Capsule Dosage Form Fall 2024 PDF

# PHRM215 - LECTURE NOTES FOR CAPSULE DOSAGE FORM - FALL 2024 ## Introduction The word capsule is derived from the Latin word 'Capsula' which means a small box or container. Capsules are solid dosage forms in which the medicinal agents and/or excipients are enclosed in a small shell, usually made...

# PHRM215 - LECTURE NOTES FOR CAPSULE DOSAGE FORM - FALL 2024 ## Introduction The word capsule is derived from the Latin word 'Capsula' which means a small box or container. Capsules are solid dosage forms in which the medicinal agents and/or excipients are enclosed in a small shell, usually made of gelatin or other substances, the consistency of which may be adjusted by the addition of substances such as plasticizer and water. The capsule shell may also contain excipients such as preservatives, opacifying agents, sweeteners, coloring agents, and flavoring substances. The capsule may have surface markings. The shells may be composed of two pieces, a body and a cap, or they may be composed of a single piece. Two-piece capsules are commonly referred to as hard shell capsules, and one-piece capsules are often referred to as soft-shell capsules. This distinction reflects differing levels of plasticizers in the composition of hard gelatin and soft gelatin shells and the fact that one-piece capsules typically are more pliable than two-piece capsules. The contents of the capsules may be solid, liquid, or of a paste-like consistency. They consist of one or more active pharmaceutical ingredients with or without excipients such as solvents, diluents, lubricants, wetting agents, preservatives, and disintegrating agents. The contents do not cause deterioration of the shell. The shell, however, is attacked by the digestive fluids and the contents are released. Several categories of capsules are distinguished such as hard gelatin capsules, soft gelatin capsules, gastro-resistant capsules, and modified release capsules ## Advantages of Capsules The use of capsules has several advantages; the most notable advantage of the capsule is its design and ease of consumption. Advantages are: - **Fast Acting:** The basic aim of any medicine is to determine how easily and quickly it relieves the patient. Fast-acting medicines are considered good options in place of slow-acting medicines. Capsules tend to break down more quickly than tablets. They may offer faster relief from symptoms than tablets. - **Consistent dosing:** Capsules provide a consistent dose of medication because the amount of medication in each capsule is pre-measured and controlled. This ensures that patients receive the exact amount of medication prescribed by their healthcare provider, which can be important for medications that require precise dosing. - **Customizable dosing:** Capsules can be customized to meet the specific needs of individual patients. For example, a patient who requires a smaller dose of medication can be given a smaller capsule with the appropriate amount of medication. This allows for more precise dosing and reduces the risk of over or under-dosing. - **Controlled release:** Some capsules are designed to release medication slowly over a period of time, which can provide more accurate and precise dosing for medications that require constant levels in the bloodstream. This can be especially important for medications used to treat chronic conditions. - **Reduced gastrointestinal irritation:** Capsules can be designed to reduce gastrointestinal irritation, which can improve the accuracy and precision of medication delivery. For example, some medications can cause stomach irritation when taken in tablet form, but capsules can be designed to dissolve slowly in the stomach, reducing the risk of irritation. - **Tasteless:** It delivers a tasteless/odorless dose form without the requirement for a further coating procedure, as tablets do. - **Easy to administer:** Swallowing is easy for maximum patients, as the shell is smooth and hydrates in the human mouth. Additionally, it floats if taken with liquid. - **Elegant in appearance:** Their accessibility in a wide variety of colours makes it visually attractive. - **High drug absorption:** The effectiveness of any medicine depends on the absorption capacity of that medicine. The faster the absorption, the higher the usage of medicines. Faster absorption of medicine provides faster relief to the symptoms. Faster drug absorption into bloodstream makes capsule dosage form slightly more effective in bloodstream than tablets - **Flexibility of formulation:** Capsules permit a degree of flexibility of formulation not accessible with tablets formulation. - **Materials encapsulated:** It is possible in soft gelatine capsules that active drugs in form of liquid or at least dissolved, solubilized, or suspended in a liquid vehicle possible to deliver. Soft gelatine capsules can deliver volatile a drug and can be more suitable for drugs that are easily oxidized in the open air. ## Disadvantages of Capsules While capsules have many benefits, such as easy swallowing, accurate dosing, and protection of the drug from light, there are also several disadvantages to their use as mentioned below: - **Less Durable:** Capsules convert stiff under very dry conditions and may crack during the filling procedure. It absorbs moisture and softens under high relative humidity. Possible stability difficulties may be related to capsules containing liquid fill materials. Leaching of ingredients from soft gelatin capsule to formulation may affect. - **Materials not encapsulated:** Highly soluble salts (e.g., iodides, bromides, chlorides) normally should not be dispensed in hard gelatin capsules. Their quick release could cause gastric irritation due to the creation of a high drug concentration in localized areas. - **Difficulty in swallowing:** Although capsules are generally easier to swallow than tablets, some people may still find them difficult to swallow, particularly if they have a small throat or a strong gag reflex. This can be particularly problematic for elderly or pediatric patients, who may have difficulty swallowing pills in general. - **Inability to split or crush:** One disadvantage of capsules is that they cannot be split or crushed without compromising their effectiveness. This means that patients who require smaller doses of medication may not be able to adjust the dose to meet their specific needs. It can also be a problem for patients who have difficulty swallowing pills, as they may not be able to break the capsule to administer the medication in a different form. - **Limited shelf-life:** Capsules are more susceptible to moisture and humidity than tablets, which can reduce their effectiveness over time. This means that capsules may need to be stored in a cool, dry place to maintain their potency, and they may have a shorter shelf-life than other forms of medication. - **Not suitable for all formulations:** Capsules are not appropriate for all types of medications, especially those that are not soluble in water. Additionally, some medications may be sensitive to light or oxygen, which can make them less effective in a capsule form. - **Risk of tampering:** Because capsules cannot be easily broken, they may be more difficult to inspect for tampering or contamination. This can be a concern in situations where medication security is important, such as in hospitals or other healthcare settings. - **Higher cost:** Capsules may be more expensive than other forms of medication, such as tablets or liquids, because of the added cost of the gelatin shell. This can be a concern for patients who have limited healthcare coverage or who are on a tight budget. ## Types of Capsule Dosage Form Several types of capsules are distinguished: 1. Hard Gelatin Capsules (Dry Fill Capsules) 2. Soft Gelatin Capsules (Soft Gels) 3. Gastro-Resistant Capsules 4. Modified-Release Capsules ### Hard Gelatin Capsules (Hard Capsules) Hard gelatin capsules are most widely used in the pharmaceutical industry. Hard gelatin capsules are an oral dosage form for the delivery of life-saving drugs, mineral, vitamins or other healthy ingredients via supplements. They are also commonly employed in clinical drug trials to compare the effects of an investigational drug with those of another drug product or placebo. The community pharmacist also uses hard gelatin capsules in the extemporaneous compounding of prescriptions. The hard gelatin shells are usually formed from gelatin; however, they also may be made from starch or other suitable substances. Hard gelatin shell sizes range from No. 5, the smallest, to No. 000, which is the largest, except for veterinary sizes. However, size No. 00 generally is the largest size acceptable to patients. Hard gelatin capsules consist of two telescoping caps and body pieces. Generally, there are unique grooves or indentations molded into the cap and body portions to provide a positive closure when fully engaged, which helps prevent the accidental separation of the filled capsules during shipping and handling. Positive closure also may be affected by spot fusion ("welding") of the cap and body pieces together through direct thermal means or by application of ultrasonic energy. Industrially filled hard gelatin capsules also are often of distinctive color and shape or are otherwise marked to identify them with the manufacturer. Additionally, such capsules may be printed axially or radially with strengths, product codes, etc. Pharmaceutical-grade printing inks are usually based on shellac and employ FDA-approved pigments and lake dyes In extemporaneous prescription practice, hard gelatin capsules may be hand-filled; this permits the prescriber a latitude of choice in selecting either a single drug or a combination of drugs at the exact dosage level considered best for the individual patient. This flexibility gives hard gelatin capsules an advantage over compressed tablets and soft gelatin capsules as a dosage form. The empty hard gelatin shells are made of gelatin, sugar, and water. As such, they can be clear, colorless, and essentially tasteless. They may be colored with various FD&C and D&C dyes and made opaque by adding agents such as titanium dioxide. Most commercially available medicated capsules contain combinations of colorants and opaquants to make them distinctive, many with caps and bodies of different colors. Gelatin is obtained by the partial hydrolysis of collagen obtained from the skin, white connective tissue, and bones of animals. In commerce, it is available in the form of a fine powder, a coarse powder, shreds, flakes, or sheets. Gelatin is stable in air when dry but is subject to microbial decomposition when it becomes moist. Normally, hard gelatin capsule shells contain 13% to 16% of moisture, However, if stored in an environment of high humidity, additional moisture is absorbed by the capsules, and they may become distorted and lose their rigid shape. In an environment of extreme dryness, some of the moisture normally present in the gelatin capsules is lost, and the capsules may become brittle and crumbling when handled. Therefore, it is desirable to maintain hard gelatin capsules in an environment free from excessive humidity or dryness. Hard-shell capsules typically are filled with powder, beads, pellets, or granules. Inert sugar beads may be coated with active ingredients and coating compositions that provide extended-release profiles or enteric properties. Alternatively, larger-dose active ingredients themselves may be suitably formed into pellets and then coated. Semisolids or liquids also may be filled into hard-shell capsules, however, when the latter are encapsulated, one of the sealing techniques must be employed to prevent leakage. In hard gelatin capsule filling operations, the body and cap of the shell are separated prior to dosing. In hard starch shell filling operations, the bodies and caps are supplied separately and are fed into separate hoppers of the filling machine. Machines employing various dosing principles may be employed to fill powders into hard-shell capsules; however, most fully automatic machines form powder plugs by compression and eject them into empty capsule bodies. Accessories to these machines generally are available for the other types of fills. Powder formulations often require fillers, lubricants, and glidants to the active ingredients to facilitate encapsulation. The formulation, as well as the method of filling, particularly the degree of compaction, may influence the rate of drug release. The addition of wetting agents to the powder mass is common where the active ingredient is hydrophobic. Disintegrants also may be included in powder formulations to facilitate de-aggregation and dispersal of capsule plugs in the gut. Powder formulations often may be produced by dry blending; however, bulky formulations may require densification by roll compaction or other suitable granulation techniques. Because moisture may be absorbed by gelatin capsules and may affect hygroscopic agents within, many capsules are packaged along with a small packet of a desiccant material to protect against the absorption of atmospheric moisture. The desiccant materials most often used are dried silica gel, clay, and activated charcoal. Thixotropic semisolids may be formed by gelling liquid drugs or vehicles with colloidal silicas or powdered high molecular weight polyethylene glycols. Various waxy or fatty compounds may be used to prepare semisolid matrices by fusion. ## Soft Gelatin Capsules (Soft gels) Soft-shell capsules made from gelatin (sometimes called soft gels) or other suitable material require large-scale production methods. The soft gelatin shell is somewhat thicker than that of hard-shell capsules and may be plasticized by the addition of sorbitol or glycerin. The ratio of dry plasticizer to dry gelatin determines the "hardness" of the shell and may be varied to accommodate environmental conditions as well as the nature of the contents. Like hard shells, the shell composition may include approved dyes and pigments, opaquing agents such as titanium dioxide, and preservatives. Flavors may be added and up to 5% sucrose may be included for its sweetness and to produce a chewable shell. Soft gelatin shells normally contain 6% to 10% water. Soft-shell capsules also may be printed with a product code, strength, etc. In most cases, soft-shell capsules are filled with liquid contents. Typically, active ingredients are dissolved or suspended in a liquid vehicle. Classically, an oleaginous vehicle such as a vegetable oil was used; however, nonaqueous, water-miscible liquid vehicles such as the lower-molecular-weight polyethylene glycols are more common today due to fewer bioavailability problems. Available in a wide variety of sizes and shapes, soft-shell capsules are both formed, filled, and sealed in the same machine; typically, this is a rotary die process, although a plate process or reciprocating die process also may be employed. Soft-shell capsules also may be manufactured in a bubble process that forms seamless spherical capsules. With suitable equipment, powders and other dry solids also may be filled into soft-shell capsules. Liquid-filled capsules of either type involve similar formulation technology and offer similar advantages and limitations. For instance, both may offer advantages over dry-filled capsules and tablets in content uniformity and drug dissolution. Greater homogeneity is possible in liquid systems, and liquids can be metered more accurately. Drug dissolution may benefit because the drug may already be in solution or at least suspended in a hydrophilic vehicle. However, the contact between the hard or soft shell and its liquid content is more intimate than exists with dry-filled capsules, and this may enhance the chances for undesired interactions. Soft gelatin capsules have grown in popularity in recent years because they enable administration of liquids in a solid dosage form with a bioavailability advantage over other commonly used solid dosage forms (e.g., tablets). They are available in a variety of sizes, shapes, and colours that may be specific to the manufacturer. Soft gelatin capsules are predominantly administered orally. Some can be formulated and manufactured to produce a number of different drug delivery systems such as - Chewable soft gels where a highly flavoured shell is chewed to release the drug liquid fill matrix - Suckable soft gels which consist of a gelatin shell containing the flavoured medicament to be sucked and a liquid matrix (or just air inside the capsule) - Twist-off soft gels which are designed with a tag to be twisted or snipped off, thereby allowing access to the fill material and - Meltable soft gels designed for use as pessaries or suppositories. ## Hard Gelatin Capsule Shell Sizes Empty gelatin capsules are manufactured in various lengths, diameters, and capacities. The size selected for use is determined by the amount of fill-material to be encapsulated. The density and compressibility of the fill will largely determine to what extent it may be packed into a capsule shell. For estimation, a comparison may be made with powders of well-known features and an initial judgment made as to the approximate capsule size needed to hold a specific amount of material. For human use, empty capsules ranging in size from 000 (the largest) to 5 (the smallest) are commercially available, Larger capsules are available for veterinary use. | Capsule Size | Volume Capacity (mL) | Approximate Fill Weight (mg) | Empty Capsule Weight (mg) | Dimensions (mm) | |---|---|---|---|---| | 000 | 1.37-1.40 | 950-1350 | 123 | 26.14 x 9.91 | | 00 | 0.90-0.95 | 650-950 | 98 | 23.30 x 8.53 | | 0 | 0.68-0.70 | 450-700 | 78 | 21.70 x 7.64 | | 1 | 0.48-0.50 | 300-500 | 63 | 19.40 x 6.91 | | 2 | 0.37-0.40 | 250-400 | 50 | 18.00 x 6.35 | | 3 | 0.30-0.32 | 200-300 | 39 | 15.90 x 5.82 | | 4 | 0.21-0.23 | 150-200 | 30 | 14.30 x 5.31 | | 5 | 0.13-0.15 | 100-150 | 24 | 11.10 x 4.91 | ## Preparation of Hard Gelatin Capsules On large or small scale, preparation of filled hard gelatin capsules consists of the following general steps: 1. Developing and preparing formulation 2. Hard Gelatin Shell Size Selection 3. Filling the capsule shell 4. Capsule sealing 5. Cleaning and polishing the filled capsules ### 1. Developing and Preparing Formulation The active and inactive components must be blended thoroughly to ensure a uniform powder mix for the fill. The formulation components are carefully selected taking into consideration the physicochemical properties of the API (s) and the additives (excipients) To achieve uniform drug distribution, it is advantageous if the density & particle size of the drug and excipients are similar. Commonly used additives in hard gelatin capsule formulation are: - **Diluents / fillers:** lactose, microcrystaline cellulose, starch-to increase bulk of powder material - **Disintegrants:** sodium starch glycolate, pre-gelatinised starch-facilitate breaking of powder plug enclosed in the hard shell in gastric environment by swelling action - **Glidants and lubricants:** colloidal silicon dioxide, magnesium stearate and calcium stearate-improve the flow of powder mixing during filling in capsule filling machines - **Wetting agents:** Sodium Lauryl Sulphate- improves the wettability of drug (s) and thus dissolution These excipients are carefully selected based on the properties of the API and the desired characteristics of the final capsule product. The combination of these excipients ensures that the hard gelatin capsules are effective, stable, and easy to manufacture. Hard gelatin capsules are used to encapsulate between about 65 mg and 1 g of powdered material. The smallest capsule (No. 5) holds 65 mg of powder or more, depending on characteristics of powder substance. ### 2. Hard gelatin shell size Selection The size of hard gelatin capsule selected for use is determined by requirements of the formulation, including the dose of the active ingredient and the density and compaction characteristics of the drug and other components. The first step in estimating the optimal capsule size for a given product is to determine the density of the formulation using tapped density for powders and bulk density for pellets, minitablets, and granules. The appropriate capsule size may then be calculated using the measured density of the formulation, the target fill weight, and capsule volume. The table below shows capsule volumes and typical fill weights for formulations with different tapped densities | Size | Capsule volume (mL) | 000 | 00el | 00 | 0el | 0.78 | 0.68 | 1 | 0 el | 1 el | 2el | 0.37 | 0.30 | 0.21 | 0.13 | |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| | **Powder tapped density** | **Capsule capacity (mg)** | | | | | | | | | | | | | | | | 0.6 g/mL | | 822 | 612 | 546 | 468 | 408 | 324 | 300 | 246 | 222 | 180 | 126 | | 78 | | 0.8 g/mL | | 1096 | 816 | 728 | 624 | 544 | 432 | 400 | 308 | 296 | 240 | 168 | 104 | | 1.0 g/mL | | 1370 | 1020 | 910 | 780 | 680 | 370 | 300 | 210 | 130 | | | | | | 1.2 g/mL | | 1644 | 1224 | 1092 | 936 | 816 | 648 | 600 | 492 | 444 | 360 | 252 | 156 | Choosing the correct size of a hard gelatin capsule is crucial for ensuring accurate dosing, patient comfort, and manufacturing efficiency. By considering the fill material's properties, calculating the required volume, and selecting a size that balances these factors, manufacturers can achieve optimal results in capsule production ### 3. Filling of Hard Gelatin Shells The filling of hard gelatin capsules involves accurately dispensing the drug formulation (which can be in the form of powders, granules, pellets, tablets, or liquids) into the empty capsule shells. The process is typically carried out using either manual, semi-automatic, or fully automatic capsule filling machines. The difference between the many methods available is the way in which the dose of material is measured into the capsule body. The basic steps in filling hard gelatin capsules include: - **Orientation of hard gelatin shells:** The capsules are first oriented so that the body and cap are aligned properly for separation. In automatic machines, this is done by orienting the capsule using vacuum systems or mechanical devices - **Separation of caps from bodies:** The cap is then separated from the body, typically by mechanical pins or vacuum. - **Filling of Hard Gelatin shell body:** The filling process varies depending on the type of formulation being used: - **Powder Filling** includes the following filling methods: - **Dosing Disc Method:** The powder blend is filled into a hopper and spread into a uniform layer. A rotating dosing disc with several holes picks up the powder. The amount of powder is determined by the depth and diameter of these holes. The powder is then ejected into the capsule body. - **Tamping Pin Method:** Powder is compressed into a slug using tamping pins before being inserted into the capsule body. This method allows for precise control over the fill weight. - **Auger Filling Method:** An auger screw is used to fill the powder into the capsule body. The amount of powder dispensed is controlled by the rotation speed and the auger's design. - **Granules/Pellets Filling** includes following filling methods: - **Volumetric Filling:** Granules or pellets are filled using a dosator system or a tamping system where a pre-measured volume is filled into the capsule body. - **Gravity Filling:** Granules are allowed to flow by gravity into the capsule body from a hopper, guided by mechanical devices to ensure accurate dosing. ### 4. Rejoining the Cap and Body After filling, the cap is rejoined with the body using mechanical devices or vacuum pressure. The capsule is then locked to secure the contents. Some machines apply a slight pressure to ensure a firm lock, while others use a liquid gelatin band to seal the capsule. ### 5. Cleaning and Polishing Capsules are cleaned to remove any powder or material adhering to the outside of the capsule. This is done using polishing machines that can involve rotating brushes, soft cloths, or a combination of both. ### 6. Quality Control and Inspection The filled capsules are subjected to various quality control checks, including weight variation, visual inspection for defects (like cracks or improperly filled capsules), and disintegration tests. Any capsules that do not meet the quality criteria are rejected and separated. ### 7. Packaging and Storage Once the capsules pass quality control, they are counted, packaged into tightly closed glass or plastic bottles or blister packs for protection from extremes of humidity and temperatures, labeled, and prepared for distribution. | Condition | Minimum | Ideal | Maximum | |---|---|---|---| | Relative Humidity | 40 % | 50 % | 60 % | | Temperature | 15 °C | 20 °C | 25 °C | ## Methods of Manufacturing Hard Gelatin Capsules These include: ### 1. Punch and Pour Method Hard gelatin capsules can be filled by hand for research or experimental purposes or when filling a small number of capsules in the pharmacy, the pharmacist may use the punch method. The powder to be encapsulated is placed on a sheet of clean paper or on a glass or porcelain plate. Using the spatula, the powder mix is formed into a cake having a depth of approximately one fourth to one-third the length of the capsule body. Filling Hard Capsule Shells, then an empty capsule body is held between the thumb and forefinger and punched vertically into the powder cake repeatedly until it is filled. Because the amount of powder packed into a capsule depends on the degree of compression, the pharmacist should punch each capsule in the same manner and weigh the product after capping. The filled capsules are then de-dusted and polished with gauze or cloth. The Pour Method is used for manual filling of granular material > Link: https://www.youtube.com/watch?v=jIvPINIaJ7Y ### 2. Hand Operated Capsule Machine On a small-scale manufacture, hard gelatin capsules can be filled manually using a hand-operated capsule machine. This is done by directly filling the powder into the capsule shell and relying on the bulk/tapped density of the powder to get the correct dose for the volume of the capsule shell used. The various types of hand-operated capsule machines have capacities ranging from 24 to 300 capsules and, when efficiently operated, can produce about 200 to 2,000 capsules per hour. Hand operated capsule machine consists of 1) Loading tray having 200-300 holes and Filler unit consisting of top and lower plate having 200-300 holes. The filling process comprises the following steps: - With empty capsules in the loader tray, the tray is placed on top of the filler unit. - The loader inserts the capsules into the filling unit and is removed, and the top plate is lifted to separate the caps from the bodies. - The powder is placed on the unit, and the capsule bodies are filled. - The top plate is returned to the unit, and the caps are placed on filled capsule bodies. ### 3. Large Scale Manufacturing of Hard Gelatin Capsules Machines developed for industrial use automatically separate the caps from empty capsule shells, fill the bodies, scrape off the excess powder, replace the caps, seal the capsules as desired, and clean the outside of the filled capsules at up to 1,65,000 capsules per hour. Powder filling is accomplished by the following dosing devices. - **Dosator Device Method:** The dosator device uses an empty tube that dips into a powder bed, which is maintained at a height approximately two-fold greater than the desired length of the plug. The dosator piston's forward movement helps form the plug, which is then transferred to the body of the capsule and released. > Link: https://www.youtube.com/watch?v=0_hBcz LMXk - **Tamping Device Method:** Tamping device operates by filling the cavities bored into the dosing disk, similar to the die-filling operation during tableting. A tamping punch slightly compresses the filled powder by repeated action, which is followed by the ejection of the plug into the capsule body. > Link: https://www.youtube.com/watch?v=Hug7SeTVFhk > Link: https://www.youtube.com/watch?v=qSfMHI-XQE - **Auger Device Method:** Auger device operates by pushing a right amount of powder or granules into capsule body using a rotating auger (screw) that sits inside the hopper. As the machine's auger rotates, it moves and dispenses predetermined quantities of dry powder/granular materials into suitable empty capsule bodies. ## Soft Gelatin Capsule Shell Preparation ### 1. Preparation of Gelatin Solution Gelatin, along with plasticizers (e.g., glycerin, sorbitol) and colorants, is mixed with water. This solution is heated and stirred until a homogenous gelatin mass with desired viscosity and color is obtained ### 2. Deaeration The mixture is deaerated to remove any air bubbles, which could lead to defects in the final capsules. ### 3. Dipping Pairs of stainless-steel pins are dipped into the dipping solution to simultaneously form the caps and bodies. The dipping solution is maintained at a temperature of about 50 °C in a heat jacketed dipping pan whereas the pins are maintained at 22 °C。 The dipping time to cast the gelatin film is around 12 secs. ### 4. Spinning/Rotating The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule cap and body ends. These are rotated by moving upward. ### 5. Drying The gelatin is dried by a blast of cool air to form a hard shell. Drying is mainly done by dehumidification by passing large volumes of dry air over the pins. Here gently moving air which is precisely controlled for volume, temperature, and humidity, removes the exact amount of moisture from the capsule halves. Temperature elevation of a few degrees is permissible to prevent film melting. Drying also must be too rapid to prevent case hardening. Under drying gives sticky film for subsequent operations. Over drying cause, the films split on the pins due to shrinkage or at least make them brittle for later trimming step ### 6. Stripping A series of bronze jaws strip the cap and body portions of the capsules from the pins. The stripped caps and bodies are delivered to collects in which they are firmly held. ### 7. Trimming and Joining The stripped cap and body portions are trimmed to the required length by stationary knives. The cap and body lengths are precisely trimmed to a ± 0.15 mm tolerance. After trimming to the right length, the cap and body portion are joined. The cap and body portions are aligned concentrically in channels, and the two portions are slowly pushed together. ### 8. Sorting The moisture content of capsules as they are ejected from machines will be in the range of 15-18% w/w. During sorting, the capsules passing on a lighted moving conveyor are observed visually by the inspector. Any defective capsules spotted are thus manually removed. The defects may cause serious problems like stoppage of a filling machine due to imperfect cuts, dented capsules, and capsules with holes. Some defects may cause usage problems like capsules with splits, long bodies. ### 9. Polishing Polishing can be done by pan, cloth polishing and brushing. - **Pan Polishing:** Accela-Cota pan is used to dust & polish. - **Cloth Dusting:** Capsule are rubbed with cloth. - **Brushing:** Capsules are fed under soft rotating brush. Finished capsules are pushed onto a conveyer belt which carries them out to a container. ### 10. Printing In general, capsules are printed prior to filling as they are easy to handle. Perfect capsules are imprinted with the client logo etc. on high-speed offset rotary presses having thorough capabilities as high as millions of capsules per hour. Available equipment can print axially along the length or radially around the circumference of capsules ## Soft Gelatin Capsules: Anatomy of a Softgel | Shell | | |---|---| | Gelatin water plasticizer | Colors, Flavors (aromas) | | Fill | Oil solution suspension | | | Common suspending agents: Lecithin, soybean oil, yellow wax | | | Softgel surface can be printed on for easy identification | ## Advantages of Soft Gelatin Capsules 1. Soft gelatin capsules are a patient-friendly dosage form for administering nonpalatable and/or oily liquids orally. 2. Unpleasant odors or tastes can be easily ingested in a soft gelatin capsule dosage form, which provides a neat appearance and convenient ingestion. 3. Appropriate vehicle selection may promote rapid dispersion of capsule contents and drug dissolution. 4. Because the liquid fill is metered into individual capsules via a positive displacement pump, a higher degree of reproducibility is achieved during the manufacture of soft gelatin capsules than is possible with powders or granules fed in the manufacture of tablets or hard gelatin capsules. 5. Soft gelatin capsules are especially useful for lipid-soluble low-dose drugs because they allow for greater content uniformity between dosage units than the traditional tablet dosage form. 6. It may also be preferable to tablet dosage forms for encapsulating liquid, water-insoluble drugs. 7. As a natural byproduct of the manufacturing process, soft gelatin capsules are hermetically sealed. As a result, this dosage form is ideal for liquids and volatile drugs. Many drugs that are susceptible to atmospheric oxidation can also be successfully formulated in this dosage form. 8. Superior patient compliance/consumer preference and pharmaceutical elegance. 9. Safer handling of highly potent or cytotoxic drug compounds. ## Disadvantages of Soft Gelatin Capsules 1. Specialized manufacturing equipment required 2. Stability issues with extremely water-soluble and hydrolysable substances 3. Higher manufacturing cost as compared to tablet dosage form 4. There are not many excipients or carriers that work with gelatin. ## Rationale for the selection of soft gelatin capsules as a dosage form Soft gelatin capsules may be selected as the preferred formulation approach for one or more of the following reasons: - **Improved oral bioavailability:** Presenting a drug substance to the gastrointestinal tract in a solubilized form overcomes the processes of disintegration and dissolution that are required from solid dosage forms before the active pharmaceutical ingredient (API) is available for absorption. This has been utilized to improve the bioavailability of drugs with a range of solubilities. Also, the use of certain lipid vehicles can be associated with increased oral bioavailability and reduced intra- and inter- patient variability by modification of gastrointestinal digestive processes. - **Improved Content Uniformity:** Presentation of drug substances in a solution form can overcome the challenges of achieving dosage unit homogeneity compared to other solid oral dosage forms. Because soft gelatin capsules are filled with liquids or suspensions, excellent content uniformity can be achieved with even the most potent of drugs. The accuracy of the filling mechanism enables the dose to be filled to a tolerance of ± 1% for solutions and ± 3% for paste - **Technological advantage for formulation of oils and low melting point drugs:** When the API is an oily liquid, has a melting point lower than about 75 °C or proves difficult to compress, liquid filling of soft gels (with or without other diluents) can provide a successful approach to presenting it in a solid oral dosage form. - **Safety reasons during manufacturing, dispensing, and usage of potent and cytotoxic drugs:** Most of the unit operations involved in the manufacture of tablets and hard gelatin capsules can generate a significant quantity of airborne powders. This can be a cause of concern for the manufacture of highly potent or cytotoxic compounds because of safety considerations for the operator and environment. In the case of soft gelatin capsules, the powder handling is restricted to drug dissolution or dispersion in a liquid medium. Therefore, soft gelatin capsules provide greater operator safety during manufacturing. In addition, as the drug formulation is hermetically sealed in a shell, the exposure to the medication is minimized during dispensing as well as use. - **Improved Stability:** Preparations of liquid-filled soft gelatin capsules have proven beneficial to oxidative degradable drugs. Varying the level of glycerol in the shell formulation will alter the permeability of the shell to oxygen. The filling process can be performed under nitrogen, so by appropriate selection of shell composition, this technology can provide excellent protection for oxygen-sensitive drugs. ## Formulation of Soft Gelatin Capsule Shell The major components of soft gelatin capsule shell are gelatin, plasticizer and water. Besides these three components, soft gelatin capsule shell may contain other ingredients such as colourants and / or opacifiers for visual appeal and / or reducing the penetration of light for the encapsulation of photosensitive drug substances. Flavours and sweeteners may be added to improve palatability. Preservatives e.g., potassium sorbate, methyl, ethyl, and propyl hydroxybenzoate are added to prevent the growth of bacteria and molds in the gelatin solution during storage. ### 1. Gelatin (Primary Component of shell) Gelatin forms the primary structural component of the capsule shell. It has excellent film-forming properties, which are essential for creating the flexible, elastic nature of soft gelatin