Pelletization Flashcards
advantages of using spheroids as a multi-unit dosage form (in terms of therapeutic)
- minimise local irritation
- maximise absorption/ bioavailability
- less susceptible to dose dumping
- reduction in GER
advantages of using spheroids as a multi-unit dosage form (in terms of technological)
- superiority for coating (able to coat well)
- uniformity in packing (all are same sizes)
- spherical in shape
- good flowability
- low friability (doesnt break easily)
pellets for multi-particulate dosage forms is used for what systems?
customised/ modified release system
- sustained-release action
4 diff methods of pelletization techniques
direct pelletization
- aq-based pelletisation
- melt-based pelletization
pelletization through extrusion step
- extrusion-spheronisation
- hot-melt extrusion
layering onto starter seeds
- powder layering
- solution layering
- suspension layering
formation of droplets
- spray drying (in lec7)
- spray congealing (in lec7)
- cryopelletization
3 methods of direct pelletization
(1) fluid bed layering
- pelletization by layering onto starter seed
- successive coats on the seed particles wo agglomerative growth
(2) balling process
- a layering process, to produce nonpareils
(3) pelletization in rotary processor
- ‘one-pot’ pelletization
- spray agglomeration media directly onto powder mass in a spheronizer to from pellets
- pellets formed in situ
- change spray media into coating media after introducing drying air into chamber
why extrusion-spheronisation is the method of choice for producing pellets
- highly spherical aggregates
- pellets are narrow size distribution
- smooth surface pellets
- low friability pellets
ease of operation
high throughput with low wastage
very efficient
steps for extrusion-spheronization process
(1) dry blending
(2) wet massing
(3) extrusion
(4) spheronization
(5) drying
(6) coating (coat for sustained release)
what happens in the extrusion step?
moistened powder mixture passed through screen aperture to form extrudates
extrudates: jagged w regular spaced shark-skinned protuberances, high-density, cylindrical
for the extrusion step, how do we determine the screen aperture size?
screen aperture size approx the desired size of pellets
what happens in the spheronization step?
spheroids are formed where extrudates are broken into uniform length and rounded w a rotating frictional plate
rounding due to a ‘rope-like’ motion
shaping is due to plastic deformation (ability to be mold)
pellets similar size to screen aperture size, highly spherical and narrow size distribution
when do we know we have gotten out desired pellet size and shape (spherical)?
using real-time imaging: size distribution becomes narrow (graph becomes narrow and sharp peak formed) (slide 22)
4 different mechanism of pellet formation (theories of how pellets are formed)?
(1) Rowe
(2) Baert and Remon
(1) and (2) was theorised based on plasticine
(3) Liew
(4) Koester and Thommes
(3) and (4): fragments of diff size come together and build up
what is required for extrusion to take place?
- cohesive
- plastic wet mass with inherent fluidity and self-lubricating properties
what is required for spheronization to take place
- extrudates with sufficient plasticity
basic formulation of forming pellets?
- pelletization aid
- drug
- filler
- moistening liquid
difference bet granulation and spheronization
spheronization: objective is to make a highly spherical particle
granulation: not this objective
other than this diff, spheronization and granulation are similar
why is Microcrystalline cellulose (MCC) a good pelletisation aid?
- good binding property
- good cohesiveness
- larger surface area (low s.a. to vol ratio); microfibrous
- high internal porosity
- prepares highly spherical granules of narrow size distribution and with desired mechanical properties
function/ ability of MCC as a pelletization aid
molecular sponge model
(1) Extrusion
- MCC absorbs water: forms cohesive yet plastic wet mass
- helps in binding and lubrication
(2) helps in binding and lubrication during spheronization
- increase surface plasticity
- helps in rounding extrudates into pellets
crystallite gel model
(1) MCC broken down into single crystallites to form crystallite gel and immobilise the liquid
- under pressure/extrusion, MCC release water
other pelletization aids, other than MCC
- cross-linked polyvinyl pyrrolidone (PVP) - v successful
- powdered cellulose
- hydroxypropyl methylcellulose (HPMC)/ Hypromellose
- Hydroxyethylcellulose
- chitosan
- carrageenan
what is considered a good pellet?
(1) well-formed extrudates
(2) breaks into short lengths
(3) rounds quickly
how to ensure pellets formed a highly spherical?
particles are 1/6-1/8 of desired pellet size
- smaller particles produce agglomerates that are more spherical
how do we know how much moistening liquid is to be added to make the pellet?
using a mixer torque rheometer (MTR), where moistening liquid (water) added to powder mass
rheological proflie of moistened powder mass is obtained
results:
use 80-90% of Tmax as a marker of how much water to add and how much torque to apply
(Tmax usually is when the capillary form is made) (slide 33)
what is the ideal forces seen in spheronization for a successful pelletization? and what pellets do we see?
cohesive force approx/equal to forces during spheronization
- round; narrow size distribution
what happens when cohesive forces are lesser than the forces during spheronization?
irregular shaped pellets; wide size distribution (not ideal)
what alterations can we do when we have cohesive forces are lesser than the forces/ pellets become irregular shaped?
(1) reduce the spheronization speed
(2) increase the wet mass/extrudate’s cohesive strength by:
- repeating extrusion step
- reduce component particle size (increase s.a.)
- widen size distribution of components
what happens when cohesive forces are greater than the forces during spheronization?
pellets become elongated
what alterations can we do when we have cohesive forces are greater than the forces/ pellets become elongated?
increase spheronization speed
packability influences spheroid formation. what does packability depend on?
- particle size (small)
- size distribution (wider)
- forces exerted during wet processing (wet massing step)
3 things that makes spheronization a success?
(1) particle/component size (small), and overall matrix cohesiveness during wet processing steps
(2) good packability
(3) optimal balance of forces (cohesive forces approx/equal to forces applied during spheronization)
ideal distribution for moistening mass (wet prcoessing step) for pellet formation
(1) *wide size distribution–> w moistening liquid: well packed, strong pellets formed (best)
(2) small particles –> w moistening liquid: well packed, strong pellets (but can trap air and require large mechanical strength for packing) (ok)
(3) not ideal:
coarse particles –> w moistening liquid: loosely packed; friable pellets
cohesivity is important for pelletization. but what is something that cohesivity can’t have
cannot have migratable stickiness (mass keeps growing)
- seen with the use of PVP/ HPMC or melt; (PVP/ HPMC are soluble in water)
- use immobile adhesive particles (e.g. micronised powders, MCC - both are insoluble)
why is migratable stickiness undesirable
makes a process less robust for controlling final product size
- particles continue to grow
- see in melt pelletization
summary: what are the critical attributes for successful pelletization?
- nature of component particles
- amount of moistening liquid
summary: main method for making drug containing pellets in the pharma industry
extrusion-spheronizarion
summary: why understanding the science of spheroid formation is impt
- ensure good quality pellets are made for use as multi-particulates for drug delivery
why everywhere is a sphere?
- minimisation of energy: reduction of friction during motion
