ADVANTAGES Elegance- smoothness and availability of different colors Ease of use and portability Odorless and tasteless Swallowing

S ll i is i easy as hydrates h d t the th shell h ll 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, tablets e.g. eg compression, granulation, drying.

DISADVANTAGES Not used N df for effervescent ff and d deliquescent d li substances b Not used for the extremely soluble drugs KCl, KBr Adhesion in the OesophagusOesophagus 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. The h requirement i for f specialised i li d manufacturing f i equipment

COMPARISON

HARD GELATIN Mixture of gelatin type A/B

Mfg dipping Powder/granules/pellets Obl Oblong shaped h d

SOFT GELATIN more flexible, plasticized gelatin used other than oral route- rectal g - vaginal - opthalmic mfg dipping rotary die process solutions/suspensions/emulsions most precise dosing spherical/oval/oblong/tube/ h i l/ l/ bl /t b / suppository type 1-480 minim 16.2 minim=1mL

0.13 -1.37 mL

COMPOSITION OF THE SHELL

Gelatin Plasticizer Opacifiers Preservatives Dyes Flavours

GELATIN
Conditioning First the raw material is cut to a manageable size, First, 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. Extraction The raw material is mixed with clean, warm water. By careful thermal t e a control, co t o , the t e gelatin ge at is s gradually g adua y and a d gently ge t y released e eased in the t e form of a liquor. Filtration Th liquor The li containing i i the h gelatin l i is i cleaned l d and d polished li h d by b filtration. This may also involve centrifuging, ultra-filtration and ion exchange, all of which ensure the final removal of any inorganic material. material

Concentration multi-stage lti t vacuum evaporators t are used. d The Th rich i h gelatin l ti liquor li is i 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. Drying The warm gelatin solution is gelled by cooling in a votator, minced, and deposited as a bed onto an open-weave open weave stainless steel belt 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. Grinding,milling G i di illi and d blending bl di After microbiological and physical testing, the gelatin particles are ground, milled and blended to suit the end use and customer specifications.

GELATIN
BLOOM 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 g that is 0.5 inches in diameter 4mm into a 62/3 % gelatin gel that has been held for 100C for 17 hours 150-250 gm

GELATIN
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 25 45 millipoise (38+2 millipoise)

GELATIN
Low viscosity y( (25-32 millipoise) p ) High bloom (180-250 g) Are used in junction with the capsulation of hygroscopic vehicles or solids. Iron Should Sh ld not t contain t i more than th 15 ppm of f iron i because b of f its effect on FDC dyes & its possible colour reactions with organic compounds

Bone gelatin- imparts firmness Pork gelatin imparts plasticity and clarity

PLASTICIZERS

The ratio by y wt of the dry y plasticizer p to dry yg gelatin determines the Hardness of the gelatin shells Hardness = wt of dry plasticizer / wt of dry gelatin

PLASTICIZERS
Hardness Ratio Dry Glycerin/ Dry Gelatin 0.4/1 Usage

HARD

Oral, oil-based, or shell-softening products d t f for h hot, t humid areas Oral, Tube, vaginal oil based, based watermiscible-based, or shell-hardening products & for temperate areas Tube, vaginal, watermiscible-based or shell h ll hardening h d i products & for cold, dry areas

MEDIUM

0.6/1

SOFT

0.8/1

COLOUR

The color of the capsule p can be definitely y affected by y the color 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

Dipping Rotation Drying Stripping Trimming Joining Sorting Printing

DEFECTS T IN THE T CAPSULE U SHELLS

Wrinkles Star ends Specks Dirt Strings Bubbles

CAPSULE VOLUME

STORAGE AND STABILITY

Moisture content- 13-16% Either brittle or too soft may 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 aldehydes Develops p SKIN or PELLICLE during g dissolution testing g Gelatin cross linking

SEALING AND SELF LOCKING CLOSURES

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

SEALING AND SELF LOCKING CLOSURES

FILLING OF HARD GELATIN CAPSULE

Rectification Separation of cap from body Dosing of fill material Replacement of caps and ejection of filled capsules Powder filling Auger fill principle Vibratory fill principle Piston tamp principle Dosator disc type Dosating nozzle type V Vacuum filli filling

AUGER FILL PRINCIPLE

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 preferred Glidant Glid t should h ld be b used d to t increase i flow fl rate(0.5 t (0 5 %) Lubricants are also added (Mg stearate, Stearic acid) to facilitate the p passage g of filling g ring g under the foot of the p powder hopper pp and thus prevents the adherence of material to the auger.

VIBRATORY FILL PRINCIPLE

The capsule p body yp passes under the feed frame, , which holds the p powder 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 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 repose

OSAKA MODEL R-180

PISTON TAMP PRINCIPLE p gp pins slightly g y compress p the Pistons or tamping individual 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 50200 N. Two types Dosing disc machine

Bosch GKF Harro Hofliger

D Dosator nozzle l machines hi

TAMP FILLING MECHANISM

DOSING DISC MACHINES

The dosing g disc forms the base of the filling g chamber, p posses no. of holes bored on it. A solid brass STOP plate lines the base of disc to close off the holes. 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. 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 y dosing g tube fitted with a movable p piston 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, 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 piston Initial i t height h i ht determines d t i the th fill weight. i ht

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. Pellets flows to the capsule body

IDEAL CHARACTERISTICS OF THE FORMULATION FOR GOOD FILLING

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 density Low bulk density-capping problem

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

FORMULATION FOR POWDER FILL

1.Active ingredients g drug g and its solubility y Should readily absorbable but with intermittent solubility Necessary to evaluate drug solubility volume Bioavailability depends not only on solubility but also on permeability

INTERPRETATION
Class I- Bioavailability yp problem Class II- Dissolution rate limited absorption Class III- Permeation rate limited absorption Cl IV Class IV- Bioavailability Bi il bili problem, bl best b be b formulated f l d in i solubilized l bili d form Scale up and post approval changes-immediate release solid dosage form (SUPAC-IR) Level 1 changechange 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 g testing g is required q for Class II Most rigorous testing for Class III Level 3 changes requires Bioequivalence testing.

Drugs with low solubility are often micronized, but particles with high surface f t to mass ratios ti may tend t d to t agglomerate l t due d to t surface f cohesive h i interactions. Smaller p particles exhibits p poor flow

FILLERS
Starch and lactose, , others include Mg g and Ca carbonate, , Ca p phosphate 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 y by y Reducing roughness by filling surface irregularities Reducing attractive forces by physically separating the bulk powder particles Modifying electrostatic charges Acting A ti as a moisture it scavenger Serving as ball bearings between bulk powder particles Colloidal silica, cornstarch, talc and Mg stearate are common examples

LUBRICANTS

Lubricants L b i t must t be b added dd d at t last l t and d must t be b blended bl d d for f a minimum of time, coz laminar lubricants (Mg/Ca stearate) are mixing sensitive Under rigors the may delaminate and forms a film over the particles, retarding wetting and dissolution time In dosator machines powder is continuously mixed by rotating di and disc d may leads l d to t delamination d l i ti

Replacement p of the Mg g stearate with more hydrophilic y p lubricant- Stear-o-wet (Mg Stearate coprocessed with sodium lauryl sulfate) soluble fillers exhibits longer dissolution time with increasing lubricant level

DISINTEGRANTS

Superdisintegrant

Crosscarmellose sodium type A, Sodium starch glycolate, Crosspovidone

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

Effect Eff t of f lubricant l b i t on soluble l bl and d insoluble i l bl filler fill with ith varying i concentration of lubricant different lubricant and at different tamping forces Lactose based capsule had shown best release even without disintegrants.

SURFACTANTS
To enhance drug g wetting g and dissolution Hydrophobic lubricants may cause Water proofing so to reduce this the surfactants are added. Most widely used are Sodium lauryl sulfate Sodium S di d docusate t

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

SOFT GELATIN CAPSULE

Advantages g Higher degree of reproducibility for filling process

Higher degree of homogeneity A content uniformity of 3% has been achieved Rapid release of contents with ith enhanced bioavailability bioa ailabilit Many drugs prone to atmospheric oxidation may be formulated, formulated as soft gelatin shell can be an effective barrier to the oxygen

DISADVANTAGES

Needs expensive instruments and expertise for manufacturing soft 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 the solubility and partition coefficient

FORMULATION OF CAPSULES (NATURE OF THE CAPSULE CONTENT)

Materials are g generally y formulated to produce p smallest possible capsule consistent with max stability, therapeutic effectiveness & manufacturing efficiency. Liquids are limited to those that do not have an adverse effect on gelatin walls pH 2.5 to 7.5 More M acidicleakage idi l k by b hydrolysis h d l i of f gelatin l i pH > 7.5 & aldehydes decrease shell solubility by tanning the g gelatin.

FORMULATION OF CAPSULES (NATURE OF THE CAPSULE CONTENT)

The types yp of vehicles used 1. Water-immiscible, volatile, or more likely non-volatile liquids such as vegetable oils, aromatic & aliphatic hydrocarbons (mineral oils), medium chain triglycerides & acetylated glycerides. 2. Water-miscible, non-volatile liquids such as low mol wt PEGs (400, (400 600), 600) readily mix with water & accelerate dissolution 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 process p Rotary Die Process Accogel process Bubble Method

II.

III.

IV.

PLATE PROCESS
The oldest commercial process p General process involved Placing the upper half of a plasticized gelatin sheet over a die plate containing numerous die pockets. 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 & Inserting the sandwich under a die press where the capsules are formed & cut out.

ROTARY DIE PROCESS

The die cavities are machined into outer surfaces of two rollers (i.e. Die rolls) The die pocket on the left hand roller form the left side of the capsule; the pockets on the right hand roller from the right side 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 paste fill between the rollers of the rotary die mechanism

ROTARY DIE PROCESS

The forceful injection j of the feed material between the two ribbons causes the gelatin to swell into the left & right hand die pockets as they converge. As the die-rolls rotate, the convergence of the matching die pockets seals & cuts out the filled capsules.

ROTARY DIE PROCESS

ACCOGEL PROCESS

A continuous p process for the manufacture of soft g gelatin capsules filled with powders or granules. This is another rotary process involving A measuring roll A die di roll ll & A sealing roll

ACCOGEL PROCESS

The measuring g roll rotates directly y over the die roll & the pockets in the two rolls are aligned with each other. The powder or granular fill material is held in the pockets of measuring roll under vacuum. Pressure develops between the die roll & roll seals & cuts out the capsule.

BUBBLE METHOD

Truly seamless, one piece soft gelatin can be made A concentric tube dispenser simultaneously discharges the molten g gelatin from the outer annulus & liquid q content from the inner tube. The liquids are discharged into chilled oil as droplets, which consist of a liquid medicament core within a molten gelatin envelope. The droplets assume a spherical shape under surface tension forces, & gelatin congeals on cooling. The finished capsules then degreased & dried

IPQC
IN PROCESS Q QUALITY CONTROL

These are simple and rapid tests or inspections that are carried out when the manufacturing of a product batch is in progress. It is i concerned d with ith providing idi accurate, t specific ifi and d definite d fi it description of procedures to be employed from the receipt of raw materials to the release of the finished dosage forms. The primary objective is to monitor all the features of a product d t that th t may affect ff t its it quality lit and d to t prevent t errors during d i processing

ALLIED OBJECTIVES

To identify y the materials, , equipment, q p ,p processes and operators. p To enforce flow of manufacturing and packaging operations according to the established rules and practices To minimize T i i i human h error or to t detect d t t the th error if and d when h does it occur. To pinpoint the responsibilities to the personnel involved in each operation of the entire process

THE IPQC FOR SOLID DOSAGE FORM

D Determining i i the h drug d content of f the h formulation f l i Checking the weight variation test for tablets and capsules at predetermined intervals Checking the disintegration test and/ or dissolution time, hardness and friability of the capsule at least during the beginning, middle and end of production or at prescribed intervals during manufacturing Testing soluble tablets for the compliance with solution time requirements Examining products by line inspection or other equally suitable means and removing the defective units prior to packaging.

CONTENT T T UNIFORMITY U T
30 capsules p are selected randomly 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 should h ld deviate d i t from f the th range.

WEIGHT VARIATION
20 capsules p are taken These 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

Not more than h 2 should h ld deviate d i by b more than h 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%.