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Capsules

Solid dosage forms in which medicinal agents are enclosed in a small shell of gelatin (hard or soft)
Contain gelatin, water, colorants, & optional materials like process aids or preservatives

Advantages of capsules

Odorless
Tasteless
Easily swallowed (consider caplets)
Elegant

Soft gelatin capsules

contain plasticizers like glycerin or sorbitol

Composition of Hard Gelatin caps

Gelatin
Water
Additives (Dyes, opaquing agent, preservative)

Hard Gelatin Cap formulation

Active ingredient
Filler/diluent (direct compression fillers preferably for flow and compactibility)
Lubricants
Glidants
Disintegrants

Gelatin

Natural - hydrolysis of collagen
Major component of caps
Nontoxic and acceptable to use worldwide
Readily soluble at body temp
Good film-forming material - strong & flexible films
Solutions of high concentration mobile at 50 C
Solution in water or in water-plasticizer blend undergoes reversible change from sol to gel at temps only a few degrees above ambient

Type A gelatin

produced by acid hydrolysis
- takes about 7-10 days, used maily for procin skins - require less pretreatment than bones

Type B gelatin

produced by basic hydrolysis
10 x as long, use for bovine bones

Limitations for properties of materials used for filling caps

Cannot react with gelatin
Cannot contain high level of free moisture
Volume of the unit dose cannot exceed the sizes of capsules available

Colorants

Water soluble dyes and insoluble pigments
Pigments and dyes mixed for range of colors
Dyes mostly synthetic, subdivided into azo and non-azo dyes
Pigments not absorbed on ingestion

Process Aids

Sodium lauryl sulfate - wetting agent
Usually no need for preservatives - water activity will not support bacterial growth (bonded to gelatin)

Hard Gelatin Capsule Shell

Mostly from gelatin, some from HPMC (hypromellose)
religious, cultural or other reasons - alternatives to animal derived components
HPMC slower speed of gelling - machine output reduced
Gelatin caps unsuitable for aq liquids because water softens gelatin, distorts cap resulting in leakage

Dipping process

metal molds dipped into hot gelatin solution, which gels to form a film
Higher the viscosity, the thicker the shell wall produced
Dried, cut to length, removed from mold & 2 parts are joined together

Fill Options

Solid at ambient temp, liquefied by heating (thermosoftening mixture)
Liquefied by stirring - thixotropic mixture
liquid filling - how to protect/guard against leakage, gelatin seal
Granules or coated pellets or tabs

Formulation Modifications

Protect stomach - enteric film coating around filled caps or formulate contents as pellets & coating with enteric polymer

Enteric coated

soluble at only high pH further down GIT for targeting specific sites or coatings that are disrupted by colon specific enzymes

Floating capsules

Contain various hydrophillic polymers that swell on contact with water and form a mass that can float on gastric fluids - dissolve slowly, releasing continuous flow of solution into intestine

Characteristics of formulations to be filled into caps

Capable of being filled uniformly to give stable product
Release active contents in form available for absorption
Comply with requirements of pharmacopeial and regulatory authorities
Release of active ingredient starts by disintegration of capsule shell

Dissolution from Hard Gelatin Cap

Dissolution rate of shell
Rate of penetration of dissolution medium
Rate of deaggregation of powder mass
Nature of primary drug particles
Cross-linking can reduce shell solubility in water

Hard Gelatin Caps advantages

Flexibility of formulation (easy compounding, strong compact not required, unique mix fills, easy for clinical trial material)
Can achieve IR and MR profiles
Once sealed, good barriers to O2

Hard Gelatin Caps Disadvantages

Encapsulation machines slower than tablet machine
Bulky material difficult to fill
Concern maintaining proper shell moisture content (too dry - brittle, fractured, too moist - too soft, sticky)
Cross-linking issues for all cap products

Encapsulation

Manual or automatic filler
Different DFs

Capsule dosage forms

Powders, pellets, microtablets, tablet, tablet/powder or pellet/tablet combinations into 2 piece gelatin capsule

Manual capsule filling machine

Loads caps in machine, removes top halves, fills remaining halves with powder, tamps, and closes capsules all in one simple procedure

Continuous motion capsule filling machines

Designed for speed, reliability, economy, and precision
Caps filled with powder or pellets using a single tower design that performs simultaneous operations.
Dosing precise to within 1%

Softgels

Similar to hard gelatin caps except plasticizer incorporated in shell
Made of modified starch
Usually filled with liquids or suspensions
Filling with dry solids and compressed tabs possible

Softgel Advantages

May result in improvement of rate and extent of drug absorption
High accuracy in filling
Good sealing
Faster onset of action
Less dustiness
Ease of swallowing, convenience, absence of poor taste

Softgel disadvantages

High specialization required for manufacturing
More costly than tabs or hard caps
Can fill only one kind of fill

Softgels

Colored, flavored, transparent,opaque
enteric or DR
PO
Chewable, suckable, twist-off, meltable

Components of Softgel

1. gel mass that will provide softgel shell
2. fill matrix of softgel contents
- drug may be present in both shell and the fill matrix, but commonly in matrix

Softgel shell

Gelatin in water at 80C under vacuum, add plasticizer
Once gelatin dissolved, add other components
HOt gell mass transferred through pipes to encapsulation machine, forming 2 separate gelatin ribbons
During casting, gelatin passes from sol to gel - carried through rollers

Liquid Fill Matrix

Drug (dissolved or dispersed in non-aq vehicle)

Selection of Liquid Fill matrix

Capacity to dissolve drug
Capacity to retain drug in solution in GI
Rate of dispersion in GIT after softgel shell rupture and release of fill matrix
Compatibility with softgel shell
Ability to optimize rate, extent and consistency of drug absorbed

Types of softgel fill matrices

lipophilic liquids
hydrophilic
self emulsifying oils
micro and nanoemulsions

Perconcentrate

softgel fill matrix is combo of lipophilic and hydrophilic liquids with surfactant components - p po admin --> disperse to form microemulsion or nanoemulsion

Manufacture of softgels

Accurately measured volumes of fill matrix injected into space between gelatin ribbons
Forces gel to expand into pockets of dies - govern size & shape
Capsule halves are sealed together with application of heat & pressure

Manufacture - careful control of

Temp - heat for cap seal formation
Timing - timing of dosing of unit quantities during formation
Pressure - pressure exerted between 2 rotary dies controls softgel shape and final cut out from gel ribbon

Softgel Formulation

Gelatin
Plasticizer
Water
Materials for appearance (colorants, opacifiers)
Flavors
Gelatin (50% of wet molten gel mass)
- most commonly type B gelatin

Plasticizers

Make softgel shell elastic and pliable
20-30% of wet gel formulation
glycerol
Amount and choice of plasticizer contribute to product hardness, may affect dissolution or disintegration
Selected on basis of compatibility with fill formulation, ease of processing, desired properties of final product

Water

ensures proper processing during gel prep & softgel encapsulation - removed by drying

Greatest advantages - softgels

To convert a liquid formulation into a solid dosage form, encapsulate into soft gelatin capsule

Product testing - in process

gel ribbon thickness
softgel seal thickness at time of encapsulation
Fill matrix weight
Capsule shell weight
Softgel shell moisture level
Softgel hardness at end of drying

Product testing - finished product

Capsule appearance
Weight variation
Disintegration
Dissolution
Moisture permeation test
Active ingredient assay
Fill weight
Content uniformity
Microbiological testing

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