Tablets 2017

Tablets
Juan M. Irache
Farmacia y Tecnología Farmacéutica
Universidad de Navarra

1. Introduction: tablets
Solid dosage forms usually obtained by single or multiple compression
of powders or granules with one or more APIs. In certain cases
tablets may be obtained by moulding or extrusion techniques. They
are uncoated or coated.
Tablets are normally right circular solid cylinders, the end
surfaces of which are flat or convex and the edges of which may
be bevelled. They may have lines or breakmarks (scoring),
symbols, or other markings.
Tablets are single-dose preparations intended for oral
administration. Some are intended to be swallowed whole, some
after being chewed and some after being crushed, some are
intended to be dissolved or dispersed in water and some have to be
retained in the mouth where the API is/are liberated.
They may contain excipients such as diluents, binders,
disintegrating agents, glidants, lubricants, substances capable of
modifying the behaviour of the dosage forms and the active
ingredient(s) in the gut, colouring matter and flavouring
substances.
http://www.who.int/medicines/publications/pharmacopoeia/Tabs-GeneralMono-rev-FINAL_31032011.pdf

1. Introduction: tablets
The different categories of tablet include:
-uncoated tablets
-coated tablets (including film-coated and sugar-
coated tablets)
-soluble tablets
-dispersible tablets
-effervescent tablets
-chewable tablets
-tablets for use in the mouth (including sublingual
and buccal tablets)
-modified-release tablets (including delayed-release
tablets (gastro- resistant/enteric-coated tablets) and
sustained-release tablets (extended- /prolonged-
release tablets)).
Controls
Uniformity of mass
Uniformity of content
Dissolution/disintegration

Uncoated tablets are made in such a way that the release of active ingredients is
unmodified. A broken section, when examined under a lens, shows either a
relatively uniform texture (single-layer tablets) or a stratified texture (multilayer
tablets), but no signs of coating.
Control: Disintegration test
Coated tablets are tablets covered with one or more layers of mixtures of
substances such as natural or synthetic resins, polymers, gums, fillers, sugars,
plasticizers, polyols, waxes, colouring matters, flavouring substances, and
sometimes also API. A broken section, when examined under a lens, shows a core
which is surrounded by a continuous layer of a different texture. Three main
categories of coated tablet may be distinguished: sugar-coated, film-coated, and
certain modified-release tablets.
Modified-release tablets: coated, uncoated, or matrix tablets containing
excipients or prepared by procedures which, separately or together, are designed
to modify the rate, the place or the time of release of the API(s) in the
gastrointestinal tract.
Sustained-release tablets (Extended-/prolonged-release tablets): designed to
slow the rate of release of the APIs in the gut.
Delayed-release tablets (gastro-resistant/enteric-coated tablets): intended to
resist gastric fluid but disintegrate in intestinal fluid.

2. Tablets: characteristics
Advantages of Tablets
Accurate dosage
Easy to administer and patient acceptance (compliance)
Can control release of active
- Delayed release (DR)
- Extended release (ER)
Stability
Economical to manufacture
Disadvantages of Tablets
Mistaken as candy
Formulation sometimes limited: large dose drugs usually lack the
properties to be formed into tablets
Cannot be administered to patients if vomiting or unconscious
Some patients have difficulty swallowing tablets
Problems in attaining acceptable content uniformity (accuracy and
precision of unit dose content) for low dose drugs
Compromised bioavailability (poor drug solubility; malformulation)

3. Tablets: formulation
Little amount of drugs / active substances can be directly
compressed (without any other ingredient): boric acid
Active (Drug)
- Compaction and flow properties (compactibility, fluidity, lubricant)
- Salt form, polymorphs
- Melting point, purity of active, particle size
Affects segregation of powders (blend uniformity)
Affects dissolution
Excipients and the method of manufacture are
selected to provide these characteristics
Selection criteria:
- Stability and compactibility with other excipients and drug
- Technological key points
Uniformity between batches
Physical properties, prize
Excipients Classification
Classical excipients (when granulation is used)
Excipients for direct compression

Manufacturing Methods
Granulation (Wet, Dry): A complex process of first forming granules from the
mix and then tableting the granules
Direct Compression: Simply mix and compress
Choice of Method Depends on Several Factors
1. Size of dose
Low doses (< 25 mg): Most of the tablet will be excipients
 Content uniformity
 Lower dose drugs generally can be compressed by DC
High Doses (> 250 mg): Most of the tablet will be drug
 Compactibility and fluidity
2. Compactibility and/or fluidity of drug: usually bad properties
- Can compensate for any lack of compactibility and/or lack of flowability by the
use of special direct compression fillers
- Can provide lubricity by addition of die wall lubricant
- Can help fluidity by adding a glidant
- Can assure rapid disintegration by adding disintegrant
3. Other considerations:
- Drug solubility (granulation, formula considerations)
- Drug stability (granulation)

Advantages of Direct Compression over Granulation
More economical (less time, space, materials, personnel, fewer steps)
Avoids heat and moisture of wet granulation
Disintegrate more directly into primary particles
Disadvantages of Direct Compression
Problem of content uniformity for low dose drugs
Not practical for large dose poorly compactible/poorly flowing drugs
Requires tight control over physical properties of filler-binder
When DC is not practical, i.e. large-dose, poorly compactible and/or poorly flowing
drugs
Granulate
Granulation is a size enlargement process: Improves Flowability
Addition of a BINDER: Improves Compactibility
The Traditional Granulation Method is Wet Granulation
Involves wetting the powders with binder solution ("glue") and then a drying step.
 Wet Massing Techniques
Fluid Bed Granulation
Not practical for drugs sensitive to water or heat.
Alternative: dry granulation

3.1. Classical Excipients
3.1.1. Fillers, Diluents / Diluyentes (their use is dependent on the drug dose)
Filler Functions :
Increase the bulk volume: final product has the proper volume for patient handling
- drugs used at low doses: < 50 mg and diameter of tablet higher than 5 mm
- to minimise incompatibilities: the contact can be reduced by dilution
- Selection criteria: compressibility, compactibility, flow
Filler Requirements: inert, non-hygroscopic, soluble, cheap, compactable, tasteful
Lactose monohydrate
Lactose may undergo a Maillard-type condensation reaction
Lactose is incompatible with amino acids, aminophylline and amphetamine
Powdered cellulose
Adsorbent, glidant, disintegrant and tablet/capsule diluent
Dibasic calcium phosphate (CaHPO4)
Incompatible with tetracycline antibiotics, indomethacin, aspirin, aspartame,
ampicillin, cephalexin and erythromycin
Starch (rice, wheat, corn, potato)
Starch has no listed incompatibilities
Filler, binder, disintegrant, glidant
Sucrose / Saccharose
Others: mannitol, sorbitol, glucose, calcium carbonate

Factors Influencing Choice of
Fillers
Compressibility
Flowability
Particle size and distribution
Moisture content
Bulk density
Compatibility with active
Solubility
Stability
Individual excipients
Finished tablets
Physiological inertness
Cost/availability
Governmental acceptability

3.1.2. Binders / Agregantes o aglutinantes (2-10%)
Binder Functions:
- To ensure mechanical strength of tablets and granules
- To “glue” (promote adhesion) the particles together into granules helping to hold
the overall tablet together: Improves Compactibility
- To provide the ¨cohesiveness¨ to a formulation enhancing its compressibility
and flow properties (maintain the integrity of the tablet)
- to improve the mechanical strength of a tablet
- to improve the flowability of the powder or granules or both
Drawback: significant effect on bioavailability and therapeutic efficacy, because
it affects hardness and friability of tablet
Binder Types:
- Dry powder added to the mixture prior to the wet granulation process
- Solution that is used in the wet granulation process
- Add right before the tabletting process (direct compression)
Hydrophillic cellulose derivatives (1-4%, water, alcohol…)
Hydroxypropylcellulose, Carboxymethylcellulose, Ethylcellulose, Methylcellulose
Starch (Starch 1500) (1-4%)
Polyvinylpyrrolidone (PVP): Plasdone (2-5%, alcohol, water)
Saccharose / Sucrose (2-20%, water)
Gelatine (1-4%, water)
Acacia gum (2-5%, water, alcohol), Tragacanth gum (1-3%, water)
PEG 4000 y 6000, Palmitate stearate glycerol / PEG
Others: glucose, sorbitol, excipients for direct compression

3.1.3. Disintegrants / disintegrating agents
Disintegrant Functions: To ensure that when tablets are in contact with water,
they are rapidly breaking into smaller fragments, facilitating their dissolution.
- important for immediate release products where rapid release is required
- more effective if added 50% intragranularly, and 50% extra-granularly
- some tablet fillers (e.g., starch and MCC) aid in disintegration
- Selection criteria: Active / drug disolution, bioavailability
Starch and starch derivatives (5-15%)
Cellulose derivatives: Avicel RC591: mixture of MCC and sodium CMC
Polysaccharides: Alginic acid, sodium alginate, tragacanth gum, Guar gum
Methylated caseine: Esma Spreng
Colloidal silicon dioxide: Aerosil, Cab-O-Sil [lubricant group]
Magnesium Aluminum Silicate: Veegum F
Superdisintegrants (0.5-2.0%, for hard gelatin capsules 4-8%)
Sodium starch glycolate: Primojel®, Explotab® (1-6%)
High concentrations may cause gelling and loss of disintegration.
Croscarmellose sodium / carboxymethylcellulose: VivaSol®, Ac-Di-Sol (0.5-5%)
Soy polysaccharides: Emcosoy®
Crospovidone / Cross-linked PVP: Polyplasdone  XL (2-4%)
L-HPC Low-substituted hydroxypropyl cellulose (1-5%)

Disintegrant Mechanisms
All are hygroscopic and draw liquid into the matrix ("liquid uptake" or "wicking action")
As they sorb liquid, they may:
Swell extensively (Sodium Starch Glycolate)
Recover shape with little swelling (Crospovidone; Starch)
Swell radially and straighten out [fibrous material] (Croscarmellose)
Together, these phenomena create a disintegrating force within the matrix

Sodium starch glycolate

3.1.4. Lubricants 0.5 a 2%.
To prevent the compacted powder from sticking to the equipment during the
tabletting. It aids ejection of the tablet from the dies, and may improve powder flow.
Lubricant Roles
True Lubricant Role: reducing friction between sliding surfaces, at the tablet-die
wall interface during tablet formation and ejection. Also applies to capsule plugs.
Antiadhesion Role: Preventing sticking to surfaces. To reduce adhesion between
the powder and the punch faces and thus prevent tablet sticking to the punches.
Glidant Role / deslizante: Improving flow by modifying the interaction between
particles
Concept of a "Lubricant System"
Frequently two substances are used in a formulation to maximize lubricant
effect in all three areas: combining magnesium stearate with a colloidal silica
Lubricant Issues
The most effective true lubricants are hydrophobic and if too much is used, they
can interfere with disintegration and dissolution
Lubricant generally interfere with bonding and can soften tablets
Alkaline metal stearates are incompatible with some drugs, e.g. aspirin and AA
Laminar lubricants (Mg stearate, Ca stearate) are "mixing sensitive” Under the
rigors of mixing they delaminate: effect equivalent to adding too much lubricant
Lubricants are always added last after all other components have been
thoroughly mixed (mixing time of 2-5 min)
Water soluble lubricants are not as effective: for water soluble tablets

Magnesium Stearate (< 1%)
Overblending can cause compaction problems.
Stearic Acid (1-5%)
Not as effective as magnesium stearate.
Vegetable based Fatty Acids (3-5%)
Sodium Benzoate, PEG 20.000, Levilita, glycine,
sodium lauryl sulphate
PRUV® (Sodium Stearyl Fumarate)
Glidants
Talc (1-5%)
Starch: Starch 1500 (5-10%)
Colloidal silicon dioxide (0.5%): Aerosil / Aerosil
200 VV or compacted CSD, Labosil
Laminar Structure of
Magnesium Stearate
Aerosil

Lubricant Typical
Level
True
Lubricant
Activity
Antiadherent
Activity
Glidant
Activity
Metallic stearates
e.g. Mg St, Ca St
0.5 - 1% Excellent Good Poor
Stearic Acid 1-5% Good Good 0
Colloidal Silica <1% 0 Good Excellent
Corn starch 5-10% Poor Excellent Excellent
Cires 3-5% Excelent Poor 0
Talc 1-5% Poor Excellent Good
Lubricants (Magnesium Stearate)
Prevent the formulation and formed tablet from sticking to machinery
Blending times critical
Weaker tablet compacts
Slower drug dissolution
Glidants (Silica / Talc)
Improves flowability of powders/granulation
Allows formulation to flow easily through tableting machine
Flowability measured using angle of repose or Flowdex

3.1.5. Miscellaneous
Sorbent: limited fluid sorbing in dry state
Colors: Self apparent
Flavors and Sweeteners
Spray-dried and other flavors
Natural sweeteners
Artificial sweeteners
Mask bad taste of drugs/excipients
Mask bad odor
Protective Agents
Other

3.2. Direct compression excipients
Characteristics
- Generally, direct compression Filler-Binders are common fillers that have
been physically modified.
- Fillers posseses both diluent and binders properties; sometimes, also
glidants
- In general, these excipients are used in a large amount (50-80%)
- Main aspect: Improving Flowability (add glidants)
Today, tableting equipment compressing 8,000 to 10,000 tablets per minute.
It is critical to have an excellent flowing granulation/powder blend. Many
sugar-based excipients, such as maltose, mannitol, and sorbitol are not
compressible in their natural state and need to be modified for use in direct
compression tableting
 Classification: 4 groups
- Cellulose derivatives
- Starch derivatives
- Sugars
- Mineral products

3.2.1. Celullose and derivatives
a) Microcrystaline cellulose, MCC
Binder properties: tablet compactibility: low friability
Inherent lubricant properties: tablets self disintegrate and require little lubricant
Most compactible material available for pharmaceutical use
Avicel PH-101, PH-102, PH-103, PH-105, PH-112, PH-200
Emcocel®: contains a little amount of calcium phosphate
ProSolv SMCC™: combination of MCC and colloidal silicon dioxide.
Others: Vivacel, VivaPur®
b) Powdered celluloses
Elcema: -cellulose
 Solka-Floc® and JustFiber®
3.3.2.2. Starch and starch derivatives
- Binder, Self-lubricant: permits to reduce the amount of traditionnal lubricants
- Super disintegrant: 2-10% of Starch 1500 provides disintegrant action
- Flow aid: excellent flow properties. In formulations containing starch, it is
necessary to include excipients able to increase the compactability (the
hardness of the resulting tablet): 5-10% Silartex® or Compressil®
Starch 1500
Sta-Rx® 1500
Paygel® 90

3.2.3. Sugars
a. Lactose
Lactochem®
Lactopress®: Lactopress® spray-dried and Lactopress® anhydrous
Microcelac 100 is a spray-dried compound containing 75% -lactose
monohydrate and 25% MCC.
Ludipress®: lactose (93.4%), Kollidon® 30 (3.2% PVP, binder) and Kollidon®
CL (3.4% cross-linked PVP, flow aid).
 Starlac: Lactose / Starch (85:15)
 Others: Zeparox®, DCL-30®, Pharmatose®, Tablettose®, Lactose Fast
Flow®, Flowlac 100, Cellactose 80
b) Compressible Sugar
Compressible Sugar (95-98% sucrose)
Di-Pac®: It contains 97% sucrose and 3% maltodextrines.
SugarTAB®
Compressuc®: Saccharose + Maltodextrines
Others: NU-TAB® 4001, Sucre CD1®: Tabfine S100 I
c) Glucose / Dextrose
Emdex®: Glucose (90-92%), maltose (3-5%) and little amount polysaccharides.
Tabfine D97 HS®: glucose (97%) and starch (3%) as binder.
d) Fructose / Levulose
Tabfine F94 M®: fructose (96%) and maltose (4%).

e) Sorbitol
Neosorb®: Neosorb60 (10%max>315 m), Neosorb60W (105-420 m)
f) Mannitol
 Pearlitol®: It allows sugar-free formulations (including chewing gums)
g) Maltose
 Advantose™ 100: It can be also used as sugar substitute for great-tasting
sugar-free and low-calorie products.
h) Maltitol
Maltisorb® is well suited to the formulation of powder forms (sachets, dry syrups,
capsules) and tablet forms, whether chewable, suckable, coated or effervescent.
3.3.2.4. Mineral products
a. Dibasic calcium phosphate dihydrate: CaHPO4·2H2O
Emcompress® (Dibasic calcium phosphate dihydrate)
Emcompress anhidrous®: especially designed for drugs sensible to moisture
A-TAB® (anhidrous), Calstar®, Di-TAB®
b. Tribasic calcium phosphate: Ca3(PO4)2 ; Ca5(OH)(PO4)3
Tri-CAL® WG, Tri-TAB®
c. Calcium Sulphate: Ca(SO4) ; CaSO4·2H2O
Compactrol, CAL-TAB®
d. Hydrated magnesium silicate
Silartex®, Compressil®

Avicel
Flow Lactose
Star-Lac
Tabletose
Microcelac

Wet
Ganulation
Direct
compression
Drug 300 mg 1 part
Filler
Filler - Binder
Lactose powder
182.5 mg
2-3 parts
Disintegrant
Superdisintegrant
CMC
15 mg (3%)
Starch
10-20%
2-5%
Glidant Colloidal silica
0.5-1%
Lubricant Mg Stearate
2.5 mg (0.5%)
Mg Stearate
(0.5-1%)
General Formula for WG and DC Tablet

4. Overview of Manufacturing Methods
Methods of Tablet Preparation
Direct Compression
Wet Granulation
Dry Granulation
4.1. Wet Granulation
Improve compressibility, flowability, and content uniformity of powder
blend
Size drug, weigh and blend with excipients
Add liquid binder to prepare damp mass
Adhesion of powdered particles to form granules for tableting (granulation)
aids in holding tablet together after compression
Binding agents: aqueous or organic
Cautions: overwetting/underwetting
Screen damp mass
Dry and size: spread evenly on shallow trays
temperature and humidity controlled ovens
drying in fluid- bed apparatus
Second screening: smaller mesh screen
Lubricate formulation
Compress into tablets

4.2. Dry granulation
Dry Granulation Method (Slugging)
Steps:
-Size drug, weigh and blend with excipients:
- Filler, binder, lubricant (disintegrant, glidant)
-Compact large masses of powders : no moisture/binding agent added
-Crush and size pieces into smaller granules
-Lubricate
- Disintegrant, lubricant
-Compress into tablets
Active or diluent/filler must have cohesive properties
Drugs that degrade in moisture or heat: ASA

4.3. Direct compression
Direct Compression: Must be a free-flowing and compressible mixture
Steps: Size drug
Weigh appropriate amounts of active and excipients
Blend with excipients
Compress into tablets
Direct Compression
Problems with high-dose drugs: compressibility
Problems with low-dose drugs: content uniformity
May require glidant to improve flowability
Segregation in hopper possible
Blending of lubricant critical: weaker tablets, slower drug release
Strategies
Decrease the size of drug particles: micronisators
Firstly, mix the fine drug with filler-binder product.
Then, add the rest of ingredients and
Magnesium stearate at the end (mix 3 minutes and compress).
Never mix all the ingredients of the formula (drug and
excipients) in only one step

4.4. Tableting / Compression
Tableting is a COMPACTION
Process and Involves Two Steps...
Compression
Reduction in bulk volume by
eliminating voids and bringing
particles into closer contact
Consolidation
Increased mechanical strength
due to interparticulate interactions

4.4. Tableting / Compression
The Role of the Compressive Force...
Is primarily to bring the adjacent particulate surfaces together so that
forces active active at surfaces may form lasting linkages.
Interparticle forces are weak and only significant if the particles are
touching one another or very close
– van der Waals
– H-bonding
The mechanical strength (e.g. hardness) is a function of the nature of
the attractive forces and the area over which they act.
Compactibility is...
The ease with which mechanically strong tablets can be made.
Tablet mechanical strength may be measured by...
– Hardness (Breaking strength)
– Friability (Resistance to abrasion and chipping)

Compaction Profiles of Some DC Fillers
(0.75% magnesium stearate)

4.4.1. Tablet presses: single-ended compression
(Máquinas alternativas / excéntricas)
Stages of Compression

4.4.1. Tablet presses: single-ended compression
Single-punch machine:
Main components
Powder hopper
Powder feed system
– Feed shoe or feed frame
Punches and dies

.
Punches and dies / punzones y matrices

4.4.2. Tablet presses multistation / Rotary punch
Double-Ended Compression or Rotary (Multi station press) tablet
machine
55 stations
495,000 tabs/hour

http://wpcontent.answers.com/wikipedia/commons/5/5a/Tablet_press_animation.gif

RDWF
EF = RDWF x w
w : coefficient friction at die wall
RDWF: residual die wall force
Tablet Ejection and Ejection Force (EF)
Die wall lubricants reduce friction by
interposing a film of low shear strength between
the tablet mass and the confining die wall…
The structure formed must be strong enough
to withstand the stresses of decompression,
as well as those induced by ejection.
Possible cause of capping/lamination
Elastic recovery + poor bonding
Capping
Lamination

Alu/Alu blister
http://www.neo-packaging.com/

Intermediate product
Tap density tester

5. In vitro tests of finished tablets
Content Uniformity: assay (HPLC, spectrophotometry …)
Weight Uniformity
Tablet density and/ or diameter
Hardness
Friability
Disintegration
Dissolution
Measuring Hardness
(Breaking Force)

Hardness
Friability: The % weight loss due to chipping, abrasion and erosion
Dissolution
Friabilator
http://www.youtube.com/watch?feature=player_detailpage&v=982gWIaXxzk

Hardness
Friability
Dissolution
Basket-rack device
Fluids: water, SGF, SIF, buffers
Record time required for disintegration
Factors affecting disintegration
- Presence of disintegrants
- Manufacturing method: granulation vs DC
- Pressure used for compression
- Tablet hardness
http://www.youtube.com/watch?v=mcFY3iLUyl4

Hardness
Friability
Dissolution
Tablet dissolution
- Apparatus I (basket) and II (paddle)
Round bottom flasks containing dissolution media, 37ºC
Dosage form placed in the basket or in the flask
Media mix by paddle or basket
Samples withdrawn at specific times intervals and analised
(HPLC, spect.)
Passing the dissolution test
All six tablets dissolved to a value that is some % of the
dose (i.e. “at least 70% within 45 min”)
Similar procedures for capsules
Slightly different for sustained and enteric coated tablets

Cell types.
1) Tablet cell 12mm
2) Tablet cell 22.6mm
3) Cell for powders and granulates
4) Cell for implants
5) Cell for suppositories and soft gelatin
capsules
6) Temperature-Measuring Head
Other official methods:
Flow through cell
http://www.youtube.com/watch?v=uA3oORxVD60

Tablets 2017

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Tablets 2017