ADVANTAGES

Elegance- smoothness and availability of different colors

Ease of use and portability Odorless and tasteless

S ll i i h d t th h ll Swallowing is easy as hydrates the shell Ready availability of the drug as less compacted and

less use of the additives Modifications are easier to made, as per desired

property Capsules are difficult to counterfeit. The use of capsules avoids many unit operations that

are associated with the manufacture of tablets e g are associated with the manufacture of tablets, e.g. compression, granulation, drying.

DISADVANTAGES

N d f ff d d li b Not used for effervescent and deliquescent substances Not used for the extremely soluble drugs KCl, KBr Adhesion in the Oesophagus delayed transit time Adhesion in the Oesophagus- delayed transit time 1/5 th production to that of tablet even on fast operating

machines Problems regarding the homogeneity of fill weight and

content may be associated with capsule formulations.h i f i li d f i The requirement for specialised manufacturing

equipment

COMPARISON

HARD GELATIN SOFT GELATIN Mixture of gelatin type A/B more flexible, plasticized gelatin

used other than oral route- rectal- vaginalg- opthalmic

Mfg dipping mfg dippingrotary die processrotary die process

Powder/granules/pellets solutions/suspensions/emulsionsmost precise dosing

Obl h d h i l/ l/ bl /t b / Oblong shaped spherical/oval/oblong/tube/suppository type

0.13 -1.37 mL 1-480 minim16.2 minim=1mL

COMPOSITION OF THE SHELL

Gelatin Plasticizer Opacifiers Preservatives Dyes Flavours

GELATINGELATIN

ConditioningFirst the raw material is cut to a manageable size then washed toFirst, the raw material is cut to a manageable size, then washed to cleanse and de-grease. It then undergoes either the Type A or Type B process to further de-grease and de-mineralise.

ExtractionThe raw material is mixed with clean, warm water. By careful thermal control, the gelatin is gradually and gently released in the t e a co t o , t e ge at s g adua y a d ge t y e eased t eform of a liquor.

FiltrationTh li i i h l i i l d d li h d bThe liquor containing the gelatin is cleaned and polished by filtration. This may also involve centrifuging, ultra-filtration and ion exchange, all of which ensure the final removal of any inorganic materialmaterial.

Concentrationlti t t d Th i h l ti li imulti-stage vacuum evaporators are used. The rich gelatin liquor is now

highly viscous, with a honey-like appearance. During this process it is subjected to high temperature flash sterilisation to prevent the risk of microbial contamination.

DryingThe warm gelatin solution is gelled by cooling in a votator, minced, and deposited as a bed onto an open weave stainless steel belt which passesdeposited as a bed onto an open-weave stainless steel belt, which passes through a drying chamber. A warm, dry air stream, which has been filtered and washed, is fed into the chamber and through the belt.

G i di illi d bl diGrinding,milling and blendingAfter microbiological and physical testing, the gelatin particles are ground, milled and blended to suit the end use and customer specifications.

GELATINGELATINBLOOM OR GEL STRENGTH: It is a measure of cohesive strength of the cross-linking

that occurs between gelatin molecules & is proportional to the mol.wt. of the gelatin.

Bloom is determined by measuring the wt in gm required to move a plastic plunger that is 0.5 inches in diameter

2/3 0g

4mm into a 62/3 % gelatin gel that has been held for 100C for 17 hours

150-250 gm

GELATINGELATIN

VISCOSITY: Is a measure of molecular chain length & determines the

manufacturing characteristics of gelatin films. Determined on a 62/3 % concentration of gelatin in water

at 600C. 25 45 millipoise (38+2 millipoise) 25-45 millipoise (38+2 millipoise)

GELATINGELATIN

Low viscosity (25-32 millipoise)y ( p ) High bloom (180-250 g) Are used in junction with the capsulation of hygroscopic

vehicles or solids. Iron

Sh ld t t i th 15 f i b f Should not contain more than 15 ppm of iron because of its effect on FDC dyes & its possible colour reactions with organic compounds

Bone gelatin- imparts firmnessPork gelatin imparts plasticity and clarity

PLASTICIZERSPLASTICIZERS

The ratio by wt of the dry plasticizer to dry gelatin y y p y gdetermines the Hardness of the gelatin shells

Hardness = wt of dry plasticizer / wt of dry gelatin

PLASTICIZERSPLASTICIZERSPLASTICIZERSPLASTICIZERSHardness Ratio

Dry Glycerin/Usage

Dry GelatinHARD 0.4/1 Oral, oil-based, or

shell-softening d t f h t products for hot,

humid areasMEDIUM 0.6/1 Oral, Tube, vaginal

oil based water-oil based, water-miscible-based, or shell-hardening products & for

temperate areasSOFT 0.8/1 Tube, vaginal, water-

miscible-based or h ll h d i shell hardening

products & for cold, dry areas

COLOURCOLOUR

The color of the capsule can be definitely affected by the p y ycolor or type of material capsulated.

The color of the capsule shell never be lighter than the capsulated material.

Darker colors are more appropriate for large-size (14-20 minim oblong)

MANUFACTURING OF THE SHELL

DippingDippingRotationDryingDryingStrippingTrimmingTrimming JoiningSortingSortingPrinting

D T T UDEFECTS IN THE CAPSULE SHELLS

Wrinkles Star ends Specks Dirt Strings Bubbles

CAPSULE VOLUMECAPSULE VOLUME

STORAGE AND STABILITY

Moisture content- 13-16%Either brittle or too softmay leads to caking of content and retarded disintegration or other stability problems.

Loss of water solubility of shells, on exposure to high humidity and temperature or to reactive aldehydesand temperature or to reactive aldehydes

Develops SKIN or PELLICLE during dissolution testingp g gGelatin cross linking

SEALING AND SELF LOCKING CLOSURES

Self locking by forming indentations and groovesg y g g Banding Spot welding (Thermal method) Spraying of hydroalcoholic solution (capsugels)

SEALING AND SELF LOCKING CLOSURES

FILLING OF HARD GELATIN CAPSULE

RectificationSeparation of cap from bodyDosing of fill materialReplacement of caps and ejection of filled capsulesReplacement of caps and ejection of filled capsules

Powder fillingAuger fill principleVibratory fill principlePiston tamp principlePiston tamp principle

Dosator disc typeDosating nozzle type

V filliVacuum filling

AUGER FILL PRINCIPLE

Empty capsules are held in the filling ring which rotates under Empty capsules are held in the filling ring which rotates under hopper

Auger mounted in hopper rotates at a constant speed, that delivers the powder at a constant rate.

Flat blade auger with a screw auger is preferredGlid t h ld b d t i fl t (0 5 %) Glidant should be used to increase flow rate(0.5 %)

Lubricants are also added (Mg stearate, Stearic acid) to facilitate the passage of filling ring under the foot of the powder hopper and p g g g p ppthus prevents the adherence of material to the auger.

VIBRATORY FILL PRINCIPLE

The capsule body passes under the feed frame, which holds the powderp y p , p In the powder a perforated resin plate is positioned that is connected to

the vibrator Powder tends to fluidized as it vibrates and flows into the bodies

through holes in the resin plate Fill weight is controlled by the vibrators and setting the position of Fill weight is controlled by the vibrators and setting the position of

body under feed frame There is overfill and then scrape-off of the excess of material as the

body pass under the feed frame. The weight variation may be due to minimum orifice diameter and not

related to the angle of reposerelated to the angle of repose

OSAKA MODEL R-180

PISTON TAMP PRINCIPLE

Pistons or tamping pins slightly compress the p g p g y pindividual doses of powders into the plugs (slugs) and eject the plugs into the empty capsule bodies.

The compression forces are low in the range of 50-200 N.

Two types Dosing disc machine Dosing disc machine Bosch GKF Harro Hofliger

D l hi Dosator nozzle machines

TAMP FILLING MECHANISM

DOSING DISC MACHINES

The dosing disc forms the base of the filling chamber, posses no. of g g pholes bored on it.

A solid brass STOP plate lines the base of disc to close off the holes. That creates the die cavity That creates the die cavity Piston compresses the powder into the cavities to form plugs.

The dose is controlled by the thickness of the dosing disc (cavity depth), powder level and the tamping pressure.

The flow of powder to disc is Auger assisted The flow of powder to disc is Auger assisted. A capacitance probe senses the powder level Carrs index 18-30% Lubricated for efficient plug ejection.

BOSCH GKF (HOFLIGER KARG MODEL)

DOSATOR MACHINES

| Consist of a cylindrical dosing tube fitted with a movable pistony g p| The end of the tube is open and the position of the piston is preset to a

particular height to define a volume| The dosator is plunged down into a powder bed maintained at a

constant preset level by agitators and scrappers.| Powder bed height is greater than the piston height so the powder| Powder bed height is greater than the piston height, so the powder

enters the open end and is slightly compressed against the piston.| The piston then exerts some pressure to form a plug, which is then

moved into capsule body

I iti l i t h i ht d t i th fill i ht| Initial piston height determines the fill weight.

DOSATOR FILLING PRINCIPLE

ZANASI MATIC 90

MG2 FUTURA

VACUUM FILLING

FILLING OF PELLLETS

Double slide method Pellets flow from the pellet magazine into the dosing chamber The dosing slide moves to the left thereby closes the dosing chamber

from pellet magazine. At the same time, opens the dosing chamber at bottom end.bottom end.

Pellets flows to the capsule body

IDEAL CHARACTERISTICS OF THE FORMULATION FOR GOOD FILLING

Fluidity is important for powder feed Fluidity is important for powder feed A degree of compactibility to prevent the loss of material from plug

during transport to the capsule shell Lubricity is needed to permit easy and efficient ejection of the plug Moderate bulk densityLow bulk density-capping problem

Non powder fillingNon powder filling- Beads, pellets, microtablets and tablets under the influence of gravity. High pumping (metered devices) for the liquids are adopted High pumping (metered devices) for the liquids are adopted

FORMULATION FOR POWDER FILL

1.Active ingredients drug and its solubilityg g yShould readily absorbable but with intermittent solubilityNecessary to evaluate drug solubility volumeBioavailability depends not only on solubility but also on permeability

INTERPRETATION

Class I- Bioavailability problemy pClass II- Dissolution rate limited absorptionClass III- Permeation rate limited absorptionCl IV Bi il bili bl b b f l d i l bili dClass IV- Bioavailability problem, best be formulated in solubilized

form

Scale up and post approval changes-immediate release solid dosage form (SUPAC-IR)

Level 1 change unlikely to have detectable impact on product qualityLevel 1 change- unlikely to have detectable impact on product quality and performance

Level 2 change- Could have significant impact Level 3 change- Likely to have significant impact Decides rigor of testing and filling requirements.

| More rigorous testing is required for Class IIg g q| Most rigorous testing for Class III| Level 3 changes requires Bioequivalence testing.

| Drugs with low solubility are often micronized, but particles with high f t ti t d t l t d t f h isurface to mass ratios may tend to agglomerate due to surface cohesive

interactions.| Smaller particles exhibits poor flowp p

FILLERS

| Starch and lactose, others include Mg and Ca carbonate, Ca phosphate, g , p p| They are also improving the flow property and compactibility- spray

dried lactose, dicalcium phosphate dihydrate.| Intrinsic dissolution rates of selected fillers (mg/min/cm2 at 370 )

GLIDANTS

Enhances the fluidity byy y Reducing roughness by filling surface irregularities Reducing attractive forces by physically separating the bulk powder

particles Modifying electrostatic charges

A ti i t Acting as a moisture scavenger Serving as ball bearings between bulk powder particles

Colloidal silica, cornstarch, talc and Mg stearate are common examples

LUBRICANTSL b i t t b dd d t l t d t b bl d d f Lubricants must be added at last and must be blended for aminimum of time, coz laminar lubricants (Mg/Ca stearate) aremixing sensitive

Under rigors the may delaminate and forms a film over theparticles, retarding wetting and dissolution timeparticles, retarding wetting and dissolution time

In dosator machines powder is continuously mixed by rotatingdi d l d t d l i tidisc and may leads to delamination

Replacement of the Mg stearate with more hydrophilicp g y plubricant- Stear-o-wet (Mg Stearate coprocessed with sodiumlauryl sulfate)

soluble fillers exhibits longer dissolution time with increasing soluble fillers exhibits longer dissolution time with increasinglubricant level

DISINTEGRANTS

Superdisintegrant- Crosscarmellose sodium type A, Sodium starch glycolate, Crosspovidone

Efficiency depends on the conc. 2-4% is suggested but to havec e cy depe ds o e co c. % s sugges ed bu o vegood results 4-6% is used for faster dissolution.

Eff t f l b i t l bl d i l bl fill ith i Effect of lubricant on soluble and insoluble filler with varyingconcentration of lubricant different lubricant and at differenttamping forces

Lactose based capsule had shown best release even withoutdisintegrants.

SURFACTANTS

To enhance drug wetting and dissolutiong g Hydrophobic lubricants may cause Water proofing so to reduce

this the surfactants are added. Most widely used are Sodium lauryl sulfate S di d t Sodium docusate

Used in a concentration of 0 1-0 5%Used in a concentration of 0.1 0.5%

SOFT GELATIN CAPSULE

Advantagesg Higher degree of reproducibility for filling process

Higher degree of homogeneity

A content uniformity of 3% has been achieved

Rapid release of contents ith enhanced bioa ailabilit Rapid release of contents with enhanced bioavailability

Many drugs prone to atmospheric oxidation may be formulated as Many drugs prone to atmospheric oxidation may be formulated, assoft gelatin shell can be an effective barrier to the oxygen

DISADVANTAGESDISADVANTAGES

Needs expensive instruments and expertise for manufacturing Needs expensive instruments and expertise for manufacturingsoft gel capsules

Additional quality control is required

More possibility of drug- shell and additive- shell interactions. Chloral hydrate with oily vehicle exerts proteolytic effect on the shell

Drug can migrate from vehicle to shell, depending on thesolubility and partition coefficient

FORMULATION OF CAPSULESFORMULATION OF CAPSULES(N(NATUREATURE OFOF THETHE CAPSULECAPSULE CONTENTCONTENT)) Materials are generally formulated to produce smallest g y p

possible capsule consistent with max stability, therapeutic effectiveness & manufacturing efficiency.

Liquids are limited to those that do not have an adverse effect Liquids are limited to those that do not have an adverse effect on gelatin walls

pH 2.5 to 7.5M idi l k b h d l i f l i More acidicleakage by hydrolysis of gelatin

pH > 7.5 & aldehydes decrease shell solubility by tanning the gelatin.g

FORMULATION OF CAPSULESFORMULATION OF CAPSULES(N(NATUREATURE OFOF THETHE CAPSULECAPSULE CONTENTCONTENT))

The types of vehicles usedyp1. Water-immiscible, volatile, or more likely non-volatile

liquids such as vegetable oils, aromatic & aliphatichydrocarbons (mineral oils), medium chain triglycerideshydrocarbons (mineral oils), medium chain triglycerides& acetylated glycerides.

2. Water-miscible, non-volatile liquids such as low mol wtPEGs (400 600) readily mix with water & acceleratePEGs (400, 600), readily mix with water & acceleratedissolution of dissolved or suspended drugs.

All liquids used for filling must flow by gravity at a temp of 350C or less.

The sealing temp of gelatin film is 37-400C

MANUFACTURING

I. Plate processp

II. Rotary Die Process

III. Accogel process

IV. Bubble Method

PLATE PROCESSPLATE PROCESS

| The oldest commercial processp| General process involved Placing the upper half of a plasticized gelatin sheet over a

die plate containing numerous die pocketsdie plate containing numerous die pockets.Application of vacuum to draw the sheet into the die

pockets Filling the pockets with liquid or paste Folding the lower half of gelatin sheet back over the filled

pockets &pockets & Inserting the sandwich under a die press where the

capsules are formed & cut out.

ROTARY DIE PROCESSROTARY DIE PROCESS

The die cavities are machined into outer surfaces of tworollers (i.e. Die rolls)

The die pocket on the left hand roller form the left side of the The die pocket on the left hand roller form the left side of thecapsule; the pockets on the right hand roller from the rightside of the die capsule.

The die pockets on the two rollers match as the rollers rotate.

Two plasticized gelatin ribbons fed with the liquid or pastefill between the rollers of the rotary die mechanism

ROTARY DIE PROCESSROTARY DIE PROCESS

The forceful injection of the feed material between the twojribbons causes the gelatin to swell into the left & right handdie pockets as they converge.

As the die-rolls rotate, the convergence of the matching diepockets seals & cuts out the filled capsules.pockets seals & cuts out the filled capsules.

ROTARY DIE PROCESSROTARY DIE PROCESS

ACCOGEL PROCESSACCOGEL PROCESS

A continuous process for the manufacture of soft gelatinp gcapsules filled with powders or granules.

This is another rotary process involvingA measuring rollA di ll &A die roll &A sealing roll

ACCOGEL PROCESSACCOGEL PROCESS

The measuring roll rotates directly over the die roll & theg ypockets in the two rolls are aligned with each other.

The powder or granular fill material is held in thepockets of measuring roll under vacuum.

Pressure develops between the die roll & roll seals &cuts out the capsule.

BUBBLE METHODBUBBLE METHOD Truly seamless, one piece soft gelatin can be made

A concentric tube dispenser simultaneously discharges themolten gelatin from the outer annulus & liquid content fromg qthe inner tube.

The liquids are discharged into chilled oil as droplets, which The liquids are discharged into chilled oil as droplets, whichconsist of a liquid medicament core within a molten gelatinenvelope.

The droplets assume a spherical shape under surface tensionforces, & gelatin congeals on cooling.

The finished capsules then degreased & dried

IPQC

IN PROCESS QUALITY CONTROLQ

These are simple and rapid tests or inspections that are carriedout when the manufacturing of a product batch is in progress.

It i d ith idi t ifi d d fi it It is concerned with providing accurate, specific and definitedescription of procedures to be employed from the receipt ofraw materials to the release of the finished dosage forms.

The primary objective is to monitor all the features of ad t th t ff t it lit d t t d iproduct that may affect its quality and to prevent errors during

processing

ALLIED OBJECTIVES

To identify the materials, equipment, processes and operators.y , q p , p p

To enforce flow of manufacturing and packaging operationsaccording to the established rules and practices

T i i i h t d t t th if d h To minimize human error or to detect the error if and whendoes it occur.

To pinpoint the responsibilities to the personnel involved ineach operation of the entire process

THE IPQC FOR SOLID DOSAGE FORM

D i i h d f h f l i Determining the drug content of the formulation

Checking the weight variation test for tablets and capsules at Checking the weight variation test for tablets and capsules atpredetermined intervals

Checking the disintegration test and/ or dissolution time, hardnessand friability of the capsule at least during the beginning, middleand end of production or at prescribed intervals duringmanufacturing

Testing soluble tablets for the compliance with solution time Testing soluble tablets for the compliance with solution timerequirements

Examining products by line inspection or other equally suitablemeans and removing the defective units prior to packaging.

C T T U TCONTENT UNIFORMITY

30 capsules are selected randomlyp y Out of these 10 capsules are assayed

Not more than one should deviate from 85-115% If more than 1 upto 3 deviates from 75-125% Then, 20 capsules are assayed and not more than 3 of 30

h ld d i t f thshould deviate from the range.

WEIGHT VARIATION20 capsules are takenpThese are weighed and average weight is calculated.

None should deviate form range of 90-110% of the average weight.

If deviates then,Net weight is taken and average is calculated

h 2 h ld d i b h 10%Not more than 2 should deviate by more than 10%None should deviate by 25%

If this is so then,,Additional 40 capsules are taken, net weight determined

not more than 6 out of 60 should deviate by 10-25%.