Soft gelatin capsules

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Chapter: Pharmaceutical Drugs and Dosage: Capsules

Soft gelatin capsules consist of a hermetically sealed outer shell of gelatin that encloses a liquid or semisolid medicament in the unit dosage.


Soft gelatin capsules

Soft gelatin capsules consist of a hermetically sealed outer shell of gelatin that encloses a liquid or semisolid medicament in the unit dosage. Soft gelatin capsules are a completely sealed dosage form and cannot be opened without destroying the capsules. Drugs that are commercially prepared in soft capsules include cyclosporine, declomycin, chlorotrianisene, digoxin, vitamin A, vitamin E, and chloral hydrate.

Figure 21.1 shows different shapes of soft gelatin capsules.


Figure 21.1 Schematic diagrams illustrating different shapes of soft gelatin capsules. The range of fill volumes is also indicated.


Advantages and disadvantages of soft gelatin capsules

Soft gelatin capsules provide a patient-friendly dosage form for peroral administration of nonpalatable and/or oily liquids. Solutions or suspensions with an unpleasant odor or taste can be easily ingested in a soft gelatin cap-sule dosage form, which offers tidy appearance and convenient ingestion.

This dosage form can be particularly advantageous for low dose drugs that are lipid soluble because it can allow greater uniformity of content between dosage units than the conventional tablet dosage form. It can also be more suitable than a tablet dosage form for the encapsulation of liquid, water-insoluble drugs. The capsules can be formulated to be immediate release (IR), slow or sustained release (SR), or enteric coated.

The use of soft gelatin capsule shell imposes significant limitations on the drug formulations that can be encapsulated in this dosage form, that is, restricted to liquids and semisolids. The manufacturing process is rela-tively tedious and difficult to optimize (e.g., ribbon thickness, fill weight, and weight variation). In addition, the breakage of even one capsule during the manufacturing can lead to the coating of drug formulation on the outer surface of several other capsules. This can also happen dur-ing storage in multiple use containers, such as high-density polyethylene (HDPE) bottles.

Soft gelatin capsules have certain disadvantages compared to liquid-filled hard gelatin capsules. Due to the relatively higher water content in soft gela-tin shell (20–30% w/w) compared to hard gelatin capsules (13–16% w/w) moisture-sensitive drugs may not be stable in soft gelatin capsules. In addi-tion, the maximum temperature of the formulation that can be filled into soft gelatin capsule without deformation of the shell and other production issues is about 35°C, whereas a formulation can be filled at up to 70°C in hard gelatin capsules without shell deformation. Extreme acidic and basic pH must also be avoided because a pH below 2.5 hydrolyzes gelatin, whereas a pH above 9 has a tanning effect on the gelatin.


Drivers for development of soft gelatin capsules

Soft gelatin capsules are often developed for one or more of the following reasons:

1. Line extension products for strategic marketing advantage in a thera-peutic area with intense competition. For example, cough and cold medicines available as a soft gelatin capsule can offer patient benefit, such as ingestion without water and portability.

2. Technological advantage such as good content uniformity of a low dose drug or formulation of a water-insoluble drug that is liquid at room temperature.

3. Safety reasons during product manufacturing, dispensing, and usage. For example, most of the product manufacturing unit operations of tablets and hard gelatin capsules involve handling of fine powders. In the case of soft gelatin capsules, the powder handling is restricted to drug dissolution or dispersion in a liquid medium. Powders inher-ently have greater exposure hazards than liquids. Therefore, soft gel-atin 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.

4. Improved oral bioavailability: The use of certain lipids can be asso-ciated with increased oral bioavailability and reduced intra- and interpatient variability by modification of GI digestive processes. In addition, presentation of the drug in a predissolved state can lead to shorter duration to the onset of action. By formulating nifedipine or ibuprofen into soft gelatin capsules after being dissolved in PEG, the bioavailability of these drugs can be improved.


Formulation of soft gelatin capsule shell

The composition of the soft capsule shell consists of three main ingredi-ents: (1) gelatin, (2) plasticizer, and (3) water. In contrast to hard gelatin capsules, a relatively large amount (~30 % w/w) of plasticizers is added in soft gelatin capsule shell formulation to ensure adequate flexibility. Water is used to form the capsule, and other additives are often added as needed.

Table 21.3 Typical composition of a soft gelatin capsule shell


A typical composition of the soft gelatin capsule shell is listed in Table 21.3 and the functional components are described as follows:

1. Gelatin: Similar to hard gelatin shells, the basic component of soft gelatin shell is gelatin. The properties of gelatin shells are controlled by the choice of gelatin grade and by adjusting the concentration of plasticizer in the shell. The physicochemical properties of gelatin are controlled to allow

·           Adequate flow at desired temperatures to form ribbons of defined thickness, texture, mechanical strength, and elasticity.

·           Ribbons to be easily removed from the drums, stretch during fill-ing, seal the temperature below the melting point of the film, and dry quickly under ambient conditions to an adequate and a repro-ducible strength.

Physicochemical properties of gelatin important to capsule formation include gel strength, viscosity, change in viscosity with temperature and shear, melting point, settling point (temperature), settling time, particle size (affects time to dissolve), and molecular weight distribu-tion (affects viscosity and strength).

2. Plasticizer: A plasticizer interacts with gelatin chains to reduce the glass transition temperature (Tg) of the gelatin shell and/or promotes the retention of moisture (hygroscopicity). The most common plasti-cizer used for soft gelatin capsules is glycerol. Sorbitol, maltitol, and polypropylene glycol can also be used in combination with glycerol. Glycerol derives its plasticizing ability primarily from its direct inter-actions with gelatin. In contrast, sorbitol is an indirect plasticizer because it primarily acts as a moisture retentive agent. Compared to hard gelatin capsules and tablet film coatings, a relatively large amount (~30% w/w) of plasticizers are added in a soft gelatin capsule formulation to ensure adequate flexibility.

3. Water: The desirable water content of the gelatin solution used to pro-duce a soft gelatin capsule shell depends on the viscosity of the specific grade of gelatin used. It usually ranges between 0.7 and 1.3 parts of water to each part of dry gelatin. After the capsule is formed, most of the water is removed by drying. The finished soft gelatin capsules contain 13–16 % w/w water.

4. Preservative: Preservatives are often added to prevent the growth of bacteria and mold in the gelatin solution during storage. Potassium sorbate, and methyl, ethyl, and propyl hydroxybenzoate are com-monly used as preservatives.

5. Colorant and/or opacifier: A colorant and/or opacifier (e.g., titanium dioxide) may be added to the shell for visual appeal and/or reducing the penetration of light for the encapsulation of a photosensitive drug. The color of the capsule shell is generally chosen to be darker than that of its contents.

6. Other excipients: Other, infrequently, used excipients can include fla-vors and sweeteners to improve palatability and acid-resistant poly-mers to impart enteric release characteristics. They can also be used to formulate chewable soft gelatin capsules, for example, ChildLife’s Pure DHA chewable 250 mg soft gel caps. A chelating agent, such as ethylene diamine tetracetic acid (EDTA), can be added to prevent chemical degradation of oxidation sensitive drugs catalyzed by free metals in gelatin, such as iron.


Drug formulation for encapsulation in soft gelatin capsules

Soft gelatin capsules may contain a liquid or semisolid solution, suspension, or preconcentrate of a self-emulsifying or self-microemulsifying system. For example, Accutane® is a suspension of isotretinoin in oil, Sandimmune® is a self-emulsifying preconcentrate, and Neoral® is a self-microemulsifying preconcentrate.

Formulation considerations for the contents of the soft gelatin capsules include the following:

·           Noninteraction with gelatin: The contents of the soft gelatin capsule should not interact with the gelatin shell.

·           Nonmoisture sensitivity: The moisture content of soft gelatin cap-sules plasticized with glycerol is considerably higher than that of hard gelatin capsules. Therefore, to ensure chemical stability of the drug, moisture-sensitive drugs should not be formulated in soft gelatin capsules.

·           Nontemperature sensitivity: The molten gelatin mass usually has a pourable viscosity at 60°C–70°C. Therefore, the sealing operation is usually carried out at a higher than ambient temperature. Hence, highly thermolabile drugs may not be encapsulated in soft gelatin capsules.

·           pH: Extreme acidic and basic pH should be avoided because a pH below 2.5 hydrolyzes gelatin (leading to leakage), whereas a pH above  9 has a tanning effect on the gelatin. Tanning process involves cross-linking of gelatin, which results in hardening of the shell. The shell becomes insoluble in water and resistant to digestion by GI enzymes: trypsin and chymotrypsin.

Drugs for encapsulation in a soft gelatin capsule are usually dissolved or suspended in a suitable carrier. Insoluble drugs are often dispersed or sus-pended in an agent such as beeswax, soybean oil, or paraffin. Surfactants are often added to promote wetting of the ingredients. The use of water or ethanol in the fill composition is only possible with special modifica-tions of the capsule shell. Drugs can be dispersed in ethylcellulose for an SR effect.


Manufacturing process

Soft gelatin capsules are filled with solutions or suspensions of drugs in liquids, and sealed in a single operation. They are prepared from a more flexible plasticized gelatin by a rotary-die process. As shown in Figure 21.4, this process involves the following sequential operations:

1.        Two heated sheets of gelatin of similar thickness are produced by the controlled flow of the fluid gelatin from its heated storage container (gelatin tank) by using a controlled pore opening and fill in a spreader box.

2.        The gelatin film flows through a series of oil rolls that stretch the sheets and direct them appropriately toward die rollers.

3.        The two sheets of gelatin merge on the metallic rollers that contain dies of appropriate shape and size and move in the opposite direc-tion toward each other. The application of vacuum inside the rollers combined with pressurized filling of the components enables the for-mation of a cavity. The application of heat and mechanical pressure enables sealing of the shells as they pass through the rollers.

4.        As the gelatin sheets are being annealed, a calibrated amount of the drug formulation is pumped into each cavity by the product pump through an injection wedge.

5.        The concurrent process of drug product injection into the die cavity and sealing of the cavity is either accompanied by the cutting and release of individual soft gelatin capsules (if the rollers are suitably designed) or, as shown in Figure 21.4, the capsules may be cut from the sheets in a separate, subsequent operation.

6.        The filled capsules are dried at ambient conditions to remove moisture from the outer surface and may be tray dried for an extended period of time (e.g., up to 48 hours).

7.        Finished capsules are passed on a conveyor belt for the next unit operations of packaging and labeling.


Figure 21.4 Manufacturing process of soft gelatin capsules. (Adapted from http:// www.sunkingpm.com/htm/PM/SCP/5.html)


Nongelatin soft capsules

The use of alternate polymers for the formation of soft capsules is driven by marketing or formulation requirements. For example, Vegicaps® are animal-free. Their shell is made from seaweed extract and gluten-free starch. For moisture sensitive drugs, HPMC capsules may be preferred, which generally have lower equilibrium moisture content than gelatin cap-sules. HPMC capsules also have better physical stability on exposure to low humidity.

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