A capsule is a type of dosage form in the pharmaceutical industry. It is a solid dosage form that is composed of small, cylindrical components made of gelatine, either soft or hard gelatin, which is filled with a powder or a liquid. Capsules are taken orally and are designed to release their contents after they have been swallowed. They are commonly used for medications that are intended to be absorbed in the stomach or small intestine. Capsules have a Body, and the upper part is called Cap the main medicament with its excipients filled in between them.
What is a Capsule?
The capsule is a unit solid dosage form. During the manufacturing process, the drug and excipients are locked within either a tough or soft gelatin shell. Pharmaceutical capsules could also be considered as a container drug delivery system that gives a tasteless/odorless dosage form without the necessity for any secondary coating step that is required in tablets.
Types of Capsule?
Capsules basically categorized based on the presence of gelatin quantity, are having two types; Hard Gelatin Capsules and Soft Gelatin Capsules. The basics difference between both types of capsules are:
A. Hard gelatin capsules
- They are less plasticized than SGC.
- HGC contains two parts. One is called a Cap, and the other is the Body.
- They are most widely used for the filling of powders, granules, and pellets.
- They are manufactured by the dipping method, which involves the following steps: Dipping, Rotation, Drying, Striping, Trimming, and joining.
But nowadays, the process becomes automated. So it is a two-step process in which the first empty capsule shells are manufactured separately followed by its filling by using different types of equipment.
Formulation of Hard Gelatin Capsules:
A. Gelatin: Gelatin is prepared by the hydrolysis of collagen obtained from animal connective tissue, and bone skin. on hydrolysis, low polypeptide chain yields 18 amino acids, the most prevalent of which are glycine and alanine. Gelatin can vary in its physical and chemical properties depending on the source of the collagen and the manner of extraction. There are two basic types of Gelatin.
Type a. (Acid hydrolyzed gelatin), which is formed by acid hydrolysis, is produced mainly from pork skin.
Type b. (Base hydrolyzed) gelatin, formed by alkaline hydrolysis, is produced mainly from bones. The two types can be differentiated by their isoelectric point as the Gelatin A type has an isoelectric point near pH value 9 while Type gelatin B has an isoelectric point near pH value 4.7.
B. Opacifing agents used in HGC: Titanium dioxide. Opaque capsules are occupied for either protection from light or to cover the contents.
C. Preservatives: most common preservatives used in capsules are Methylparaben (Lipid soluble)-and propyl Parabens (aqueous soluble)
D. lubricants: Lubrication is used to lubricate the granules or powder-filled in capsules quantity less than 2%.
E. Moisture content: Finished Hard gelatin capsule normally contains stable moisture content, from 12 to 15%. It is determined by the toluene distillation method. This moisture content is critical for the physical properties of the shell as lower content. This causes gelatin film to brittle or has a moisture content of less than 18 % causing softness in capsules. Capsules are kept on RH 40-60% and temperature 21°C – 24°C to avoid extreme temperature during handling and sorting of capsules.
Types of excipients used in powder-filled capsules:
Diluent — Diluents are the excipients that are usually present in the greatest concentration in a formulation, and they make up the necessary bulk when the quantity of the active ingredient is deficient in making up the required bulk, e.g., Lactose, maize starch, calcium sulfate, etc.
Lubricants and Glidants — This reduces powder to metal adherence and promotes free flow properties, e.g., Magnesium stearate talc.
Wetting agents — A wetting agent helps in the penetration of Water for less soluble drugs, e.g., Sodium lauryl sulfate.
Disintegrates– Disintegrates help in splitting the powder mass. e.g., cross povidone and sodium starch glycolate.
Hard gelatin capsules filling:
Hard gelatin capsule filling is done by the following process:
Rectification: During Rectification empty capsules are oriented so that they can be laying in the same direction, i.e., laying the capsule Body end in downward direction. Moving forwards caps will separate from the Body as the upper plate slides towards the left, leaving the lower plate exposed to the filling. it leads to feeding coming from the hopper filling the capsule body. the last step is the replacement of caps on the Body and the ejection of filled capsules from the die, parallelly de-dusting, polishing, and printing are done.
Equipment for filling of Hard gelatin capsule: 1. Lilly Park devis 2. Rotofil 3. Hofliger 4. Macofar 5. MG2 6. Osaka 7. Zanasi 8. Perry/ Accofil In the case of farmatic, Rotofil, Macofar, MG2, and Zanasi equipment, the power must be sufficient cohesiveness to retain slug or pellet during the delivery to the capsules.
Equipment for de-dusting of Hard gelatin capsule: 1. Rotosort: A mechanically shorting device that removes loose powder, and unfilled joined capsules. Filled or unfilled Bodies and loose caps. 2. Erweka KEA: For both de-dusting and polishing 3. Seidender machine: for visual inspection by using a belt.
Machines are used to determine the weight of the capsule: 1. Rotoweigh 2. Vcricap 1200 machine
Rotator Bottle Method: is used for dissolution rate studies in capsules.
Test for Gelatin includes:
I. Picric acid test
2. Tannic acid test, which gives white ppt of Gelatin because it is protein and tannins ppt the protein.
Advantages of Hard gelatin capsule:
The Gelatin shell dissolves rapidly and ruptures, which results in the rapid release of a drug, although in capsule no compression force is required to manufacture as in tablets. So it gives more bioavailability rather than tablets.
The solubilities limits of empty capsules are:
(a) Water resistance: Fails to dissolve in 1-10 at 20-30° C in 15 minutes.
(b) Acid solubility: Dissolve in less than 5 minutes in 0.5% aqueous HCI at 36-38° C.
Disadvantages of Hard gelatin capsule:
Disadvantages of Hard gelatin capsules including; Highly soluble salts like iodides, bromides, and chlorides generally should not be dispensed in HGC. It may cause gastric irritation due to Its rapid release and formation of high drug concentrations in localized areas.
In the evaluation of capsules, the following terms are used:
Soft spot: The site at which the capsule lies next to the tray or against another capsule dries slowly is called a soft spot.
Bloating: in this case, capsule size enlarges (bloated) if stored at high humidity (60%).
Foreign capsules: Unfilled capsules are called foreign capsules.
Difficulties in filling capsules:
1. Deliquescent or Hygroscopic powders — the water present in Gelatin is absorbed by the drug, which leads to the cracking of the capsule. The addition of an absorbent like magnesium carbonate, heavy magnesium oxide, or light magnesium oxide overcomes this difficulty provided the capsules are packed in tightly closed glass capsule vials.
2. Eutectic mixtures — Eutectic mixtures are the formation of pasty mass due to liquefication of the substances when they are mixed together due to the formation of a mixture that has a lower melting point than room temperature. To avoid these types of problems, they are mixed separately and then mixed together and filled in capsules.
B. Soft Gelatin Capsules
Soft gelatin capsules contain a drug that is encapsulated, dissolved, solubilized, or suspended in a liquid vehicle. The wetting agent (lecithin) is used in suspension that has to be filled in a soft gelatin capsule.
- They are sometimes referred to as soil gels as they are made from the more plasticized gelatin film.
- They are completely sealed dosage forms and cannot be opened without destroying the shell.
- With some exceptions, generally, the formulations that enclosed in the SGC are mostly liquids like suspensions or solutions of drugs that do not solubilize the gelatin shell.
The most common method for the preparation of SGC is:
- Rotary die process
- Plate process
- Bubble method
- Accogel (for filling of powders or granules in SGC) Depending upon the machine tooling, they may become spherical, oval, oblong, tube, etc.
Composition of SGC:
A. Gelatin: it is plasticized by using the plasticizer, sorbitol, glycerin, and propylene glycol. The ratio of dry plasticizers to dry gelatin measures the hardness of the capsule shell.
The hardness of gelatin shell = Dry weight of plasticizer / Dry weight of Gelatin
The basic gelatin formulation from which the plasticized films are cast usually consists of one part of Gelatin, one part of Water, and 0.6-0.8 part of plasticizer. The moisture content inside the gelatin shell ranges from 6-10%.
B.Preservatives: Preservatives generally added up to 0.2% and the most common combination is 4 parts of methylparaben and 1 part of propylparaben, other preservatives, such as beta-naphthol.
C. Opacifier: Titanium dioxide in the concentration range of 0.2 to 1.2 %.
D. fumaric acid: To increase the solubility of acids and reduces the aldehydic tanning of Gelatin, 1% fumaric acid is added.
E. 5 % Sugar: To form a chewable shell and enhance the taste
F. Essential oils: Essential oil concentration is about 2% for increased taste and odor.
- Do not add an iron content of more than 15 PPM. Iron comes into the Gelatin due to the hot extraction process. If iron is greater than 15 ppm, then it can react with colorants resulting in color spots.
- To prevent the decomposition of Gelatin, add 0.15 % sulfur dioxide (SO2).
- Formaldehyde hampers the disintegration of the gelatin shell as it results in the molecules’ cross-linkage in the gelatin molecule initiated by aldehyde.
- The other agents that alter the solubility of Gelatin are Salol, shellac, and CAP.
The physicochemical properties of Capsule gelatin
1. Bloom strength
1. Bloom strength Bloom strength refers to the force required to compress a gelatin capsule, A capsule with a high bloom strength is typically considered to be of good quality, as it can withstand handling and packaging without breaking or leaking. Lower bloom strength may indicate a weaker capsule that is more prone to breaking or leaking.
Empirical gel strength measure, the molecular weight of Gelatin, which gives an indication of the firmness of the gel, i.e., cohesive strength or internal cross-linking. It is measured by using Bloom Gelometer, that determines the load in grams required to depress a typical plunger (0.5 inches in diameter) a hard and fast distance of 4 mm deep into (6.66%). the raw materials gelatin has the highest bloom strength. Bloom strengths in the range of 150-280 gm are considered suitable for capsules.
2. Viscosity of gelatin: Viscosity of gelatin is used to Measure the chain length of Gelatin. The viscosity of gelatin solutions is vital to the control of the thickness of the cast film or essential for the manufacturing characteristic of gelatin film. Viscosity is determined using 6.66% w/w of gelatin solution in Water at 60°C using a capillary pipette. The range must be 25-45 mill poise.
3. Sealing temperature of the Gelatin film is between 37-40° C.
4. Minimum till volume in capsulation is calculated from the specific gravity of a liquid.
5. Capsules at equilibrium with 20-30% Relative humidity at 21-24° C are considered dry, and the shell of the such capsule contains 6-10% water depending upon the Gelatin formula used.
6. Moisture content of the shell is determined by the toluene distillation method.
Disadvantages of Soft gelatin capsule:
- There is more intimate contact between the shell and liquid contents than exists with dry-filled HGC, which increases the possibility of interactions. For E.g., chloral hydrate formulated with oily vehicles exerts a proteolytic effect on the gelatin shell; however, this effect can be reduced by replacing the vehicle with PEG.
- Drug components can drift from oily liquid vehicles to the surface of Gelatin depending upon their partition coefficient because the gelatin shell has a certain % of moisture. E.g., 4-hydroxybenzoic acid encapsulated solutions.
- The pH of the liquid can be between 2.5 to 7.5 and a more acidic pH liquid would favor causing hydrolysis which leads to leakage. pH > 7.5 and aldehydes decrease shell solubility by the tanning of the Gelatin.
- Aqueous emulsions cannot be filled in soft gelatin capsules because they may chance to release water which can affect the shell.
Determination of Base absorption and M/G factor:
Base absorption is defined as the minimum amount of base or vehicle in grams required per gram of solid drug to form a mixture that can easily be encapsulated in SGC. So it is a unitless value because both parameters are in grams.
M/G factor used to are determined when the soft gelatin shell contains suspension, it becomes crucial to find the Minimum quantity of base / inert liquid/vehicle required to form the suspension. If the concentration of solids is on the higher side, then the flow of material to the injection wedge is hindered.
Determination of Base absorption by using formula is = Weight of base (grams) / weight of drug (1 gram). For this drug is taken in a beaker, and the vehicle or wetting agent used is 5% lecithin is added at the rate of 1 ml/min each time and triturated (at an angle of 45°C) till the uniform flow is achieved, then stop adding oil and measure the consumed volume. The value depends upon the following factors:
I. Particle size and distribution
2. Density of drug
3. State of a drug, i.e., crystalline, amorphous
4. Hydrophobicity and hydrophilicity of drug
Determination of M/G factor: The above uniform mixture obtained is homogenized in a colloid mill and subject deaeration in a desiccator and find out the specific gravity/density.
M/G factor formula =BA + S x 16.23 minims /D
BA: Base absorption value, S: Solid drug, D: Density of mixture, 1 ml = 16.23 minims
M / G factor is defined as the volume of mixture in minims required for a solid drug to produce a mixture that can be encapsulated, e.g., M / G = 50 mean I gm of the drug in a mixture occupies 50 minims. Thus lower the adsorption of the solid (s) and the higher the density of the mixture, the smaller the capsule size will be.
Quality control test for Capsules:
Before release, a product to the market, all of them are required to comply with the following test eg. disintegration test by using D.T. Apparatus, weight variation test, and percentage of medicament test, but a visible inspection is also done to check the uniformity in shape, size, color, and filling.
As the capsules move ahead for the inspectors, the Capsule defects like; visibly, defective or suspected of being removed and the right are picked out. The hard and soft gelatin capsules should be subjected to the following tests for standardization.
- Shape and size
- The thickness of the capsule shell
- Leakage test
- Disintegration tests
- Weight variation test
Disintegration test: As per B.P. to perform the Disintegration test on capsule, Use disc whenever required. One capsule is to be put in each tube which is then suspended in the beakers. Then start it to move up and down for 30 minutes, unless otherwise stated in the monograph, The capsules Pass the test it no residue of drug or other than fragments of shell remaining on mesh size10.
Weight variation test: The weight variation test for capsules is done by using Twenty (20) capsules randomly followed by weighing and calculating their average weight. The capsule passes the test if the weight of individual capsules falls within 90-110% of the average weight, if the requirements are not met, then the weight of the content of each individual capsule is determined and compared with the average weight of the contents.
The content from shells can be removed just by emptying or with the help of a small brush. From soft gelatin capsules, press the content after cutting it carefully. The remaining contents are removed by washing with a suitable solvent: After drying the shells, they are weighed, and the content weights of the individual capsules are calculated.
The requirements are met if not more than 2 of the differences are greater than 10% of the average net content and no case the difference is greater than 25 %.
Capsule stability: Unprotected soft capsules (i.e., capsules that will breathe) rapidly reach equilibrium with the atmospheric conditions under which they’re stored. inherent characteristic warrants a quick discussion of the consequences of temperature and humidity on these products and points to the need for proper storage and packaging conditions and also the need of selecting an appropriate retail package.
The variety of materials capsulated, which can have an impact on the gelatin shell, alongside the various gelatin formulations which will be used, makes it imperative that physical standards are established for each product.
General statements relative to the consequences of temperature and humidity on soft gelatin capsules must be confined to an impact capsule that contains oil( mineral oil), with a gelatin shell having dry glycerin to dry gelatin ratio of about 0.5 and a Water to dry gelatin ratio of 1:1, and that is dried to equilibrium with 20 to 30% RH at 21 to 24° C.
The physical stability of soft gelatin capsules is associated with the pick-up or loss of Water by the capsule shell. If these are prevented by proper packaging, the capsule should have satisfactory physical stability at a temperature starting from just above freezing to as high as 60°C, for the unprotected capsule, low humidities (less than 20 % RH), low temperature (less than 2°C) and high temperature (greater than 38° C) or combinations of these conditions have only transient effects.