Hard Gelatin Capsules
The hard gelatin capsules constitute two half parts, named the cap and the body. While manufacturing solid oral dosage forms, by using many different mechanical techniques, the formulation is filled into the body and then the cap is pressed onto the body (one slipping over the other) to fix the capsule on the defined place.The separation of the cap and body does not occur normally under storage conditions or in clinical use because of the tight fit between the two halves of capsules.
Additives of Gelatin Capsules
| Additives | Functions with Examples |
|---|---|
| Gelatin Extenders | To minimize the quantity of gelatin required per capsule (Hydroxylalkylstarch) |
| Preservative | Gelatin is good medium for fungal and bacterial growth (Sulfur dioxide) |
| Coloring Agent | Aesthetic, Identification, Psychological effect (E122, E127, E171) |
The hard gelatin capsules contain 12 to 15% water which can vary as per the storage conditions.
At low humidity, the capsules can become brittle and if stored at high humidities, the capsules can become sticky, and lose their shape as well.
The qualities of high gelatin capsules can also be affected by the storage of the capsules at high-temperature areas.
As moisture can readily diffuse through the gelatin wall so, the gelatin capsules do not protect the filling materials of capsules from atmospheric water vapor.
There are a variety of sizes of capsules available that can be swallowed, ranging from 5 (smallest) to 000 (largest).
For use in veterinary medicine, the largest size (000) is required. The capacity of capsules from 5 to 000 ranges from 30 mg to 600 mg. It is depending upon the powdered drug material densities.
While prescribing the capsule dosage forms, the pharmacist should be determined the size of the capsules as needed.
The correct size of capsules can be determined from the volume of the material that is to be held by a single capsule.
The sealing of hard gelatin capsules can be done by two methods That are:
At low humidity, the capsules can become brittle and if stored at high humidities, the capsules can become sticky, and lose their shape as well.
The qualities of high gelatin capsules can also be affected by the storage of the capsules at high-temperature areas.
As moisture can readily diffuse through the gelatin wall so, the gelatin capsules do not protect the filling materials of capsules from atmospheric water vapor.
There are a variety of sizes of capsules available that can be swallowed, ranging from 5 (smallest) to 000 (largest).
For use in veterinary medicine, the largest size (000) is required. The capacity of capsules from 5 to 000 ranges from 30 mg to 600 mg. It is depending upon the powdered drug material densities.
While prescribing the capsule dosage forms, the pharmacist should be determined the size of the capsules as needed.
The correct size of capsules can be determined from the volume of the material that is to be held by a single capsule.
The sealing of hard gelatin capsules can be done by two methods That are:
1) Hydroalcoholic Solvent Sealing Methods
The hydroalcoholic solution contains the ratio of water or ethanol (1:1 water/ethanol). This solution is applied between the two halves of the capsule which is the middle of the capsule. Now, due to this, the capsule get softens and heats it at 45°C, hence, the interface of capsules gets fused to produce a seal.2) Gelatin Band Sealing
In gelatin band sealing a dilute solution of gelatin is applied to the capsule center that is between the two halves of the capsule. After drying it gives an air-tight seal.Hard Gelatin Capsule Benefits
1) Hard gelatin capsules can be filled very easily.2) Hard gelatin capsules are very cost-effective.
3) The shelf life of hard gelatin capsules is very long.
4) Hard gelatin capsule digest very easily.
5) Minimum maintenance is required while manufacturing the hard gelatin capsule.
Manufacturing Process of Hard Gelatin Capsules
The hard gelatin capsule manufacturing is done by the dip-coating method. The steps are as follows:
Step 1- Gelatin Solution Preparation (Dipping Solutions)
In demineralized hot water with continuous stirring, a concentrated solution of gelatin is prepared. To remove the entrapped air, a vacuum is then applied to the mixing vessel, following the dissolution of the polymer.Step 2- Dip-coating of Gelatin Solution onto Metal Pins (Moulds)
The machine that is used to manufacture the capsules contains two sets of bars, each of which contains a sequence of pins that are aligned in the column and have lubricated before starting the preparation.The pins are dipped into a pan that contains the heated gelatin solution (temperature ranges from 35 to 45°C).
There are two sets of pins are available. One set is used for the production of the cap and one set is used for the production of the body of the capsule.
Step 3- Rotation of The Dip-coated Pins
The adsorption of the gelatin solution occurs on the surface of the pins. The bar that contains pins is then removed and rotated.The temperature of the gelatin is reduced and the rotation converts the gelatin to the gel form on the surface of the pins in a uniform manner.
Step 4- Drying of The Gelatin-coated Pins
Then the pins are advanced through a series of air driers in which the air of the required humidity is passed through the surface of the gelatin film.Step 5- Stripping and Trimming
When gelatin is dried, the capsule is pulled off the mould and trimmed to a specific length.Step 6- Joining The Trimmed Capsule Shell
By following this method the capsules are removed from the pins and cut to the defined size before joining the two halves of the capsule.Step 7- Printing
Finally, for improving identification the capsule shells can be printed. Printing can be done by using one or two colors that contain information like product name of the product or code number, logo or manufacturer’s name, and details of dosage.The printing also minimizes the risk as users can easily identify the product by the printing.
Control of The Viscosity of The Gelatin Solution
It is very important to control the viscosity of the gelatin solutions Because it regulates the thickness of the capsules.The thickness of the capsule will decreases if the viscosity will be lowered.
Properties of The Final Capsule
The water content exhibited by a final capsule should be in a range of 13 to 16% w/w. As per the mechanical properties of the capsules, it is an important consideration.For gelatin, water acts as a plasticizer. It ensures that the mechanical properties of the capsule are enough strong so that the capsule does not either permanently spoil or deform and crack while manufacturing, handling, or storage.
If the water content is lower then the capsule will become brittle and will crack when the stress will be applied. If the water content will higher then the capsule will lose its shape.
During the drying phase of the manufacturing process, the required water concentration in the capsule must be achieved.
Also, capsules should be stored under such conditions that do not adversely affect this parameter.
A wide range of capsule sizes is available that can adapt fill volumes between 0.20 and 0.67 ml.
The manufacturing process of colored capsules requires the mixing of the appropriate color and opacifying agent (titanium dioxide) in the heated gelatin solution.
Formulation Motive for Hard Gelatin Capsules
The hard gelatin capsules can be formulated as either granules or powder that contains the desired drug or liquid into which the drug or medicament is dissolved or dispersed. The formulation reasons/motives are described below.Solid Capsule Fills
For the filling of solid capsules, many excipients are used that are also used in the formulation of tablet dosage forms.Read more - What is the tablet dosage form?
Properties of Solid Fills
The properties of solid fills for the formulation of capsule fills are as follows:The distribution of particle size of various components of powder mixture including curative (therapeutic) agents should be similar to ensure homogeneous mixing as well as to minimize the segregation.
The particle size distribution of the powder blend exhibit low standard deviation to ensure reproducible flow during the filling process of capsules.
While filling particles with an irregular shape like a needle shape, the problem may also persist.
Filling of Hard Gelatin Capsules
For filling hard gelatin capsules there are two methods are used. These are dependent and independent methods.
Dependent Method
In the dependent method, the lower half of the capsule is placed into slots that are located within a revolving turntable. The upper part of the capsule is also placed in a similar turntable.The turntable which contains the lower half of the capsule is rotated under a hopper which consists of the powder formulation, and powder falls into the capsules.
The homogeneity of the powder mixture and flow of the powder through the hopper is preserved or maintained by the circular movement of an auger.
At the end of the process, the two halves of the capsule are brought together to form the finished product.
The powder mass is depending upon the length of time that the hopper spends above the capsule. After finishing the process the capsules are removed from the turntable.
Read more - What are 4 types of capsules
Independent Method
This method involves the physical transfer of a plug stopper of powder from the mixed powder into the capsule.In this technique, a tube that contains a spring-loaded piston is depressed or pressed down into a powder bed enabling a volume of powder to enter the tube.
The spring-loaded piston controls the volume of powder that enters the tube.
If needed, by increasing the pressure of compression the bonding between the particles within the plug may be enhanced.
The tube that contains the powder is then lifted out of the powder bed, located above the lower half of the capsule, and rotated and then the powder is dispensed into the capsule through the lowering of the piston.
Incorporation/Mixing of Other Constituents (Raw materials) for Hard Gelatin Capsule Manufacturing
The excipients that may be added in the heated gelatin solution, like;Gelatin
Gelatin is the most common material used to prepare hard capsule shells. It is obtained from the irreversible hydrolytic extraction of collagen, from the skin, white connective tissue, and bones of animals.Depending on the source of the collagen and the method of extraction, two types of gelatin can be produced that are type A gelatin and type B gelatin.
Read more - Capsules - What kind of pill is a capsule
Colourants
To enhance the aesthetic appearance the hard gelatin capsules are colored and also it is very important for the identification of products. Due to this reason, the selected dye is added at the required concentration into the heated gelatin solution.Examples of some commonly used colorants are synthetic dyes like iron oxide pigments, xanthene dyes, and azo dyes.
Opacifying Agents
These are used to prepare the opaque gelatin if the gelatin is clear. Opaque capsules protect against light. Generally, titanium dioxide is used as an opacifying agent.lubricants/Wetting Agents
It is admissible to prepare hard gelatin capsules with sodium lauryl sulphate to increase the wetting properties of the capsule shell with an aqueous solution and hence, it enhances the dissolution properties of the formulation within the capsule.In heated gelatin solution the presence of sodium lauryl sulphate will enhance the wetting of gelatin solution on metal pins while manufacturing capsules. Due to this, during the production of gelatin capsules, uniform thickness occurs.
Plasticizer
Plasticizers are added to gelatin to minimize the hardness of the polymer and make it more flexible. Water is used as a plasticizer and it is naturally present in gelatin. Glycerine and polyhydric alcohol are also used as a plasticizer.Preservatives
Preservatives are mainly added to hard capsules to prevent microbiological contamination during manufacturing. Because the moisture bound to the gelatin molecules very strongly. So, in the finished capsules, the level of moisture that is 12 to 16% w/v provides water activity that will not support bacterial growth.Method of Filling Hard Gelatin Capsules
The process through which the filling of hard gelatin capsules is employed is mainly powders, tablets, liquids, or semisolids. These are as follows:Filling of Powder into Hard Gelatin Capsules
Good Flow Properties
The filling of hard gelatin capsules requires a good flow rate of the powders with the help of the filling apparatus into the capsules.The filling is done as per the volume of the powder so, it is important that the packing of the particles is also very consistent, because variations in the flow property of powder will result in differences in the mass of powder that is to be filled into each capsule.
Angle of Repose (f)
It is the angle that the powder makes with the horizontal plane. This technique measures the cohesion within the powder mass.If an angle of circa 25°, it is expected to exhibit a suitable flow for the manufacturing process and if the measured angle exceeds 50°, the flow properties of the powder are poor.
If the powder gives a high angle of repose then there is a requirement for the addiction of glidants to minimize the cohesion between the particles.
Torque Rheometry
It is a rheological technique in which stress is applied to the powder bed and the subsequent rate of shear of the powder bed is determined.If the powder bed shows high cohesion then it requires high shearing stress to maintain the flow.
This technique is mainly required in the wet granulation process mainly to examine the mixing in the granulation process.
Tap Density
Shaking the powder at a defined rate and for a defined period is known as tapped density and it measures the volume occupied by the powder bed.The shaking of the powder bed before and after is known as the Hausner ratio.
The acceptable Hausner ratio of circa is 1.2 for filling into the capsules. If these ratios will be increased then it may result in erratic filling due to arching.
Compatibility between formulation components and the capsules
The excipients that are used in the formulation of powder fills for hard gelatin capsules are the same as those used in the tablet dosage forms.Read more - What are the Excipients used in Tablet Manufacturing?
There are following excipients are used for the formulation of powder fills:
Diluents
Diluents are used to increase the mass of the powder bed and increase the reproducibility of the filling process.Examples - Maize starch, Lactose (monohydrate), and Microcrystalline cellulose.
Glidants are used to minimize the interparticle interactions and hence minimize the clomping and increase the powder flow.
Examples - Magnesium stearate (lubricant), and colloidal silicon dioxide (Glidant).
Examples - Microcrystalline cellulose, Sodium starch glycolate, Maize starch, croscarmellose, and crospovidone.
The powder fill should be easily dispersed within the gastrointestinal contents to achieve rapid drug release.
The presence of surfactants in the hard gelatin capsule shell enhances the uptake of fluid into the capsule shell.
Example - Sodium lauryl sulfate
Lubricants or Glidants
Lubricants are used to minimize the interaction of the powders with the metal dossator as well as the components of the filling machine.Glidants are used to minimize the interparticle interactions and hence minimize the clomping and increase the powder flow.
Examples - Magnesium stearate (lubricant), and colloidal silicon dioxide (Glidant).
Disintegrants
It is used to break the powder mass that releases into the stomach.Examples - Microcrystalline cellulose, Sodium starch glycolate, Maize starch, croscarmellose, and crospovidone.
Surfactants (surface-active agents)
Surfactants are added in the powder filling of hard gelatin capsules to increase the wetting properties of the powder bed, for release in the gastrointestinal tract.The powder fill should be easily dispersed within the gastrointestinal contents to achieve rapid drug release.
The presence of surfactants in the hard gelatin capsule shell enhances the uptake of fluid into the capsule shell.
Example - Sodium lauryl sulfate
Filling of Tablets into Hard Gelatin Capsules
Generally, film-coated tablets are used for capsule filling to prevent dust formation. The sizes of tablets should be defined so that they can be filled freely into the body of the capsules.Tablets are linked to the hopper and at the bottom of it, a gate (device) is present that allows the required number of tablets to be passed from the gate.
The tablets fall through gravity into the body of the capsule as they passed below the hopper.
Liquids or Semisolid Fills for Hard Gelatin Capsules
Liquid or semisolid fills for hard gelatin capsules may be subdivided into various categories:
Lipophilic liquids or oils containing dissolved or dispersed therapeutic agent
Examples - Vegetable oils (sunflower, Arachis, olive), Fatty acid esters (glyceryl monostearate)Water-miscible liquids containing dissolved/dispersed therapeutic agent
Example - Polyethylene glycols (PEGs) that are solid at room temperature but on heating, becomes liquefy, Liquid polyoxyethylene-polyoxypropylene block co-polymers.The stability of capsules is the major concern when liquid fill formulations are used in the filling of capsules.
If the solvent that is used to fill the hard gelatin capsule will hygroscopic then it will enhance moisture uptake and this result in the splitting or cracking of the capsule shell.
To stabilize the liquid fill formulations for hard gelatin capsules, other excipients will be required, like
Surfactants
These are used in liquid fills for hard gelatin capsules to:
1) To stabilize the suspended therapeutic agent
2) To solubilize the therapeutic agent within the solvent
3) To enhance the dissolution of poorly water-soluble therapeutic agents within the gastrointestinal tract
1) To stabilize the suspended therapeutic agent
2) To solubilize the therapeutic agent within the solvent
3) To enhance the dissolution of poorly water-soluble therapeutic agents within the gastrointestinal tract
Viscosity-Modifying Agents
These are used in liquid fills for hard gelatin capsules to:
1) To stabilize the suspended therapeutic agent
2) To modify the viscosity of the formulation to optimize the filling of the capsule
Generally, values of viscosity within the range of 0.1-25 Pa/s are acceptable as the liquid fills for hard gelatin capsules.
From this range, If the viscosity is lower then there will be a loss in the capsule contents due to splashing or drowning (overflow) of the liquid from the capsule during filling.
I tried to give all the important information in detail about the Manufacturing Methods of Hard Gelatin Capsules. If you did not understand any point please ask in the comment.
1) To stabilize the suspended therapeutic agent
2) To modify the viscosity of the formulation to optimize the filling of the capsule
Generally, values of viscosity within the range of 0.1-25 Pa/s are acceptable as the liquid fills for hard gelatin capsules.
From this range, If the viscosity is lower then there will be a loss in the capsule contents due to splashing or drowning (overflow) of the liquid from the capsule during filling.
I tried to give all the important information in detail about the Manufacturing Methods of Hard Gelatin Capsules. If you did not understand any point please ask in the comment.
Read more - What is film coating of tablets?
Read more - Pre-compression evaluation of tablets
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