Hard Gelatin Capsules

Introduction

The word capsule is derived from the Latin word”capsula” meaning a small box.
In pharmacy, the word is used to describe an edible package made from gelatin or other suitable material which is filled with medicines. To produce a unit dosage, mainly for oral use. There are two types of
capsule, ‘hard’ and ‘soft’.

Raw Material

The raw materials used in the manufacture of both types of capsule are similar. Both contain gelatin, Water, colourants and optional materials such as Process aids and preservatives. Soft capsules contain
various plasticizers.

1. Gelatin

Gelatin is the major component of the capsule. The reason for this is that gelatin possesses five basic properties:

It is non-toxic, widely used in foodstuffs, and acceptable for use worldwide.
It is readily soluble in biological fluids at body temperature.
It is a good film-forming material, producing a strong flexible film. The wall thickness of a hard gelatin capsule is about 100 jam.
Solutions of high concentration, 40% w/v, are mobile at 50°C. Other biological polymers, such as agar, are not
A solution in water or in a water-plasticizer blend undergoes a reversible change from a sol to a
gel at temperatures only a few degrees above ambient.

Gelatin is a substance of natural origin but does not occur in nature. The raw materials used in formation of gelatin are animal skins and bones, and it is prepared by hydrolysis of collagen, which is the protein main constituent of connective tissues.

Types of Gelatin

There are two types of gelatin:

Type A and
Type B.

Type A gelatin is produced by acid hydrolysis. This process takes about 7-10 days and is used mainly for animal skins, because they require less pretreatment.
Type B gelatin is produced by basic hydrolysis, and takes about 10 times as long as acid hydrolysis process. It is used mainly for bovine bones. The bones must first be decalcified by washing in acid, which gives a sponge-like material called ossein, and calcium phosphates as a by-product. The ossein is soaked for several weeks in lime pits.
The following process then takes place:

After hydrolysis of the material, the gelatin is extracted from the treated material using hot water, the first extract having the gelatin with the highest physical properties. As temperature is raised, the quality of gelatin produced falls. The resulting weak solution is then concentrated via
evaporators and then chilled to form a gel.
The gel is extruded to form strands, which are then dried in a fluidized-bed system. The dried material is then blended according to different specifications required.

The properties that are important most to capsule manufacturers are

Bloom strength and
The viscosity.

Bloom Strength
This is a measure of gel rigidity, and can be defined as the load in grams required to push a standard plunger 4mm into the gel. It is determined by preparing a standard gel (6.66%w/v) and maturing it at 10°C. The gelatin used for hard capsules has a higher bloom strength (200-250g) than that used for soft capsules (150g) and this is because a more rigid film is needed for hard gelatin capsule manufacturing.
Viscosity
With viscosity, thickness of resulting shell wall can be determined – the higher the viscosity, the thicker the shell wall.
Due to the outbreak of BSE, which started in the UK, strict rules were introduced by the EU to minimize the risk of transmitting animal spongiform encephalopathy agents (TSEs). All parts of bovine animals are rated for infectivity and high risk parts (e.g. brain and spinal cord) are removed before any
processing. The EU rules specify that all animals used must come from BSE free herds, and subjected to pre- and post-mortem veterinary inspection, and be processed by defined manufacturing processes by quality assured companies.

2. Colorants

The colorants used are either water soluble or insoluble pigments, formulated as solutions or suspensions. The dyes used are mostly of synthetic origin and can be divided into azo dyes and non-azo dyes. Azo dyes have an –N=N- linkage and are not widely used. Non-azo dyes, however, are varied in their chemical classes and are commonly used – the three most widely used are erythrosine (E127), indigo
carmine (E132) and quinolone yellow (E104).
Two types of pigments used in manufacturing are:

iron oxides (71) – black red and yellow and
titanium dioxide (E171) which is white and used to make the capsule opaque.

The colorants to be used are governed by legislation, which is based on toxological testing but varies from country to country.
In the present times, pigments are preferred over soluble dyes, especially iron oxides, due to not being absorbed on ingestion.

3. Process Aids

Wetting agents used in hard gelatin capsule manufacture includes the use of gelatin containing not more than 0.15%w/w of sodium lauryl sulphate as described by the USNF. This ensures uniform coverage
of the lubricated moulds when dipped into the gelatin solution.
Preservatives were formerly added in-process during hard gelatin capsule manufacture to prevent microbial contamination. However according to GMP guidelines, they are no longer to be used. In
finished capsules, moisture levels (13.0-16.0%w/v) are such that microbial growth is not supported, because the moisture is strongly bonded with the gelatin molecule.

Manufacturing Process of Hard Gelatin Capsules

The process in use today was described in the original patent of 1846 (Jones 2000), the only difference being that today, the operation is fully automated, carried out as a continuous process on large machines housed in air-conditioned buildings. Two companies which pioneered work in this field, are Shionogi Qualicaps – formerly Eli Lily & Co, (1897), and Warner Lambert’s Capsugel – formerly Parke Davis, (1902). The raw materials are first prepared. A concentrated solution of gelatin is prepared using demineralized hot water (60-70°C) in jacketed pressure levels. This is stirred until the gelatin is dissolved and a vacuum applied to remove any bubbles. The solution is then dispensed into suitable containers and required dye solutions and pigment suspensions added. Viscosity is measured and adjusted to a target value by adding hot water. The prepared mixes are then transferred into a heated holding hopper on the manufacturing machine, where the manufacturing process takes place.
The manufacturing machines are approximately 10m long, 2m wide and 3m high. They consist of two parts, one on which the capsule cap is made, and the other, the capsule body. The machine is also divided into a higher and lower level. The moulds, called ‘pins’, are approximately 40,000 per machine.
The machines are normally operated on a 24-hr basis 7 days a week, stopping only for maintenance. The output per day is about 1 million capsules, depending on the size – the bigger the capsule, the lower the output. The “prelocked’ capsules (not fully closed) then pass through a series of sorting and checking process, (manual, mechanical or electronic), quality levels checked and, if required, printing can be done at this stage.
The capsules are then packed for shipment in moisture-proof liners, sealed for storage.

Empty Capsule Properties

Empty capsules contain a significant and essential amount of water that acts as a plasticizer for the gelatin. The standard moisture content is specified to be between 13.0 – 16.0%w/w. This value may
vary depending on the conditions to which they are exposed. Capsules are readily soluble in water at 37°C, and when temperature falls below this, rate of solubility decreases. This is an important factor to take into account during disintegration and dissolution testing.

Capsule Filling

Capsule sizes

Hard gelatin capsules are made in a range of fixed Sizes; the standard industrial sizes in use today for Human medicines are from 0 to 4 . For a powder, the simplest way in which to estimate the fill weight is
to multiply the body volume by its tapped bulk density For liquids, the Fill weight is calculated by multiplying the specific gravity of the liquid by the capsule body volume x 0.8.

Capsule shell filling

Hard gelatin capsules can be filled with a large variety of materials of different physicochemical properties. Gelatin is a relatively inert material. The substances to be avoided are those which are known
to react with it,e.g. formaldehyde, which causes a cross linking reaction that makes the capsule insoluble, or those that interfere with the integrity of the shell, e.g. substances containing free water, which can be absorbed by the gelatin causing it to soften and distort.

Limitations in properties of materials for filling into capsules

Must not react with gelatin
Must not contain a high level of moisture
The volume of the unit dose must not exceed the size of capsules available.

Types of Materials for Filling into Hard Gelatin Capsules

Dry solids.

Powders
Pellets
Granules
Tablets

Semisolids.

Thermosoftening mixtures
Thixotropic mixtures
Pastes

Liquids.

Non-aqueous liquids

Capsule Filling Machine

The same set of basic operations is carried out whether capsules are being filled on the bench for extemporaneous dispensing or on high-speed automatic machines for industrial products. The major difference between the many methods available is the way in which the dose of material is measured into the capsule body.

Filling of Powder Formulation

There are three main ways powder formulations are filled:

Bench scale filling
Industrial scale filling
Instrumented capsule-filling machines and simulators

1. Bench-Scale Filling

There is a requirement for filling small quantities of Capsules, from 50 to 10 000, in community pharmacy, in hospital pharmacy, or in industry for special Prescriptions or trials. There are several simple pieces of equipment available for doing this, e.g. the ‘Feton’ from Belgium or the ‘Labocaps’ from Denmark. These consist of sets of plastic plates which have Predrilled holes to take from 30 to 100 capsules of a specific size.

2. Industrial-Scale Filling

The machines for the industrial-scale filling of hard gelatin capsules come in great variety of shapes and Sizes, varying from semi- to fully automatic and Ranging in output from 5000 to 15 000 per hour.
Automatic machines can be either continuous in motion, like a rotary tablet press, or intermittent, Where the machine stops to perform a function and then indexes round to the next position to repeat the Operation on a further set of capsules.
The dosing systems can be divided into two Groups:
a. Dependent: dosing systems that use the capsule body directly to measure the powder. Uniformity Of fill weight can only be achieved if the capsule is filled completely.
b. Independent: dosing systems where the powder is measured independently of the body in a special measuring device. Weight uniformity is not dependent on filling the body completely. With this system the capsule can be partfilled.
There are two types of plug-forming machine:

Those that use a dosator system.
Those that use a tamping finger and dosing disc system.

Dosators :
This consists of a dosing tube inside which there is a movable spring-loaded piston, thus forming a variable-volume chamber in the bottom of the cylinder. The tube is lowered open end first into a bed of
powder, which enters the tube to fill the chamber and form a plug. This can be further consolidated by applying a compression force with the piston. The assembly is then raised from the powder bed and positioned over the capsule body. The piston is lowered, ejecting the Powder plug into the capsule body.
The weight of powder filled can be adjusted by altering the position of the piston inside the tube, i.e. increasing or decreasing the volume, and by changing the depth of the powder bed. Examples of machines that use this System are:
Intermittent motion: Zanasi (IMA), Pedini,Macophar and Bonapace. Their outputs range from 5000 to 60 000 per hour.
Continuous motion: MG2, Matic (IMA).TheirOutputs range from 30 000 to 150 000 per hour.
TAMPING FINGER AND DOSING DISC:
The dosing disc Forms the bottom of a revolving powder Hopper. This disc has in it a series of sets of accurately drilled holes in which powder plugs are formed by several sets of tamping fingers – stainless steel rods that are lowered into them through the bed of powder. At each position the fingers
push material into the holes, building up a plug before they index on to the next position. At the last position the finger pushes the plug through the disc into a capsule body. The powder fill weight can be
varied by the amount of insertion of the fingers into the disc, by changing the thickness of the dosing disc and by adjusting the amount of powder in the hopper. The machines that use this system are all intermittent in motion. Examples are the Hofliger and Karg
PELLET FILLING
Preparations formulated to give modified-release Patterns are often produced as granules or coated Pellets. They are filled on an industrial scale using Machines adapted from powder use. All have a dosing system based on a chamber with a volume that can easily be changed. Pellets are not compressed in the process and may have to be held inside the measuring devices by mechanical means, e.g. either by
inverting the dosator or by applying suction to the dosing tube. In calculating the weight of particles that can be filled into a capsule it is Necessary to make an allowance for their size.
TABLET FILLING
Tablets are placed in hoppers and allowed to fall down tubes, at the bottom of which is a gate device that will allow a set number of tablets to pass. These fall by gravity into the capsule bodies as they pass underneath the hopper. Most machines have a mechanical probe that is inserted into the capsule to check that the correct number of tablets has been transferred. Tablets for capsule filling are normally film coated to prevent dust, and are sized so that they can fall freely into the capsule body.
SEMISOLIDS AND LIQUID FILLING
Liquids can easily be dosed into capsules using Volumetric pumps (Jones 2001). The problem after Filling is to stop leakage from the closed capsule. This can be done in one of two ways, either by formulations or by sealing of the capsule.
Semisolid mixtures are formulations that are solid at ambient temperatures and can be liquefied for filling by either heating thermosoftening mixtures, or by stirring Thixotropic Mixtures. After filling they cool and solidify, or revert to their resting state in the capsule to form a solid Plug. Both types of formulations are filled as liquids using volumetric pumps. These formulation are similar to those that are filled into soft gelatin capsules, but differ in one important respect: they can have melting points higher than 35°C, which is the maximum for soft gelatin capsules because this is the temperature used by the sealing rollers during their manufacture.
Non-aqueous liquids, which are mobile at ambient temperatures, require the capsules to be sealed after filling. The industrially accepted method for this is to seal the cap and body together by applying a
gelatin solution around the Centre of the capsule after it has been filled.

Formulation

All formulations for filling into capsules have to meet the same basic requirements:

They must be capable of being filled uniformly to give a stable product.
They must release their active contents in a form that is available for absorption by the patient.
They must comply with the requirements of the Pharmacopoeias and regulatory authorities, e.g. Dissolution tests.

POWDER FORMULATION

The majority of products for filling into capsules are formulated as powders. These are typically mixtures of the active ingredient together with a combination of different types of excipients. The ones selected depend upon several factors:

The properties of the active drug
Its dose, solubility, particle size and shape
The size of capsule to be used.

Types of Excipient Used in Powder-Filled Capsules

Diluents: This gives plug-forming properties
Lubricants: This reduces powder to metal adhesion
Glidants: This improves powder flow
Wetting agents: This improves water penetration
Disintegrants: This produces disruption of the powderMass
Stabilizers: This improves product stability

Formulation for Filling Properties

There are three main factors in powder formulation:

Good flow, (using free-flowing diluent and Glidant)
No adhesion (using lubricant)
Cohesion (plug-forming diluent).

The factor that contributes most to the uniform filling of capsules is good powder flow. This is because the powder bed, from which the dose is measured, needs to be homogeneous and packed reproducibly in
order to achieve uniform fill weights. Low-dose actives can be made to flow well by mixing them with free-flowing diluent, e.g. lactose. The diluent is chosen also for its plug forming properties: the most frequently used ones are lactose, maize starch and microcrystalline cellulose. When space is limited then either glidants, which are materials that reduce interparticulate friction, such as colloidal anhydrous silica,
or lubricants, which are materials that reduce powder to metal Adhesion, e.g. magnesium stearate, are added, enabling the dosing devices to function efficiently.

Formulation for Release of Active Ingredients

The first stage in active ingredient release is disintegration of the capsule shell. When capsules are placed in a suitable liquid at body temperature, (37°C) the gelatin starts to dissolve and within 1 minute the shell
will split, usually at the ends. With A properly formulated product the contents will start to empty out before all the gelatin has dissolved.
The rate-controlling step in capsule disintegration and product release is the formulation of the contents, which ideally should be Hydrophilic and dispersible. The factors that can be modified to make the active Ingredients readily available depend upon their Properties and those of any excipients being used. The active ingredients have a fixed set of physicochemical properties which, except for the particleSize, are out of the control of the formulator.
The diluent used should be chosen in relationship to the solubility of the active. If a soluble diluent such as lactose is added to a poorly or insoluble compound it will make the powder mass more hydrophilic, enabling it To break up more readily on capsule shell disintegration. Actives that are readily
Soluble are best mixed with insoluble diluents such As starch or microcrystalline cellulose, because they help the powder mass to break up without interfering with their solubility in the medium. Some
excipients, such as lubricants and glidants are added to formulations to improve their filling properties, and these can sometimes have an effect on release. The important thing to avoid in formulations are materials that tend to make the mass more hydrophobic.
The most commonly used lubricant for both encapsulation and tabletting is Magnesium Stearate.

Formulation Optimization

The formulator has to produce a product that complies with the three formulation goals. This can be done by using various statistical tools based on analysis of variance, experiments that can identify the
contribution of each excipient and process operation to the product performance, e.g. uniformity of fill weight and Content, dissolution rate, disintegration, yield etc.
The main factors in powder formulations release are:

Active ingredient, optimum particle size
Hydrophilic mass, relating solubility of active to excipients
Dissolution aids, wetting agent, superdisintegrant
Optimum formulation for filling and release.

Formulation for Position of Release

Many products are formulated to release their contents in the stomach. Capsule formulation can be readily manipulated to release their contents at various positions along the gastrointestinal tract. A common
problem with oral dosage forms is making them easy to swallow. In the stomach the release of the active ingredient can be modified in a number of ways. It has been suggested that for some compounds the best way to Improve their absorption is for the dosage form to be retained in the stomach so that it will dissolve slowly, Releasing a continuous flow of solution into the intestines.