Table of Contents
Capsules are solid dosage forms in which the drug substance is enclosed in either a hard or soft soluble container or shell of a suitable form of gelatin.
Different Steps in capsule production:
1. Mixing of ingredients
2. Granulation and lubrication
3. Making of capsules
4. Filling of capsules
5. Uniformity testing
6. Packing and labeling
Both tablets and capsules are produced from ingredients that may be either dry blended or wet granulated to produce a dry powder or granule mix with uniformly dispersed active ingredients. To produce capsules on high-speed equipment, the powder blend must have the uniform particle size distribution, bulk density, and compressibility required to promote good flow properties and result in the formation of the compact of the right size and sufficient cohesiveness to be filled into capsule shells.
Manufacturing of Hard Gelatin Capsules
- Gelatin: It is prepared by the hydrolysis of collagen. There are two basic types of gelatin: Type-A and Type-B. The two types can be differentiated by their isoelectric points (7.0 – 9.0 for type-A and 4.8 – 5.0 for type-B) and by their viscosity and film-forming characteristics. A combination of pork skin and bone gelatin is often used to optimize shell characteristics. The physicochemical properties of gelatin of most interests to shell manufactures are the bloom strength and viscosity.
- Colorants: Various soluble synthetic dyes (coal tar dyes) and insoluble pigments are used. Colorants not only play a role in identifying the product but also play a role in improving patient compliance. For example, white – analgesia, lavender – hallucinogenic effects, orange or yellow – stimulants and antidepressants.
- Opaquing agents: Titanium dioxide may be included to render the shell opaque. Opaque capsules may be employed to provide protection against light or to conceal the contents.
- Preservatives: When preservatives are employed, parabens are often selected.
- Dipping: Pairs of the stainless-steel pins are dipped into the dipping solution to simultaneously form the caps and bodies. The pins are at ambient temperature; whereas the dipping solution is maintained at a temperature of about 50o C in a heated, jacketed dipping pan. The length of time to cast the film has been reported to be about 12 sec.
- Rotation: After dipping, pins are elevated and rotated 2-1/2 times until they are facing upward. This rotation helps to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends.
- Drying: The racks of gelatin-coated pins are then passed into a series of four drying ovens. Drying is mainly done by dehumidification. A temperature elevation to only a few degrees is permissible to prevent film melting. Under drying will leave the films too sticky for subsequent operation.
- Stripping: A series of bronze jaws strip the cap and body portions of the capsules from the pins.
- Trimming: The striped cap and body portions are delivered to collects in which they are firmly held. As the collects rotate, knives are brought against the shells to trim them to the required length.
- Joining: The cap and body portions are aligned concentrically in channels and the two portions are slowly pushed together.
- Sorting: The moisture content of the capsules as they are from the machine will be in the range of 15-18% w/w. During sorting, the capsules passing on a lighted moving conveyor are examined visually by inspectors. Defects are generally classified according to their nature and potential to cause problems in use.
- Printing: In general, capsules are printed before filling. Generally, printing is done on offset rotary presses having throughput capabilities as high as three-quarter million capsules per hour.
- Sizes and Shapes: For human use, empty gelatin capsules are manufactured in eight sizes, ranging from 000 to 5. The largest size normally acceptable to the patient is a No. 0. Three larger sizes are available for veterinary use: 10, 11, and 12 having capacities of about 30, 15, and 7.5 gm, respectively. The standard shape of capsules is a traditional, symmetrical bullet shape. Some manufactures have employed distinctive shapes. For example, Lilly’s pulvule tapers to a bluntly pointed end, Smith Kline Beacham’s spansule capsules taper at both the cap and body end.
- Sealing: Capsules are sealed and somewhat reshaped in the Etaseal process. This thermal welding process forms an indented ring around the waist of the capsule where the cap overlaps the body.
- Storage: Finished capsules normally contain an equilibrium moisture content of 13-16% to maintain a relative humidity of 40-60% when handling and storing capsules.
Filling of Hard Gelatin Capsules:
- Equipment used in capsule filling operations involve one often of two types of filling systems:
- Zanasi or Martelli encapsulator: Forms slugs in a disaster which is a hollow tube with a plunger to eject capsule plug.
- Holliger-Karg machine: Forms compacts in a die plate using tamping pins to form a compact.
- In both these systems, the scale-up process involves bulk density, powder flow, compressibility, and lubricant distribution. Overly lubricated granules are responsible for delaying capsule disintegration and dissolution.
- Osaka Model R-180 Semi-Automatic Capsule Filling Machine.
Manufacturing of Soft Gelatin Capsules
Composition of the shell:
- Similar to hard gelatin shells, the basic component of a soft gelatin shell is gelatin; however, the shell has been plasticized.
- The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3-1.0 for the very hard shell to 1.0-1.8 for the very softshell.
- Up to 5% sugar may be included to give a “chewable” quality to the shell.
- The residual shell moisture content of finished capsules will be in the range of 6-10%.
- The formulation for soft gelatin capsules involves liquid, rather than powder technology. Materials are generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness, and manufacturing efficiency. The liquids are limited to those that do not harm gelatin walls. The pH of the lipid can be between 2.5 and 7.5. The emulsion cannot be filled because water released from it will affect the shell.
- The types of vehicles used in soft gelatin capsules fall into two main groups:
- Water immiscible, volatile, or more likely more volatile liquids such as vegetable oils, mineral oils, medium-chain triglycerides, and acetylated glycerides.
- Water miscible, non-volatile liquids such as low molecular weight PEG have come into use more recently because of their ability to mix with water readily and accelerate the dissolution of dissolved or suspended drugs. All liquids used for filling must flow by gravity at a temperature of 35°C or less. The sealing temperature of gelatin films is 37°C – 40°C.
1. Plate Process: The process involves:
- Placing the upper half of a plasticized gelatin sheet over a die plate containing numerous die pockets,
- Application of vacuum to draw the sheet into the die pockets,
- Filling the pockets with liquor or paste,
- Folding the lower half of the gelatin sheet back over the filled pockets, and
- Inserting the “sandwich” under a die press where the capsules are formed and cut out.
2. Rotary Die Press:
- In this process, the die cavities are machined into the outer surface of the two rollers.
- The die pockets on the left-hand roller form the left side of the capsule and the die pockets on the right-hand roller form the right side of the capsule.
- Two plasticized gelatin ribbons are continuously and simultaneously fed with the liquid or paste fill between the rollers of the rotary die mechanism.
- As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the filled capsules.
3. Accel Process:
- In general, this is another rotary process involving a measuring roll, a die roll, and a sealing role.
- As the measuring roll and die roll rotate, the measured doses are transferred to the gelatin-linked pockets of the die roll.
- The continued rotation of the filled die converges with the rotating sealing roll where a second gelatin sheet is applied to form the other half of the capsule. The pressure developed between the die roll and sealing roll seals and cuts out the capsules.
4. Bubble Method:
- The Globex Mark II encapsulator produces truly seamless, one-piece soft gelatin capsules by a “bubble method”. A concentric tube dispenser simultaneously discharges the molten gelatin from the outer annulus and the liquid content from the tube. Using a pulsating pump mechanism, the liquids are discharged from the concentric tube orifice into a chilled oil column as droplets that consist of a liquid medicament core within a molten gelatin envelope. The droplets assume a spherical shape under surface tension forces and the gelatin congeals on cooling. The finished capsules must be degreased and dried.
Soft/Liquid-filled Hard Gelatin Capsules
- Three formulation strategies based on having a high resting viscosity after filling have been described:
– Thixotropic formulations,
– Thermal-setting formulations,
– Mixed Thermal-Thixotropic systems.
The more lipophilic contents, the slower is the release rate. Thus, by selecting excipients with varying HLB balance, the varying release rate may be achieved.
- To produce capsules on high-speed equipment, the powder blend must have,
– Uniform particle size distribution.
– Bulk density.
– Formation of the compact of the right size and of sufficient cohesiveness to be filled into capsule shells.
- Types of equipment:
– Zanasi or Mercalli
– Dosator (hollow tube).
– Tamping pins.
Weight variation problems can be encountered with these two methods. Overly lubricated granules – delaying disintegration.
- Humidity affects the moisture content of:
– On empty gelatine capsules.
- At high humidity: Capsule swells make separation of the capsule parts difficult to interfere with the transport of the capsule through the process.
- At low humidity: Capsule brittle increased static charge interferes with the encapsulation operation.
Examination of the formula to determine:
1. Ability to withstand batch-scale.
2. Process modification.
3. Compatibility of the equipment with the formulation.
4. Cost factor.
5. Physical space required.
6. Market requirement.
7. Layout of the related functions.
8. Availability of the raw materials meeting the specifications.
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