Solid Oral Dosage Forms 2

Question 1

What is granulation?

Answer 1

Process to make primary powder particles form larger multi-particulate entities called granules
Pharmaceutical granules are in size range 0.2 to 4.0 mm
For tablets and capsules are in size range 0.2 to 0.5 mm

Question 2

Why make granules?

Answer 2

To prevent segregation of components in a powder mixture, to improve flow properties and compaction properties
Specific applications: increase density of powder mix, reduce dust when handling toxic materials, prevent slightly hygroscopic materials caking when stored
Two processes, wet and dry

Question 3

Particle bonding mechanisms

Answer 3

Mixtures of particles and liquid
Adhesion and cohesion forces in the immobile liquid films between primary particles
Interfacial forces in the mobile liquid films within granules
Solid bridges formed after solvent evaporation
Attractive force between particles
Mechanical interlocking

Question 4

What holds the granule together?

Answer 4

Individual particles accumulate into balls during granulation process
Liquid bridges- temporary structures, removed in drying step
Solid bridges- hardening of binders, crystallisation of dissolved substances, partial melting (low melting point materials)

Question 5

Drying of wet solids

Answer 5

Moisture content of wet solids- kg of water per kg of moisture free solid
Total moisture content- not all water can be removed easily, bound and unbound water
Equilibrium moisture content (EMC)- moisture content of a solid under steady-state ambient conditions, depends upon temperature, humidity and nature of solid

Question 6

Convective drying fluidised bed

Answer 6

Advantages: efficient heat and mass transfer, drying from all surfaces, bed temperature can be controlled, avoids risk of soluble material migration
Disadvantages: fines collected in bag filters, care needed to avoid segregation and loss

Question 7

Dry granulation

Answer 7

Primary particles formed into granules without the use of liquids by the use of compaction
Used for labile actives that are sensitive to liquids and heat
Two step process: mix powders, then compact on heavy duty machines to form large tablets (slugs) or use roller compactors to form sheets of material
Mill materials to obtain required particle size

Question 8

Dry granulation advantages and disadvantages

Answer 8

Advantages: use with water and heat sensitive actives, simple two-step process, requires less labour and equipment
Disadvantages: requires actives with compaction properties, only used for high dose actives, requires additional excipients for slugging process, extra lubricant required

Question 9

Wet granulation advantages and disadvantages

Answer 9

Advantages: overcomes problems with compaction properties of active, makes particles more hydrophilic, a reliable process, easy to transfer
Disadvantages: requires many pieces of equipment and uses more labour, cannot be used with water sensitive drugs

Question 10

Tablets definition

Answer 10

Solid preparations each containing single dose of one or more active substances, usually made by compacting uniform volumes of particles
Most intended for oral administration

Question 11

Types of tablets

Answer 11

Standard- designed to break up in the stomach and release the active
Chewable
Buccal/sub-lingual
Orally-disintegrating
Effervescent
Modified release

Question 12

Standard tabletting process

Answer 12

Compaction: process of a two-phase system (particulate solid/gas), involving:
Compression- reduction in bulk volume by displacement of air from bed of material and deformation of particles to fill voids
Consolidation- an increase in mechanical strength due to inter-particulate interactions

Question 13

Role of the compression force

Answer 13

Primarily to bring the adjacent particulate surface together so that forces active at surfaces may form lasting linkages
Inter-particulate forces are weak and only significant if the particles are touching one another or very close
Mechanical strength e.g. breaking force is function of nature of attractive forces and area over which they act

Question 14

Paddle feeder

Answer 14

High speed machines require faster delivery of granules to dies
Granule flow assisted by rotating paddles that fluidise the granules, reducing attraction between particles

Question 15

Powder flow through an orifice

Answer 15

Factors affecting: orifice diameter, hopper width, head size, hopper wall angle
Power arches can form at outlet preventing flow

Question 16

Flow from hoppers

Answer 16

Ideal, first in first out, no de-mixing at exit
Requires a constant rate of flow, related to angle of wall friction
Mass flow hoppers requires more head space in building

Question 17

Process using direct compression

Answer 17

No heat or moisture- better product stability
Fewer unit operations- less handling and segregation
Disintegrates into primary active particles
Less dependent on operators skills

Question 18

Disadvantages of direct compression process

Answer 18

Compaction properties of active critical
Excipient properties more critical, most are granulated and more expensive
No hydrophilisation of surfaces
Small particle size affects flow
Difficulties with content uniformity
Potential for post-blending segregation
Sensitivity to over-lubrication 
May require adaptation to feeding system on tabletting machine

Question 19

Tabletting using dry granulation advantages and disadvantages

Answer 19

Advantages- granulation with no heat or solvents, increases bulk density, improves flow, limits segregation
Disadvantages- loss of compactibility, need high lubricant level, no hydrophilisation of surfaces, significant recycling of material

Question 20

Tabletting using wet granulation disadvantages

Answer 20

Exposure of active to heat and solvents
Non-uniform distribution of ingredients
Additional excipients required (binders and solvents)
Many unit operations involved

Question 21

Tabletting using wet granulation advantages

Answer 21

Improves flow properties
Limits segregation tendency
Improves compactibility
Makes surfaces more hydrophilic
Permits addition of a liquid phase
Improves uniformity of bulk density
Facilitates control of particle size
Reduces amount of fine dust