Paddle

Specialty Capsules

• Enteric-coated capsules – enteric-coated capsules resist disintegration in the stom

• Altered Release: The rate of release of capsule contents can be varied according to the nature of the drug and the capsule excipients. ach but break up in the intestine.

Hypromellose(HPMC) capsules• Hypromellose overcomes the problemof brittleness when the capsules are exposed to

dry conditionsHypromellose solutions are converted into

gelling system by adding a material to act as a network former, such as carrageenan or gellan gum, and a gel promoter such as potassium chloride

• main advantage is that their moisture content is much lower, and even if this is removed, they retain their mechanical strength.

Vegicap capsules

• VegiCap Soft, developed by Cardinal Health, utilized the combination of iota carrageenan and modified starch, as a gelatin substitute. The combination of the two hydrocolloids leads to a synergistic interaction that produces a gel network, which is suitable for Softgel production using rotary die process. VegiSoft Capsules have been used in the nutritional market

Oceancaps capsules

These capsules made from all natural fish gelatin derived from farm-raised fish, they have the same characteristics as traditional gelatin capsules, including appearance, machinability, mechanical properties, hygroscopic and oxygen properties, chemical stability, and versatility. Plus, they are odorless and tasteless

Capsules for packing of Ophthalmic ointments

• be sterile and free from irritant effect. • use is to pack it in single dose containers.

Now a days soft gelatin capsules are very commonly used for filling ophthalmic ointments. These capsules are meant for single application to the eye.

• Just before application, the capsule is punctured with a sterile needle, the contents instilled into the eye and the shell discarded.