Chapter 3

Capsules

PRESENTED BY:

HARI KESH MEENA

LECTURER OF PHARMACEUTICS G.D.MEMORIAL COLLEGE OF PHARMACY,JODHPUR
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Introduction - The definition of capsules

Capsula Latin word: small box (fixed volume!) From a pharmaceutical stand point: Capsules are solid dosage forms in which medicinal agents and/or inert substances are enclosed within a small shell of gelatin. Gelatin capsule shells may be hard or soft depending on their composition. Administration route of capsules orally (whole or mixed with food or drink after 2 opening capsules)

Introduction - The definition of capsules

Capsules are solid dosage forms in which the drug substance is enclosed in either a hard or soft soluble container or shell of a suitable form of gelatin. Steps in capsule production Mixing of ingredient Granulation and lubrication Making of capsules Filling of capsules Uniformity testing Packing and labeling 3

1.

2.
3. 4. 5. 6.

Introduction Advantages of capsules for oral administration

1. conveniently carried 2. readily identified 3. easily taken 4. prescribing flexibility 5. Efficiently and productively manufactured 6. Packaged and shipped at lower cost and with less breakage 7. More stable and have a longer shelf-life 8. Empty hard gelatin capsules are often used in the extemporaneous compounding of prescriptions. 9. Tablets and capsules are sometimes used as the source of a medicinal agent when it is not 4 otherwise available.

Introduction - Dosage forms that

must be left intact
Dosage forms that must be left intact include:

enteric coated tablets: designed to pass through the stomach for drug release and absorption in intestine extended/controlled release dosage forms: designed to provide prolonged release of the medicament sublingual or buccal tablets: formulated to dissolve under the tongue or in the mouth

If a patient is unable to swallow an intact solid dosage form, an alternative product may be employed, such as chewable tablet, instant dissolving tablet, oral liquid, suppository or injection.

Types of capsules
Gelatin capsule shells may be hard or soft depending on their composition.
Hard gelatin capsules

Soft gelatin capsules

Hard gelatin capsules: two-piece capsules (body and cap). Soft gelatin capsules: one-piece capsules.
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Hard gelatin capsules

The application of hard gelatin capsules used to manufacture most medicated agents employed in clinical trials, to compare the effect of an investigational drugs with those of another drug product or placebo used in the extemporaneous compounding The empty capsule shells consist of gelatin, sugar, water, colorants (various dyes), and opaquants (titanium dioxide). They can be clear, colorless and essentially tasteless or they may be coloured with dyes 7

Gelatin: Nature

Gelatin is a mixture of water soluble proteins (Mw ranges from 20-250 kDa). Prepared by the hydrolysis of collagen (protein of the connective tissues), followed by purification, concentration and drying. Main sources of collagen: Animal bones and skin. It is available in the form of a fine powder, a coarse powder, shreds, flakes or sheets. Average molecular weight of gelatin varies 8 between 20,000 and 2,00,000.

Types of gelatin
According to the hydrolysis processing: Two popular grade of gelatin: Pharmagel A and Pharmagel B Type A: produced by acid hydrolysis, IEP 4.7 and pH 4.8 to 5.2 Type B: produced by basic (alkaline) hydrolysis, IEP 9.0 and pH 6.5 to 9.5 A mixture of the two types or only one can be used according to the required properties.
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Gelatin: Important properties

The main quality control item of gelatin Bloom strength (a measure of gel rigidity) Viscosity degradation Moisture content transparency ash value pH value Iron: Its concentration depends on the iron content of the water used in its manufacture. 15ppm for gelatin used in 10 soft gelatin capsules.

Gelatin as a capsule shell: WHY?

Non toxic FDA approved in food stuff!!! (risk of disease transmission). Soluble in biological fluids at body temperature. Good film-producing material. Displays thixotropic properties.

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Hard gelatin capsules

Capsule shell: Gelatin Opecifier Water Preservative Colourants Wetting agents Materials to be filled (formulation): Active ingredients Diluents (filler) Glidants lubricants Wetting agents Disintegrants
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Capsules shell: Water content

Normally, hard gelatin capsules contain between 13 to 16% of moisture. High % of water: softening and deformation, microbial contamination. Low % of water: brittle, breakdown upon use. 12-16 %: acts as a plasticizer. Very critical during manufacturing and storage. The solubility property of gelatin: Insoluble in cold water, soften through the absorption of up to ten times its weight of water; soluble in hot water and in warm gastric fluid. Gelatin, being a protein, is digested by proteolytic enzymes.
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Capsule shell: Colourants

Mainly synthetic. Water-soluble or water-insoluble. Azo- or non-azo dyes. Usually, a mixture is used. Examples: erythrosine, indigocarmine.

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The manufacture of hard gelatin capsule shells

The shell consists of two parts, the capsule body and the capsule cap. The body is longer and slightly smaller in diameter than the cap. Shape is mainly oblong.

The process of capsule shell production with the peg/pin method:

dipping drying stripping trimming joining a) The thickness of the gelatin walls must be strictly controlled. b) The caps are slightly larger in diameter than the bodies.

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Manufacture of Hard Gelatin Capsules

1. Shell composition : Gelatin : Prepared by the hydrolysis of collagen. Gelatin in its chemical and physical properties, depending upon the source of the collagen and extraction. There are two basic types of gelatin: Type A and Type B. The two types can be differentiated by their isoelectric points (7.0 9.0 for type A and 4.8 5.0 for type B) and by their viscosity and film forming 16 characteristics.

Manufacture of Hard Gelatin Capsules

Combination of pork skin and bone gelatin are often used to optimize shell characteristics. The physicochemical properties of gelatin of most interest to shell manufactures are the bloom strength and viscosity. Colorants : Various soluble synthetic dyes (coal tar dyes) and insoluble pigments are used. Not only play a role in identifying the product, but also may play a role in improving patient compliance. E.g., white, analgesia; lavender, hallucinogenic effects; 17 orange or yellow, stimulants and antidepressants.

Manufacture of Hard Gelatin Capsules

Opaquing agents : Titanium dioxide may be included to render the shell opaque. Opaque capsules may be employed to provide protection against light or to conceal the contents. Preservatives : When preservatives are employed, parabens are often selected.
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2) Shell manufacture :

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I.

Dipping : Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies. The pins are at ambient temperature; whereas the dipping solution is maintained at a temperature of about 500C in a heated, jacketed dipping pan. The length of time to cast the film has been reported to be about 12 sec. II. Rotation : After dipping, pins are elevated and rotated 2-1/2 times until they are facing upward. This rotation helps to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the 20 capsule ends.

III.Drying : The racks of gelatin coated pins then pass into a series of four drying oven. Drying is mainly done by dehumidification. A temperature elevation of only a less degrees is permissible to prevent film melting. Under drying will leave the films too sticky for subsequent operation. IV. Stripping : A series of bronze jaws strip the cap and body portions of the capsules from the pins.
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Trimming : The stripped cap and body portions are delivered to collects in which they are firmly held. As the collects rotate, knives are brought against the shells to trim them to the required length. VI. Joining : The cap and body portions are aligned concentrically in channels and the two portions are slowly pushed together.
V.
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The manufacture of hard gelatin capsule shells

Some improvements to hard gelatin capsule shells capsule-making pegs (body-making or cap-making pegs): general rounded shape pegs tapered pegs tapered rims, indentations and locking grooves: straight-walled capsule shell tapered rim capsule shell with indentations and locking grooves a) The tapered rims avoid splitting; b) The indentations prevent premature opening; c) The grooves lock the two capsule parts together after the capsule has been filled. extension capsule cap (CONI-SNAP SUPRO) increase the security of the contents and the integrity of 23 the capsule

The manufacture of hard gelatin capsule shells

Tamper-evident sealing and imprinting

Tamper-evident sealing : through various capsule sealing techniques Imprinting which signals will be imprinted on finished capsules? a) names and monograms of the manufacturer b) the assigned national drug code (NDC) number c) other markings making the product identifiable and distinguishable from other products

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Capsule sizes

How to select capsule size?

1) the amount of fill material to be encapsulated 2) the density and compressibility of the fill 3) The final determination largely may be the result of trial.

The sizes of empty capsules

There are different sizes: from OOO (biggest) to 5 (smallest), different filling capacity (60 mg to 1 g) depending on the density.
For human use: 000(the largest), 00, 0, 1, 2, 3, 4, 5 (the

smallest)
For veterinary use: Larger capsules are available.
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Capsule size and body fill volumes

S.No. 1. 2. 3. 4. 5. Capsule Size 000 00 0 1 2 Body Volume (ml) 1.30 0.95 0.68 0.50 0.37 Body Weight (gm) 1.00 0.65 0.50 0.32 0.25

6.
7. 8.

3
4 5

0.30
0.21 0.13

0.20
0.15 0.10

For veterinary use larger capsules No., 10, 11 and 12 approx 26 capacities of 30, 15 and 7.5 gms. are also marketed.

Preparation of filled hard gelatin capsules

The general steps of preparation

1) developing and preparing the formulation and

selecting the size of capsule. 2) filling the capsule shells. 3) capsule sealing (optional). 4) cleansing and polishing the filled capsules.

The selection of capsule size

For a commercial product: during the product development stage In the extemporaneous compounding of prescriptions

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Developing the formulation and selection of capsule size

The goal of developing a capsule formulation is to prepare a capsule with How to get to the goal? 1) pharmaceutical processing 2) pharmaceutical excipient The pharmaceutical processing in the preparation of filled hard gelatin capsules 1) blending: uniform powder mix, uniform drug distribution 2) comminution/milling: 50~100 microns, suitable for a drug of low dose (10mg or greater) 3) micronization: 10~20 microns, suitable for drugs of 28 lower dose

Developing the formulation and selection of capsule size

The pharmaceutical excipient in the preparation of filled hard gelatin capsules 1) Diluents/filler: to produce the proper capsule fill volume; to provide cohesion to the powders, e.g. lactose, microcrystalline cellulose and starch 2) Disintegrants/disintegration agents: to assist the break-up and distribution of the capsule contents e.g. pregelatinized starch, crosscarmellose , and sodium starch glycolate (SSG) 29

Developing the formulation and selection of capsule size

The pharmaceutical excipient in the preparation of filled hard gelatin capsules (continued)
3) Lubricant or Glidant: to enhance the flow properties of the powder mix e.g. fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, or talc #: magnesium stearate, water-proofing characteristics, retard penetration of the GI fluids, delay drug dissolution and absorption 4) Wetting agents: to facilitate wetting of the dry powder e.g. surfactants, as sodium lauryl sulfate
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Developing the formulation and selection of capsule size

The form of filling material in capsules: 1) powder or granulate 2) pellet mixture 3) paste or wetted mass: the mixture of liquid and an inert powder 4) capsule 5) tablet 6) liquids: fixed or volatile oils (locking or sealed gelatin capsules) 7) eutectic mixtures: mixed with a diluent or absorbent to separate the interacting agents and to absorb any liquefied material
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Developing the formulation and selection of capsule size

Examples of filled hard gelatin capsules
1) Tetracycline capsules

Active ingredient: Tetracycline hydrochloride, 250 mg Filler: Lactose Lubricant/Glidant: Magnesium stearate Capsule colorants: omitted Capsule opaquant: Titanium dioxide

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Filling hard capsule shells

For filling the hard gelatin capsule shell, there are four methods 1. The punch method 2. The pouring method 3. Hand-operated capsule filling machines 4. Machines for industrial use 1. The punch method suitable for filling a small number of capsules in the pharmacy 1) placing the powder on paper 2) forming the powder mix into a cake 3) punching the empty capsule body into the powder cake 1) non potent drugs: The first filled capsules should be weighed. The other capsules should be weighed periodically. 2) potent drugs: Each capsules should be weighed. 33

Filling hard capsule shells

2. The pouring method suitable for filling a small number of capsules in the pharmacy suitable for granular material 3. Hand-operated capsule filling machines Hand operated and electrically operated machines are in practice for filling the capsules but for small and quick dispensing hand operated machines are quite economical. These machine are very simple to operate, can be easily dismantled and reassembled. 34

A hand operated hard gelatin capsule filling machine consists of the following parts.

A bed with 200 or 300 holes. A capsule loading tray. A powder tray. A pin plate having 200 or 300 pins corresponding to the number of holes in the bed and capsule loading tray. A lever. A handle. A plate fitted with rubber top. All the parts of the machine are made up of 35 stainless steel.

Filling hard capsule shells

Hand-operated capsule filling machines consist of a couple of plates

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Filling hard capsule shells

4. Machines for industrial use The process of working: separating the caps from empty capsules filling the bodies scraping the excess powder replacing the caps sealing the capsules cleaning the outside of the filled capsules 165,000 capsules per hour

SCF-10

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Filling of hard gelatin capsules

Equipment used in capsule filling operations involves one often of two types of filling systems. Zanasi or Martelli encapsulator: Forms slugs in a dosatar which is a hollow tube with a plunger to eject capsule plug. Hofliger-Karg machine: Formation of compacts in a die plate using tamping pins to form a compact.
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ZANASI AUTOMATIC CAPSULE FILLING MACHINE

HOFLIGER KARG AUTOMATIC CAPSULE FILLING MACHINE 39

In this both system, the scale-up process involve bulk density, powder flow, compressibility, and lubricant distribution. Overly lubricated granules are responsible for delaying capsule disintegration and dissolution.

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OSAKA MODEL R-180 SEMI AUTOMATIC CAPSULE FILLING MACHINE 41

Difficulties in filling the capsules

Deliquescent and hygroscopic powders: a

gelatin capsule contains water which is extracted or taken up by a hygroscopic drug and renders the capsule very brittle which leads to cracking of the capsule. The addition of absorbent like magnesium carbonate or light magnesium oxide overcomes this difficulty provided the capsules are packed in tightly closed glass capsule vials.

Eutectic mixtures: certain substances when

mixed together tend to liquefy or form a pasty mass due to the formation of a mixture which has a lower melting point than room temperature. 42

Difficulties in filling the capsules

The absorbents used are magnesium oxide and kaolin. Another method in dealing with such type difficulty is that the substances are mixed together so as to form a eutectic mixtures, then absorbent like MgCO3 or Kaolin is used Addition of inert powders: when the quantity of the drug to be filled in capsules is very small and it is not possible to fill this much small amount in capsules then inert substances or a diluents is added so as to increase the bulk of the powder which can be easily filled in 43 capsules.

Difficulties in filling the capsules

Filling of granular powders: some powders which lack adhesiveness and most granular powders are difficult to fill in the capsule by punch method because they are not compressible and flow out of the capsule as soon as they are lifted from the pile of the powder in to which they are punched. To overcome this difficulty the non adhesive powder should be moistened with alcohol and the granular powders should be reduced to powder before filling in to capsules.
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Difficulties in filling the capsules

Use of two capsules: some of the manufactures

separate the incompatible ingredients of the formulation by placing one of the ingredients in smaller capsule and then placing this smaller capsule in a larger capsule containing the other ingredients of the formulation.

Liquids: oil and liquids which will not dissolve

gelatin may be filled into hard gelatin capsules. When the quantity of the liquid to be incorporated is small, it is first mixed with an inert absorbent which is then added to another ingredient, mixed thoroughly and filled in to 45 capsule.

Capsule sealing
Sealing of the caps on to bodies is possible by moistening the upper part of the body and slipping the cap on make the capsules tamper-evident 1) sealing with a colored band of gelatin 2) heat welding 3) Thermally bonding at 40-45 with the help of a melting-point-lowering liquid wetting agent 4) extemporaneously, by lightly coating the inner surface of the cap with a warm gelatin 46 solution

Cleaning and polishing capsules

Small amount of powder may adhere to the outside of capsules after filling. 1) On a small scale, cleaning with a clean gauze or cloth. 2) On a large scale, cleaning vacuum The following steps are involved in the finishing process:
1. salt polishing 2. cloth dusting 3. brushing 4. inspection

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Soft gelatin capsules

The definition of soft gelatin capsules Manufactured in one piece in which the drug is in a liquid form inside the soft shell
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.

The advantages of soft gelatin capsules

1) pharmaceutically elegant 2) easily swallowed by the patient
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Soft gelatin capsules

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Differs from HGC in:

1. 2. 3.

Bloom strength: less than HGC Amt of water and humidity. Hydrophilicity.

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Soft gelatin capsules

The pharmaceutical applications of soft gelatin capsules are 1) as an oral dosage form for human or veterinary use 2) as a suppository dosage form for rectal use or for vaginal use 3) as a specialty package in tube form, for human and veterinary single dose application of topical, ophthalmic, and otic (ear) preparations, and rectal ointments. 4) in the cosmetic industry, may be used for breath fresher's, perfumes, bath oils & skin creams. 51

Soft gelatin capsules

The components of soft gelatin capsules 1) gelatin 2) glycerin or polyhydric alcohol 3) water/moisture 4) preservative 5) colorant 6) markings 7) opaquants 8) Flavors may be added and up to 5% sucrose may be included for its sweetness and to produce a chewable shell.
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Manufacture of Soft Gelatin Capsules

I. Composition of the shell:
Similar to hard gelatin shells, the basic component of soft gelatin shell is gelatin; however, the shell has been plasticized. The ratio of dry plasticizer to dry gelatin determines the hardness of the shell and can vary from 0.31.0 for very hard shell to 1.0-1.8 for very soft shell. Up to 5% sugar may be included to give a chewable quality to the shell. The residual shell moisture content of finished capsules will be in the range of 6-10%. 53

Soft Gelatin Capsules

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II. Formulation : Formulation for soft gelatin capsules involves liquid, rather than powder technology. Materials are generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness and manufacture efficiency. The liquids are limited to those that do not have an adverse effect on gelatin walls. The pH of the liquid can be between 2.5 and 7.5. Emulsion can not be filled because water will be released that will affect the shell. 55

The types of vehicles used in soft gelatin capsules fall in to two main groups:
1.

2.

Water immiscible, volatile or more likely more volatile liquids such as vegetable oils, mineral oils, mediumchain triglycerides and acetylated glycerides. Water miscible, nonvolatile liquids such as low molecular weight PEG have come in to use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs.

All liquids used for filling must flow by gravity at a temperature of 350c or less. The sealing temperature of gelatin films is 3756 400C.

Preparation of soft gelatin capsules

III Manufacture process :

A. Plate process :
The process involved
Placing the upper half of a 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 57 the capsules are formed and cut out.

Preparation of soft gelatin capsules

The plate process (using a set of molds)
The plates contain die pockets. 1) placing a warm sheet of gelatin on the bottom plate 2) pouring the liquid-containing medications 3) placing the second sheet of gelatin 4) putting the top plate of the mold into place 5) pressing the mold to form, fill, and seal the capsules simultaneously 6) removing and washing the capsule Today, this equipment can no longer be purchased.
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B. Rotary die press:

In this process, the die cavities are machined in to the outer surface of the two rollers. The die pockets on the left hand roller form the left side of the capsule and the die pockets on the right hand roller form the right side of the capsule. Two plasticized gelatin ribbons are continuously and simultaneously fed with the liquid or paste fill between the rollers of the rotary die mechanism. As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the filled capsules. 59

Preparation of soft gelatin capsules

The rotary die process (1933, R. P. Scherer) more efficient and productive 1) Liquid gelatin is formed into two ribbons 2) The two ribbons are brought together 3) Metered fill material is injected between the ribbons 4) These pockets of fill-containing gelatin are sealed

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Rotary die press

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Rotary die soft capsule machine

The dies for production of soft capsule

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C. Accogel process:
In general, this is another rotary process involving
A measuring roll, A die roll, and A sealing roll.

As the measuring roll and die rolls rotate, the measured doses are transferred to the gelatinlinked pockets of the die roll. The continued rotation of the filled die converges with the rotating sealing roll where a second gelatin sheet is applied to form the other half of the capsule. Pressure developed between the die roll and sealing 64 roll seals and cuts out the capsules.

Preparation of soft gelatin capsules

The Accogel machine (1949,
Cyanamid company)

This equipment is unique in that it is the only equipment that accurately fills powdered dry solids.

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D. Bubble method:
The Globex Mark II capsulator produces truly seamless, one-piece soft gelatin capsules by a bubble method.

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 A concentric tube dispenser simultaneously discharges the molten gelatin from the outer annulus and the liquid content from the tube. By means of a pulsating pump mechanism, the liquids are discharged from the concentric tube orifice into a chilled-oil column as droplets that consists of a liquid medicament core within a molten gelatin envelop. The droplets assume a spherical shape under surface tension forces and the gelatin congeals on cooling. The finished capsules must be degreased and 69 dried.

Preparation of soft gelatin capsules

E. The reciprocating die process
(1949, Norton company) is similar to the rotary process in that ribbons of gelatin are formed and used to encapsulate the fill, but it differs in the actual encapsulating process. 1) A set of vertical dies continually open and close to form rows of pockets in the gelatin ribbons. 2) These pockets are filled with the medication and are sealed, shaped, and cut out of the film. 3) The capsules fall into refrigerated tanks which prevent the capsules from adhering to one 70 another.

IV. Soft/Liquid-filled hard gelatin capsules:

Important reason: the standard for liquid filled capsules was inability to prevent leakage from hard gelatin capsules. As banding and of self-locking hard gelatin capsules, together with the development of highresting state viscosity fills, has now made liquid/semisolid-filled hard gelatin capsules. As with soft gelatin capsules, any materials filled into hard capsules must not dissolve, alter or otherwise adversely affect the integrity of the shell. Generally, the fill material must be pumpable. 71

 Three formulation strategies based on having a high resting viscosity after filling have been described.
1. Thixotropic formulations, 2. Thermal-setting formulations, 3. Mixed thermal-Thixotropic systems.

The more lipophilic contents, the slower the release

rate.

Thus, by selecting excipients with varying HLB

balance, varying release rate may be achieved.
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The nature of soft gelatin capsule shell

1) The gelatin is Pharmacopoeial grade with additional specifications required by the capsule manufacturer.
a) Bloom strength(measure of rigidity) :Load in gms required to push a stand plunger 4mm into the gel.

The gelatin used in HGC is of higher bloom strength (200-250 gm) than that used for SGC(150gm) b) viscosity: Generally, 25 to 45 millipoise is acceptable. c) iron: 15ppm

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The nature of soft gelatin capsule shell

2) Plasticizers glycerin or Sorbitol or combinations of these The ratio by weight of dry plasticizer to dry gelatin determines the hardness of the gelatin shell. 0.4/1 hard 0.6/1 medium 0.8/1 soft The ratio by weight of water to dry gelatin can vary from 0.7-1.3 to 1.0. 3) The color of the gelatin shell
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Formulation of soft gel

Gelatine: Alkali processed(Type B) 40% of gel mass. We can also use Type A acid gelatin. Plasticizer:20-30% of gel mass,its amount depends on: 1-Hardness 2- dissolution and Disintegrant. 3- Stability. 4-Compatabile with all.5- appearance. Water:30-40% of gel mass, ensure proper processing, excess water is removed by drying. In dry soft gels water 5-8% w/w, thus good stability. Colourants and opacifier: as HGC

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Properties of soft gelatin shells

O2 permeability:
Good barrier against O2 diffusion. O2 permeability decrease With % relative humidity.

2-Residual H2O content:

(little in SGC)

About 7% in shell while H2O content in the fill in equilibrium with atm.
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(add glycerol for max. Protection 30-40%)

The gelatin shell.

The SGC formed outlet.

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The fill material of soft gelatin capsules

1) liquids a) water-immiscible volatile and nonvolatile liquids b) water-miscible, nonvolatile liquids c) water-miscible and relatively nonvolatile liquids e.g. propylene glycol, isopropyl alcohol d) Liquids that can easily migrate through the capsule shell cannot be encapsulated into soft gelatin capsules 2) solids (solutions, suspensions, pasty mass, dry powders, granules, pellets, or small tablets.)

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Disadvantages of SGC
Special manufacturing equipment. 2. Limited choice of excipients. 3. Any change in water % affect hardness. 4. Hygroscopic & volatile compounds cause hardening. 5. Acid & Alkalis cause hydrolysis & leakage. 6. Not for product Extract But, Product Extract + carrier oil + beeswax + lecithin =encapsulation) 7. Fish oil has bad odour & taste, thus includes Conc. Of flavor.
1.
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HGC

Comparison between HGC & SGC SGC

Prepared in one step.

Shell prepared by machine(company) and filled by the other.

13-16% moisture.

30-40% during manufacture but finally 7%. Used with water labile substances.

Not used with water labile substances.

Bloom strength 200-250gm Bloom strength 150 gm. Not with O2 sensitive API With O2 sensitive API
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Compendial requirements for capsules

1. 2.

3.
4. 5. 6. 7. 8.

9.

Added subtances:Harmless-effective... Containers:Tight,closed,light resistant. Disintegrant test Dissolution test. Content uniformity( 9 of 10 85-115%,none out of 75-125%) Content labelling requirements. Stability test. Moisture permeation test. Inspecting,counting,packaging&storing capsules.
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Compendial requirements for capsules

Substances added to official preparations, including capsules, to enhance their stability, usefulness, or elegance, or to facilitate their manufacture may be used only if they
1) are harmless in the quantities used 2) do not exceed the minimum amounts required to provide their intended effect 3) do not impair the products bioavailability, therapeutic efficacy or safety 4) do not interfere with requisite compendial assays and tests
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The container and preservation condition described in USP

containers 1) light resistant container: 2) well-closed container: 3) tight container: 4) Hermetic seal Container : Preservation conditions 1) Freezer: -25 ~ -10 ; 2) Cold: <8 ; 3) Cool: 8 ~ 15 ; 4) Room Temperature: The temperature prevailing in a working area. 5) Controlled Room Temperature: 20 ~ 25 ; 6) Warm: 30 ~ 40 ; 7) Excessive Heat: >40 ; 8) Protection from Freezing: (breakage of the container, loss of strength or potency, destructive alteration of its 83 characteristics)

Compendial requirements for capsules

Disintegration test for capsules The disintegration tests for hard and soft gelatin capsules follows the same procedures and uses the same apparatus as for uncoated tablets.
1) Method The capsules are placed in the basket-rack assembly, which is repeatedly immersed 30 times per minute into a thermostatically controlled fluid at 37 and observed over the time described in the individual monograph. 2) To fully satisfy the test, the capsules disintegrate completely into a soft mass having no palpably firm core, and only some fragments of the gelatin shell. 84

Compendial requirements for capsules

Dissolution test for capsules
1) The apparatus, dissolution media and test is the same as that for uncoated and plain coated tablets. If the capsule shell interfere with the analysis, the content of specified number of capsules can be removed and the empty capsule shells dissolved in the dissolution medium before proceeding with the sampling and chemical analysis. 2) Generally, when a dissolution test is applied to an existing capsule product, the disintegration test is unnecessary.
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Compendial requirements for capsules

Weight variation and content uniformity show the uniformity of dosage units.

Weight variation

Wcapsule Wemptied shell = Wcontent 10 capsules labeled amount or average amount, 10% 1) For hard capsules #1: Wcapsule should match Wemptied shell. 2) For soft capsules #1: evaporating the washing solvent over 30 mins #2: avoid uptake or loss of moisture

Content uniformity

The amount of active ingredient should be within the range of 85% to 115% of the label amount for 9 of 10 capsules, with no unit outside the range of 70% to 125% of label amount.
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Compendial requirements for capsules

Other requirements:
1) content labeling: the quantity of each active ingredient in each dosage unit. 2) stability testing method: long-term stability testing, accelerated stability test aim: storage condition, shelf life 3) moisture permeation test: the USP requires determination of the moisture permeation characteristics of single- unit and unit dosecontainers to ensure their suitability for 87 packaging capsules.

Inspecting, counting, packaging, and storing capsules

1) Inspecting
visual or electronic inspection uniform in appearance

2) Counting
a) counting tray; b) counting and filling machines

3) Packaging
unit dose and strip packaging (sanitary, identifiable, safe)

4) Storing
in tightly capped container in a cool, dry place
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CAPSULE POLISHING MACHINE

AUTO MATIC CAPSULE ARRANGEMNT 89

The Gel Mass (Capsule shell)

The gel is prepared in a 300-litre stainless steel vessel.

HOW?

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The Gel Mass (Capsule shell)

Gelatine powder mixed with water and glycerine that is then heated and stirred under vacuum. The molten gelatin mass is then decanted into 200kg mobile vessels where colours and flavours can be added using a turbine mixer that ensures consistency of the gelatin mass.

This mass is kept at a constant temperature until it is needed for the next stage of the process

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The Medicine (Capsule fill)

The medicine preparation area has a standard range of mixers, homogenizers and milling equipment for the preparation of the fills. The product being prepared dictates what equipment has to be utilized. For simple oils the material is decanted into a 200 kg mobile vessel, positioned on a floor scale, blanketed with Nitrogen, if required, and then sealed ready for the next stage of the process. Blends of oils follow a similar process but a Silverson mixer is used to ensure a uniform mix is achieved. 92

Encapsulation

The gel and fill mobile vessels are then taken to the encapsulation bays where each encapsulation machine is segregated in individual bays. The molten gel is pumped to the machine and two thin ribbons of gel are formed, one either side of the machine. These ribbons then pass over a series of rollers and over a set of dies that determine the size and shape of the capsules. The fill is fed from its container to a positive displacement pump, which accurately doses the fill and injects it between the two gelatin ribbons prior to them sealing together through the application of heat and pressure. The resultant capsule is incredibly flexible due to the water added to the gel mass and this excess has to be removed 93

Capsules fall from the machine and pass along a conveyor into tumble dryers. These remove some 30% of the excess moisture, but the capsules are still not dry enough for packing. Dry air is forced over the capsules to remove any remaining free moisture from the capsules and complete the drying process.

Once dried, the capsules are removed from the drying room to an inspection area. Here they undergo visual inspection, which ensures the quality of the product. The capsules are tipped into intermediate containers and transferred to the packing room. The capsules are 94 mechanically graded to ensure size uniformity.

Inspection

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To Summarize!

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References
1. The theory and practice of industrial pharmacy. Leon Lachman, Herbert A. Lieberman, Joseph L. Kanig. Third edition. Varghese publishing house. Page no. 681-703. 2. Pharmaceutical dosage forms: Tablets. Volume 3. second edition. Leon Lachman, Herbert A. Lieberman, Joseph B. Schwartz. Page no. 303-365. 3. Pharmaceutical process scale up edited by Michael Levin. 4. Modern pharmaceutics. Edited by Gilbert S. Banker & Christopher T. Rhodes. 4th edition. 99 5. www.google.com

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