Tablet Formulation

A tablet formulation should possess the following properties to optimize the technical

Feasibility قابليه التنفيذ, stability, and bioavailability of the formulation:

1-Compatibility of drug substance with excipients

2-Flowability

3-Compactibility

4-Lubricity

5-Appearance

6-Disintegration

7-Dissolution

Compatibility

Compatibility studies have particular importance in tablets due to the compaction process increasing the

contact area between particles drug and excipients and hence the potential for reactivity

Tested by DSC, IR.

Flowability

The formulation Should have sufficient flowability to ensure that the appropriate quantity of powder flows

into The dies of the tablet machine on a consistent basis. The flow properties of a powder can be enhanced by

the inclusion of a glidant. To overcome powder cohesiveness glidant is added which lowers the

interparticulate friction.

Commonly used glidants are listed inTable

% used Glidant

1-5 Talc

0.25-1 Colloidal Silicon Dioxide (Aerosil 200)

1-10 Starch

0.5-2 Calcium silicate

1-3 Magnesium CARBONATE

1-3 Magnesium oxide

Talc is traditionally one of the most commonly used glidants, having the additional Benefit of being an

excellent anti-adherent.The level of talc that can be added to a formulation is restricted by its hydrophobic

nature,too high levels resulting in reduction in the rate of dissolution

Starch has been used as a glidant, though relatively large amounts aided the disintegration properties

Determination of the Flowability : The fixed height cone method was used. A cut-stem glass funnel was put at

a height 2.5 cm from the horizontal plane. The powder sample (either the drug alone or its blends) was allowed

to flow gently from the funnel till a cone was formed and reached the funnel surface orifice. Powder flow was

then stopped and the average diameter of the formed cone (D) was determined. The area of the base of the cone

formed was taken as a measure of the internal friction between particles. The angle of repose (θ) was calculated

from the equation: tan θ = 2h/D.

Table : angle of repose as an indication of powder flow

angles of repose Type of flow

<20 Excellent

20-30 Good

30-34 Fair

>40 Extremely poor

Compactibility (compressibility):

Five grams of the drug or its blends were placed in graduated cylinder and the volume occupied (bulk volume Vb)

was recorded the cylindrical graduate was tapped till a constant volume is obtained and the volume of the powder

was then recorded (true or tapped volume Vt). The bulk density was obtained by dividing the weight of the

powder under test by Vb while the tapped density was obtained by dividing the weight of the powder under test by

Vt

% Compressibility (Carr's index) was determined from the equation: Carr's index = (1- Vt/Vb) × 100

Hausner ratio was obtained by dividing Vb by Vt

Table : Carr's index as an indication of powder flow

Carr's index Type of flow

5-15 Excellent

12-16 Good

18-21 Fair

23-35 Poor

33-38 Very poor

>40 Extremely poor

A Hausner ratio of less than 1.25 (equivalent to 20% Carr) indicates good flow, while greater than 1.5

(equivalent to 33% Carr) indicates poor flow. A Hausner ratio between 1.25 and 1.5 added glidant normally

improves flow.

Lubricity

lubricants are anti-adherent excipients, which reduce friction between powder and tablet punches, and die-wall

during and after compression to enable easy ejection of tablets

% used Lubricant

0.5-2% Magnesium stearate

0.5-4 Calcium stearate

0.25-2 Stearic acid

Magnesium stearate is most used lubricant.The lubricant activity of magnesium stearate is related to its

readiness to form Film on die wall surface.When it ismixed in a tablet formulation,it displays the same film on

the surface drug and excipients can reduce dissolution due to The hydrophobic surfaces created

Appearance

Appearance of a tablet, its shape, size, color and marking can contribute to patient expectations of a medicine.

The size of a tablet is often governed by the dose being administered the aim being to produce the smallest possible

tablet for ease of swallowing for low-dose drugs, the quantity of filler added is determined by the minimum

acceptable size for a tablet. Most of tab are circular however capsule-shaped tablet,sometimes called caplet is

popular for high dose compression weight is necessarily high, as the elongated shape makes the tablet easier to

Swallow than round tablets of equal weight

The coloring of tablets can be achieved either by incorporating a dye or pigment into powder prior to

compression,or by applying a colored coat to the tablet following the compression

Colorants come in three forms: soluble dyes, insoluble pigments,and lakes.

Lakes are Formed by adsorbing dyes onto the surface of an inert substrate, usually aluminum hydroxide. If the

colorant is being added to a granulate, soluble dyes can be dissolved in the granulating fluid to ensure a uniform

mix. When adding colorants as solids, the mixing process is sufficient. The choice of color is severely restricted

by the number of regulatory acceptable dyes and pigments such as FD&C Red2 andD&CRed30

Disintegration;

This is achieved by adding disintegrants and superdisintegrants such as Ac-DI-SOL

swelling and rate of swelling have been regarded as the most important characteristics of disintegrants to

optimize the biopharmaceutical properties of the formulation, the tablet should disintegrate rapidly,which can

be achieved by increasing the level of disintegrants

commonly used disintegrants

% Disintegrant

5-10 Starch

Microcrystalline cellulose

2-8 Sodium starch glycolate

1-5 Croscarmellosesodium(Ac-Di-Sol)

1-5 Crospovidone

An alternative mechanism of disintegration is used in effervescent tablets utilizes gas-liberating chemical

reaction to effect rapid disintegration. These tablets contains acid and an alkali metal carbonate,which,when

added to water prior to administration, react to produce carbon dioxide

Dissolution

Methods of preparation of tablets :

1) Wet granulation

2) Roller compaction dry granulation

3) Direct compression

1)wet granulation: Involve s wet massing of the powder blend with granulating solution, wet sieving and drying

Important steps involved:

a) Mixing of drug and excipients

b) Preparation of binder solution

c) Mixing of binder solution with powder mix to form wet mass

d) Drying of moist granules

e) Mixing of screened granules with disintegrant , glidant and lubricant’

f) Tab compression

Advantages:

1) Permits mechanical handling of powders without loss of mix quality

2) Improves flow of powders by increasing particle size

3) Increase and improves the uniformity of powder density

4) Improves cohesion during and after compation

5) Reduces air entrapment

6) Reduce the level of dust and cross contamination

7) Allows addition of liquid phase to powders

8) Makes hydrophobic surfaces hydrophilic

Limitation(disadvantages)

1) Expensive because of labor, time, equipment and energy

2) Loss during various stages of processing

3) Stability concern for moisture sensitive or thermolabile drugs

4) An inherent limitation of wet granulation, incomptability in formulation components is aggravated

2) roller compaction:

The compaction of powder by means of pressure roll can be achieved by Chilsonator which produce a

compacted mass in continuous flow. The pd is fed down between the rollers from hopper which

contains a spiral auger to feed the powder into compaction zone. Like slugs, the aggregates are screened

or milled for production into granules

Use: production of directly compressible excipients

Compaction of drug and drug formulation

The granulation of inorganic materials

Advantages:

1) It uses less equipment and space

2) It eliminate the need of binder solution

3) Slugging can be used for the following:

a) For moisture sensitive materials

b) For heat sensitive

c) For improved disintegration since powder particles are not bonded by binder

Disadvantages

1) Require specialized heavy duty tb press to form slug

2) Does not permit uniform color distribution

3) The process tends to create more dust than wet granulation

3) direct compression process

Definition: the process by which tab are compressed directly from powder blends of drug and excipients

No pretreatment by wet or dry granulation is involved . the use of directly compressible excipients are

Advantages:

1) Cost effective

2) Stability

3) Faster dissolution

4) Less wears &tears of punches

5) Simplified validation and less contamination

Disadvantages:

1) Less flowability and compressibility which can be enhanced by addition of certain additives

2) Segregation due to difference in density between drug and excipients which may lead to weight variation

and content become not uniform

3) Cost: some directly compressible excipients are patented so they are more expensive

4) Low dilution potential since most drugs are not compressible so to improve its flow large % of excipients are

needed. So, the size of tab becomes large which may be difficult to be swallowing in case of large dose

5) Lubricant sensitivity

6) Variation in functionality: when excipients have various sources there is a need for greater quality control in

purchasing of raw materials

Machines used in tableting

Tablets are made by compression on machine called presses. Tablet presses are designed with following basic components: 1) Hopper for holding and feeding granulation,2) Dies that define the size and shape of the tablet. 3) Punches for compressing the granulation within the dies. 4) Cam tracks for guiding the movement of the punches. 5) A feeding mechanism for moving granulation from hopper into the dies Tablets machines:

a) Single punch tab machine:

2- Rotary tab machine:

Steps:

1)die filling: the lower punch is directed downward to increase the volume of die cavity and the hopper

overfills the die with too much powder

2)weight adjustment: the lower punch moves up to allow the scrapper to sweep the excess powder off

the surface of the die tab(remove overfilling)

3) under filling: the lower punch downward again to cause the powder in the die to be down which is

called “under filling” to prevent the effect of centrifugal forces from removing the powder out of the

die cavity

4) precompression: it is done by passing between two rolls with low pressure to help tamp( دك)the

powders together with slightly compress the powder for deareation

5) main compression: by passing between two large rolls with higher pressure than precompression

where the final tab is formed

6) ejection: the lower punch moves upward to push the tab out of the die and the tab is removed by

centrifugal force during rotation

→Here the job of lower punch is more complex than that of the upper punch which are:

1- over filling

2- weight adjustment

3- under filling

4- precompression

5- main compression

6- tab ejection

N.B.

1) The press does not weigh powders, it fills volumetrically

i.e. the volume created by position the tooling (position of lower punch)for filling and that wilI

determine weight of tab

2) the upper punch help compression only

3) pressure causes weak and strong bonds between tab particles and after release of pressure of main

compression and ejection of tab is done, weak bonds breaking cause slight expansion in tab size & this

prevents tab from falling down again in the die cavity

The rotary machine compress the granules by both upper and lower punches

The compression cycle in rotary compression machine

Differences between single punch machine & rotary compression machine

Problems in tableting

Due to the following factors:

I. Tableting Process

II. Excipient

III. Machine

Tab defects

1) Capping and lamination

CAPPING: It is partial or complete separation of the top or bottom of tablet ii) LAMINATION: It is separation of tablet into two or more layers These occurs due to

- 1) Air entrapment during compression capping lamination - 2)Excess pressure (forms excess weak bonds)

2) Picking

and sticking

PICKING: It is the removal of material from the surface of tablet and its adherence to the face of punch. STICKING: It is the adhesion of granulation material to the die wall This occurs due to

1) Insufficient lubricant 2) High moisture 3) Bad punches 4) Excipients with low melting point

3) Mottling It is irregular distribution of colour on tablets surface This occurs due to:

1-Poor mixing 2-Improper drying rate(we must allow the colour to be distributed on tab surface before drying)

4) Weight variation

This occurs due to : 1) Improper die filling 2) Wide range of particle size of granulation 3) Poor flow of particles 4) Non uniform punch length 5) Bad scrape off

5) Chipping and cracking

Chipping: loss of parts of tab edges Cracking: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’. Due to: 1)rough punch surface 2) dirty dies 3)incorrect lower punch motion 4)increased tab expansion 5) improper lubrication 6) high moisture content

Granulation:

Granulation is defined as a process size enlargement whereby small particles are brought together to form

physically strong agglomerates.

Reasons for granulation(objectives)

1-Improve flow

2-Densify materials

3-improve content uniformity

4-Improve compression characteristics

5- Facilitate metering or volume dispensing

6-Decrease dust generation and reduce employee exposure to drug product

Different types of granulation:

1-Wet granulation

2- dry granulation

3-fusion granulation

4-extrusion granulation

5-spray granulation

Choice of granulation type depends on:

a) Drug properties(ex: easily hydrolysis drug not suitable with wet granulation)

b) Available equipment

c) Dose of drug

1-Wet granulation

This involves adding of liquid binder to a fine powder or mix of fine powders and mixing until coherent paste is obtained,

the paste is then granulated by forcing it through a screen

Advantages of wet granulation:

1- Improved cohesiveness & compressibility

2- Suitable for high dose drugs with poor flow and compressibility

3- Good distribution of soluble dose drugs and colorants

4- Control of dissolution rate by selection of binder hydrophobicity

N.B.: The more hydrophilic binder solution give faster dissolution

5- Suitable for dusty powders

Limitations of wet granulation(disadvantages)

1- Many steps

2- Not suitable for hydrolysable drugs

3- Time consuming

4- The large number of operations allow many variations possibilities and loss

Equipment:

a)Oscillating granulator:

Oscillating granulator conical granulator

Oscillating granulator consists of hopper the base is curved sieve .the sieve is changeable according to the mesh size

required. A set of four bars or rollers arranged in cylindrical form oscillating through of about 180 angle continuously

press the mass against the sieve. The granules obtained are collected in trays and dried

N.B.: screen is changeable to control granule size

Modification of oscillating granulator is conical granulator

In the conical screen chamber, a rotating impeller imparts a vortex flow pattern of wet mass

The wet mass is forced out the opening of screen surface by centrifugation

b) the reciprocating horizontal granulator: consists of cylindrical container to the bottom of which is attached a flat sieve fitted in suitable frame. -A central spindle with heavy blades moves horizontally through a semi-circle , forcing the mass through the sieve

c)the perforated roller granulator :

- cosists of two perforated cylinders which rotate in opposite directions and the moist mass is fed in between the cylinders where it is pressed and passes through the perforations N.B.. 1) sometimes one of the two rolls is not perforated 2) size of perforations is changeable

d) the perforated basket granulator:

-consisting of a cylindrical container and the curved wall of which is perforated. -The perforated wall is fitted to a frame so that walls of different pore sizes can be used. -A rotor carrying two blades is located at the bottom of perforated basket. As the rotor rotates, the blades force the wet mass through perforations. -The wet granules are collected in trays and then dried

e)twin shell mixer :

Is modified V-shaped mixer where the granulation solution is sprayed over the suspended powder bed The device should be equipped with air drying system Steps:

1) Operating the device 10-20 min to mix 2) Spray the binder solution from nozzles on axis of

rotation , the spray is in the form of pulses to allow particles to form particles

3) Hot air is introduced to allow partial drying of the formed granules Limitations: the powder used should be free flowing

f) high shear mixer granulator

It consists of three bladed mixer rotates horizontally and a chopper is applied to help granulation. The device can be used for non free flowing powders Advantages: 1)Dust free, high density granules 2)For uniform pellet shaped particles 3)Mixing and granulation are done in short time 4)Economic process

N.B.:

Blades used may horizontal or vertical

Blades lift powder in the opposite direction of spraying the binder solution to ensure that all the surfaces of

the particle are available for the binder solution

Factors affecting the product:

1- Impeller speed

High impeller speed results in denser and smaller granules

Low impeller speed results in porous and larger granules

2- Chopper speed

3- Water addition rate

High rate will cause local over wetting of the powder mass

Low rate will make the process time and power consuming

Rate should be fast enough to accommodate the processing time 2- 5 min

4- Load of mixer:

The load of the mixer is less than 2/3 (two third ) the volume of the mixer to achieve good mixing

5- Massing time: normally 1 to 10 min

Long massing time (more than 10 min ) may lead to decreased dissolution rate due decreasing of

disintegration or may be due to formation of denser granules

2) granulation by fusion:

Used in preparation of effervescent granules by mixing fillers with a mixture of sodium carbonate and citric acid

and heated the citric acid releases its water of crystallization which causes adhesion of particles of the solids

resulting coherent mass is pressed through a sieve or any mechanical granulators. The granules are dried to

remove the remaining of water of crystallization at temp not exceeding 54⁰ C

3- spray granulation in a fluidized bed:

The feed powder is introduced into the chamber where it is fluidized by fluidizing warm air. The warm

granulating liquid is sprayed over the powder by means of atomizing nozzle that is placed vertically within the

fluidization section of the chamber . the spray is directed in downward direction and the vertical position of

nozzle can be changed. Agglometares are thus formed and are simultaneously dried. The dry granules are

discharged from outlet at the bottom of the fluidizing section. Produce free flowable spherical granules with

smooth surfaces

4)granulation by extrusion:

utilizes equipment like meat grinder to which cutting device is attached a helical agitator cuts and folds the wet mass as it flows toward the discharge end the mass is forced out through the extrusion die at the discharge end with intense shear , and it is cut into coarse particles by cutting device. The wet particles are then dried

Extruder with cutting device

4) Dry granulation:

Dry granulation is recommended for handling that are sensitive to heat and moisture the method subjects the

drug to compression twice which may affect its stability

a)Slugging machines:

by heavy duty tab presses. They are fitted with punches and dies of about one inch in diameter . pressures up to

20,000 psi can be done by such machine. Forming flat faced tab called slugs or sheets are then broken up into

the required granular size.

b) roller compaction :

The powder mix is passed between two rolls

As solid sheet is formed where it then broken into fragments and recompressed into tab

c) Chilosonator:

It is similar to roller compactor but different in having a pre-mixer and the grooved rolls rotate toward each other . the material is fed in between rolls at controlled rate and the pressure between is regulated by hydraulic means N.B. The pre-mixer acts for de-aeration mainly The product is in form of irregular sheets which can be broken up into granules of the desired size.

Advantages of dry granulation

1- lower space and equipment required

2- no liquid phase is used(can be used for hydrolysable drugs)

3- applicable for moisture and heat sensitive drugs

4- maintain the disintegrant efficacy

diasadvantages of dry granulation

1- high press is required

2- high tendency for dust formation

3- poor color distribution(i.e. can not dissolve colour in binder for good distribution)