SOFT GELATIN CAPSULES:

A soft gel capsule is a one piece, hermetically sealed soft gelatin shell containing a liquid, a suspension or a semisolid; referred to as a fill. The soft gel shell is usually comprised of a film-forming material such as gelatin, and a water-dispersible or water-soluble plasticizer (to impart flexibility). The soft gel shell could also include minor additives such as coloring agents, flavors, sweeteners, opacifying agent, medicaments, acid and preservatives. Soft gel capsules can also be enteric coated for certain applications.

Soft gelatin capsules or also known as soft gels are becoming a popular dosage form for the administration of liquids, suspensions, pastes, and dry powders in the dietary supplement industry. Softgels can be an effective delivery system for oral drugs, especially poorly soluble drugs. This is because the fill can contain liquid ingredients that help increase solubility or permeability of the drug across the membranes in the body. Liquid ingredients are difficult to include in any other solid dosage form such as a tablet.

Here are the complete review of advantage and disadvantage of soft gelatin capsule

The advantages of soft gelatin capsule : Soft gels are easy to swallow, once swallowed, release their contents very

quickly. have the ability to mask odors and unpleasant tastes have an elegant appearance readily dissolve in the gastric juices of the digestive tract they may enhance the bioavailability of the active ingredient In specialized dosage form, soft gel can be made into chewable, extended

release, captabs, etc. It can also be used for ophthalmic preparations, e.g. aplicaps, vaginal/rectal suppositories.

Dosage Accuracy. Uniformity and precision dosage Product Security. Dosage and formulation are tamper-resistant (a punctured or

tampered softgels will leak or become discoloured). Protection against counterfeit

Product Stability. Sealed container, Protection from light for photosensitive formulations, Protects drug from oxidation and degradation

Soft gel also had some disadvantages point : water soluble material are difficult to incorporate Highly moisture sensitive. Gelatin is extremely water soluble, which helps it

dissolve in the body. The downside is that soft gelatin capsules are very sensitive to heat and humidity. In hot or humid climates, soft gel caps may stick together or even break open before you have a chance to use them. Keeping your soft capsules in the bathroom may also decrease their life expectancy, since showers create a hot, humid climate that may not dissipate quickly.

Efflorescent material can not be incorporated, they may cause softening/leaching Deliquescent materials cannot be incorporated. They may cause hardening or

brittle capsule.

More Costly. Many pharmaceutical companies do not have the equipment necessary to fill soft gelatin capsules and have to transport the drugs to have them processed, adding to the cost. This cost can increase the price the consumer pays. Certain health supplements, such as cod liver oil, come in liquid and soft gel cap form. In most cases, the price is greater for the soft capsules than for the liquid.

Dietary Restrictions. Gelatin is traditionally made out of the bones and skins of pigs and cows. Many groups, however, have dietary proscriptions that prevent them from consuming animal products found in soft gelatin capsules. Soft gel caps violate the religious dietary restrictions of observant Jews, Muslims, Buddhists and Hindus. Because soft capsules are made out of animal parts, many vegetarians also opt not to use them. There are animal-free substitute gelatin capsules made out of seaweed extract or other sources, but they are generally more expensive and harder to find.

EQUIPMENT AND FACILITIES

A company would have a minimum of 24,000-square feet of space to house the soft gel manufacturing operation. This would be efficient for a one- or two-encapsulation machine operation.

Equipment needs to produce soft gelatin capsule include: 1. stainless-steel mixing tanks2. a cold-milling operation. Used for particle reducing, and evacuation for the removal of air in multivitamin products3. ingredient-fill holding tanks, about three tanks

4. stainless-steel gelatin heating tanks, about four tanks approximately 600 to 800 kilos each5. Kathabar system for drying dehumidification6. trays for spreading the soft gels7. inspection tables8. standard polishing pan or a converted Pelligrini machine for the removal of the mineral oil residue that remains on the sof tgel9. a sizing unit for the removal of any slugs and gel particles and for the removal of any over- and under-fills prior to packaging.

Once the equipment is purchased for a one-machine operation, the manufacturer can then very easily convert to a two- or three-machine operation. Following this, the only purchases other than the machinery would be the gelatin itself.

The typical output of an eight- to nine-inch encapsulation machine is approximately 87,600 soft gels per hour. Most manufacturers run the machines an average of 21 to 22 hours daily for such products such as vitamin E and fish oils.

Downtime includes changing gelatin and changing fill materials. If a company is running machinery under strict cGMP guidelines to produce OTC products, the

machinery needs to be shut down for taking full sets of weights and verifying adjustments of ribbons for correct thickness.

MANUFACTURING PROCESS

Manufacturing process of soft gelatin process divided into some steps, there are:1. Gelatin Preparation2. Material (Fill) Preparation3. Encapsulation4. Drying5. Inspection6. Polishing7. Packaging

Gelatin Preparation

Raw granular gelatin is mixed with glycerine and water. Coloring agent can also be added at this stage. Glycerine acts as a plasticizer in the gelatine compound. Other plasticizers can also be used either alone or in combination with glycerine, such as sorbitol. The proportions of each ingredient involved in the mixture should be considered carefully because the shell material needs to be adapted to formulation and/or environmental requirements. For instance the gelatin recipe may need to be adjusted to account for acidity, water content of the fill material or high humidity environmental conditions.

 Gelatin Melting Tank

After the ingredients are combined, the mixture is placed into a reactor called as gelatin melter. The reactor surrounded by a thermal jacket heats the mixture while a very high torque tribune mixer stirs it under vacuum. At this stage, approximately 20% of gelatin mixture consists of water.

 Heated Tank

This process takes around 3 hours until the gelatin turns into a molten liquid mass. As soon as the liquid gelatin mass is ready for encapsulation process, it is transferred to ground heated tanks which are wheeled into the clean room where the main encapsulation machine is. It is really important to keep the liquid gelatin warm before or during the encapsulation process. Because the only way to keep the gelatin mixture as liquid is to keep it warm otherwise it will solidify like jelly. It is really important to plan and schedule the gelatin production in terms of time and quantity. At least, it requires 2 shift operational time.

Material (Fill) Preparation 

A homogeneous fill material plays a vital role to ensure the uniformity of each Softgel dose. Various equipment should be available, such as processing tanks, high-shear mixer, homogenizer and variety of mills is use.

There are two types of fill materials: oil mixtures or pastes.

Oil mixtures are very easy to formulate. The oils are mixed, deposited into a ground material tank and moved into the hopper of the encapsulation machine (i.e., vitamin E, fish oils).

Pastes are oils or polyethylene glycols added with powders. Two important factors that affect the homogeneity and flow of the paste should be considered:1. particular size of powder. In order to allow homogeneous mixture, powder particles must not be thicker than 80 mesh.2. viscosity of the mixture. If the mixture is not thin enough, it will not flow correctly through the machine injections.

Natural or artificial flavours, sweeteners and fragrances are commonly used to make chewable softgels or to mask the unpleasant taste and odor of the fill material such as fish oils. These can go into fill or gelatin material.

Encapsulation 

Encapsulation is the manufacturing process that brings the gelatin shell and the fill material together to form Softgel capsules. It takes place in a closed environment called clean room where the relative humidity is around 20%. The gelatin shell and fill material are brought together simultaneously in the encapsulation machine.

The process is basically performed as described; a pump delivers the warm gelatin over two chilled drums which are located at both opposite sides of the machine, through a spreader box that sits over each drum. The revolving stainless steel drum is about 24” in diameter and exposed to 400 CFM of 57-59°F air at 20% RH. The warm liquid gelatin flows over the drums and this transforms the liquid gelatin into two solid ribbons of gel. The left and right ribbons pass over rollers which feed them through two die rolls. These die rolls determine the shape and size of softgels and cut the Softgel shell from the ribbons as they turn around.

Simultaneously, a sensitive and high accuracy positive displacement pump delivers the fill material into a heated wedge which sits between rotary dies. This wedge injects the fill material into the die cavities between ribbons just right before the die rolls cut the ribbons and seal the two halves together. The cool, dry air congeals the gelatin as the drum rotates so that a tacky, elastic band rolls off of the other end. This thin band is then automatically formed into capsules; filled with medicine, vitamins or other products; sealed; and dropped into a tray.

If the air blowing against the drum has too low a temperature, the gelatin will set too rapidly and become brittle which can cause the manufacturing process to grind to a halt. Too high of an air velocity will disturb the consistent thickness of the gelatin ribbon being formed. If the air temperature and humidity are too high, or the air velocity is too low, the gelatin will not solidify into a ribbon.

Thus, the need for constant control of the air being introduced to the drum is critical in the process. From the capsulating machines, the soft, moist capsules are transferred to drying drums or chambers for rapid drying. The extent of moisture to be removed

during drying depends upon the size of the capsule, the number of capsules, and the period of time over which this moisture can be removed.

Drying

Drying process purpose is to decrease the moister content to create a hard and durable finished softgel capsules ready for packaging. After the softgels are formed through the die rolls, they contain around 20 percent water. This amount of water content is needed to keep the gel flexible enough to form the capsules.

Drying process requires an environment with low relative humidity in the air but not hot air. This process divided into two stages :

Fluid Bed Tumble Drier for Softgel

1. First stage : performed by a tumble dryer consists of sections. This equipment tumbles the softgels around 30 to 40 minutes and removes approximately 25 percent of the water content in the softgel capsules.

2. Second stage : softgel capsules are spread on stackable trays and transferred to the drying room or tunnel where high air flow exists and they stay around 24 to 48 hours or until the softgels become hard enough. This process is called natural manual drying. By using a fully automatic Softgel drying machine, this long drying process time can be reduced to a few hours which enables you to save time and money.

 Soft Gelatin Capsule Drying Machine

Typically the environment to be maintained for effective and rapid drying corresponds to a dew point of 25° F or an absolute humidity level of 20 grains per pound of air. The following are typical design conditions: Temperature Humidity 78°F 15% RH 68°F 20% RH In order to achieve the controlled air requirement listed above, refrigeration equipment alone becomes uneconomical, impractical and cumbersome to design, operate and maintain. On the other hand desiccant type dehumidifiers combined with refrigeration can offer a simple and economical solution to controlling both temperature and humidity levels as low as necessary Bry-Air desiccant dehumidifiers have been utilized in many capsulating and soft gel manufacturing applications all over the world resulting in millions of dollars saved annually.

Inspection, In Process Control and Finished Product Testing

Due to air pockets in the gelatin and fill material and district production tolerances, the Softgel capsules may vary in size and need to be inspected visually. Any misshaped, damaged and/or not fully filled capsules are removed manually by using an inspection table. Manual inspection process can be preferred if you have small batch size production but if you intend to manufacture softgel capsules in mass quantities. Manual inspection will be time consuming process which leads to accuracy problems. In order to reduce process time and increase the accuracy, fully automatic softgel sorting machine equipped with electronic sensors can be used to sort and remove the damaged, misshaped, broken etc. gelatin capsules. Two to three percent is an acceptable reject rate.

In-process testing

During the encapsulation process the four most important test 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: Capsule appearance Active ingredient assay & related substances assay Fill weight Content uniformity Microbiological testing/

Polishing

The final step before packaging is to clean and polish the Softgel capsules to remove any mineral oil or glycerine that the capsules may have on their exterior skin. Tumbling is the most used production method to clean the Softgel capsules among others such as washing with solvent.

Packaging

There is no difference between packaging softgels and traditional tablets or hard capsules. Any finished Softgel product should be stored in an environment with temperature around 20-24 oC and relative humidity 35%.

FORMULATION OF CAPSULE FILL

The formulation of capsule fill can be developed to fulfill the specifications and end-use requirements of the product.

Capsule content: May be liquid or a combination of miscible liquids Solution of a solid in a liquid or a suspension of a solid in a liquid 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,

eters, or alcohols. Solid that are not Sufficiently soluble in liquids or in combination of liquids are

capsulated as suspension Suspending agents used are Lecithin, Soybean oil, Yellow wax.

Capsulation of liquids that are immiscible with water and non-volatile, such as vegetable oils and vitamin E, are easy and require little or no formulation. However, solids that are not sufficiently soluble in liquids are capsulated as suspensions. Such materials should have a particle size of 80 mesh or finer.

Capsulation of suspensions is the most common form for a large group of dietary products. Suspension formulation requires a suspending agent to prevent the settling of the solids and to maintain homogeneity throughout capsulation. The most widely used suspending agent for oil-based formulation is wax (e.g beeswax), and polyethylene glycols in a non-oil-base.

Powdered extracts are usually combined with soybean oil (as a carrier), yellow beeswax (as a suspension and thickening agent), and lecithin (as a lubricant) for formulation in soft gels. The relative amounts of the extract and the other ingredients depend upon the desired extract dose to be administered.

Some Limitations in Formulating Soft Gelatin Capsule

Filling of soft gel capsules with liquid and semi-solid materials is possible if the "fillings" selected do not dissolve the gelatin. Thus aqueous solutions would not be appropriate. But, substances in which gelatin is not soluble are suitable.

The following types of compounds may not be suitable candidates for soft gel encapsulation:

liquids that can easily migrate through the gelatin shell, such as water (more than 5 percent of the fill), and hygroscopic and volatile compounds

aldehydes, which have the ability to harden the shell and hence affect its dissolution property

acidic or alkaline solutions should be avoided, unless they are pictures on a blackboard. adjusted to become neutral; acids and alkalis can cause hydrolysis and leakage of the gelatin shell

water-soluble solid compounds that may affect the gelatin shell unless they are minor constituents of a formula or combined with a carrier that reduces their effect on the shell.

FORMULATION OF CAPSULE SHELL

Capsule shell composition: Water : 45% w/w. The ratio by weight of water to dry gelatin can vary

depending from 0.7-1.3 (water) to 1.0 (dry gelatin) depending on the viscosity of the gelatin being used.

Plasticizer. Used to make the soft gel shell elastic & pliable. Ration used is between 0.3- 1.8 for soft to hard shell on dry basis. Plasticizer usually used : Glycerin and sorbitol.

Coloring Agent. Colour used in shell has to be darker than color of encapsulating material. Color may be natural or synthetic.

Opacifier. Usually used is 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. Concentration of oacifier 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 colors.

Gelatin

Soft Capsule’s Gelatin

Gelatin is derived mostly from collagen by thermal denaturing with the aid of diluted acid or alkali. Gelatin contains a mixture of water-soluble proteins (84-90 percent), mineral salts (1-2 percent), and water (8-15 percent). These proteins contain a significant amount of the amino acids: glycine, proline, hydroxyproline, glutamic acid, alanine, arginine, aspartic acid, lysine; in addition to other amino acids in smaller amounts.

There are two types of gelatins:1. type A : derived from pork skin by hydrolysis with an acid2. type B : derived from bones and animal skin by hydrolysis with an alkaline solution. Gelatin used in soft gels is a blend of both types, or used individually.

Gelatin is odorless, tasteless, colorless, and insoluble in most organic solvents, but soluble in glycerin, diluted acids and alkalis. Gelatin swells and absorbs room-temperature water, up to five to 10 times its weight. It dissolves in hot water, and forms a gel upon cooling.

The main source of gelatin is collagen, which is found in the skin and bones of animals such as deep-water fish. Most of the soft gel capsules on the market are made from an animal source, bovine or porcine. There are non-animal based forms of gelatin to meet the needs of those wishing alternatives to meat products for vegetarian, ethical or religious reasons. A vegetarian gelatin made from Irish moss, which is derived from seaweed and grows off the coast of Ireland, is available but is costlier than the animal-sourced gelatins. The brand name called Vegicap soft capsule.

Typical Formula of Soft Gelatin Capsule Shell for 1 batch = 120 L

Ingredients/Materials Amount (kg) Function

Glycerin 52 Plasticizer

Propylmethyl Paraben 0.512 Preservative

Methyl Parabe 0.128 Preservative

Gelatin 120 Bloom 152 Basis of gelatin

Briliant Blue Ponceau 0.3 Coloring agent

Sunset Yellow 0.3 Coloring agent

Titanium Dioxide 16 Opacifier

Water 120 L Solvent

Sorbitol Liquid 16 Plasticizer

Preparation of Soft Gelation Capsule Solution:The gel is prepared in a 100 liter stainless steel vessel:

1. Gelatin Powder is mixed with water and glycerin, then heat and stir it.2. After the molten gelatin mass is formed, decanted into 200 kg mobile vessels.3. Mix the molten gelatin mass using turbine mixer then add color and flavors

agent.4. It ensure consistency of gelatin mass5. This mass is kept at a constant temperature until it is needed for the next stage of

the process

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