CAPSULE

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 1. Mixing of ingredient 2. Granulation and lubrication 3. Making of capsules 4. Filling of capsules 5. Uniformity testing 6. Packing and labeling

The manufacturing process for capsulated products often same to that tablets. Both tablets & capsules are produced from ingredients that may be either dry blended or wet granulated to produce a dry powder or granule mix with uniformly dispersed active ingredients. To produce capsules on high speed equipment ,the powder blend must have the uniform particle size distribution, bulk density & compressibility required to promote good flow properties & result in the formation of compact of the right size and sufficient cohesiveness to be filled in to capsule shells.

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 characteristics.

 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; orange or yellow, stimulants and antidepressants.

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.

2) Shell manufacture :

I.

II.

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. 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 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.

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.

3) Sorting : The moisture content of the capsules as they are from the machine will be in the range of 15 18% w/w. During sorting, the capsules passing on a lighted moving conveyor are examined visually by inspectors. Defects are generally classified according to their nature and potential to cause problems in use. 4) Printing : In general, capsules are printed before filling. Generally, printing is done on offset rotary presses having throughput capabilities as high as three-quarter million capsules per hour.

5) Sizes and shapes : For human use, empty gelatin capsules are manufactured in eight sizes, ranging from 000 to 5. Capsule capacities in table:
Empty Hard Gelatin Capsule Physical Specifications
Outer Diameter (mm)
000 00 0 1 2 3 4 5 9.91 8.53 7.65 6.91 6.35 5.82 5.31 4.91 Height or Locked Length (mm) 26.14 23.30 21.70 19.40 18.00 15.90 14.30 11.10

Size

Actual Volume (mL)

1.37 0.95 0.68 0.50 0.37 0.30 0.21 0.13

Typical Fill Weights (mg) 0.70 Powder Density 0.70 g/cm3 960 665 475 350 260 210 145 90 0.80 g/cm3 1.096 0.760 0.544 0.400 0.296 0.240 0.168 0.104

The largest size normally acceptable to patient is a No: 0. Three larger size are available for veterinary use: 10, 11, and 12 having capacities of about 30, 15, and 7.5 g, respectively. The standard shape of capsules is traditional, symmetrical bullet shape. Some manufactures have employed distinctive shapes. e.g. Lillys pulvule tapers to a bluntly pointed end. Smith Kline Beachams spansule capsules taper at both the cap and body ends.

6) Sealing : Capsules are sealed and somewhat reshaped in the Etaseal process. This thermal welding process forms an indented ring around the waist of the capsule where the cap overlaps the body. 7) Storage : Finished capsules normally contain an equilibrium moisture content of 13-16%. To maintain a relative humidity of 40-60% when handling and storing capsules.

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.

ZANASI AUTOMATIC CAPSULE FILLING MACHINE

HOFLIGER KARG AUTOMATIC CAPSULE FILLING MACHINE

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.

OSAKA MODEL R-180 SEMI AUTOMATIC CAPSULE FILLING MACHINE

SOFT GELATIN CAPSULE

DEFINITION:soft Gelatin capsules are one piece, hermetically sealed, soft gelatin shells containing a liquid, a suspension, or a semisolid. The Nomenclature for this dosage form has now been changed to soft gel . They have long been preferred dosage form for those, taking Health & Nutritional supplements.

ADVANTEGES
Easy to administer Easy to Manufacture Liquids can be encapsulated ( non water soluble) Small to large sizes possible Elegance Portability Odour and taste masking Ready availability of drug hence faster action. Specialised dosage forms can be made e.g.

chewable, extended release, captabs etc. Can be used for ophthalmic preparations e.g. aplicaps, vaginal / rectal suppositories

DISADVANTEGES
Water

soluble material are difficult to incorporate Highly Moisture sensitive Efflorescent material cannot be incorporated, they may cause softening / leaching Deliquescent materials cannot be incorporated, they may cause hardening or brittle capsules.

Shapes of Capsules -

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 0.3-1.0 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%.

CAPSULE SHELL

GELATIN:-Obtain from partial hydrolysis of collagen derived from the skin, connective tissue & Bones of animals. May have viscosity of 38 mpa Bloom strength:-150-250 cost of gelatin Bloom strength

COLOUR used in shell has to be darker than colour of encapsulating material colours may be natural or synthetic. OPACIFIER, usually titanium dioxide, may be added to produce an opaque shell ,when the fill formulation is a Suspension or to prevent photo degradation of light sensitive fill ingredients. Conc. Of opacifier may be up to 0.5%

Chelating Agents:- Iron is always present in raw gelatin, & should not contain iron more than 15 ppm Additionally chelating agent may be used for preventing the reaction of iron with materials or colours.

TYPICAL FORMULA FOR GELATIN SHEET

Glycerin

I.P. PropMethyl Paraben I.P. Methyl Paraben I.P. Gelatin 120 Bloom I.P. Brilliant Blue Ponceau 4R Sunset Yellow I.P. TiO2 I.P. Water I.P. Sorbitol Liq. I.P.

52.0 Kg 0.512Kg 0.128Kg 152.000Kg 0.300Kg 0.300Kg 16.000Kg 120.00Ltr 16.00Kg

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 lipid can be between 2.5 and 7.5. Emulsion can not be filled because water will be released that will affect the shell.

GELATIN MASS MANUFACTURE

The gel is prepared in a 300-litre stainless steel vessel. Gelatin powder is mixed with water and glycerine. Heating Stirring The molten gelatin mass is formed. It is decanted into 200-kg mobile vessels. Turbine mixing where colours and flavours can be added.

It ensures consistency of gelatin mass. This mass is kept at a constant temperature until it is needed for the next stage of the process.

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 37-400C.

CAPSULE CONTENT Content may be liquid, or a combination of miscible liquids, A solution of a solid(s) in a liquid(s) or a suspension of a solid(s) in a liquid(s). It can be a liquid like a volatile oil composition e.g.Pudin hara.

Vegetable oils like arachis oil or aromatic or aliphatic hydrocarbons, ethers, esters, or alcohols.

 Solids

that are not Sufficiently soluble in liquids or in combination of liquids are capsulated as Suspension. Suspending agents used are Lecithin, Soyabean oil, yellow wax.

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 the capsules are formed and cut out.

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.

ROTARY DIE ENCAPSULATING MACHINE

IN-PROCESS TESTING

a.
b.

c. d.

During the encapsulation process the four most important tests are:The gel ribbon thickness; Soft gel seal thickness at the time of encapsulation; Fill matrix weight & capsule shell weight; Soft gel shell moisture level and soft gel hardness at the end of the drying stage.

FINISHED PRODUCT TESTING

These normally includes Capsule appearance, active ingredient assay & related substances assay Fill weight Content uniformity and Microbiological testing.

VEGICAPS SOFT CAPSULES

VegicapsSoft capsules are an alternative animal free capsule. The shell is made from seaweed extract and gluten free starch, and contains no modified sugars or artificial ingredients. The shell can be clear or coloured and there is a wide range of shapes, sizes and colours available.

An alternative to gelatin for those who prefer an animal free product Those with a level of concern about animalderived products Vegetarians Those with religious or cultural restrictions Consumers looking for the most natural alternative.

Benefits of VegicapsSoft capsules Free of all animal derivatives no pork or beef content. Easy to swallow Soft Natural Perception of a healthier product Plant based shell Low shell odour.

Thursday, April 19, 2012

Dept. of Pharmaceutics

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