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Flashcards in Solid Oral Dosage Forms 2 Deck (21):

What is granulation?

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


Why make granules?

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


Particle bonding mechanisms

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


What holds the granule together?

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)


Drying of wet solids

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


Convective drying fluidised bed

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


Dry granulation

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


Dry granulation advantages and disadvantages

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


Wet granulation advantages and disadvantages

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


Tablets definition

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


Types of tablets

Standard- designed to break up in the stomach and release the active
Modified release


Standard tabletting process

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


Role of the compression force

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


Paddle feeder

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


Powder flow through an orifice

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


Flow from hoppers

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


Process using direct compression

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


Disadvantages of direct compression process

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


Tabletting using dry granulation advantages and disadvantages

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


Tabletting using wet granulation disadvantages

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


Tabletting using wet granulation advantages

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