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7/23/2019 Capsules Production
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
CAPSULES
Dr Mine ORLU GUL
Lecturer in Pharmaceutics
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
Capsules Types (functionality)
• Immediate Release Capsules
• Modified Release Capsules – Gastro-resistant Capsules
– Sustained Release Capsules
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
Original
Hard Gelatin Capsule Design
Better sealing
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
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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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
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Capsule Filling Process
Feeding &Orientation
Transfer
Opening &Separation
Dosing
Closing
Ejection
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
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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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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)
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
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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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
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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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
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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
UCL SCHOOL OF PHARMACY
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UCL SCHOOL OF PHARMACY
BRUNSWICK SQUARE
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
UCL SCHOOL OF PHARMACY