Capsules Production

7/23/2019 Capsules Production

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UCL SCHOOL OF PHARMACY

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CAPSULES

Dr Mine ORLU GUL

Lecturer in Pharmaceutics

[email protected]




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Outline

• Overview of Capsules: Why Capsules ?

• Types of Capsules

• Capsule Formulation – Excipients

– Optimization

• Capsule Filling Process

• Testing and Evaluation of Capsules




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Why Capsules?

• Early discovery

• Production lines

• Application range – Powder

– Granules

– Pellets

– Mini-tablets

– Semisolids

– Liquids

+ Capsules are well suited for

patient centric dosage forms due to

their flexibility in terms of

fixed dose combinations,

dose strengths, release profiles

and formulations as well as

multiparticulate options




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Capsules Types• Hard-shell capsule

– Two piece capsules:

"body" and "cap"

– Capsule material

• Gelatin

• HPMC

• Starch

– Contents may be solids or liquids

– Three stage manufacturing process

i) shell, ii) contents, iii) filling

• Soft shell capsule

– One piece

– Gelatin

– Contents are liquids

– Two stage manufacturing process

i) contents, ii) shell manufacture and filling combined




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Capsules Types (functionality)

• Immediate Release Capsules

• Modified Release Capsules – Gastro-resistant Capsules

– Sustained Release Capsules




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Original

Hard Gelatin Capsule Design

Better sealing




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Gelatin Raw Material

• The 1 structure of gelatin is an unbranched amino acid chain,

with a molecular weight range of 40,000 to 100,000

• The repeat amino acid sequence is glycine - X - Y

• X is mainly proline• Y is variable, often hydroxyproline

• Some residues are ionisable, so will be charged at different

pH values

• The individual gelatin chains have a left-handed spiral 2

structure

• Three of these form a right-handed spiral structure, giving

a rod-like overall molecular structure




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Gelatin Raw Material

• Prepared by hydrolysis of collagen

• protein in connective tissue

• sourced from bones and skin (bovine, porcine)

• The raw material is cleaned, macerated, hydrolysed witheither acid or base, washed and dried

• Acid-treated = Type A gelatin

• Base-treated = Type B gelatin

• Gelatin is characterised by its "Bloom strength"

• measurement based on the force required to move a

plunger a set distance into a 6.66% solution at 10oC




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Capsule Size vs. Fill Weights (mg)

To estimate the fill

weight for a powder, the

simplest way is to

multiply the body

volume by its tapped

bulk density

Eight different sizes:

000 (largest) to 5

(smallest)




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Capsule Size vs. Fill Weights (Softgels*)

*Softgel consists of a liquid matrix inside a one-piece outer gelatin gel

cubic centimeters (cc)

capsule fill volume depends upon

the density of the

encapsulated material




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Why Use Hard Gelatin Capsules?

Small-scale simplicity• Hand-filling possible

• Limited initial formulation work required (cf tablets)

Blinding easy• For clinical trials

• Use opaque coloured capsules

Marketing issues

• Product line maintenance / extension

• Use of company livery

Product identification

• Body, cap, sealing band may be different colours / opacities




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Why Use Hard Gelatin Capsules? (continued)

"Sensitive" drugs

• No water involved in the dry powder mix (cf wet granulation)

good for water-sensitive drugs

prevent hydrolysis, change in hydrate status

• No heat involved in the dry powder mix (cf wet granulation)

good for heat-sensitive drugs

• No compression involved in filling of dry powder mix (cf

tabletting)

avoid possible changes of physical state (amorphous v

crystalline, polymorphic changes)

prevent change in dissolution profile




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Why Use Soft Gelatin Capsules ?

Similar to liquid-filled hard gelatin capsules

Poorly water-soluble drugs

• Drug is in solution in the fill

• avoids dissolution step in the gastro-intestinal tract• promotes bioavailability cf tablets, especially if in a self-

emulsifying formulation




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Capsule Formulation

• Drug – Dose

– Solubility

– Particle size

• Excipients

– Diluents (filler), which give plug-forming properties

– Lubricants, which reduce powder-to-metal adhesion

– Glidants, which improve powder flow

– Wetting agents, which improve water penetration

– Disintegrants, which produce disruption of the powder mass




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Capsule Formulation: Excipients

• Diluents

– Considerations

• Dose of drug

• Particle size

• Particle shape

• Solubility

• Stickiness

•Powder flow

– Example:

Lactose, Starch (natural or pregelatanised), MCC,

Calcium phosphate , Mannitol




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Capsule Formulation: Excipients (continued)

• Glidants and Lubricants

– Improves the flow

–

Prevention of friction between powder particles and metalsurfaces of capsule machine

– Examples:

•

Fumed (colloidal) silicon dioxide• Magnesium stearate

• Stearic acid

• Glyceryl monostearate

• Sodium stearyl fumarate




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Capsule Formulation: Excipients (continued)

• Disintegrants

– Powder plug porosity (50-70%) (higher than in tablets)

– Example:

Sodium starch glycollate (Explotab)

Croscarmellose sodium (Ac-Di-Sol)

• Wetting agents

– Low solubility drugs

– Low wettability drugs

– Example:

Sodium lauryl sulphate




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Capsule Formulation: Fills For Hard Gelatin Capsules• Powder

• Granules

Improve mixing; reduce segregation (same as for tablets)

• Pellets

Controlled release; individual pellets may contain different drugs or have

multiple release profiles

• Mini-tablets

Individual mini-tablets may contain different drugs or have different release

rates

• Liquids

Must be non-aqueous (oils or oil/surfactant mixtures)

May be liquid at room temperature

May be solid at room temperature (filled when molten)

Drug has very low aqueous solubility





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Capsule Formulation: Important aspects

• Overall powder properties key to success

– initial mixing low dose potentially problematic

– segregation potential low dose potentially problematic

– flow high dose potentially problematic

• Particle size and shape important

– should be matched between drug and excipients

– spherical shape improves mixing and flow

– small size may lead to agglomeration





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Capsule Formulation: Optimize

• Particle size and shape to assure homogeneity and flow

• Uniformity of particle size throughout the formulation to

assure constant fill weights

• Homogeneity of the mixture to assure content uniformity

• Good flow properties to assure accurate fill weights

– use of free-flowing diluent

– optimizing the amount of diluent (may require a different size of

capsule to fill more of the powder)

– optimizing the amount of glidants and lubricants

– modification in particle size and/or shape of the drug

• Appropriate moisture content to give a stable capsule

formulation





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Capsule Filling Process

Feeding &Orientation

Transfer

Opening &Separation

Dosing

Closing

Ejection





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Powder Filling of Hard Gelatin Capsules

• Capsules opened and two parts separated

• Vertical powder hopper feeds into a horizontal reservoir

• Dosator tube plunges into powder bed andpowder rises into the tube

• the amount of powder in the dosator is

controlled by volume not weight

• powder is slightly compacted into a "plug"

• forces are 10 to 100 N cf 10 to 100 kN

for tabletting

• Powder plug is transferred to the capsule body

• Capsule lid attached





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Manufacture of Hard Gelatin Capsules

• Gelatin dissolved in hot water (80C)

• use high Bloom strength gelatin

• colour is added as necessary

• viscosity of solution is important

• Stainless steel pins (fingers) dipped into the gelatin solution

• the coating on the pins will become one part of the capsule

• the pins are rotated to ensure constant thickness of coating

• the coating is dried, removed and trimmed

• the two halves of the capsules are joined together

• Moisture content of shell is 13 % to 16 %

• recommended storage conditions are 21C / 50 %RH to

prevent drying and cracking (Source: Capsugel)





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Manufacture of Soft Gelatin Capsules

Preparation of the ribbon

• Use low Bloom strength gelatin

• Gelatin dissolved in hot water

• Plasticisers added (eg glycerol, sorbitol, PEG, propylene glycol)

• Colour is added as necessary• A gel "ribbon" is formed

Preparation and filling of the capsules

• Two gel ribbons are placed on the rollers

• Ribbons are partially sealed to provide a "cup"

• The liquid fill is added to the cup

• The ribbons are sealed above the fill,

making an intact capsule

• The capsules are dried





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Evaluation of Capsules

• Uniformity of drug content

– To establish the homogeneity of a batch

– Capsules are assayed individually

• Uniformity of weight

– Capsules from a batch are weighed individually

– A BP deviation percentage is set which depends on therequired tablet weight





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Evaluation of Capsules

•Disintegration Test – Disintegration does not imply complete dissolution of the unit or

even of its active constituent

– It is the breaking of Capsule Shell on contact with water (37°C)

releasing its contents

– Complete disintegration is a state in which any residue of the unit,

except fragments of insoluble coating or capsule shell, remaining

on the screen of the test apparatus or adhering to the lower

surface of the discs, if used, is a soft mass having no palpably firm

core (British Pharmacopoeia)• Dissolution Test

– Release of drug from the capsule into the dissolution medium at

37°C (gelatin will dissolve in water at 37C, but is practically

insoluble below 30C)

– Dissolution of the capsule shell itself will take about 3 to 5 mins





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Quality Issues Related To Capsules• Gelatin

Processed natural product batch-to-batch variation ?Animal product acceptability ?

• Colours

Worldwide acceptability ?

• Tamper-evidence

More difficult than with tablets

Banding (over-wrapping after filling)

• Leaking

• Consistency of performance over time

More of an issue with soft gelatin capsules

• Control over process

Hard gel capsules can be filled in-house

Soft gel capsules must be filled using a contractor





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Further reading

• Aulton’s PharmaceuticsMichael E. Aulton

• Pharmaceutical CapsulesFridrun Podczeck and Brian E. Jones

Documents

Capsules Production