TABLETS

TABLETS

TABLETS

Ø  90% of drugs are in oral dosage form.

Ø  Tablet is unit dosage form.

Ø  Liquid dosage forms r given in dose of medication 5-30%.

Ø  Tablet should have 2-4% of moisture.

Evaluation

Ø  General appearance

• Size and shape – compressed tablets shape and dimensions are determined by the tooling during the compression process.

Rem-when compression force is constant, tablet thickness varies with changes in die fill, with particle size distribution, packing of particle mix and tab. Weight.

When die fill is constant, thickness varies with variation in compressive load.

*         Crown thickness of tablet measured by micrometer.

*         Total crown thickness is measured by vernier calliper.

*         Tablet thickness should be controlled with ±5% of std. Value.

*         The more the convex the tablet surface more is the capping problem so one has to use slower tablet machine or one with pre compression capabilities.

*         Unique identification markings-given in Physicians Desk Reference(PDR).

*         Product code is given from National Drug Code (NDC).

*         Mottling-non uniformity of colour over tablet surface.

*         For colour quantification 3 methods-reflectance spectrophotometry, tristimulus colorimetry and micro-reflectance photometry.

Ø  Hardness and Friability

• Hardness of tablet directly effects dissolution behaviour.
• It is the force req. to break the tablet in diametric compression test.
• Hardness also called crushing strength.

Devices used

*         Monsento tester (stockes tester)-easy to handle.Manually operated,gives strength in kgs.

*         Strong-cobb tester-force applied by hydraulic pressure and later air pressure not manually. It gives value 1.6 times higher than the original strength. it gives strength in kgs.

*         Pfizer tester-same principle as pair of pliers.(kgs)

*         Two testers to eliminate operation variations:-

1.Erweka tester-gives strength in Kgs.

2.Schleuniger tester-operates in horizontal position-gives strength in KGs and Strong Cobb units.

• Hardness and thickness of tablet is a function of die fill and compression force.
• At constant compression force, hardness increase with increasing die fill.
• At constant die fill, hardness increase and thickness decrease when compression force is applied.
• Roche friabilator machine is used for measuring friability of tablet.

Tablets fall from-6 inch distance

Total Rpms-25

Total revolutions-100

Time-4 minutes

Limits-0.5-1.0% (USP),not more than 1% (IP).

• Effervescent tablets and chewable tablets show higher friability value than above so stack packaging for them.
• Vickers test is used to measure the surface hardness.
• ‘Whiskering’ phenomenon is related with tablets with deeply concave surfaces or punches used were in poor condition and such tablets have higher than normal friability values.

HARDNESS LIMITS

TABLET

HARDNESS LIMIT

SOFT

2 KG

SUSTAINED RELEASE

8 KG

GENERAL

4 KG

HARD

6 KG

EFFERVESCENT

1.3 KG

STANDARD HARDNESS SHOULD BE MIN. 4 KG

Ø  Webster and Van Abbe tester-indicate edge damage during handling.

Ø  Weight variation

• Total tablets taken-10.
• Limits-Tablets meet USP if not more than 2 tablets are outside the limit and no tablet should differ by more than 2 times the original limit.
• This test is used if the tablet contains 90-95% API. It is not appropriate for low dose containing tablets.API should be more than 50mg. (i.e-potency). For these content uniformity test is used.

Average wt of tablets(mg)

Max. % diff. allowed

130 or less

10

130-324

7.5

More than 324

5

I.P limits

Average wt of tablets(mg)

Max. % diff. allowed

80 or less

10

80-250

7.5

More than 250

5

CONTENT UNIFORMITY TEST:

• It should be between 95-105%.
• Tablet potency for this test should be less than 50mg.
• For digitoxin it is 90-110%.
• If  larger wt. Variation ,no good content uniformity.

Test:

Total tablets-30

Total assayed-at least 10

9 of the tablets should contain 85-115% API.10th tablet may contain 75-125% API. Test passed

If above conditions not met other 20 tablets should be assayed, and no one should fall outside 85-115% range.

Ø  Disintegration

• Apparatus:-

-6 test tubes

-mesh size:10 mesh i.e 1.7mm(USP),8 mesh i.e 2mm(IP)

-glass tubes are 3 inches long

-beaker contains 1L of water, simulated gastric fluid or simulated intestinal fluid.

-temperature: 37±2 degree Celsius. (Remember with reference to difference with dissolution)

-tablets remain 2.5 cm below surface of liquid on upward movement and vice versa.

-no. of cycles per minute:28-32

                                                          IP LIMITS

Tablet/Capsule

liquid

Disintegration time(min)

Uncoated tablet

water

15 min (USP-30 min)

Sugar coated

water

60 min

Enteric coated

0.1N HCl with phosphate buffer

2 hr in gastric fluid media and 1 hr in intestinal fluid(USP it is reverse)

Film coated

Water or 0.1N HCl

30 min

Vaginal tablets

water

30 min

Soluble, dispersible and effervescent tablets

Water

(19-21 deg. Celcius)

3 min

Hard gelatin capsules

water

15 min

Soft gelatin capsules

water

60 min

Ø  Dissolution

USP

Apparatus 1-Basket type

• Mesh screen-10 mesh(USP)
• -temperature: 37±0.5 degree Celsius.
• 900 ml flask.

Apparatus 2-paddle type

• 900 ml. Flask.
• Contains wire helix to prevent tablet from floating.

Limits(USP)

ü  Not less than 75% should be dissolved in 45 min.

ü  90% of the drug should be dissolved in 30 min.(this is not USP limit, it is industrial limit)

ü  Above both values are Q values.

ü   

Dissolution acceptance criteria(IP)

stage

No. Of dosage units tested

Acceptance criteria

S1

6

No dosage unit is less than Q+5%.

S2

6

Average of 12 dosage units is equal to or not more than Q% and no unit is less than Q-15%.

S3

12

Average of 24 dosage units is equal to greater than Q% and not more than 2 dosage units are less than Q-15% and no dosage unit is less than Q-25%.

Ø  Tablet compression apparatus

• Dies define shape and size of tablet.
• Cam tracks guide the movement of punches.
• Multi-station presses are called rotary presses.
• Turrets-the portion of the head that hold the upper and lower punches.
• Fette machines-they chill the compression components to allow compression of low melting solids such as waxes use (in case of suppositories0.

TOOLING

• BB tooling-most commonly used.length-5.25 inch,nominal barrel diameter-0.75 inch,1 inch head diameter.
• B tooling-5.25 inch, nominal barrel diameter-3 9/16 inch,1 inch head diameter.
• D tooling-used for larger tablets. 5.25 inch, nominal barrel diameter-1 inch,1.25 inch head diameter.
• Dwell time-time for which tablet remains under compression.
• Remember-Devices which measure compression force at each compression station.

-Pharmakontroll, Killiani Control System, Thomas Tablet Sentine

Ø  PROCESSING PROBLEMS IN TABLET

1)       Capping and lamination-capping is partial or complete separation of top or bottom parts of tablet from main body of tablet.Lamination is separation of tablet into 2 0r more distinct layers. It is due to:-

- deformational properties of formulation i;e plastic deformation

-deep concave punches.

- absence of adequate moisture.

-tablet tooling

-incorrect setting of press.

 2) picking and sticking-picking occurs due to engraving and embossing.In  sticking tablet material sticks to die wall.

 3) Mottling-uneven distribution of color on tablet.

4) wt. Variation

5) poor flow-talc or colloidal silica helps in improving the flow.poor flow can result in bridging,arching and rat holling.

6) poor mixing

7)punch variation

8)hardness variation

9)double impression

Ø  TABLET GRANULATION

• It improves flow properties of tablet.
• Shape factor of granule should be 6 just like sphere for good flow.
• The method used for measurement of surface area solid granules or particles are air permeability method and gas-adsorption method(He gas is used).
• Dense granules require higher compression force to form cohesive compact and they are less friable.
• For determining granule density-Mercury displacement method is used. O                                       ther method uses benzene as organic solvent.
• As granule size increase bulk density decreases.
  As particle becomes more spherical bulk density increases.
• The strength of tablet is mainly due to surface tension of liquid and capillary forces.
• For measuring granule strength and friability ASTM(American Society For Testing Materials) specification is taken into account and compression strength are taken into account.

Ø  TYPES OF GRANULATION

• Dry granulation

*         Also called compression granulation.

*         Used when drug is sensitive to moisture.

*         Slugs are formed in this.so process also called slugging.

*         Roller compactor instrument is used.Can produce 500 kg of slugs.

*         Main advantage is that no need to use excess lubricants.

• Wet granulation

*         Granules formed by adhesive forces.

*         Surface tension forces and capillary pressure are initially responsible for wet granulation.

*         Solvents are used considering EPA(Environmental Protection Agency) regulations.

EQUIPMENTS FOR WET GRANULATION

1.        Littleford Lodige mixer- capable of both wet massing and blending.

*         Time taken-30-60 sec.

*         Horizontal in operation.

*         Temperature rise of 10-15 deg. is expected.

2. Diosna mixer or granulator-contains bowl in vertical position.

*         Total time 11-12 min.

3. Littleford MGT mixer-vertical in operation.

4.Gral mixer-modification of planetary mixer(IMP).

• Direct compression

*         E:g Nacl,KCl can be directly compressed.

*         Uses directly compressible diluents like spray dried lactose.

*         They have good flow and compressibility.

*         Maximum of 30% of API is used in direct compression tablet.

Ø  TABLET INGREDIENTS 

• Diluents:

*         Used to increase bulk of tablet.

*         5-80% can be used.

*         All the sugar containing diluents have tendency to undergo reaction with drugs containing –NH2 group. This is called Maillard reaction which only changes color not content.

STARCH

ü  11-14% moisture present

ü  Dried starch has 2-4% moisture. Their moisture level increase to 6-8% following moisture exposure.

ü  Two types:

Directly compressible starch (Sta-Rx 1500)-used as diluents, binder and disintegrant.

Contains 10% of moisture.

Hydrolysed starch (Emdex, Cellutab: contain 90-92%dextrose and 3-5% maltose)-directly compressible. Used in chewing tablets and have 8-10% of moisture.

LACTOSE

Ø  Three types of lactose.

1.        Alfa-lactose monohydrate-crystalline nature, has 5% moisture, poor flow and compressibility and used in wet granulation. It gives Maillard reaction.

2.        Spray dried lactose-<3% moisture.good flow and compressibility. Used in direct compression.it gives Maillard reaction.(in Maillard reaction furfuraldehyde is formed).

3.        B-lactose(anhydrous)-hygroscopic. used in direct compression and does not gives Maillard reaction.

DEXTROSE

• Also called cerelose.
• Can be used instead of lactose.

MANNITOL

• Used in chewable tablet due to negative heat of solution.
• Non-hygroscopic.
• Non-cariogenic.
• Used in vitamin formulations.

SORBITOL

• Optical isomer of mannitol.
• Hygroscopic.

SUCROSE

• Available as co-processed form such as SUGARTAB(90-95%sucrose + 7-10% invert sugar), DIPAC(97%sucrose + 3% modified dextrins) and NUTAB(95%sucrose+4%invert sugar+Mg.stearate+corn starch).
• Used in direct compression.
• Hygsroscopic

Important point-Kaolin and bentonite,diluents, is not used with cardiac glycoside,synthetic estrogens and alkaloids                           

                                                                MICROCRYSTALLINE CELLULOSE

• Trade name-AVICEL
• DIRECTLY COMPRESSIBLE
• Two grades:-PH101(powder) and PH102(granules)
• Also act as disintegrating agent.
• Hygroscopic
• May delay the release of drug.

DICALCIUM PHOSPHATE

• Non-hygroscopic(just like mannitol)
• Moisture sensitive drugs can be used with it
• Not used with tetracycline due to complex formation.

Classification in other way

Wet granulating diluents-alfa lactose,kaolin,bentonite, dicalcium sulphate

Direct compression-spray dried lactose,colloidal silica,NaCl and NaHCO3 for dental cones, direct com. starch.

Binders and adhesives

• Used to provide cohesive qualities.
• More the binder, harder is the tablet.

NATURAL GUM

• Acacia and tragacanth are examples
• Used in 10-25%

GELATIN

• Natural protein
• 10-20% in solution form.
• Upon storage disintegration time will increase with the use of such binders

Starch

• 10-20%solution.
• Give translucent paste.
• It undergoes hydrolysis to dextrin and glucose.
• Liquid glucose is 50%solution in water.

Modified natural polymers

•  Methylcellulose(alcohol soluble, more soluble in cold water than hot water)
• Hydroxy propylcellulose(alcohol sol.)
• Hydroxy propyl methylcellulose(water soluble)
• Ethylcellulose(alcohol soluble,retard D.T)
• PVP(polyvinyl pyrrolidone) used in 2%.used in aqueous and alcoholic solution.
• IPA(isopropyl alcohol)-widely used binder.

Ø  Another classification

ü  solution binders-strach,sucrose,gelatine,acacia,tragacanth.

ü  Dry binders-HPMC.Cross linked PVP.

Ø  LUBRICANTS

ü  Decrease friction between diewall and tablet surface

ü  Can be used intragranularly(PEG,Vegetable oils) and extragranularly(talc,stearates).

ü  They are hydrophobic in nature.

ü  Fluid lubricant-liq. Paraffin

ü  Boundary lubricant-stearic acid

ü   

Ø  What is bolting of lubricant?

Lubricant is passed through 60-100 mesh nylon cloth in order to get fine particles this is called bolting of lubricant.

ü  Hydrocarbon/mineral oil

• Applied as fine spray.
• Mostly used for aspirin tablets

ü  Calcium and Mg. Stearate

• used in 1%
• may cause delay release

ü  Mg.stearate is used with SLS due to its hydrophobic property.

ü  It is not used with acidic drugs

                     

Ø  Compritol 888

ü  It is glyceryl monoester of behenic acid.

Ø  Water soluble lubricants

ü  Sodium enzoate,sodium acetate,NaCl,leucine,PEG etc.

Ø  GLIDANTS

1)       Talc

• Used in 5%.
• Can also be used as anti-adherent.
• Contains traces of iron so may act as catalyst for the drugs which are degraded by Fe.
• Also contain calcium so not used with tetracycline.

2)       Colloidal silica

ü  Available in 3 forms

ü  Cab-o-sil(<1%)

ü  Aerosil(0.25-3%)

ü  Syloid.

Corn starch

ü  Use in 5-10%

                                                                                DISINTEGRANTS

Ø  Facilitate breaking up of tablet

Act by 3 mechanism

1.        By swelling

Alginate, starch dye, PVP

2.        By wetting

SLS, Clay, Bentonite

3.        Effervescent

NaHCO3 and citric acid

Examples

STARCH

ü  5-20%

ü  Modified starches are used which are: Primogel and Explotab. they are low substituted carboxymethyl starches.(1-8% used,but 4%is optimum)

Ø  Clays

ü  Veegum (Mg. Aluminium silicate)(10%)

ü  bentonite(10%)

• both are used only for colored tablets
• they are most effective in sulfathiazole tablets.

Ø  Super disintegrants

ü  They are used in lower concentration. of 2 % to 6 %,while traditional disintegrants such as starches often require concentrations of about 20 %. 

  

Sodium Starch Glycolate

  

Sodium Carboxymethyl Starch

  

Croscarmellose Sodium

Soy Polysaccharides

Ø  Primojel®, sodium starch glycolate, and Primellose®, croscarmellose sodium, which show outstanding disintegration characteristics for tablets prepared by direct compression, wet granulation and for capsule formulations. 

COLORING AGENTS

ü  Lake are the dyes that have absorbed on hydrous oxide

ü  As coloring concentration increases, mottling increases.

ü  To improve photosensitivity of dye use of UV absorbing chemical such as benzophenone can be used.

v  DI-PACLINE is a commercially available directly compressible sugar.

SWEETENERS

ü  Used in (0.5-0.75%)

ü  Cyclamates can be used.they are 70 times more sweeter than sugar. But are carcinogenic

ü  Aspartate(phenyl ester of methylacetic acid).180-200 times sweeter than sugar and non-carcinogenic.

ü  Saccharin is carcinogenic and 500 times more sweeter than sugar.

ü  Mannitol is used in chewable tablets and 72 times more sweeter than sugar.

SOME INSTRUMENTS

MIXING

ü  For large qt. Of powder-twin-shell blender,double-cone blender,planetary mixer.

ü  For continuous production-ribbon blender,roto cabe-blender

ü  Mass mixer-sigma blade mixer

ü  High speed granulators-Diosna mixer,Littleford MGT,Gral mixer

ü  For continuous production extruders are used E:g Reitz extruders

ü  Topo granulators-to prepare granules under high vaccum.

ü  Spheronization-refers to formation of spherical particle from wet granulation.

ü  Marumerizer and CF-granlator are used for spherozination

Ø  Spray congealing/spray chilling

ü  It is the process consist of melting solid and reducing them to beads or powders by spraying molten feed into stream of colder air or gases.

ü  Monoglycerides are spray congealed at 50 deg F

ü  Carbohydrates are sparay congealed at 167 deg F

Ø  Important information

ü  Versa press is used for the the preparation of layered tablets.

ü  Manestey dry cota instrument is used.implantation tablets should have size of less than 8mm.

ü  Kern-injector-contain hollow needle and plunger. used for administration of rod shaped tablet.

ü  For sub-lingual and vaginl tablets, lactose is used as diluent.