Tablet manufacturing process 322 PHT

1. Tablet manufacturing process322 PHT Nahla Barakat, PhD King Saud University Dept. of Pharmaceutics 1431/1432

2. Introduction • The manufacture of oral solid dosage forms such as tablets is a complex multi-stage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. • Traditionally, tablets have been made by granulation, a process that imparts two primary requisites to formulate: compactibility and fluidity. • Both wet granulation and dry granulation (slugging and roll compaction) are used. • Regardless of weather tablets are made by direct compression or granulation, the first step, milling and mixing, is the same; subsequent step differ. • Numerous unit processes are involved in making tablets, including particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating.

3. Compressed tablet • Uncoated tablet • Coated tablet • A tablet prepared, usually as a large-scaleproduction, by means of great pressure; most compressed tablet's consist of the activeingredient and a diluent, binder, disintegrator, and lubricant.

4. Tablet tooling; punches and dies

5. Caplet Shape Dies Star Shapes Dies Oval Shapes Dies Round Shapes Dies

6. Tablet production • Powders intended for compression into tablets must possess two essential properties: • 1- Powder fluidity • The material can be transported through the hopper into the die to produce tablets of a consistent weight • Powder flow can be improved mechanically by incorporate the glidant • 2- Powder compressibility • The property of forming a stable, intact compact mass when pressure is applied

7. Tablet Manufacturing Tablet Compression Machine • Design: 1. Hopper for holding and feeding granules or powder to be compressed. 2. Dies that define the size and shape of the tablet. 3. Punches for compressing the granules within the dies. 4. Cam tracks for guiding the movement of the punches. 5. A feeding mechanism for moving granules from the hopper into the dies.

8. Stages of Tablet Formation (Compaction Cycle) • 1- Die filling • Gravitational flow of the powder from hopper via the die table into the die . (The die is closed at its lower end by the lower punch). • 2- Tablet formation • The upper punch descends, enters the die, the powder is compressed until a tablet is formed. • after maximum applied force is reached, the upper punch leaves the powder i.e. compression phase. • 3- Tablet ejection • The lower punch rises until its tip reaches the level of the top of the die. • The tablet is subsequently removed from the die and die table by a pushing device.

9. Tabletting Process • Basics – powders fed into a die Powder compressed between punches

11. Tablet press Single Punch press (Eccentric Press): bench-top models that make one tablet at a time (single-station presses) Disadvantages: Production of small batches of tablets (200 tablets per minute).

12. 2- Rotary Press( Multi station Press): • It was developed to increase the output of tablets (10 000 tablets per minute), used for Large scale production. • It consists of a number of dies and sets of punches ( from 3 up to 60). • The dies are mounted in a circle in the die table and both the die table & the punches rotate together during operation of the machine.

13. Rotary Press Machine

15. Direct compression • The term “direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. • It involves only two unite operations powder mixing and tabletting. Advantages of Direct Compaction: • Reduced production time &cost. • product stability can be improved. • Faster drug dissolution due to fast disintegration into primary particles. • less number of equipments are required, less process validation • Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermolabile and moisture sensitive API’s. • The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer.

16. Disadvantages of Direct Compaction 1. Large particles must be used → (acceptable flowability and bulk density) 2. Many active ingredients are not compressible either in crystalline or amorphous forms. 3. Needs directly compressible filler that is usually expensive, e.g. microcrystalline cellulose (Avicel), spray dried lactose 4. Problems in the uniform distribution of low dose drugs. 5. High dose drugs having high bulk volume, poor flowability and poor compressibility are not suitable for direct compression. For example, Aluminium Hydroxide, Magnesium Hydroxide 6 . Non-uniform distribution of colour, especially in tablets of deep colours

18. Dispensing (weighing and measuring) • Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps in pharmaceutical manufacturing; • during this step, the weight of each ingredient in the mixture is determined according to dose. • Issues like: • weighing accuracy, • dust control (laminar air flow booths, glove boxes), during manual handling, • lot control of each ingredient, • material movement into and out of dispensary should be considered during dispensing.

19. Sizing • The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit operation) involved in the tablet manufacturing. • In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of pharmaceuticals is easier and more uniform if the ingredients are approximately of same size. • Advantages associated with size reduction in tablet manufacture are as follows: • i) It increases surface area, which may enhance an actives dissolution rate and hence bioavailability. • ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit weight. • iii) Improved flow properties of raw materials. • iv) Improved colour and/or active ingredient dispersion in tablet excipients.

20. Powder blending • The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. • Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired product. • So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. • The various blenders used include blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder blender, etc.

21. Drying • Drying is a most important step in the formulation and development of pharmaceutical product. • It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. • The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc.

22. Tablet compression • After the preparation of ingredients (in case of direct compression), they are compressed to get final product. • The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press). • The tablet press is a high-speed mechanical device. It 'squeezes' the ingredients into the required tablet shape with extreme precision. • It can make the tablet in many shapes, although they are usually round or oval. Also, it can press the name of the manufacturer or the product into the top of the tablet. • Each tablet is made by pressing the granules inside a die, made up of hardened steel. • The die is a disc shape with a hole cut through its centre. The powder is compressed in the centre of the die by two hardened steel punches that fit into the top and bottom of the die.

23. Tablet compression process

24. Stage 1: Top punch is withdrawn from the die by the upper cam, Bottom punch is low in the die so powder falls in through the hole and fills the die. • Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder • Stage 3: Top punch is driven into the die by upper cam; Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder. • Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate • Stage 5: Return to stage 1

25. Tablet weight monitoring devices • High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring devices like Thomas Tablet Sentinel, Pharmakontroll and Killan control System-MC.

26. Tablet Deduster • In almost all cases, tablets coming out of a tablet machine bear excess powder on its surface and are run through the tablet deduster to remove that excess powder.

27. Packaging • Pharmaceutical manufacturers have to pack their medicines before they can be sent out for distribution. • The type of packaging will depend on the formulation of the medicine. • 'Blister packs' are a common form of packaging used for a wide variety of products. • They are safe and easy to use and they allow the consumer to see the contents without opening the pack.

28. Wet Granulation • In the pharmaceutical industry, granulation refers to the act or process in which primary powderparticles are made to adhere to form larger, multiparticle entities called granules. • It is the process of collecting particles together by creating bonds between them. • Bonds are formed by compression or by using a binding agent. • Granulation is extensively used in for the manufacturing of tablets, pellets (or spheroids). • The granulation process combines one or more powders and forms a granule that will allow tableting or spheronization process to be within required limits.

29. Granulation is carried out for various reasons, one of those is to prevent the segregation of the constituents of powder mix. Segregation is due to differences in the size or density of the component of the mix. • Normally, the smaller and/or denser particles tend to concentrate at the base of the container with the larger and/or less dense ones on the top • An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule and segregation of granules will not occur.

30. Some powders are difficult to compact even if a readily compactable adhesive is included in the mix, • but granules of the same powders are often more easily compacted.

31. Wet Granulation • A process of size enlarging a mix of active ingredient and excipient powder particles into stable aggregates exhibiting desired • properties of: • Compressibility • Cohesiveness • Flowability • Bulk density • Granules may be a final product or an intermediate product that needs further processing

32. It involves massing of a mix of dry primary powder particles using a granulating fluid. • • The fluid contain a solvent that must be volatile and non-toxic e.g water, or organic solvent. • • The granulating solvent may contain a binding agent to ensure particle adhesion after drying. • Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the most commonly used pharmaceutical binders. • PVP is dissolved in water or solvent and added to the process.

33. Typical liquids include: • 1.water : may adversely affect drug stability, causing hydrolysis ,it needs a longer drying time. This increases the length of the process. The advantage :non-flammable and economic. • 2.Ethanol, Isopropanol ,or combination (organic solvents) used with water sensitive drugs ,alternative to dry granulation or when rapid drying time is required.

34. The moist mass is broken up into coarse, granular aggregates (using screens with large perforations). • The purpose is to increase surface area to facilitate removal of moisture. • Mixing with other tablet excipients • (lubricant, glidant, remaining of disintegrant) and then compaction.

35. Production via Wet Granulation: • Process description: • Agitation of a powder in the presence of a liquid. • It forms the granules by binding the powders together with an adhesive. • Once the granulating liquid has been added, mixing continues until uniform dispersion is attained (15 min. to an hour).

36. Steps of granules formation

37. Product characteristicsDust free Good flow behaviour Easy to dose Good dispersibility Good solubility Highly suitable for making into tablets Compact structure Low hygroscopicity High bulk density Wide grain size distribution

38. Drying process • A process of evaporating the liquid contained within aggregates produced by a wet granulation process to a predetermined moisture content  • Accomplished via • 1. Tray dryer (direct contact with heating medium) • 2. Fluidized bed dryer (indirect contact of the product with the heating medium

39. • Single machines utilized for both the wet granulation and drying process in one unit operation. • Use Fluid Bed Dryer (FBD) • It is a multiple step process performed in the same vessel to mix, granulate and dry the powders. • Combines wetting the powders to for granules &then, dryingthem in the same piece of equipment. Single Step Technology for Wet Granulation

40. Advantages of FBD A. Reduced product handling • B. Closed process suitable to: •   Gentle product handling. • Intensive mixing of the solid material. • Uniform spraying of all particles in the fluid bed. • Uniform, reproducible product quality. • Potent compounds • Minimizing product/operator exposure • Minimizing cross contamination and product loss •  Reduced cleaning and overall process time •  Reduced equipment and floor space requirements

41. Fluid bed dryer Tray dryer

42. Mixer and blender

43. Dry Granulation • The dry granulation process is used to form granules without using a liquid solution because the product to be granulated may be sensitive to moisture and heat. • Forming granules without moisture requires compacting and densifying the powders. • In this process the primary powder particles are aggregated under high pressure. • Dry granulation can be conducted under two processes; either a large tablet (slug) is produced in a heavy duty tabletting press or the powder is squeezed between two rollers to produce a sheet of materials (roller compactor, commonly referred to as a chilsonator).

44. Tablet Produced by Compression Granulation (Dry Granulation) • Advantage: (1) avoid exposure of the powder to moisture and heat. (2) Used for powders of very low bulk density to ↑ their bulk density. • Disadvantages: – Tablet disintegration and dissolution may be retarded due to double lubrication and compaction

45. Methods of dry granulation • A. Slugging technique • B. Roller compaction technique

46. Steps of Dry Granulation: • The blend of finely divided powders is forced into the dies of a large capacity tablet press. • Then, compacted by means of flat faced punches (Compacted masses are called slugs and the process is slugging) or roll compactor to produce sticks or sheets. • Slugs or sheets are then milled/screened to produce granules (flow more than the original powder mixture).

48. Unit operations in tablet manufacturing Dry granulation Wet granulation Direct compression Drug Diluent Lubricant Mixing Drug Diluent Glidant disintegrant Mixing Drug Diluent Mixing compression Wetting granulation Binder solvent comminution Drying Disintegrant Glidant Lubricant screening Disintegrant Glidant lubricant Screening lubricant Mixing Mixing Mixing Compression Mix Fill die, Compress tablet, Eject tablet Metal check, dedusting, coating, package

49. TABLE.2. TYPICAL UNIT OPERATION INVOLVED IN WET GRANULATION, DRY GRANULATION AND DIRECT COMPRESSION

50. Sources of Tablet Defects : • Sources of Tablet Defects • Moisture • Improper drying • High speed machines • Tools setting problem • Excess use of binders • Lack of proper lubricant selection • Air interaction • Lack of knowledge • Improper training • Abnormal ratio of excipients • Temperature adjustment • Size, shape