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

Hard Gelatin Capsules (Body and Cap)

Soft Gelatin Capsules (One Piece)

ADVANTAGES
Elegance
Ease of use and portability Provide smooth, slippery, easily swallowed and

tasteless shell for drugs Minimum excipients required

LIMITATIONS
Not 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

MATERIALS
Gelatin blends
Small amounts of certified dyes Opaquing agents Plasticizers Preservatives

GELATIN
A 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 GELATIN

Dry bones Degreasing Grading Demineralization (5% HCL, 10-15 days) Lime 10% (4-8 weeks)
wash

pH adjustment
Water wash

Lime removal Lime 10% (6-12 weeks) Acid(1-5% HCL) 10-30 hrs Filter

Calf skin

Acid removal

wash

Pork skin

Hot water extraction

Vacuum filtration

Mill to size

Air dry

Cool to solidify

 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 fraction Demineralisation to free collagen before it can be

conditioned and extracted as gelatin Conditioning 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 Spinning Drying Joining Stripping Trimming

(Cycle of 40-45min)

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)

 The pinbar are gently lowered in gelatin solution of

carefully controlled viscosity to form capsand 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 body Color Moisture contnt

 Inspection process:

Visual inspection II. Electronic sorting mechanism (Eli Lily & co.)
I.

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 METHOD
Preweighed 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 SYSTEM

300 capsules/hr
Operated

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 DOSATOR
Calibration 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 hopper

The dosator dip in to it whilst it is in the motion

As 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 operation Lubricants are not required Possible 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 FINISHHING
1) 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 Capsules with improved gloss Rubbed with a cloth (imprignated with inert oil

Removal of resistant material

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 capsules Moves the capsules between soft plastic tassels against a perforated plastic sleeves, under vacuum Any residual powder is removed by vacuum

CAPSULE PRINTING
Company and/or product identification information

placed on each capsule Best 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/ BANDING

Two 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

Capsule Size
000 00 0 1

Volume (mL)
1.37 0.95 0.68 0.50

Fill weight (mg)

950 650 450 300

2
3 4 5

0.37
0.30 0.21 0.13

250
200 150 100

SELF LOCKING CAPSULES

Coni-snap

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

Parke Davis

Tapered rims(1) avoid telescoping

The identification (2) premature opening

The grooves (3) lock the two capsule parts together

after the capsule has been filed

 Coni- snap supro

Lower portion of the capsule shell consealed except

for rounded end Separation of two parts more difficult and contribute to capsule integrity

Coni-snap supro

FILLING HARD GELATIN CAPSULES

SOFT GELATIN CAPSULE

Pharmaceutical 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 Tube

Oval Miscellaneous

Oblong

NATURE OF THE CAPSULE SHELL

Basic Components: Gelatin, Plasticizer, Water

Additional Components:
Ingredients Concentration Purpose

Methyl Paraben Propyl Paraben Water Soluble dyes, Certified lakes, Pigments, Vegetable colors
Titanium dioxide Ethyl Vanillin Essential oils Sugar (Sucrose) Fumaric acid

0.2% Q.s

Preservative Colorants

0.2 to 1.2 % 0.1% 0.2% 5% 1%

Opacifier Flavoring for odor & Taste Flavoring for odor & Taste Chewable shell & Taste 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 molecules Measured 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 10C for 17 Hrs Significance: Higher the bloom strength of gelatin used, the more physically stable is the capsule shell Cost of gelatin is proportional bloom or gel strength Imp factor in cost of soft capsules Range: 150 to 250 gm

2. Viscosity of gelatin: Determined on a 6

2/3 %

concentration of

gelatin in water at 60C Range: 25 to 45 millipoise Low 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 SHELL

The ratio by weight of dry plasticizer/dry gelatin shell
Hardness Hard Dry glycerin/Dry gelatin 0.4/1 Usage Oral, Oil based or Shell softening products For products in hot , humid areas Oral, tube, vaginal oil based or shell hardening products Products in temperate areas Tube, vaginal, water miscible based or shell hardening products Products in cold/dry areas

Medium

0.6/1

Soft

0.8/1

NATURE OF CAPSULE CONTENT

Content 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

LIQUIDS
Liquid 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 shellsusceptible 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

SOLIDS
Solids that are not sufficiently soluble in liquid or in

combination s of liquid are capsulated as suspension Water soluble solids can not be encapsulated ability to affect gelatin shell eg strong acids: Citric acids, salt of strong acids &bases (NaCl), NH4 salts Substances unstable in the presence & moisture eg: Aspirin can not be encapsulated Formulation Technique: Suspension Base 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 required eg 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 Oily bases Type of suspending agents White wax, Paraffin wax, aluminum monostearate, PEG 4000, PEG 6000, solid nonionic, solid glycol esters

Non oily bases

SOFT CAPSULE MANUFACTURE

Gelatin 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 inch Thicker shells For product requiring greater structural strength Ribbons 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 CHECKS
Seal thickness: Seals are measured under microscope, change in the ribbon thickness, heat or die pressure are made if necessary Acceptable seal thickness: One half or two third of the ribbon thickness 2. Fill weight: Weigh whole fresh capsule- slitting it openexpressing the content. Was with suitable solvent (pet ether)- empty shell reweigh
1.

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 21-24C 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 40C

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)

Average weight of capsule content Less than 300 mg % Deviation

10

300 mg or more

7.5

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 %

DISINTEGRATION TEST (DT)

Use water as DT medium If capsule floats on the surface, a disc may be added If 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 assembly For hard capsule :operate apparatus for 30 min For 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 machine
Capsules 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