1. PM3125: Lectures 18 to 21 Content of Lecture 18:
Compression & Compaction in Tablets Formation
Prof. R. Shanthini Oct 2012

2. Active substance synthesis Blending and Granulation
Principle of tablet production
Active substance synthesis
Blending and Granulation
Compression
Coating
The manufacturing process of tablets can be divided into two different sub-processes:
-Active substances synthesis (production of pharmaceuticals in multi-level procedures)
-Pharmaceutical manufacturing
Blending and granulation: Tablets are most commonly compressed using powder mixtures which are previously granulated. The blending itself is done in so-called blenders wherein active substances and additives are blended homogeneously. This mixture is granulated afterwards in e.g. fluidized bed granulators where coupling agents are added. Granulate is produced from these moistly particles.
Compression: Homogeneously and accurately dosed granulate is compressed into tablets or pill cores under high pressure by high performance tablet presses.
Coating: Tablets are coated in so-called coaters by protective finishes or suspensions. Film-coated tablets are coated by polymer solutions and pills by sugar.
Package
Package
Prof. R. Shanthini Oct 2012

3. Compressed tablets Advantages and disadvantages of compressed tablets
Types of tablets
Tablet compression machine
Tableting methods
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

4. Advantages Production aspect User aspect (doctor, pharmacist, patient)
Large scale production at lowest cost
Easiest and cheapest to package and ship
High stability
User aspect (doctor, pharmacist, patient)
Easy to handling
Lightest and most compact
Greatest dose precision & least content variability
Coating can mark unpleasant tastes & improve acceptability
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

5. Disadvantages Some drugs resist compression into dense compacts
Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability
Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

6. Types of tablets – Production process
Compressed tablets
Multiple compressed tablets
Tablet within a tablets: core and shell
Multilayer tablet
Sugar coated tablets
Protect tablets from moisture
Mask odor and flavor
Elegance
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

7. Types of tablets – Production process
Film coated tablets
Thin film coat
Soluble or insoluble polymer film
Chewable tablets
Rapid disintegrate
Antacid, flatulance: rapid action
Children drug
Effervescent tablets
Dissolve in the water before drink
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

8. Ingredients used in tablet formulations
Drugs
Fillers, diluent, bulking agent
To make a reasonably sized tablet
Binders
To bind powders together in the wet granulation process
To bind granule together during compression
Disintegrants
To promote breakup of the tablets
To promote rapid release of the drug
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

9. Ingredients used in tablet formulations (contd.)
Lubricants
To reduce the friction during tablet ejection between the walls of the tablet and the walls of the die cavity
Glidants
Reducing friction between the particles
To improve the flow properties of the granulations
Antiadherants
To prevent adherence of the granules to the punch faces and dies
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

10. Ingredients used in tablet formulations (contd.)
Dissolution (enhancers and retardants)
Wetting agents
Antioxidants
Preservatives
Coloring agents
Flavoring agents
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

11. Essential properties of tablets
Accurate dosage of medicament, uniform in weight, appearance and diameter
Have the strength to withstand the rigors of mechanical shocks encountered in its production, packaging, shipping and dispensing
Release the medicinal agents in the body in a predictable and reproducible manner
Elegant product, acceptable size and shape
Chemical and physical stabilities
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

12. Tablet production
Powders intended for compression into tablets must possess two essential properties
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 the use of vibrators, incorporate the glidant
Powder compressibility
The property of forming a stable, intact compact mass when pressure is applied
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

13. Tableting procedure Filling Compression Ejection
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

14. Prof. R. Shanthini Oct 2012

15. A — Die filling
B — Compression
C — Decompression
D — Lower punch removal and reapplication of load to the upper punch
E — Tablet fully ejected
1 refers to the final compaction conditions
 Schematic diagram showing the manufacture of single and bilayer tablets utilising uniaxial compaction.
Prof. R. Shanthini Oct 2012

16. 1. Milling and mixing of drugs and excipients
WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
1. Milling and mixing of drugs and excipients
2. Preparation of binder solution
2. Compression into slugs or roll compaction
2. Compression of tablet
3. Wet massing by addition of binder solution or granulating solvent
3. Milling and screening of slugs and compacted powder
4. Screening of wet mass
4. Mixing with lubricant and disintegrant
5. Drying of the wet granules
5. Compression of tablet
6. Screening of dry granules
7. Blending with lubricant and disintegrant to produce “running powder”
8. Compression of tablet
Prof. R. Shanthini Oct 2012

17. Granulation
It is a process in which primary powder particles 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.
Prof. R. Shanthini Oct 2012

18. Granulation (contd.)
The most common reasons given to justify granulating are:
To impart good flow properties to the material,
To increase the apparent density of the powders,
To change the particle size distribution,
Uniform dispersion of active ingredient.
Prof. R. Shanthini Oct 2012

19. Binders
Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling.
In some instances the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult.
This problem can be overcome by adding some or all binding agents in the dry powder prior to granulation.
Prof. R. Shanthini Oct 2012

20. Some granulation, when prepared in production sized equipment, take on a dough-like consistency and may have to be subdivided to a more granular and porous mass to facilitate drying.
This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all.
Prof. R. Shanthini Oct 2012

21. Oscillating type granulator Hammer mill
Prof. R. Shanthini Oct 2012

22. Drying
The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity.
The important factor to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays.
If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules.
Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load.
Prof. R. Shanthini Oct 2012

23. Fluidized bed dryers are an attractive alternative to the circulating hot air ovens.
The important factor considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity.
Prof. R. Shanthini Oct 2012

24. Reduction of Particle size
Compression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity.
First step in this process is to determine the particle size distribution of granulation using a series of “stacked” sieves of decreasing mesh openings.
Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device.
Prof. R. Shanthini Oct 2012

25. Oscillating type granulator Hammer mill
Prof. R. Shanthini Oct 2012

26. Blending
Type of blending equipment often differs from that using in laboratory.
In any blending operation, both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and density, and of the dynamics of the mixing action.
Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used.
When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender.
Prof. R. Shanthini Oct 2012

27. Equipments used for mixing Sigma blade mixer. Planetary mixer.
Twin shell blender.
High shear mixer
Planetary mixer
Prof. R. Shanthini Oct 2012

28. Dry Granulation (slugging)
A dry powder blend that cannot be directly compressed because of poor flow or compression properties.
This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less.
Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts.
If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation.
Prof. R. Shanthini Oct 2012

29. Dry Compaction
Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch.
Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression.
One of the best examples of this process is the densification of aluminum hydroxide.
Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties.
Prof. R. Shanthini Oct 2012

30. Compression
The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press.
During compression, the tablet press performs the following functions:
Filling of empty die cavity with granulation.
Precompression of granulation (optional).
Compression of granules.
Ejection of the tablet from the die cavity and take-off of compressed tablet.
Prof. R. Shanthini Oct 2012

31. Tablet compression machines
Hopper for holding and feeding granulation to be compressed
Dies that define the size and shape of the tablet
Punches for compressing the granulation within the dies
Cam tracks for guiding the movement of the punches
Feeding mechanisms for moving granulation from the hopper into the dies
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

32. Singe punch machine The compression is applied by the upper punch
Stamping press
Prof. R. Shanthini Oct 2012
Source: Assoc. Prof. Dr. Jomjai Peerapattana, Faculty of Pharmaceutical Sciences, Khon Kaen University

33. Singe punch rotary machine
Prof. R. Shanthini Oct 2012

34. Singe punch machine
Upper and Lower Collar
Collar locker