Capsule Dosage Forms

Capsule Dosage Forms

• The word "capsule" comes from the Latin "capsula," meaning small box
• In pharmacy, the word describes an edible package (shell) of gelatin or other suitable material filled with medicines for oral use

Types of Capsules

• Gelatin capsule shells can be hard or soft; depends on composition
• Hard Gelatin Capsules (HGC) consist of two pieces
• Soft Gelatin Capsules (SGC) are composed of one piece

Administration Route

• Most capsules are for oral administration
• Some soft capsules are for rectal or vaginal administration
• Some soft capsules can be cut open for external application of the contained medication, for example, ophthalmic use

Advantages of Capsules

• Can administer drugs with unpleasant odor/taste by containing in a tasteless shell
• Become smooth and slippery when moist, enabling easy swallowing
• Economical
• Easy to handle and carry
• Release medication when desired in the gastrointestinal tract
• Gelatin based
• Therapeutically inert
• Have an elegant appearance to enhance patient acceptance
• Solid, liquid, and viscous drugs can be encapsulated
• Formulations provide better drug stability compared to uncoated tablets and liquid dosages
• Development time is shorter compared to tablets

Disadvantages of Capsules

• Not suitable for substances that react with or dissolve gelatin
• Deliquescent ingredients cannot be encapsulated as they absorb water and become brittle
• Efflorescent substances cannot be encapsulated as they soften shells by releasing moisture
• Potential instability problems may be associated with liquid fills
• Manufacturing requires specialist techniques and is cost intensive

Hard Capsules

• Rigid and composed of two cylinder pieces closed at one end
• Are made in two halves; the 'body' which has a lower diameter is filled with drugs, and is then sealed with a 'cap' which has higher diameter
• Manufacturing involves two separate operations:
  • Shell manufacture
  • Shell filling

The Manufacture of Hard Gelatin Capsule Shells

• Shells are made in two sections: a body and a shorter cap
• Parts overlap when joined; the cap fits snugly over the body

Capsule Shell Composition

• Similar raw materials used for both types of capsules

Ingredients for Shells

• Gelatin
• Water
• Colorants

Optional Materials

• Process aids
• Preservatives
• Plasticizers

Gelatin

• Main component
• It is a heterogeneous product derived by irreversible hydrolytic extraction of treated animal collagen obtained from skin, white connective tissue and bones
• Does not occur naturally
• Shells are best when made from a mixture of bone and skin gelatin
• Bone gelatin creates a tough, firm but hazy and brittle film
• Skin gelatin adds plasticity and clarity, reducing haze or cloudiness in capsules
• Available as a fine or coarse powder, shreds, flakes, or sheets
• Physical and chemical properties are dependent on the parent collagen, extraction ,method and pH value

Gelatin Types

• Two types
  • Type A: produced by acid hydrolysis, exhibits an isoelectric point at pH 9
  • Type B: produced by basic hydrolysis, with an isoelectric point at pH 4

Type A Characteristics

• Acid process takes 7-10 days
• Used mainly for animal skins because they require less pretreatment than bones

Type B Characteristics

• Basic process takes about 10 times longer than the acid process
• Used mainly for animal bones

Properties of Gelatin

• Major component in capsules due to five basic properties
  • Non-toxic, widely used in foodstuffs, and acceptable worldwide
  • Soluble in biological fluids at body temperature
  • Good film-forming material, producing a strong flexible film
  • High concentration solutions (40% w/v) are mobile at 50°C, which other biological polymers (excluding agar) are not
  • Solutions in water or water-plasticizer blends undergo reversible change from sol to gel at temperatures slightly above ambient

Effects of Moisture on Gelatin

• Stable when dry but subject to microbial decomposition when moist
• Hard gelatin capsules contain 13-16% moisture and must be stored in conditions free from humidity or dryness
  • High humidity causes distortion and loss of rigid shape
  • Low humidity causes brittleness and crumbling
• Capsules are packaged with a desiccant to protect against atmospheric moisture

Gelatin Solubility

• Soluble in water at 37°C, rapidly dissolves in warm gastric fluid, and exposes contents
• Below this temperature rate of solubility will decrease
• Below 30°C gelatin is insoluble but softens in cold water, absorbing up to 10 times its weight in water
• Gelatin, being a protein, is digested by proteolytic enzymes and absorbed

Gelatin Alternatives

• Shell gelling materials are
  • Plant polysaccharides and derivatives (e.g., Hydroxy propyl methyl cellulose [HPMC])
  • Cellulosec.
  • Starch
  • Copolymer: poly-vinyl-alcohol (PVA)

Major Pharmacopoeia

• (European, Japanese and US) permits gelatin and other suitable material use
• Recent years shows hard capsules also manufactured from HPMC to produce shell alternatives

Alternative Shell Characteristics

• A low moisture content where percentages are generally 4-6 % less than gelatin capsule percentages (13-16%)
• Soluble at temperatures as low as 10°C

General Characteristics of Gelatin

• Include bloom strength and viscosity

Bloom Strength

• Bloom strength is a measure of the rigidity and stiffness of gelatin, and it indicates cross-linked gelatin strength
• Determined by preparing a standard gel (6.66% w/v) and maturing it at 10°C
• Also defined as the load in grams required to push a standard plunger 4 mm into the gel

Gelatin Required for Hard Capsule Manufacture

• Higher bloom strength (200-250 g), since a more rigid film is needed compared to softer capsules which only require (150 g)

Viscosity

• Determined on a 6.67% gelatin concentration in water at 60°C
• Measure of the molecular chain length, determines gelatin film characteristics
• Standard used: 25-45 millipoise
• When viscosity is lowered capsule thickness will decrease

Iron Content

• Always present in raw gelatin, its concentration depends on the water used in manufacture
• Limit: Gelatins in used should not contain more than 15ppm of iron

Water

• Essential component in gelatin mass prep
• Hard Gelatin Capsules contain 13–16% water
• Water content maintains the flexibility and mechanical strength of capsule shell
• Water content can vary depending on the storage conditions

Colorants

• Used to give capsules unique appearance
• Two types
  • Water-soluble dyes
  • Insoluble pigments

Water-Soluble Dyes

• They are mainly synthetic, and subdivided into
  • Azo dyes typically marked using the -N=N- linkage
  • Non-azo dyes, the most widely used
• The three most widely used:
  • Erythrosine (E127)
  • Indigo carmine (El32)
  • Quinoline yellow (E104)

Insoluble Pigments

• Two types
  • Titanium dioxide (El71) which is a white opacifier
  • Oxides of iron (El72) (black, red & yellow) for bicolored manufacturing

Mixtures

• Made by mixing together a range of colors with dyes and pigments

Ingestion

• Preference in current times has been moving away from soluble dyes toward pigments, specifically iron oxides, to ensure that they are not absorbed on ingestion

Process Aids

• Include wetting agents, preservatives and plasticizers

Wetting Agent

• USNF describes gelatin containing not more than 0.15% w/w of sodium lauryl sulphate for hard capsule maufacturing
• It acts to ensure lubricated metal moulds are uniformly covered by gelatin solution

Preservatives

• Formerly added to hard capsules as an in-process aid to prevent microbiological contamination during manufacture

Plasticizers

• Added to gelatin to confer softness, hardness, elasticity, and capsule shell thickness
• Added amounts depend on the capsule type (hard/soft) and storage conditions, and include glycerin, sorbitol and propylene glycol

Capsule Shell Manufacture

• The general process in use today is consistent with the original patent set in 1846
• Today this is fully automated, is continuous using large machines housed in air-conditioned buildings

Specialist Companies

• There are comparatively few that can manufacture empty capsule shells to supply to the pharmaceutical and health-food industries
• Examples of long standing companies include
  • Shionogi Qualicaps (formerly Eli Lilly & Co.) since 1897
  • Warner Lambert's Capsugel (formerly Parke Davis) since 1902

Preparation of Raw Materials

• First step: Prepare raw materials to produce a gelatin 'dipping solution'
• A 35-40% concentrated gelatin solution is prepared using demineralized hot water at 60-70°C in jacketed pressure vessels
• Stir until dissolved, then apply a vacuum to remove air bubbles
• Aliquots are dispensed to suitable containers, processing aids (plasticizer, colorant, opaquing agents, etc.) may be added
• Viscosity is measured and adjusted to target value with hot water addition
• The latter controls capsule shell production thickness; the higher the viscosity, the thicker the shell wall
• The prepared mixture 'dipping solution' is transferred to a heated holding hopper 'dipping pan' on the manufacturing machine

Shell Manufacturing Process

• Number of stages
  • Dipping
  • Spinning
  • Drying
  • Stripping
  • Trimming
  • Joining
  • Sorting
  • Printing
  • Testing
  • Packaging

Dipping

• The machine consists of two mirror image halves that form both cap and body halves
• Moulds known as 'pins' are made of stainless steel and mounted in sets on metal strips, called 'bars'
• Pairs of desired shape and diameter pins are dipped into a temperature-controlled reservoir of melted gelatin mixture solution to simultaneously form caps and bodies
• The pins are lubricated with a mold-release agent
• Temperatures: ambient temperature is at 22°C whereas dipping sollution is at 50°C in heated jacketed pan
• Cap and body are dipped in the same time into a solution of similar viscosity
• Solution viscosity, rate and time of dipping determine shell thickness

Spinning

• Pins are slowly withdrawn from the solution and rotated during transfer to the upper machine level to:
  • Help distribute gelatin uniformly over the pins
  • Form a film of uniform thickness
  • Avoid bead formation at the capsule ends
• After rotation, they receive a blast of cool air to set the film

Drying

• Racks of gelatin-coated pins pass into a series of four drying ovens
• Drying occurs through dehumidification by passing significant volumes of dry air over the pins; temperature can only be increased a few degrees to avoid film metling
• Rapid drying can cause shell hardening

Drying Over Control

• Gelatin films may shrink.
• Over drying on any pins may split
• This leads films to be brittle for the next trimming stage
• Under drying will leave the films too pliable or sticky for subsequent stages

Stripping

• A series of bronze jaws strip dried cap and body portions from the pins

Trimming

• Stripped cap and body parts are delivered to collets where they are held firmly
• As collet rotates, knives held against the shells trim to desired length

Joining

• Caps and bodies are joined together, and the complete capsule is delivered from the machine
• Pins are cleaned and lubricated for the next cycle
• The joined capsules are not fully closed but in a 'prelocked' position to prevent separation before filling

Sorting

• Capsules are passed on a lighted moving conveyer for visual examination
• Defective capsules are manually removed
• Serious defects include imperfect cuts, dented capsules, or capsules with holes

Printing

• Capsules are printed while empty (if required)
• Empty capsules are handled faster than filled ones; avoids material loss from damage during printing
• The following is printed: product name, strength, company name/logo, or an identification code.

Testing

• Testing occurs once the printing has completed
• Capsules undergo rigorous quality checks including: size, moisture content, single wall thickness, and color to ensure desired quality and shelf life.

Packaging

• Manufactured empty capsules are packaged for shipment in moisture-proof liners (preferably heat-sealed aluminum foil bags) inside cardboard boxes
• This storage enables long periods without quality compromise as long as sudden temperature changes are avoided (these will affect moisture content)

Capsule Sizes

• Empty gelatin capsules are manufactured in various lengths, diameter, and capacities
• Size selected depends on the amount of fill material being encapsulated and bulk density/compressibility to pack into a capsule shell
• For human use, empty capsule sizes range from 000 (largest) to 5 (smallest), larger capsules available for veterinary use

Determination of Capsule Fill Weight

• Fill weight relies on the powder density, and particle size
• Some powders are denser than others, but fill rate depends on fine-ness

Estimating Fill Weight

• The simplest way to estimate the fill weight is
  • Capsule fill weight = Tapped bulk density of formulation × capsule volume

For Liquids

• Equation
  • Capsule fill weight = the specific gravity of the liquid × the capsule body volume x 0.8

Capsule Shell Shape and Design

• Distinctive-looking capsules made by altering capsule-making pegs shape; tapering the body-producing peg while leaving the cap-making peg rounded prepares capsules as those made by other manufacturers (Pulvules, Eli Lilly)
• The ends of both bodies and caps can be tapered (Spansule Capsules, SmithKline Beecham)

Another Innovation in Capsule Shell Design

• Snap-fit capsule
  • Original construction enables positive joining of the two halves via locking grooves in the shell walls
  • Grooves fit to ensure the filled capsule closes reliably

Coni-Snap Capsule

• Occurrences such as high-speed capsule filling machine defects of splitting (telescoping) and denting led to its development
• In these capsules, the rim is not straight but slightly tapered, which reduces capsule joining rims and substantially eliminates splitting during a large-scale filling process

Coni-Snap Supro Capsule

• The cap extends far enough over the body that only the rounded edge of the body remains visible
• This creates difficult and more secure handling

Filling of Hard Capsules

• Hard capsules can be filled with a variety range of different materials/ properties
• Gelatin and Hypromellose (HPMC) are inert with limitations in the materials that can be used

Material Limitations

• Cannot react with gelatin (e.g., formaldehyde causes crosslinking, making the capsule insoluble)
• Must not interfere with the integrity of the shell (high free water levels can be absorbed by gelatin, causing softening/distortion)
• The unit dose volume is limited so as to ensure the capsule can still be closed

Types of Materials for Hard Capsule Filling

• Are
  • Dry Solids
  • Semisolids
  • Liquids

Dry Solids

• Powders
• Pellets
• Granules
• Tablets
• Capsules

Semi-Solids

• Thermo-softening mixtures
• Thixotropic mixtures
• Pastes

Liquids

• Non-aqueous liquids

Preparation of Filled Hard Gelatin Capsules

• The preparation scales into the following steps:
  • Formulation development/preparation, and capsule size selection
  • Filling the capsule shell
  • Optional capsule sealing
  • Cleaning/polishing the filled capsules

Formulation Development and Preparation

• In developing a capsule formulation, the goal is to prepare a capsule that shows:
  • Accurate Dosage
  • Good Bioavailability
  • Ease of Filling and Production
  • Stability and Elegance

Pharmaceutical Processing

• The the pharmaceutical processing for filled hard gelatin capsules
  • In dry formulations, it is uniform to achieve drug distribution where active and inactive components must be made

Milling

• Milling is used to mix particles ensuring uniform powder for the fill
• Particle sizes should range from about 50 to 1,000 µm, and is suitable for lower dose drugs i.e 10 mg or greater
• Micronization produces particles ranging from about 1 to 20 µm

Powders Formulation

• Most products for encapsulation are powders
• They are typically mixtures of the API and various excipients

Excipients

• Selection depends on several factors
  • Properties of the API (dose, solubility, particle size, shape)
  • The filling machine to be used
  • Size of the capsule to be filled

Excipients Used in Powder Filled Capsules

• The types of excipients summarised in the following table are as:
  • Diluent (filler)
  • Disintergrates
  • Lubricant or glidant
  • Wetting agents

Diluent Example

• Lactose
• Microcrystalline cellulose MCC
• Starch

Diluent Fillers

• To produce the proper capsule fill volume
• To provide cohesion to the powders
• Gives plug-forming characterisitics

Disintegrates Example

• Pregelatinized starch
• Croscarmellose and sodium starch glycolate

Disintegrates Function

• Cause disruption of the powder mass

Lubricant function

• Fumed silicon dioxide
• Magnesium stearate
• Calcium stearate
• Stearic acid
• Talc

Lubricant or Glidants Function

• To reduce powder adhering to metal surfaces

Wetting Agents

• Surfactants Such as sodium lauryl sulfate

Wetting Agents Function

• To improve water penetration to the dry powder

Main Factors in Powder Formulation

• Good Flow (using a flow diluent and glidant)
• Cohesion (using a lubricant)
• No adhesion (plug-forming diluent)

Capsule Filling Process

• The same basic operations is carried out being filled by the bench for extemporaneous dispensing or on high-speed automatic machines for industrial products
• Basic operation if
  • Rectification

Rectification

• The empty capsules oriented in a way they are at the same direction
• The body would be downward which means frictional grip
• Capsule will always be aligned body end downward

Main Processes

• The processes include steps such as:
  • Capsules comveying
  • Pressing capsule head
  • Clamping
  • Capsule insertion

Separation of Cap From Bodies

• This process depends on the difference in cap diameter and body of the rectified capsules delivered with capsule downwards
• Vacuum applied is used to pull the bodies downwards to the lower portion, split bushing capsule that is
• Split bushings are separated to expose the capsule for filling

Dosing of Fill Material

• The bodies are passed under a a dosing mechanism and filled with the chosen formulation

Main Processes include

• A condition before or vaccum connecting capsules
• Condition with complete vaccum applied to capsules

Scrapping of Excessive Powder

• In this process the excess power being used is scraped

Replacement of Cap and Ejection of Filled Capsule

• Following the steps is the replacing the cap after filling
• A capsule filling machine uses this principle

Capsule Filling Methods

• Capsule filling methods and machines include:
  • Bench scale Filling
  • Industrial scale filling
  • Extemporaneous filling

Bench-Scale Filling:

• Is done in two ways: - Manual filling - Hand operated filling machine

Industrial-Scale Filling:

• Is done in to ways: - Semi Automatic Machine filling - Fully Automated Capsule filling machine

Extemporaneous Filling (bench-scale filling):

• Is done by - Is done be manually to a small quantity of capsules, in small laboratories or facilities

Manual Filling:

• Is done by - Punching Method: this a clean method of using a porcelain plate which is used to extract formula into the capsule bodies

Hand Operated Machine Filling

• The 'Feton' by Belgium
• The 'Labocaps' by Denmark These sets are made up of plates comprising holes to take capsules with sizes ranging from 200 - 300 in a specific sie
• Autoclaved steel plated may complie with GMP requirements

A hand operated gelatin capsule filling machine

1. a bed with 200-300 holes
2. a capsule loading tray
3. a powder tray
4. a pin plate having 200 or 300 pins corresponding to the number of holes in the bed and capsule loading tray.
5. a lever
6. a handle
7. a plate fitted with rubber top.

Capsule Insertion Method

1. Empty capsules are fed into the wholes, either manually or with a simple loading device.
2. The bodies are locked in their plate by a screw and the caps are separated in their plate.
3. The bodies are released and dropped below the plate surface.
4. Powder is placed onto the surface and is spread with a spatula so that is fills the bodies.
5. The cap plate is then repositioned over the body plate and the capsules are rejoined using manual pressure.

Large Scale Machine filling

• With a greater number of shapes, sizes, and ranges, industrial machines are fully automatic and can range from 3000 to 150 000 per hour

There are two systems

• Dependent
• Independent

Dependent Machines

• They use Dosing systems (Auger machines):.
• They Use Capsules and directly measure the given formula

Independent Machines

• These use Doing Systems (Pistin-tamp Machines):.
• Dosing systems use powder independently which is measured independently in specialized devices with multiple process

Types of Independent Machines

1. Dosator machines
2. Dosing-Disk Machines

Semi Automatic Machines

• They use Dependent systems - (Auger Machines): . - Are more manual with manual operations compared to others

In Insemi-Automatic machines

• Empty Capsules are fed to a pair of ring holders that have the capsules being in one had and bodies in the with the body holder being on
• The hopper has various speeds using a revoluting table and a auger feed for various capsule ring holders
• Pneumatic and mechanical force is involved to eject caps to the other locations

Types of Systems for Capsule Formula and Manufacturing

• Material Hopper Peg Rings Joiner Plates Rectifier Raceway

Fully Automatic Capsule Machines

• Independent dosing systems - Piston Tamp Machines
• Pillows which are lightweight compres and lightly compress soft tablet like drugs in the machine

Operation of Fuly Automatic Machines

• Has two disk machines called the - Disator and the Dosing Has components like a Dosing tube like a Piston but has a volume chamber with with a spring
• Operates in several stages

Operation Stages of Automatic Machines

• 1 the open end fube is lowered to a powder bed like surface to fill capsule chamber
• 2 - The plug is compressed by force applying pressure
• 3 - Then Tuber is shifted to the chamber to postion the final capsule
• 4 The pistins ejected into the capsule

Types of Capsule Dosing Machines

1. Dosing Plate
2. Rotary Plate Both are high production volume machines, rotary typically being faster depending on the conditions

• The amount of powder can be determined
• By the position by volume

Examples of Machines

• Zanasi (IMA)......
• They have rates from 3000-6000+
• MG2 rates 3000+

Dosing disk and tamping finger machines

are called Disators

• has steel piston rodding used to compres tablets and holes to form cavities
• has sliding brass to plate on the bottom to close cavities

Dosing Piston Operation Stages

• 1 Powder is maintained over a consistent layer
• 2 Pressure is consistently applied to add powder in form and the set pistion
• 3 Finaly the powder scraped and plugged and pushed via transfer
• Aligner,

Other Factors

Tamping Pressure being applied Adjusting the drum the powder is applied The amount powdered applied

Difficulties In Capsule Filling

• Deliquescent / Hygroscopic powders.

Remedy: of Capsules

• Adsorbent [magnesium carbonate, heavy / light magnesium oxide]

Eutectic mixture

• (Mixtures that tend to liquefy),

Remedy Mixtures

• may require a diluent or absorbent to separate physically the interacting agents and to absorb any liquefied material [magnesium carbonate, kaolin]

Other Remedies

• Increase inert Formula
• Change size to fix incmpatblities
• With adhesion methods alchol or reduce molecules with powder

Capsule Sealings

• Is a process to prevent tampering of tampering the capsule

Sealing Types

1 - Banding: two capsuel are joint be gerlating polymer 2 - Water Ethanal: Contact the area with this process at 40-15 degrees

Capsule Sealing production

• 150,000 pre unit

Cleaning and Polishing

• Can be completed as follow as some powder formulation will attach to the outside
• May have a taste or reduce the overall capsule

Pan Polshing

• Polish the capsule by adding cheese colth dust and adding it the liner
• Remove dust to imprat capsule and glosse

Cloth Dusting

• In this method:
  • Large numbers can be brushed easy -Powder canbe removed
• May need further steps

Brushing Techniques

• Adding capsule and brushes via brushes and or dusters - may have vacuming and automation

Commercial Types

• ROTOCORD - Removed powder for unfilled joiunts etc...
• Ewarka
  • Polishing/ Dusters
• Scidener and Other are avalible