Teknologi Farmasi II - Padat

Najma Annuria Fithri, S.Farm., MSc., Apt.

Universitas Sriwijaya
Genap 2013/204
Solid dosage form (tablet) -
Excipients
Pertemuan ke -3
Decision factors in design
Medical aspect
Economical aspect
Competitors aspect
Tablet formulation process
1. Preformulation
2. Lab scale formulation
3. Stability testing
4. Trial product (scale up) formulation
5. Trial product production
6. Validation
7. Master formula
Components of dosage form
Active compounds
Excipients
Ideal characteristic of active
compounds in tablet dosage form
Purity
Stability
Compatibility
Particle characteristics
Flowability
Optimum moisture content
Absence of static charge on surface
Compressibility/compactibility
Organoleptic characteristics
Excipients
International Pharmaceutical Excipents Council
(IPEC) = substansi selain obat atau prodrug yang
telah dievaluasi keamanannya dan dimaksudkan
untuk sistempenghantaran obat.
Handbook of Pharmaceutical Excipients = zat
tambahan yang digunakan untuk merubah zat
aktif menjadi bentuk sediaan farmasi yang sesuai
untuk digunakan pada pasien.
Purpose of excipents
1. Helps manufacturing processes
2. Protects, supports and enhances stability and
bioavailability
3. Identification of products
4. Increase safety and efficacy of products in
shipments and usage.
Criteria of excipients
1. Physiologically neutral
2. Stabile (chemical and physical)
3. Legal (under the law from officials)
4. Does not reduce the bioavailability of drugs
5. Free from pathogen microbes
6. Available in market, with relatively easy
purchase and shipments.
7. Economically reachable
Categories of excipients
1. Binders (pengikat)
2. Disintegrants (penghancur)
3. Fillers/diluents (pengisi)
4. Lubricants (pelicin)
5. Glidants
6. Antiadherents
7. Wetting agents (pembasah)
8. Dissolution retardants
9. Dissolution enhancers
10. Adsorbents
11. Buffers
12. Antioxidants
13. Chelating agents
14. Preservatives (pengawet)
15. Colours
16. Flavours
17. Sweeteners
Fillers/diluents
Function:
1. So tablets can be formed (compressed)
Tablet = > 2 mm and > 50 mg; some active
compounds dose is small
Fillers 5 80% final weight
2. Enhance compressibility and fluidity of powder
Better cohesion and flow
Fillers/diluents
Criteria for good filler:
1. No reaction towards active compound or other
excipients
2. No physiologic or pharmacologic effect
3. Possess consistent physicochemical
characteristics
4. Does not promote microbiological growth
5. Does not affect dissolution or bioavailability
6. No color
7. No odour
Categories of fillers
1. Organic material (carbohydrates and modified
carbohydrate)
Ex: lactose, sucrose, manitol, microcrystalline celulose
(MCC)
2. Inorganic material
Ex: CaPO4
3. Co processed fillers/diluents
Ex: filler binder for direct compression (Fast Flo
lactose, Cal-Tab)
Or
1. Soluble in water (lactose, mannitol)
2. Insoluble in water (CaPO4, starch, MCC)
Lactose
Lactose monohydrate not good for direct
compression low compressibility
Poor flowability
Soluble in water
Increase in hardness during shelf life
disintegrant
Incompatible with materials containing amine
groups / base change of colour (yellow
brownish)
Anhydrous lactose has good compressibility but
poor flowability
Ex: Pharmatose, Respitose
Spray Dried Lactose (SLD)
Can be used for direct compression
Good flowability
Compressibility increase when dried until 3% of
moisture content
In high humidity colour can change to a darker
shade
Interact with amine and furaldehyde
More expensive than normal lactose
Ex: Spray Process 315
Sucrose
Non compressible needs high pressure
Good binding ability in liq. Form
Hygroscopic
Cheap
Taste masking sweet
Cariogenic
Mannitol
An optic isomer of sorbitol
Poor flowability needs lubricants
The most expensive sugar form of filler
Non cariogenic
Non hygroscopic
Low calorie
Used in tablet that dissolve in the mouth
Ex: Pearlitol, Mannogem, Parteck
Sorbitol
Usually combined with manitol to reduce cost,
sorbitol is cheaper
Good compressibility
Hygroscopic RH >65%
Low calorie
Non cariogenic
Ex: Sorbifin, Neosorb
Both mannitol and sorbitol has low absorbtion
decrease small intestinal transit time less
drugs absorbed
Cellulose
Amorph and -crystalline form
Poor compressibility
Poor flowability
Poor binding effect
Insoluble in water
Cheap
Ex: Elcema G-25o
Microcrystalline cellulose (MCC)
Very good compressibility used in direct
compression
Good flowability
Possess deformation plastis characteristic
sensitive towards lubricant
Can increase disintegration process
Insoluble in water
Relatively expensive
Ex: Avicel (2 grades; 101 powder and 102
granule), Emcocel
Calcium Phosphates
Anhydrate and hydrate form
Dibasic and tribasic
Higher bulk density compared to organic filler
Used in vitamin and mineral formulation
Granul form is spherical good flowability direct
compression
Hygroscopic in RH >70%
Abrasive can cause exhaustion to tools
Ex: Di-Tab, Tri-Tab
Filler Binder
Filler-Binder Description
Single modification
Avicel Modified MCC
SDL Sprayed lactose
Di-Tab Modified dicalcium phosphate dihydrate
Co-processed
Fast-Flo Lactose Sprayed result of -crystalline lactose monohydrate and amorph
lactose
Microcellac 75% lactose and 25% MCC
Ludipress 93% -lactose monohydrate, 3,5% PVP and 3,5%crospovidone
Sugartab 90-95% sucrose and 7-10% inverse sugar
Cal-Tab 93% Calcium sulfate, 7% gom
Calcium 90 90% Calcium carbonate, 10% starch
Nu-Tab 95-9&% sucrose, 3-4% inverse sugar, 0,5% Mg stearate
Di-Pac 97% Sucrose and 3% modified dextrin
Emdex 93-99% dextrose, 1-7& maltose
Binders
Function:
Add adhesion force to powder during
granulation/direct compression
Add cohesion force that already exists in filler so
the powder can become a mass solid dosage form
Addition method
1. Dry (extra granular)
2. Wet (intragranular)more effective
Categories of binders
1. Natural binders
Ex: tragacanth, gelatin, starch, alginate acid
2. Sugar
Ex: Sucrose, glucose
3. Synthetic/semisynthetic polymers
Ex: ethyl cellulose, hydroxypropylmethylcellulose
(HPMC), polivinyl pyrolidone (PVP), polyethylene
glycol (PEG), poly vinyl alcohol (PVA)
Types of binder
Binder name Concentration in formula (%) Solvent
CMC-Na 10-50 Water
HPC 1-5 Water
HPMC 1-5 Water
EC 2-7 Alcohol
PVP 2-7 Water
Gelatin 2-5 Water
Natural Gom 1-3 Water
Tragacanth 1-5 Water
Acasia gom 1-3 Water
Sucrose 10-25 Water
Na-alginate 5-10 Water
PEG 5-10 Water
Amount of binder used according to
filler
Binder solution (ml) Fillers (3000 g)
Sucrose Lactose Dextrose Mannitol
Gelatin 10% 200 290 500 560
Glucose 50% 300 325 500 585
MC 2% 290 400 835 570
Water 300 400 660 750
Acasia 10% 220 400 685 675
Mucillago amylum 10% 285 460 660 810
Alcohol 50% 460 700 1000 1000
PVP in water 10% 260 340 470 525
PVP in alcohol 10% 780 650 825 900
Sorbitol in water 10% 280 440 750 655
Disintegrants
Function:
Helps tablet to disintegrate into smaller particles
Addition method
1. Intragranular
2. Extragranular
3. Combination of intra and extra
Superdisintegrant lower amount with the same
effect
Method of action of disintegrants
1. Capillary action
2. Swelling
3. Heat of wetting
4. Repulsion forces
5. Deformation
6. Release of gases
7. Enzymatic reaction
Examples of enzyme
Amilase starch
Protease Gelatin
Cellulase cellulose and its derivates
Invertase sucrose
Examples of disintegrants
Starch
Pregelatinized starch
Modified starch
Cellulose modification (ex: CMC Na, MCC)
Alginate
Ion exchange resin (ex: AmbreliteIPR-88)
Superdisintegrants:
Crosscarmellose, Ac-Di-Sol, Kollidon,
Satialgine
Starch
One of the earliest excipient used
Potato and corn
Disintegrant actioncappilary, swelling, break
down of hydrogen bonds
When compressed has the ability to from
hidrophillic bridge
Amount of starch is a crucial factor less = less
formation of hydrophillic channel, more = poor
compressibility
Pregelatinized starch
Modified form of starch through hydrolisis
and milling
Better compressibility than normal starch
Mechanism of disintegration through swelling
Modified starch
Modified with methylation carboxyl through
cross linking
Faster disintegration
Ex: Primojelmodified through substitued
carboxymethyl
Too much cause film/gel forming because of
gelling retards disintegration and dissolution
CMC-Na
Very hydrophilic
If modified through cross linking crosslinked
cellulose
Ex: Crosscarmellose sodium hardly soluble,
swelling ability very high
MCC
Insoluble in water
Through wicking process water break down
hydrogen bonds
Can form static charges problem while
granulation drying to be optimized
Alginate
Coloid hydrophilic
Has good absorption capacity
Acid or salt form
Good for manufacturing acid multivatimin
Disintegrant concentration
Disintegrant Concentration (%)
Starch 5-20
Starch 1500 5-15
Avicel 5-10
Alginic acid 5-10
Explotab (Na starch glycolate) 2-8
Guar gum 2-8
MC 5-10
CMC 5-10
HPMC 5-10
Amberlite IPR 88 0,5-5
Policlar AT (crosslinked PVP) 0,5-5
Superdisintegrants
Superdisintegrants Modification Mechanism of
Action
Crosscarmellose Crosslinked cellulose Swelling < 10 s
Ac-Di-Sol Cross linked cellulose Swelling and wicking
CrossPovidone Cross linked PVP Capillary and a little bit
swelling
Explotab Cross linked starch Swelling < 30 s
Satialgine Cross linked alginic acid Fast swelling and
wicking
Calcium silicate Cappilary
Factors that affect disintegration
Fillers
Binders
Lubricants
Surfactants
Effect of surfactant towards
disintegration
SLS depends on drugs
Polysorbate 20 good
Polysorbate 40-60 bad
Polysorbate 80 Good
PEG bad
Lubricating agents
Composed of 3 different types:
1. Lubricants
2. Glidants
3. Anti adherent
Lubricants
Function:
To lessen friction between tablet and die walls
during compression and ejection
Added while mixing
Two types:
1. Water soluble (ex: boric acid, sodium benzoate,
sodium acetat)
2. Water insoluble (ex: stearate [Mg, Ca, Na],
talc, liq. Paraffin)
Lubricants
Lubricants Concentration (%)
Water insoluble
Stearate (Magnesium, Calcium,
Sodium)
0,25-1
Talc 1-2
Sterotex 0,25-1
Waxes 1-5
Stearowet 1-5
Glyceryl behapate 1-5
Liq paraffin <5
Water soluble
Boric acid 1
Sodium benzoate, oleate, acetate 5
SLS 1-5
Magnesium lauryl sulphate 1-5
Glidants
Function:
To increase fluidity/flowability of powder that will
be compressed
Ex:
Stearat
Talk
Starch
Glidants
Glidants Concentration (%)
Stearate <1
Stearic acid 1-5
Talc 1-5
Starch 1-10
Sodium benzoate 2-5
Sodium chloride 5-20
SLS 1-3
MLS 1-3
PEG 4000 2-5
PEG 6000 2-5
Antiadherents
Function:
To prevent sticking of tablet surfaces on punches
(upper and lower)
Ex:
Talk
Mg stearate
Corn starch
Antiadherents
Antiadherents Concentration (%)
Talc 1-5
Mg stearate <1
Corn starch 3-10
Colloidal silica 0,25-3
DL-Leucine 3-10
SLS <1
Colours/Pigments
Function:
1. To enhance better aesthetic appearance and
brand image
2. Hide deformation of colours
Two types:
1. Water soluble migration
2. Water insoluble better appearance result
Colouring agent
Colouring agent Name
Red 3 Erythrosine
Red 40 Allura red AC
Yellow 5 Tartrazine
Yellow 6 Sunset Yellow
Blue 1 Brilliant Blue
Blue 2 Indigotine
Green 3 Fast Green
Flavours and Sweeteners
Usually used in chewable, buccal, sublingual,
effervescent tablets
Sweeteners:
1. Synthetic (ex: saccharine, siclamate,
aspartame)
2. Natural (ex: mannitol, lactose, sucrose,
dextrose)
Flavours and Sweeteners
Function:
1. To hide unsatisfactory taste especially for
tablets that are intended to dissolve in mouth
2. Increase patient acceptability
Method of addition:
1. Liquid form
2. Spray dried
Wetting agents
To increase water absorption into tablet
increase disintegration and dissolution
Non ionic surfactant such as SLS are used
Usually added towards hydrophobic mixture
Dissolution retardants
Used for controlled release to slow the release of
active compound
Ex:
stearic acid fat
stearic acid esther
Dissolution enhancers
To increase dissolution so active compound will
be released quicker
Ex:
Fructose
Povidone
Surfactant
Adsorbent
To adsorb an amount of liquid
Ex:
CaPO4 anhydrous
Starch
Mg CO3
MgO2
SiO2
MgSiO4
Buffer
To maintain pH balance stability of drugs
Ex:
NaCO3
CaCO3
Antioxidant
To prevent oxidation of active compound
Ex:
Ascorbic acid
-tocopherol
Natriummetabisulfit
BHT
BHA
Chelating agents
To prevent autooxidation formed complex
with heavy metals prevent catalytic reaction
Ex:
EDTA
Citric acid
Tartaric acid
Preservatives
To prevent microbial growth
Ex:
Paraben (methyl, propyl, benzyl, butyl)