FILLING HARD GELATIN CAPSULES

CAPSULES “Capsules are solid preparations with hard and

soft shells of various shapes and capacities, usually containing a single dose of active ingredients.”

Capsules

Soft Gelatin Capsules

(One Piece)

Hard Gelatin Capsules

(Body and Cap)

ADVANTAGESEleganceEase of use and portabilityProvide smooth, slippery, easily swallowed

and tasteless shell for drugsMinimum excipients required

LIMITATIONSNot used for administration of extremely

soluble material such as potassium chloride, potassium bromide or ammonium chloride (Sudden release of such compounds in stomach could result in irritating concentrations

Highly efflorescent material causes capsule to soften

Highly deliquescent material results in drying of capsule shell to excessive brittleness

MATERIALSGelatin blends

Small amounts of certified dyes

Opaquing agents

Plasticizers

Preservatives

GELATINA heterogeneous product derived by

irreversible hydrolytic extraction of treated animal collagen

Sources of collagen: Animal bones, hide portions, frozen pork skin

Two types of gelatin Type A: derived from acid treated precursor

isoelectric pH in region of 9 Type B: derived from alkali treated precursor

isoelectric pH in region of 4.7

PROCESS OF MANUFACTURING GELATINDegreasing

Dry bones Grading

Demineralization(5% HCL, 10-15

days)Lime 10%

(4-8 weeks)Lime removal

pH adjustment

Calf skin

Pork skin

Lime 10%(6-12 weeks)

Acid(1-5% HCL)

10-30 hrs

Acid removal

wash

wash

Water wash

Hot water extraction

Filter

Vacuum filtration

Cool to solidify

Air dryMill to size

Degreasing: fresh bone contains about 15% fat . Fat may become partially emulsified in gelatin producing poor quality liquors which is difficult to filter

Methods: Treatment of bone with boiling water Use of hot organic solvents Cold degreasing

Bone High speed impulses (transmitted trough water) Generated by hammer mill

Mechanical rupture of cell membrane

Fat liberated

Removed by water

Grading: Hard bone, soft bone, sinew fractionDemineralisation to free collagen before it can

be conditioned and extracted as gelatinConditioning of collagen: Liming/ acid

conditioning to obtain gelatin with desired physical properties and good yield

Blends of bone and pork skin gelatins of relatively higher gel strengths are used for capsule production

Bone gelation → tough and firm films but tends to be hazy brittle

Pork skin → imparts plasticity and clarity to the blend therefore reduces clouding

PREPARATION OF HARD GELATIN CAPSULES

Completely automatic machines are used for capsule production

Dipping:Moulds on which capsules are formed are called

“pins” and groups of these are set in line on metal bars; the whole assembly is called “pinbar” (stainless steel)

Dipping

Spinning

Drying Stripping Trimming

Joining (Cycle of 40-45min)

The pinbar are gently lowered in gelatin solution of carefully controlled viscosity to form “caps”and “bodies” simultaneously, then slowly withdrawn

Immediately after withdrawal on the top of the pins gelatin film is formed

Spinning:To spread the gelatin evenly over the surface of

the mould pins, the pinbars are rotated about a horizontal axis as they are transferred from lower level to higher level

As they rise they pass through a stream of cool air which helps to set the gelatin solution and fix them on the mould

Drying: The pins are moved through a series of controlled air

drying kilns for gradual and precisely controlled removal of water

Stripping and trimming: The capsules are stripped from the pins by bronze

jaws, placed around each pin on the bar and trimmed to length by stationary knives

Trimmings are removed by suction and usually recycled

Joining: The capsule parts are then transferred to a central

joining block where the two halves are fitted together

In process controls:Periodic monitoring and adjustment of film

thickness (Thickness of capsule wall- viscosity of the gelatin solution, speed and timing of dipping

Cut length of both cap and bodyColorMoisture contnt

Inspection process:I.Visual inspectionII.Electronic sorting mechanism (Eli Lily & co.)

Equipment mechanically orients the capsule and transport them a past series of optical scanners

Defect in the capsule surface will deflect the beam; this deflection is detected by sensors which activate the rejection mechanism

Moisture content of empty capsules: 12-15% Below 10% become brittle and may shrink to

the of not fitting into the filling equipment Above 16% loss of mechanical strength

CAPSULE FILLING PROCESS

Supply Rectification

Rectification: all the capsules are positioned cap uppermost in the machine ready for separation

Separation

Filling Joining

Discharge

PLATE METHODPreweighed powder

to give required fill weight spread evenly over the block

Tamping action to fill the material in to the capsule bodies (depending on density of the material)

AUGUR FEED SYSTEM300 capsules/hrOperated only while

hopper positioned above the capsule body and timing control on augur drive regulated the fill weight

Hopper is fixed and capsule bodies are moved by the plate

TAMPING METHOD

Powder initially flows into the holes in the dosage disc, which is machined to provide a certain fill weight in the capsules

A tamping punch compresses the powder against the base plate and then rises

Filling and tamping takes place in five successive stages

After fifth stage the dosage hole moves off the base plate and the plug of the powder is ejected into the capsule body

The dose is controlled primarily by the thickness of the transfer disc the adjustment of the tamping punches and depth of powder in the dosage hopper

INTERMITTENT COMPRESSION FILLING

Powder is fed into the dosage hopper and its level is adjusted to about twice the depth of the compressed plug (h)

Dosage tube enters the powder bed and the powder inside it is pressed by dosage punch just sufficiently to form a coherent plug that can be lifted by the dosator carried to the capsule body and ejected by piston

Compression force: just sufficient to allow clean transfer to the capsule body and to ensure that plug does not breaks up on ejection from dosage tube

CAPSULE DOSATORCalibration scale: used to set up

each dosator assembly to an identical point at the commencement of a filling operation

Fill weight: adjusted by regulating the height of the dosing piston inside dosing tube

Depth of powder: in the dosage hopper affects the fill weight

Lubricants: Magnesium stearate to minimize fill weight variations

Flow aid: Aerosil to avoid binding of plug on ejection from dosing tube and sticking of powder to the end of piston

Extra compression head adjusted to come in contact with the top of the piston when the dosator assembly is at the bottom of its stroke forming ‘plug’

CONTINUOUS COMPRESSION FILLING

Dosage trough rotates and it is fed from a bulk hopperThe dosator dip in to it whilst it is in the motionAs the speed of filling of machine increases the ‘dwell

time’ (the time taken for the dosage tube to dip into the powder and compress the plug of material)

become shorter therefore powder must be of uniform density, easily compressible and not too elastic, should be free flowing but yet possess some cohesiveness

Fill weight affected by behavior of the powder left in the hopper after the plug of material has been removed

Free flowing material and noncohesive: cavity will collapse and simple stirring device will produce a homogeneous mixture

Very cohesive: powder must be thoroughly mixed before next entry of dosator

VACUUM FILLING

Powder drawn into the dosator by suction applied through the filter pad, compression takes place

Material held by vacuum until the dosage tube is in position over the capsule body, when the powder is ejected by releasing the vacuum and applying positive pressure

Advantages:Does not rely on the movement of the

mechanical parts during filling operationLubricants are not requiredPossible to fill single substance especially for

high dose drugs

Dosage tube consists of two parts a ‘cylinder’ and an ‘adjustable piston’ of polyethylene fitted with nylon filter

Adjusting the piston → alters the volume of the powder that is picked up

Assembly is connected to vacuum and air pressure system by a snap – closure connector

Incorporates ‘no capsule no dose’ feature: activated when capsules have not been separated or when an empty capsules feed tube becomes blocked and prevent capsule entering the holding bush

Powder taken into he dosage tube → blown out by blast of compressed air back in to dosage trough

FILLING CAPSULES BY DRUGPACK SYSTEM

Vacuum: used to remove air from capsule body through an exhaust passage → causes the powder to flow from hopper down an inclined delivery tube in to capsule body

Flow of material ceases following restoration to normal atmospheric pressure

Vacuum system adjusted to cause a predetermined quantity of material flows in to capsule

PISTON METHOD FOR FILLING CAPSULES WITH PELLETS

DOUBLE SLIDE METHOD FOR FILLING CAPSULES WITH PELLETS

PISTON AND SLIDE METHOD FOR FILLING CAPSULES WITH PELLETS

FILLING OF CAPSULES WITH TABLETS

CAPSULE FINISHHING1) Pan polishing:

Accela cota tablet coating pan (dusting and polishing)Polyurethane or cheese cloth liner is placed in the pan and the liner is used to trap the removed dust as well as to impart a gloss to the capsule

2) Cloth dusting:

Bulk filled capsules

Rubbed with a cloth (imprignated with inert oil

Removal of resistant material

Capsules withimproved gloss

3) Brushing:Capsules are fed under rotating soft brushes which serves to remove the dust from capsule shell

Disadvantage: scratches or deformation of the capsule

Rotosort (Eli Lilly & co.)Mechanical sorting device that removes loose

powder, unfilled joined capsules, filled or unfilled bodies and loose caps

Can handle up to 150,000 capsules/hour

Erweka KEA (Key Industries):Dedusting and polishing machine for hard

gelatin capsulesMoves the capsules between soft plastic

tassels against a perforated plastic sleeves, under vacuum

Any residual powder is removed by vacuum

CAPSULE PRINTINGCompany and/or product identification

information placed on each capsuleBest performed on empty capsules

Method:Legend to be printed is engraved on highly

polished metal cylinder (stainless steel or chromium plated brass ) ‘Rotogravure cylinder’

Cylinder revolves in a reservoir of printing ink

The ink fills the engraving and as the cylinder revolves it comes in contact with the sharp edge of metal strip called ‘doctor blade’ which removes the ink from its surface, leaving only that fills the engraving

Ink is transferred to a rubber offset geared to and in contact with rotogravure cylinder

Capsules pass under these rubber roll and image is then transferred to them

CAPSULE SEALING/ BANDINGTwo parts of capsule are sealed with a gelatin or

polymer band at the seam of the cap and the body

Tamper resistant seal:

Contact area of the cap and the body wetted with the mixture of water and ethanol and then thermally bonded at 104° to 113° F (for tamper resistant packaging and protective sealing of capsules)

CAPSULE SIZES AND TYPES

CapsuleSize

Volume(mL)

Fill weight(mg)

000 1.37 95000 0.95 6500 0.68 4501 0.50 3002 0.37 2503 0.30 2004 0.21 1505 0.13 100

SELF LOCKING CAPSULES

o Snap-fit ™o Coni-snap ™o Coni-snap supro™

Tapered rims(1) avoid telescopingThe identification (2) premature openingThe grooves (3) lock the two capsule parts

together after the capsule has been filed

ParkeDavis

Coni-snap

Coni- snap suproLower portion of the capsule shell

consealed except for rounded endSeparation of two parts more difficult and

contribute to capsule integrity

Coni-snap supro

FILLING HARD GELATIN CAPSULES

SOFT GELATIN CAPSULEPharmaceutical applications:

Oral dosage forms: human & veterinary use

Suppository dosage form: Rectal use & vaginal use

Single dose application of topical, ophthalmic, Otic

preparation, rectal ointment

SIZE & SHAPES OF SOFT GELATIN CAPSULES

Round

Oval

Oblong

Tube

Miscellaneous

Basic Components: Gelatin, Plasticizer, WaterAdditional Components:

NATURE OF THE CAPSULE SHELL

Ingredients Concentration PurposeMethyl ParabenPropyl Paraben

0.2% Preservative

Water Soluble dyes, Certified lakes, Pigments,Vegetable colors

Q.s Colorants

Titanium dioxide 0.2 to 1.2 % Opacifier

Ethyl Vanillin 0.1% Flavoring for odor & Taste

Essential oils 0.2% Flavoring for odor & Taste

Sugar (Sucrose) 5% Chewable shell & Taste

Fumaric acid 1% Reduced tanning of gelatin

ADDITIONAL SPECIFICATION FOR GELATIN

1. Bloom or gel strength: of gelatin is a measure of cohesive strength of cross linking that occurs between gelatin molecules & is proportional to molecular weight of gelatin moleculesMeasured By: Measuring the weight in gm required to move a plastic plunger (0.5 inch diameter), 4 mm in to a 62/3 %, gelatin gel that has been held at 10°C for 17 HrsSignificance: Higher the bloom strength of gelatin used, the more physically stable is the capsule shellCost of gelatin is proportional bloom or gel strengthImp factor in cost of soft capsulesRange: 150 to 250 gm

2. Viscosity of gelatin: Determined on a 6 2/3 % concentration of gelatin in water at 60°CRange: 25 to 45 millipoiseLow viscosity (25 to 32 millipoise) gelatin are used in conjuction for the capsulation of hygroscopic vehicles or solids

3. Iron: Gelatin used in manufacturing of soft gelatin cap should contain more than 15 ppm of this element

4. Plasticizers: Glycerin USP, Sorbitol USP

HARDNESS OF GELATIN SHELLThe ratio by weight of dry plasticizer/dry gelatin

shellHardnes

sDry glycerin/Dry gelatin Usage

Hard 0.4/1 Oral, Oil based or Shell softening productsFor products in hot , humid areas

Medium 0.6/1 Oral, tube, vaginal oil based or shell hardening productsProducts in temperate areas

Soft 0.8/1 Tube, vaginal, water miscible based or shell hardening productsProducts in cold/dry areas

NATURE OF CAPSULE CONTENTContent of soft gelatin capsule is a liquid, or a

liquid, or a combination of miscible liquids, a solution of a solid in a liquid or suspension of the solid in a liquid

The maximum capsule size & shape for convenient oral use in a humans is the 20 minim oblong, 16 minim oval, 9 minim round

LIQUIDSLiquid both that are water-miscible & volatile can not be

included as a major constituents – they can migrate in to hydrophilic gelatin shell & volatilize from its surface

Glycerin & propylene glycol can not be major constituents & capsule contents- softening effect on the gelatin shell- susceptible to heat and humidity

Water & alcohol: up to 5% of the capsule content can be used as a co solvents

Most widely used liquids: Oily active ingredients 9clofibrates), vegetables oils (soybean oils), mineral oils, non ionic surfactants (polysorbate 80), polyethylene glycol(400 or 600) either alone or in combination

pH of the preparations for encapsulation should be between 2.5 to 7.5

Acidic Preparation: Hydrolysis & leakage of gelatin shell

Alkaline Preparation: Tanning of the gelatin shell & affect the solubility of the gelatin shell

Combination of miscible liquids:Vitamin A & polysorbate 80 for increased or more rapid absorption

Dilution or partial substitution with thinner liquids: (Improve flow properties)

Improved solubility: Steroids with oils & benzyl alcohol

SOLIDSSolids that are not sufficiently soluble in liquid or in

combination s of liquid are capsulated as suspensionWater soluble solids can not be encapsulated –

ability to affect gelatin shelleg strong acids: Citric acids, salt of strong acids &bases (NaCl), NH4 salts

Substances unstable in the presence & moistureeg: Aspirin can not be encapsulated

Formulation Technique: SuspensionBase absorption of the solids: NO ole mixture f gram

of liquid base required to produced capsulatable mixture when mixed with 1 gm of solid(s)

Base absorption influenced by : Particle size, Physical state, density, moisture content, oleophilic & hydrophilic nature of the substance

Solid molecular wt be completely wetted by the liquid base . For vegetable oil bases , wetting agents requiredeg soya lecithin (2-3% by wt of the oil

Suspending agents: TO prevent setting of the solid and to maintain homogeneity prior to, during & after capsulation

Type of bases Type of suspending agents

Oily bases White wax, Paraffin wax, aluminum monostearate, PEG 4000,

Non oily bases PEG 6000, solid nonionic, solid glycol esters

SOFT CAPSULE MANUFACTUREGelatin mass is fed by gravity to a marketing device

(spreader box) which controls the flow of the mass on to air cooled (13-14 °C) rotating drums, to form gelatin ribbons of controlled thickness

Wet shell thickness: 0.022 to 0.045 inchThicker shells – For product requiring greater

structural strengthRibbons are fed through mineral oil lubricating

bath , over guide rolls & then down between wedge and die roll

Material to be encapsulated: Flows by gravity in to positive displacement pump, The pump accurately meters the material through the leads & wedges and in to the gelatin ribbons between the die rolls

The bottom of the wedge contains small orifices lined up with the die pockets & the die rolls

The capsule is about half sealed when the pressure of the pumped material forces the gelatin in to the die pockets, where the capsule are simultaneously filled, shaped, hermetically sealed and cut from the gelatin ribbon

The sealing of the capsule is achieved by mechanical pressure on the die rolls and heating (37-40 °C) of the ribbons by the wedge

IN PROCESS CHECKS1. Seal thickness: Seals are measured under

microscope, change in the ribbon thickness, heat or die pressure are made if necessaryAcceptable seal thickness: One half or two third of the ribbon thickness

2. Fill weight: Weigh whole fresh capsule- slitting it open- expressing the content. Was with suitable solvent (pet ether)- empty shell reweigh

Adjustment in the pump stroke to obtain proper fill weight• Naptha wash until – to remove the mineral oil

lubricant• Preliminary infra red drying – 60 to 70% of

water is removed. Capsule sprade on trays and allowed to come in equilibrium with forced air condition of 20-30% RH at 21-24°C

• Moisture content of the capsules: 6 to 10 % • Moisture content of the shell: toluene

distillation method collecting the distilate over a period of one hour. Additional water removed by further heating. Eg at 40°C

CONTROL TEST

1. Seal thickness

2. Total or shell moisture content

3. Capsule fragility or rapture tests

4. Determination of freezing & high temperature effect

PHYSICAL CONTROL PROCESSING

Capsule diameter sorter: Allows to pass to the next unit any capsule within ± 0.02 inch of theoretical diameter & capsule being tested, overfills, underfills & foreign capsules discarded

Capsule color sorter: Capsules fed from diameter sorter by a pneumatic conveyer. Any capsule whose color does not confirm to the reference color standard for hat capsule

Electronic counting unit: 8000 capsules/min. directly in to the bulk shipping carton

Cartons→ labeled→ sealed→ palletized

UNIFORMITY OF WEIGHT (IP 96)

Not more than two individual weights deviate from the average weight by more than % deviation in table

None should deviate from by more than twice that %

Average weight of capsule content

% Deviation

Less than 300 mg 10

300 mg or more 7.5

DISINTEGRATION TEST (DT)

Use water as DT mediumIf capsule floats on the surface, a disc may be

addedIf capsule adhere to discs, attach a removable

piece of stainless steel wire gauze with mesh aperture opening of 2mm to the upper plate of basket rack assemblyFor hard capsule :operate apparatus for 30 minFor soft capsule :operate apparatus for 60 min

For enteric coated capsules• One capsule in each tube• Operate apparatus for 2 hours without the disc

in 0.1 M HCL ( No signs of disintegration or rupture of capsule permitting escape)

• Replace the medium in vessel with mixed phosphate buffer pH 6.8, add disc to each tube and operate the apparatus for further 60 minutes

• No residue on screen or on the underside of the screen

ROTOWEIGHT (ELI LILLY&CO.)High speed capsule weighing machineCapsules→ gravity fed on to vacuum pins→

weight detection system→ measure the reflected energy (black scatter) of low power X-ray beam directed at each capsule

Reflected energy is directly proportional to weight of filled capsules→ permitting automatic rejection of any individual capsule above or below present weight

Speed – 73,000/hr