Capsules are defined as the unit solid dosage form of medicaments available as small containers (shells) made up of gelatin enclosing with accurately measured drug substance.
The term capsule is derived from a Latin word Capsula meaning a small container.
Capsules occupy a significant position in the drug development. They are often believed as the primary oral dosage form because of their simple manufacturing process compared to other oral dosage forms. Gelatin has the property of disintegrating when it comes in contact with water, thereby releasing the medicament completely.
Instead of Gelatin, denatured gelatin, methyl cellulose, and polyvinyl alcohol can also be used to make the capsule shells.
Capsules are broadly divided into two types based on composition of gelatin:
- Hard gelatin capsules
- Soft gelatin capsules
Advantages of capsules
- The shells of the capsules are tasteless. Hence, drugs with unpleasant odor and taste can be enclosed in these capsules.
- These capsules are easy to swallow as they are smooth in nature.
- Capsules are economical.
- Improved and rapid bioavailability is provided by capsules.
- As capsules are readily soluble in gastric pH (due to gelatin), they release the medicaments when desired in the gastrointestinal tract.
- Capsules are easy to carry and handle.
- Capsules are therapeutically inert (not reacting with any other substance) since they are made up of gelatin.
- Tightly sealed capsule shells provide protection to the enclosed drug from harsh conditions of the environment.
- Capsules, especially hard gelatin capsules, are best suitable for enclosing coated beads which helps in sustained release action.
- The capsules contain materials with the negligible or minimal amount of excipients.
- Capsules are best suited for all types of medicaments since these are available in various sizes.
- Capsules are now considered popular dosage form due to their attractive appearance or elegance, ease of use, and portability.
- The desired quantity of medicament can be administered within the capsule shell, as they are meant for a single dose.
- Capsules can also contain a combination of drugs in a single capsule shell.
- Capsules are also considered as the ideal dosage form for modified release formulations.
- Cytotoxic or highly potent drugs can also be enclosed in a capsule.
- Improved patient compliance is seen due to the tasteless nature of gelatin.
- Capsules serve as a convenient medium for dispensing solid, semi-solid and liquid forms of drug substances.
- Rectal and vaginal capsules are used as substitutes for suppositories based on oleaginous or water-soluble bases.
- Drugs filled within the capsules are protected from oxygen due to proper sealing of the capsules.
Disadvantages of capsules
- Exact filling of capsules is not easy.
- The manufacturing process is costly.
- The pH of the contents of the soft gelatin capsules requires strict monitoring.
- Large sized shells or more than one shell is required to fill large quantities of single doses.
- Interactions or reactions may occur between the contents of the shell and fill materials.
- for example; Powders which are deliquescent or efflorescent in nature, cannot be filled or enclosed in capsules as they make the shell of the capsules moist.
- The drugs which are hygroscopic in nature absorb water from the capsule shell and make it brittle, thereby breaking the capsule shell into pieces. Therefore, capsules are not suitable for filling hygroscopic substances.
- Even liquid material such as water, glycerin or any solution of hydrocarbons cannot be filled in capsules, as they dissolve the shell of the capsules.
- Compounds which are volatile, organic, water-soluble or having low molecular weight, cannot be filled in capsules as they get evaporated from the capsule shell.
- Even the concentrated preparations cannot be enclosed in capsules as these preparations cause irritation in the stomach.
- Drugs which are highly acidic or alkaline in nature, cannot be filled in capsules. This is because acidic drugs lead to hydrolysis of gelatin, whereas alkaline drugs cause tanning effect which reduces the solubility of gelatin.
- Drugs which rapidly release salts such as potassium chloride (KCl), potassium bromide (KBr) and ammonium chloride (AlCl3) cannot be enclosed in capsules as they may cause irritation in the stomach.
- Capsules, when stored in low humid conditions, become brittle and tends to crack whereas when they are exposed to high humid conditions the gelatin gets softened and sticks. This is due to the fact that 10 – 15 % of water is present in capsules which accounts for its plasticizing property.
Advantages of capsules over tablets
The demand for capsules has been considerably increased over the past few years, which is largely because of the following advantages which capsules have over tablets
- Production advantage
- Formulation advantage
- Consumer advantage
- Trade-related advantages
- Capsules require a lesser number of instruments for manufacturing.
- The procedure for manufacturing is easier.
- They need to undergo a lesser number of quality control tests.
- The steps for manufacturing are lesser.
- Sine empty capsule shells are manufactured by a different manufacturer, manufacturing of medicated capsules or filling empty capsules with active pharmaceutical ingredient is a much simpler task in comparison to the manufacturing of tablets.
- Filling materials may be in the form of powders, pellets, liquids, semi-solids or small tablets. These ingredients may be filled alone or in combination of two or more ingredients.
- Filling materials include a very few numbers of additives.
- Hard gelatin shells decreases the problems of stability for storing sensitive drugs.
- Capsules are perfectly suitable for filling medicaments for delayed release.
- Capsule shells are considered as ideal containers for storing traditional medicines.
The number of end users or consumers of capsules is increasing day by day due to the appreciable qualities of capsules, which are as follows:
- The glossy or polished surface which helps in easy swallowing.
- Bitter and acrid taste fo the medicaments is masked by the shells.
- Distinct colors and shapes help in intensifying capsule identity.
- The efficiency of capsules helps the manufacturers to maintain their good position in the market.
- Radial or axial printing of the company name or any such identity helps in advertising the company.
Tablet manufacturing steps
Capsule manufacturing steps
Weighing of ingredients
Processing of ingredients
Blending of ingredients
Granulation of ingredients
Sieving of ingredients
Lubrication of ingredients
Comrpession of ingredients into tablets
Packaging of tablets
Weighing of ingredients
Processing of ingredients
Blending of ingredients
Filling of ingredients into the capsule shells
Packaging of capsules
Formulation of the capsule shell
The constituents used in the formulation of capsule shell are properly studied before selection. Their character, role and quality are taken into consideration as they have effect on the finished capsules. The constituents used in the formulation of hard and soft gelatin capsules are same. They only differ in the concentration of water and plasticizer.
The ingredients or constituents used in the formulation or manufacturing of capsule shells should be of good quality.
The constituents used in the formulation of capsule shells are restricted in many ways because;
- They affect the manufacturing process.
- They are costly.
- Their concentration which is required to achieve sufficient effect varies.
It has its own Physical, physiological and chemical properties which make it the best possible ingredient in the manufacturing of capsule shells. It has unique solubility characteristics in the stomach and contains 12 – 16% of moisture.
It is obtained by hydrolysis of collagen processed from bones, connective tissues and skin of animals. It is of two types i.e., type A and type B.
Pork skin ======Acid hydrolysis=====⇒Type A gelatin
Bones or animal skin ======Alkaline hydrolysis=====⇒ Type B gelatin
Capsule shells can be prepared by using either of the two types of gelatin, but the use of a mixture of both the types is in practice. Pork skin is responsible for plasticity while gelatin from bones is responsible for firmness of the gelatin capsules. The isoelectric point of type A gelatin lies around pH 9 while that of type B gelatin lies around pH 4.7.
They are used to impart softness, elasticity and thickness to the capsule shell. The accurate amount of plasticizer to be added depends upon the use and storage conditions of capsules. They are used as single or in a combination of two or three.
They are used to retard the growth of microorganisms. They are usually added to maintain the stability of the shell for a desired period of time.
They are used to make the capsule shells elegant and easily swallowable.
They are used to minimize the transparency of capsule shells.
Addition of colors gives a pleasant appearance to the shells. Single or a combination of two or more colors can be added when desired, provided that they should not impart color to the enclosed medicaments.
They are added to impart good flavour to the capsule shell. They also neutralize the undesirable odor of other ingredients.
They are used to impart sweet taste to chewable gelatin capsules and to mask the objectionable taste of other ingredients. They are used very rarely.
These are used to reduce the aldehydic tannings of gelatin.
These are added to adjust the viscosity of gelatin.
Water content varies in the capsule shells depending upon the storage conditions. Hard gelatin capsules contain 12 – 16% of water.
Properties of gelatin
According to USP, gelatin has special parameters like bloom strength, iron content, and viscosity which makes it the best possible ingredient for capsule shells.
It is defined as an assessment of the cohesive strength of the cross-linking taking place in between the molecules of gelatin. It is also known as gel strength or gel rigidity of gelatin and depends upon its molecular weight. The harder the gelatin, the higher is it’s bloom strength. It is directly proportional to the molecular weight.
Determination of Bloom strength:
A gelatin solution having a concentration of 6.66% w/v is kept for 17 hours at a temperature of 10ºC. A plastic plunger of 0.5 inches in diameter is taken. The weight in gm required to move the plastic plunger by 4mminto the stored gelatin solution determines the bloom strength of gelatin. Depending upon the requirements of capsule manufacturing, bloom strength lies in between 150 – 250 gm.
Physical stability of capsules is directly proportional to bloom strength of gelatin i.e., on increasing the bloom strength, the physical stability of capsules increases. Also, the cost of gelatin capsule shells largely depends upon the bloom strength. More the bloom strength, higher is the cost. Because of this reason, the capsules of higher bloom strength are rarely used or used only when capsules of high physical stability are needed, like in the preparation of larger sized capsules of capacity 50 minims. For preparing larger sized capsules, more structural strength is needed than for smaller ones.
The hardness of gelatin is determined by correlating the weight of dry plasticizer(dry glycerin) with the weight of dry gelatin present in the gelatin capsule shell. This is determined when it is supposed that the fill material does not execute any effect over the gelatin shell.
Depending upon the viscosity of gelatin in use, the ratio of the weight of water can fluctuate between 0.7 to 1.3 and the weight of dry gelatin can fluctuate between 0.7 to 1. However, for many formulations, their ratio is about 1:1. As only water evaporates when the capsule shell is processed for drying, the ratio of plasticizer to gelatin is kept constant although their quantity is increased.
It is defined as the assessment of chain length of gelatin molecules in 6.66%w/v concentrated solution in warm water at 60ºC.
It decides the manufacturing aspects of gelatin sheet. The quality of the required gelatin sheet depends upon the standard gelatin formulation. Accordingly, the manufacturing is carried out at an appropriate drying condition on a fixed sealing temperature. The gelatin sheets so produced are pharmaceutically elegant, hard non-viscous and are easy to cut. The required viscosity of gelatin lies in between 25 – 45 millipoise.
Iron is present in the raw gelatin as well as in the water used for manufacturing of gelatin capsule shells. Excess quantity of Iron in the soft gelatin capsule shells can affect the FD&C certified dyes and may also react with other organic compounds. Because of this reason, iron is not used in the concentration os more than 15 ppm in their manufacturing.
Manufacturing of gelatin sheets for storing hygroscopic drug substances need the following adjustments in their properties:
- Adjustment of viscosity between 25 – 32 millipoise.
- Adjustment of bloom strength between 180 – 250 mg.
- Adjustment of the amount of water (reduced to half) for satisfactory working of the capsulating machine and also to prevent the uptake of moisture from capsule shells.
These adjustments help in increasing the physical stability of the fill.
Other Information on hard gelatin capsules
- Hard gelatin capsules are also known as dry-filled capsules or two-piece capsules.
- A large number of capsules manufactured by pharmaceutical companies are hard gelatin capsules.
- Community pharmacists use these capsules in extemporaneous preparations or compounding of prescriptions.
- Hard gelatin capsules consist of two parts known as capsule body – the longer part and the capsule cap – the shorter part.
- The drug is placed or filled in the body and the cap is slided over it which encloses the drug.
- According to USP, gelatin contains 0.15% sulfur dioxide which prevents the decomposition of gelatin during manufacturing of capsule shells.
Sizes of hard gelatin capsule shell
The characteristics helpful in selecting the size of the capsule shells are:
- A thorough knowledge of the density and compressibility of both, therapeutically active as well as inactive agents.
- Comparison of properties of all the inactive agents.
- Practical knowledge of selecting capsule sizes.
Manufacturing of hard gelatin capsule shell
The major suppliers of hard gelatin capsule shells throughout the world include companies like Lilly, Parke – Davis and Scherer and Smith Kline. Several other companies supply smaller amounts of these shells while a few other companies manufacture for their own use.
The manufacturing equipment consists of pins or pegs made up of stainless steel to produce capsule shells of desired shapes and sizes. About 50 of these pins are attached to the plates which are movable. Both caps and bodies are prepared simultaneously.
The capsule shells are manufactured by fully automatic machine in the following steps:
- Joining of caps and bodies
Gelatin solution of required viscosity is taken in a reservoir. The plate holding the pins is lowered into the reservoir to the suitable depth for the required period of time. This helps in achieving proper length and thickness of shells. The pins are then spinned so that the gelatin solution is uniformly distributed over them,
The pins are then slowly raised from gelatin solution and are subjected to blow drying with air having controlled temperature and humidity. During this period, the gelatin sets or forms a gel over the pin.
The dried capsule shells are then stripped or removed off from the pins by using jaws made up of bronze.
The stripped capsule shells are then trimmed or shortened by stationary knives to the required length.
The trimmed caps and bodies are joined and released from the machine.
Important aspects related to manufacturing of capsule shells
The width of walls of capsule shells is to be strictly controlled for accurate fitting of caps over bodies. This can be achieved by controlling the following parameters:
- Viscosity of gelatin solution
- Time duration of dipping
- Speed of spinning pins
The pins used for making capsule bodies have diameter smaller than those used for making caps. This helps in perfect compressing of caps over the bodies. Hence, in the manufacturing of capsule shells, all the above 5 steps are carried out one after the other with extreme care.
The following techniques are adopted by various manufacturers to make different kinds of capsule shells:
- Altering the round shape of both the capsule body and cap making pins.
- Tapering the ends of both the capsule body and cap making pins
- Addition of different coloring agents to make different colored and attractive looking capsules.
- Addition of opacifying agents to produce opaque capsules.
- Imprinting markings like the company name, symbols or codes in numbers on the outer surface of capsule shells
- Remodeling the gelatin capsule shells into coni-snap, snap-fit or coni-snap supro hard types. This enables the caps and bodies to join positively by sealing the grooves of the shell bodies into the walls of the shell caps. Hence, in this way the two grooves fit into each other and confirms well closing of the filled capsules.
Important features of the coni-snap capsule shells
- The tapered rim of the base helps to prevent the telescoping (shrinking) of capsules.
- The grooves help to lock the caps with the bodies.
- Indent helps to avoid untimely opening of caps and bodies
Formulation of the fill material of hard gelatin capsule
Hard gelatin capsule shells are filled with therapeutic agent and additives.
Requirement of additives
- To make the process of preparation or filling of capsules easy.
- To maintain the stability of the drug.
- To prevent microbial degradation of the capsules
Ideal properties of additives
- They should not alter the therapeutic activity of the drug.
- They should not react with other additives or with capsule shells.
- They should be of good quality and free from impurities.
- They should be stable throughout the shelf life of the drug.
- Diluents are also known as fillers.
- These are used when the bulk of the drug is too small to handle by the machineries of the manufacturing unit.
- Also, in the case of highly potent drugs, diluents help in measuring the accurate dose of the drug.
- Diluents also provide cohesion to the powdered drug, which is helpful while transferring the blend of the drug into empty capsules.
- The amount of diluents to be added depends upon the quantity of the bulk, amount or dose of the drug, potency of the drug and the capacity of the capsule shell.
- Diluents with coarse and medium-sized particle size are regarded as well suitable additives for capsules.
- They also play an important role in the disintegration of capsules.
Diluents can be broadly classified into two types:
- Example: lactose, mannitol, microcrystalline cellulose (MCC), starch, sorbitol etc
- Example: calcium carbonate, calcium phosphate, magnesium carbonate etc.
- They promote breaking up of capsule contents in stomach resulting in faster therapeutic effect.
- Sodium starch glycolate, crospovidone, croscarmellose sodium and pregelatinized starch are examples of some superdisintegrants which are used in capsules.
- These are also known as lubricants.
- Glidants help in increasing the flow property of the powdered blend in either one or more of the following ways:
- Prevention of moisture
- Reduction of coarseness by stuffing the surface irregularities.
- Reduction of attractive forces between the particles of the formulation by separating the particles from each other.
- Imparting of easy movement to the formulation particles.
- Alteration of surface charges.
- Examples of Glidants: calcium stearate, corn starch, colloidal silica, magnesium stearate, stearic acid and talc.
- The powdered drug having good flow property needs no addition of Glidants but those powders lacking this property need the addition of the suitable amount of Glidants.
- These agents minimize the waterproofing properties of certain water-insoluble agents filled in capsules. Hence, after the dissolution of the capsule shell in the stomach (GI fluid), these agents displace the air surrounding the drug within the GI fluid. Hence helps in penetration of GI fluids into the drug, thereby enhancing the dissolution and absorption of the drug.
- Surfactants used in capsule formulation are classified as:
- Hydrophilic surfactants
- Example: sodium docusate, sodium lauryl sulfate, N-lauryl sulfate, sodium stearoyl 2 lactylate, sodium stearate, polox-cuner 188, cetyl pyridinium chloride
- Lipophilic surfactants
- Example: glyceryl monostearate
- Hydrophilic surfactants
- These agents are added to retard moisture absorption by hygroscopic agents and also for physical separation of incompatible or eutectic agents.
- Inert substances are used as protective sorbents.
- Example: magnesium oxide, magnesium carbonate, calcium oxide and calcium carbonate.
- Dust is considered to be the major problem in the large-scale operation of capsule filling technique.
- If dust comes in contact with the potent drugs or inhaled by the operators, it may lead to severe health problems.
- The ratio of anti-dusting agents to the drugs has to be strictly monitored as its excess quantities may lead to the cohesion of drug particles.
- The commonly used anti-dusting agents are edible oils.
- Lubricants are added because:
- They facilitate the ejection of plugs from dosator and dosing-disc type machines.
- They prevent the adhesion of powders over pistons and metal surfaces.
- They reduce the friction between the sliding surfaces and the powder plug.
- Example: Calcium stearate, Magnesium Stearate, and Stearic acid are some examples of hydrophobic lubricants.
- Polyethylene glycols, Sodium stearyl fumarate, and hydrogenated vegetable oils are some examples of less hydrophobic lubricants.
Preparation of formulation
Hard gelatin capsules are commonly filled with dry substances. But when needed, suitable liquids can also be filled.
The various forms of drug substances filled in capsule shells are as follows:
- Dry formulation
- In dry formulation, therapeutically active ingredients are thoroughly mixed with suitable additives. The uniform mixture so obtained is filled into the capsule shells. Powders, Pellets, small capsules or tablets are filled using this technique.
- Wet formulation
- Fixed oils or volatile oils which do not permeate through gelatin, are filled into capsule shells.
The drug substances which are eutectic in nature or possess the property of liquefying in presence of other ingredients, are mixed with adsorbents or diluents like kaolin, magnesium carbonate or light magnesium oxide. These agents help to separate the interacting drug substances and absorb the liquids produced.