TABLET MANUFACTURE FORMULATION AND PROCESSING

1. TABLET MANUFACTURE FORMULATION AND PROCESSING

2. TABLET MANUFACTURE FORMULATION AND PROCESSING • Why are tablets the most popular dosage form for medicines? • Tablet compression • What is a ‘good’ tablet? • Tablet constituents • Direct Compression • Granulation • Sieving/milling • Blending • Common Tablet Problems • Questions

3. WHY TABLETS? 90% of medicines are taken orally with the majority being tablets. Other routes of administration include injections, inhalation, rectal and topical. Why are tablets the most common means of drug delivery?

4. WHY TABLETS? • Can be self administered • Painless • Accurate dose delivery • Portable and discreet • Can be packaged to aid patient compliance • Easily identifiable (colour, shape, size, logo etc) • Simple to use • Low cost of manufacture • Normally stable to heat and moisture • Not easily contaminated with micro-organisms • Good bioavailability for most drugs • Release can be modified

5. TABLET MANUFACTURE In order to make a ‘good’ tablet the powder to be compressed must have the correct characteristics: • The powder must be able to flow freely • The powder must be compressible (bind together to form a tablet) • The powder must be homogenous (uniform mix of active and excipient) • The tablet must be able to be ejected freely from the die without damage

6. TABLET COMPRESSION • Lower punch drops as die passes feed frame • Powder fills to ‘over-fill’ • Lower punch rises to expel excess (weight control) • Upper punch enters die • Pass between compression roller • Upper punch withdraws and lower punch rises • Tablet ejected by tablet take-off plate

7. What Is A ‘Good’ Tablet? • Must contain the correct amount of active • This is measured during the process by ATW and U of W measurements • Have suitable physical properties • Hardness • Friability • Thickness/Diameter • Disintegration/dissolution In order to ensure a good tablet is made the granule may need pre-conditioning and addition of excipients will be necessary

8. GRANULE MANUFACTURE • Three principle methods of preparing powder formulations for compression • Direct Compression • Wet Granulation • Dry Granulation

9. DIRECT COMPRESSION • This is the ideal option but is rarely achievable due to: • Active particle size/density mismatch with excipients causing poor homogeneity • Large quantity per tablet of poorly compressible active resulting in weak friable tablets

10. DIRECT COMPRESSION • Process flow for direct compression Dispense Security Sieve Lubricant Blend Compress

11. Problems Associated With Direct Compression • If the material is a powder rather than a granule: • it will have poor flow characteristics, which can lead to uneven tablet weights. • The pressure transmission through a powder mass is poor, due to low packing density. Consequently particles do not ‘knit’ together very readily. • Powders, especially fine ones tend to blow out of the die at the top and seep out at the bottom • Dusty powders tend to mix with oil/grease and eventually cause sticking of the punches in the dies or turret bores. • Powders containing two or more components may segregate. The heavier or smaller particle size components separate to the bottom of the bulk, this is made worse by the vibration of the Tablet Press. • Direct compression materials are more expensive than non-DC equivalents

12. Advantages of Direct Compression • Few stages involved • Low handling costs • Losses near zero • No water or heat involved • Reduces the risk of degradation of the active

13. PROCESS AIDS • Regardless of whether a tablet is manufactured by direct compression or granulation, processing aids will be required: • These materials are called excipients and are either: • Diluents • Lubricants • Disintegrants • Glidants • Binders • Direct compression formulations will contain as a minimum diluents, disintegrants and lubricants. • N.B. some excipients have more than one function

14. DILUENTS • A diluent is simply an ingredient that is used as a bulking agent to make tablets large enough to handle and swallow. • Diluents must therefore be: • Pharmacologically inert • Cheap • No supply issues • Compatible • Stable • Processable • Diluents are commonly easily compressible especially in DC formulations. • Examples include: • Micro-crystalline cellulose • Lactose • Di-calcium phosphate

15. LUBRICANTS • Lubricants are materials that lubricate powder mixes and aid tablet ejection. • Without lubrication powder may stick to the punches especially if is too moist. • Lubricants are typically added at a late stage and blended for the shortest possible time as they have adverse effects. • Adverse effects if over-blended are poor compressibility and increased dissolution due to waxy layer covering the surface of the granule • Examples include: • Magnesium Stearate • Stearic Acid • Talc

16. GLIDANTS • Glidants are materials that improve the flow of powder mixes • An example is Colloidal Silicon Dioxide • Most powders, without the aid of flow agents, simply cannot flow at speeds required for high speed tabletting. • Flow agents can decrease the capacity of powders to form bridges, create rat holes and stick to contact surfaces. • Good flow into the die will lead to uniform tablet weight as the volume of material flowing into the die will be constant

17. DISINTEGRANTS • A material to promote disintegration of the tablet when swallowed • Enhances water penetration by wicking effect • Increases porosity • Swells in contact with water and breaks cohesive bonds • Examples include: • Starch • Croscarmellose • Sodium Starch Glycollate • Crospovidone

18. BINDERS • A material that imparts cohesiveness to the formulation • Helps bind powder particles into granules during granulation • Helps bind granules together during the compression process • Examples include: • Hydroxypropyl methyl cellulose (HPMC in water) • Starch paste in warm water • Gelatin • Polyvinyl pyrrolidone (PVP)

19. WHY GRANULATE? • To improve powder flow. • To improve compressibility. • To reduce fines. • To control the tendency of powders to segregate. • To control density. • To capture and fuse small quantities of active material.

20. TRADITIONAL WET GRANULATION Dispense Security Sieve Granulate Dry Moisture Test Sieve/Mill Lubricant Blend Compress

21. TRADITIONAL WET GRANULATION • Most commonly performed using a high shear mixer e.g. ‘Fielder’ but can be performed using low shear e.g. ‘Hobart’. • Fielder Granulator: • Two blades, main blade and chopper • Main blade speed is typically 100-500rpm • Chopper blade up to 3000rpm • Main blade mixes and chopper breaks wet mass to form granules

22. TRADITIONAL WET GRANULATION • Powders are loaded into the bowl and mixed for a defined time before granulation starts • Granulating solution added at defined rate or sprayed (binder is usually incorporated into the solution) • Wet mass is chopped to form granule • Granulation end point can be measured by current draw on main blade • Process is controlled by the mixing times/speeds before and after addition of the granulating solution and the amount of solution added. • Process relies on the binder and/or water soluble elements dissolving upon granulation, then on drying forming a solid bridge between particles.

23. ADVANTAGES OF WET GRANULATION • Increases cohesiveness • Good for high dose/poorly compressible drugs • For example Kalms has large amount of poorly compressible Hops • Good for distributing soluble low dose drugs • For example in Kwells the hyoscine is added to the granulating solution • Prevents segregation of actives

24. DISADVANTAGES OF WET GRANULATION • Processing parameters are derived by trial and error • Mixing time varies with batch size and can be sensitive to variation in starting materials • Danger of over granulation • Cost (multi-stage process) • Incompatibilities (chemical instability with moisture or subsequent drying)

25. A TYPICAL WET GRANULATION FORMULATION • Wet Binder • Polyvinyl pyrrolidone (PVP) • Increases granule size strength and compressibility • Enhances dissolution relative to DC • Granulation process aid • Micro-crystalline cellulose • Reduces water/energy requirements • Reduces process sensitivity • Less risk of over granulation • Easier wet massing and screening • Intra granular filler • Lactose • Better wet binding than insoluble fillers • Intra-granular disintegrant • Croscarmellose sodium

26. DRYING • The removal of water or liquid to form a dry solid • It is necessary as too much residual water can result in: • Poor flow • Poor lubrication (sticking to punches) • Chemical instability • Susceptibility to microbial growth • 2 main methods • Tray drying • Fluidised Bed Drying • Others include microwave and vacuum drying (not commonly used)

27. TRAY DRYING • Fan assisted convection of hot air over loaded trays • Not commonly used due to: • Large floor space • Manual handling • Labour intensive • Long drying times (up to 24 hours) • Can get non-uniform drying • Can result in hard caked product

28. FLUIDISED BED DRYING • Heated air is pulled through the bed of material in a removable bowl. • Filters prevent fines from escaping • Temperature can be controlled by probes monitoring input, output and bed temperatures • Airflow is adjusted according to particle size and density • Most efficient drying (minutes vs. hours)

29. SIEVING AND MILLING • Sieving of the granule may be performed to remove large particles that may then be milled to reduce size • Oversize or all of the dried granule may be milled. • Various types of mill are usually used depending upon the process requirements • Mills used routinely at GR Lane include Comill (Cone mill), Apex and Tornado.

30. MILLING • Comills (cone mills) produce granule of more uniform size and shape than Apex or Tornado mills with a smaller proportion of fines • Fines are powders that are very small and ‘dusty’, which will pass through a 200 mesh screen. • Fines impede the flow, do not compress well • Mills may also be used to ‘de-lump’ granules without reducing particle size.

31. MILLING • Apex mills have the rotational shaft in a horizontal orientation vs Tornado that is vertical • Tornado mills have 360° mill screens and consequently produce marginally less fines than an Apex mill that has a 180° screen. • Both tornado and apex mills can be used with varying numbers of blades that throw material against the mesh that controls the maximum particle size • Hammers may also be used. These pulverise the material to a finer particle size

32. SPRAY GRANULATION • This is when granulation and drying is combined in a one-pot process • Granulation solution is sprayed into a fluidised bed • There is a greater degree of control over the size of granules formed. • Control is via spray rate, inlet temperature and air flow. • There are less losses by this method • Granule has an even moisture distribution However • Higher attrition may lead to fines • Control of rates is critical • Longer process time (may lead to de-mixing)

33. DRY GRANULATING • Dry granulating, also called slugging, or roller compaction, involves the pressing of mixed powders into an object to be reground into a precise powder. • This action increases particle density, improves powder flow and captures fines. • Useful for materials which are sensitive to heat and/or moisture. • Can be performed on tablet press followed by milling or by using specialised equipment • However pressure during dry granulation can result in: • granules with low porosity • Weaker tablets • May produce tablets with longer disintegration time • Dusty process

34. BLENDING • There are many different types of blenders • Y cone blenders • Double cone blenders • Drum blenders • IBC blenders • Majority are low shear tumble blenders. GR Lane has opted for IBC blending to reduce handling • Blend studies are performed to determine the determine the optimum endpoint • Given enough time, components will pass from an unblended state to a relatively homogenous blend and back to an unblended state.

35. COMMON TABLET PROBLEMS • Weight variation • Friability variation • Capping • Laminating • Chipping • Cracking • Sticking/Filming • Picking • Binding

36. WEIGHT VARIATION • Weight variation can be caused by a number of factors: • Poor flow of granule • Granule too wet • Insufficient glidant • Poor granule homogeneity • Over or under-blended • Material has settled over time • Separation of fines in hopper • Poor formulation • Tablet press set-up • Dropping punches • Sticking punches • Feed frame speed • Uneven wear or damaged tooling

37. POOR FRIABILITY • Poor friability can be caused by a number of factors: • Low hardness • Tablet press set-up • Overblending • Poor granule • Too dry • undergranulated • insufficient binder • too many fines • Inappropriate tablet shape

38. CAPPING • Capping is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. • Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. • Causes related to the formulation are • Large amount of fines • Granule too dry • Granule too wet • Insufficient lubricant • Causes related to the press: • Ringing in dies • Lower punch remains below the face of die during ejection. • Incorrect adjustment of take-off blade. • High turret speed • Possible remedial actions are: • Move position of compression in die • Adjust take-off blade • Slow down press

39. LAMINATION • Lamination is the separation of a tablet into two or more distinct horizontal layers. • Reason: Air–entrapment during compression and subsequent release on ejection • Causes related to the formulation: • Over lubrication of formula • Oily material in formula • Causes related to the tablet press: • Rapid relaxation of the peripheral regions of a tablet, on ejection from a die. • Rapid decompression • Possible remedial action: • Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°. • Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

40. CHIPPING • There are number of causes of chipping that can be due to: • Machine setup • Insufficient dwell time • Compression force too low • Tooling wear • worn punches • Poor granule • too much fines • Granule too dry • Insufficient binder • Excessive lubricant • Not homogenous mix • Possible remedial actions • If clawed tooling, remove claws • Increase pressure • Slow down press

41. CRACKING • Cracking is where small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall • Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used • Causes related to the granule: • Large size of granules. • Too dry granules • Causes related to the tablet press: • Tablet expands on ejection due to air entrapment • Deep concavities cause cracking while removing tablets • Too much pressure • Possible remedial action: • Use tapered die • Use special take-off plate • Reduce compression force

42. STICKING/FILMING • Sticking refers to the tablet material adhering to the die wall. • Filming is a slow form of sticking and is largely due to excess moisture in the granulation. • Reason: Improperly dried or improperly lubricated granules. • Possible remedial action: • Increase pressure. • Reduce speed.

43. PICKING • Picking is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. • The problem is more prevalent on the upper punch faces. The problem worsens with time into the run because more and more material is added to the already stuck material on the punch face. • Common causes related to the granule: • Excessive moisture in granules • Too little or improper lubrication • Too warm granules when compressing. • Too much binder. • Common causes related to the tablet press: • Rough or scratched punch faces • Unpolished tooling • Insufficient pressure • Possible remedial actions: • Increase compression pressure • Polish tooling by hand • Reduce press speed

44. BINDING • Binding in the die, is the term used when the tablets adhere or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and they may crumble apart • Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies. • Causes due to worn dies: • Poorly finished dies • Rough dies due to abrasion • Possible remedial action: • Clean the dies properly • If worn die is due to abrasion investigate use of other steels • Reducing pressure in the tablet press may decrease binding.

45. Thank You Any Questions