Revision Flashcards
Why is powder/particles used?
Due to the greater surface area as smaller particles have larger surface area
WHat are the concerns around using powder?
Powders can stick which reduces the surface area so we granulate and keep a passage of air to increase interaction between liquid and solid
What is a crystalline structure?
Where atoms are well distributed periodically e.g. salt, sugar,lactose
What is a amorphous structure?
Atoms are randomly distributed and liquid can penetrate easily e.g. maltodexterine
What is a solid bridge and how is it formed?
A liquid binder at high temperature is added to material which will become solid after room temp creating a solid bridge
Adding liquid to crystalline or amphorus it will dissolve part of the material and when concentration is high then it will solidfy with time to produce a solid bridge
What is viscocity and what does it represent?
It is the internal resistance to flow
Represents the bonding between molecules in liquid when bonding is strong viscocity is strong but flowability is limited e.g. honey
WHat molecule has the second highest surface tension?
Water
When does surface tension occur?
When cohesion between molecules of liquid is strong but between liquid and air is weak
When do electrostatic forces occur?
Through friction caused by particle collisions and rubbing against equipment surfaces
What units consist in Primary Manufacturing?
Reactor, centrifuge, crystalliser and dryer
What units consist in secondary manufacturing?
Blending, granulation, drying and tabletting
Types of lactose?
Crystal, amorphous, aggregate
WHat does milling produce?
Particles of less purity due to stress acting on particle
What type of lactose does spray drying produce?
Amorphous
What type of lactose does a rotating drum produce?
Aggregate
Wet Granulation process?
Powder+liquid -> Wtting(liquid bridge) -> agglomeration(solid bridge)
Particles interlock to push liquid to the surface and allow particles to stick
Dry Granulation process?
under high pressure particles come close together to make them stick
What is porosity?
ratio of volume occupied by air divided by total volume of granules
What is segregation?
Where all tablets have different amounts of API
describe the interaction between hydrophobic powder and water and how to overcome issues?
Difficult interaction as droplet wont penetrate and bounce.
Use spray drying to overcome this and produce a amorphous which is easy to penetrate
What is plastic deformation?
Changes to shape when stress is applied bringing particles close increasing contact area and adhesion forces
WHat is a brittle fracture?
High adhesion forces, when force is applied to break structure
What is the NIR range?
780-2500mm
What is the optical range?
380-780mm
Direct tabletting Process
Dosing -> Blending -> Tabletting
Continuous via dry granulation process?
Dosing -> belnding -> granulation -> milling -> blending -> tabletting
Continuous via wet granulation process?
Dosing -> blending -> Wet granulation -> drying -> milling -> blending -> tabletting
Future end to end process?
Synthesis -> crystallisation -> purification -> blending -> wet/dry granulation -> drying -> milling -> blending -> tabletting
What are the benefits of continuous manufacturing?
- Speed up introduction of new drugs
- smaller production facilities
- fewer people needed during operation
- reduction in energy consumption and waste
- monitoring drug quality
- easy scale up
- high efficiency
When is it diffucult to do dry granulation?
When powder is cohesive dry granulation is diffcult and if material is brittle
What is unbound moisture?
Surface moisture
What is bound moisture?
Liquid may become bound in solids by retention in small capillaries, by solution in cells or by chemical absorption
hot air heats granules(heat transfer) and liquid is passed to air (mass transfer)
what is a mill?
A rotating arm to hit granules and break them and reduce granule size
Why does segregation occur?
Due to:
- size distribution
- shape
- density
What is convective mixing
macromovement
What is diffusive mixing
Micromixing
how are granules tabletted?
placed in a die and are compressed
particles plastically deform to be in contact easier
fragmentation makes them mechanically interlock
High Shear mixer?
A bed of powder where binder iis added and agitated using impellers
Fluidized bed?
hot air enters from bottom
twin screw granulation?
two screws rotating to mix powder and binder, quick process
roller compactor?
two rollers to push stress on material and compact powder to produce a ribbon
WHat are the granulation research goals?
- Better system control
- Better product quality
- Better process understanding
- understand microscopic interactions
What type of NIR do high shear mixer, twin screw and roller compactor use?
Mixer -> optical, monitors change in size with time
Twin screw-> optical, measures velocity and size
Roller compactor -> thermal camera
Industrial needs of drug development?
Flowability, density, compressability, productivity
Clinical needs of drug development?
Dosage and efficiency
Paitent needs of drug development?
taste colour, compliance feeling
Challenges of drug development?
- Poor compactability (alter excipent amount or moisture content)
- Poor flowability (Solve via granulation)
- Non Uniform (due to segregation caused by particle size)
Advantages of roller compaction?
- No liquid binder so suitable for heat sensitive materials
- Economical
- No drying so environmentally friendly
Disadvantages of roller compactor?
- low strength
- Must be compressible
- Produces fines
What is a critical quality attribute?
Physical, chemical, biological or microbiological property e.g. particle size distribution or moisture content
What is a critical process parameter?
Process parameter whose variability impacts CQA and should be monitored
What is a critical material attribute
characterstic of input material to ensure quality
How does a feed system work?
powder is red into roller compactor and there is an agitator and multiple screws
what is a screw feeder?
powder is forced between rollers so good for materials with poor flowability
What is a gravity feeder?
depends on flowability if cohesive then amount of powder entering will be inconsistent affecting quality
what is a deaeration system?
Consists of sintered metal filter or mesh screen and removes air from powder bed as air will resist compaction and prevent particles getting close to each other
how do rollers work?
Powder is sealed on sides of rolls by cheek plates on either size and rolls apply compressive force to the powder compressing the material to form densified compact (ribbon)
Describe the three roller orientations?
Horizontal -> High material loss in nip region, incorporation of side sealing system reduces material by pass
Vertical -> direct bypass is minimised because material is not governed by gravity
Incline -> reduces material bypass by 15%
Desribe different roll designs?
Smooth, corrugated are commonly used surfaces. Smooth minimises sticking
Fluted and corrugated are suitable for increasing density of light materials
Main phases of powder densification?
Particle rearrangement, deformation, particle bonding, elastic recovery after pressure release
Describe the slip region?
slipping of particles, roll surface moves faster than powder.
Weak compaction forces
particle rearrangement is prevalent and deaeration should occur
the entry to the slip region is governed by friction between wall and particle which drives particles to NIP
Describe NIP region?
MAx stress formation of the ribbon
particles move at the same speed as roller
particle deformation os prevelant
Describe the Release region?
decrease in roll pressure as roll gap increases
ribbon cracks at high eleasticty
Ribbon tensile strength
min tensile strength required for fracture initation within a ribbon
describe relationship between solid fraction and tensile strength?
positive correlation
ribbons of adequate solid fraction produce better flowing granules
low fraction: high fines, poor flow and good compactability
what is the most crucial quantatity in roller compaction?
Nip angle or pressure graident at slip and nip region
Nip angle can be determined from where the slip and nip pressure gradients cross
What happens when you increase roll pressure?
increases ribbon density, granule mean particle size and granule flowability
Increasing pressure increases ribbon strength
increasing pressure decreases porosity
fines decrease with pressure
Roll gap is the point where…?
max compaction occurs which dictates ribbon thickness
roll speed characterstics?
- inversely related to residence time for particle compaction which affects ribbon density
- roll speed needs to be adjusted to screw speed and flow of powder
if speed is too high segregation can occur - roll speed is material dependent
Formulation challenges using roller compactor?
- Compactability of primary particles
- uniformity
- plastic deformation
- fractures
relationship between hardness and other CQAs roller compaction?
lower hardness, higher ribbon strength and more fines
when does drying occur?
When the vapour pressure of the solvent at the surface is greater than the vapour pressure of the solvent in the gas surronding the solid
4 types of drying equipment?
- Vaccum
- conical
- double cone
- agitated filter
Describe two types of liquid feed drying?
Drum drying - A thin film of liquid is spread over the surface of the drum and heat transfer via conduction is present and dried material is scraped off. However there is limited opportunity for heat transfer
Spray Drying - Liquid feed is atomised into small droplets by spraying into a tower. Hot air dries the droplets and rapid drying is used for heat sensitive materials
Describe two types of particultate feed drying?
Rotatory tray - Liquid added at the top onto rotating stack of trays and is used with heat sensitive material but takes a long time
Flash Drying - Wet particles are dispersed into a hot air stream with high agitation. Rapid drying occurs due to high air temperatures and fine particles are carried out by air flow but only removes surface moisture
Describe Fluid Bed Drying?
Fluidisation of feed materials. There is a rapid upward flow if air through the bed of moist particles which lifts the wet solids and suspends them(fluidised state). The vapourised liquid is carried away by drying gas. there is excellent heat and mass transfer
What is fluidisation?
when a fluid is passed through a bed of particles a point is reached when the upward drag force is equal to the weight
What is voidage?
Amount of air space compared to particle space
What are the drawbacks of using fluidisation correlations?
- Scatter in results
- Error is greater for non spherical particles
What is the typical value of min fluidisation velocity and what does it increase with?
0.5-1 m/s
increases with granule size and density
what is particle densisty
real granule density
what is absolute true density?
literature value
when do bubbles appear?
Beyond fluidisation velocity
desribe condiur and gill plates?
create swirling air flows which stops particles from settling, increases pressure drop and inhibits local defluidisation.
They are more effective than plain mesh
Geldarts classification of powders?
Group A: smooth, when fluidised have a region of non bubbling followed by bubbling as Umf increases
Group B: Bubbling from start, sand like
Group C: Fine, cohesive powders, incapable of fluidisation, clump due to size
Group D: Large Particles
Particles size and density have the main effect
When does slugging occur?
When bubbles are greater than 1/3 of diameter. Slugging causes large pressure fluctuations
WHat happens when velocities are too low in drying?
Bed can defluidise and revert back to packed bed, reduction in heat transfer and uniform mixing is lost
WHat happens when velocity is too high in drying?
Reaches terminal velocity and particles are blown out
Smaller particles have lower fluidisation elutration velocity
What design measures can be implemented to reduce elutration and entrainment?
- Increase dryer diameter to reduce air velocity
- freeboard above bed to allow disentraintment
- bag filter to collect fines
what is equilbrium moisture content?
what does it depend on and typical value?
Point where drying stops and depends on RH and temp with a typical value of 1-2%
Solids can regain moisture as T falls and RH increases
Describe the 3 drying stages?
Induction period: Where the solids are preheated and vapour transport is limiting
Constant rate period: All heat input is used for evaporation and unbound moisture is removed
Falling rate: Bound moisture is removed and moisture transport from interior becomes limiting
desribe 3 heat transfer mechanisms?
Conduction: Heat transfer across stationary medium in which there is a temperature gradient
Convection: Heat transfer occuring between surface and moving fluid
Radiation: Surfaces emit energy
What type of heat transfer is dominant in fluid bed drying?
convection
Why do multiple drying periods occur?
- Moisture transport: Multiple mechamisms
heat transfer to evaporate moisture: driving force is gas to solid - vapour transport in gas
What is the effect of rapid heat and mass transfer in drying?
- small HTU
- Large NTU
exhaust air saturated
high energy efficiency
how to scale up fluid bed dryer what needs to be considered?
scale up by keeping air velocity constant to maintain fluidiation.
evaporation rate and throughput increase with air flow and area but not with bed depth and drying time is proportional to bed depth
describe 3 macro- scale modelling techniques?
- Heat and mass balance - gives overall perfomance
- scoping design (charts)- used for constant drying rate with exhaust at adibatic saturation
- Scaling(integral method) - gives basic falling rate affects
Desrcribe micro scale modeeling?
particle tracking , which is rearely needed
What are the limitations of modelling in drying?
A theoretical model is a representation of real phenomena and model may be mechanistic or data driven
what velocity favours shorter drying time e.g. high/low?
high velocity shorter drying time and good fluidisation
what temperature favours shorter drying time e.g. high/low?
high temperatures, which also leads to greater energy input, lower RH
Describe fluid bed granulation?
granulation and agglomeration or layering
spray rate needs to balance evaporation rate
if too dry particles wont adhere and of too wet tan bed defluidises
air flowrate must keep particles fludised
What is a hard capsule shell made from?
Gelatin
Hydroxy propyl methyl cellulose (HPMC)
Starch
Soft shell is made from?
oily liquid fill
What is the process to produce capsules?
compress powder into a plug and eject.
sift and blend each ingreident one at a time
Differences between tablets and hard capsules?
Capsules can hold pellets and minitablets
there is quick development of capsules and reduced usage
capsules are not amendable to PAR
Capsules are not directly weighed and have issues with moisture uptake
Advantages and disadvantages of gelatin capsules?
- Cheap and readily available
- contains 12-16% moisture so not good for moisture sensitive materials
- hydrpscopic so will crack at low humidity
Advantages and disadvantages of HPMC capsules?
- More expensive
- More brittle -> can split easily
- low moisutre 6-7%
- free from animal concerns
CQA standards for capsules?
Assay - 90-110 USP
Content uniformity - RSD 6-7%
Dissolution: Q=85% at 30mins
Disintegration: <15mins in 37 degrees of water
rank tablets, plugs, ribbons, powders and capsules in terms of highest solid fraction
tablets -> ribbons -> capsules -> plugs -> powders
Describe the texture analyser experiment
Plugs formed at different densities via force control and are inserted into capsules
dissolution testing is carried out to examine effects of the force
How is solid fraction calculated?
solid fraction = enevelope denisty/ true density
true density -> known density
envelope density -> density of material after compression
what are formulation challenges in capsule production?
- ingriendent compatability and stability
- powder blending and homgenity
- powder flow and lubrication
- powder compressability and plug formation
What formualtion considerations need to be considered in capsule production?
- API:Particle size
- Filler: material properties
- Disintegrant: Reduces dissolution variability and range
- Glidant: improves flow and weight variation
Lubricant: Impacts dissolution and plug strength
Process differences between plugs and tablets?
- compression forces generally under 200N and tablets up to 50kn
- high height to diameter ratios but tablets <1
- Breaking strength =1N tablets>100N
Capsule process challenges
- ability to measure out accurate precise volumes of powder
- ability to quantively transfer such dry solids to solid capsule shells is a dertmining factor in weight variation and uniformity
Capsule process challenges
- ability to measure out accurate precise volumes of powder
- ability to quantively transfer such dry solids to solid capsule shells is a dertmining factor in weight variation and uniformity
Describe a dosator and examples?
pin goes down, sleeve moves in to bed to collect powder and pin tamps it to produce plug and lifts out and drops into shell.
piston height and powder bed height impact the weight
compression distance and force impact density hence dissolution
e.g. IMA north american, MG american, Romaco
Describe dosing discs?
Disc rotates and powder gets pushed into each hole at the 6th holr it gets pushed into a capsule
disc thickness and powder bed height impact weight
e.g. Bosch, Index, Bohanan
What is design space?
tells you where it is most suitable to operate
formulation requirements for dosator and dosic dics?
- flowability
- lubricity
- compactability
- piston heighr
- powder bed height
How is flow measured for powder properties in capsules?
carr index
higher carr index then better the flow
typically 15-25%
describe two blenders used in mixing and which is better?
drum and ribbon blender.
in ribbon blender powder gets stuck to corners which is not desired
What is dissolution a function of in capsules ?
- dissolution rate of shell
- rate of penetration of disso medium
- rate of de aggregation of powder mass
- Nature of drug particles
How long does it take for shell to dissolve
4 mins
cross linking can reduce gelatin shell solubuility in water
Why is micronisation used?
to improve dissolution of porrly soluble drugs but has adverse affects on flow and mixing
poorly soluble drugs we increase size to increase surface area to increase dissolution
Common fillers?
lactose monohydrate, spray dried lactose, anhydrous lactose, starch, partially pregelatinsed starch, dicalcium phosphate and MCC
Glidants?
conc<1%
typically 0.25-0.35%
used to make powders flow
Lubricants?
0.5-1%
hydrophobic so avoid over lubrication since dissolution can be affected and plugs can soften
avoid overmixing
more lubricant dissolution is worse
disintegrants?
promote dissolution by enhancing liquid penetration and dispersion
4-8%
effectiveness may improve with increasing compression force
surfactants?
can enhance dissolution rate by increasing wetability of powder mass
what do tablets disintegrate into?
agglomerates and disperse into primary particles
what is dispersion?
process of breaking down an agglomerate.
Mechanical stress can be applied through collisions and exposure to shear, agglomerates break down into primary particles when applied stress exceeds a fracture strength that scales the interparticle forces and hold the particle together
What is tensile strength
when particles collide with each other or a boundary
what does agglomerate strength depend on
structure and strength of primary particle bonds
dispersion of an agglomerate in a liquid involves which processes?
wetting, inhibition of fluid and dispersion of aggglomerate
what do kinetics of dispersion depend on
stresses applied to agglomerate by flow field
high viscosity -> increased drag on particles -> lower reynolds -> less particle collision -> poor dispersion
fragmentation induced by shear is more important in?
liquid phase dispersion acheived by shear
Dissolution of solid bridges or primary particles lead too..
reduction in contact area between particles leading to reduction in adhesion forces
generation of internal mechanical stress
if agglomerate particles absorb fluid they expand
if it is rigid it can generate an internal mechanical stress that can faciltate fracture of agglomerate
modification of van der waals
immersing particles in a liquid reduces van der waals relative to its value in a gas
dispersant can aid the creation of a net replulsive electrostatic force between particles which faciltates and maintains dispersion
modification of van der waals
immersing particles in a liquid reduces van der waals relative to its value in a gas
dispersant can aid the creation of a net replulsive electrostatic force between particles which faciltates and maintains dispersion
creation and modification of cappilary forces
as liquid penetrates and displaces the gas it forms a cappilary bridge around the particle contacts which adds strength.
Liquid saturation increases so number of cappilary bonds increase and yield strength increases however reduction in tensile strength as strength of bonds will also decrease
wetting
dry particles must be able to imbide the fluid
wetting solid surfaces can be assessed using contact angle, which is where vapour liquid interface meets surface
poor wetted solids have a high contact angle, dispersion kinetics and are controlled by the rate of enfulgment into the fluid.
spherical agglomerates can be spontaneously engulfed at what interface?
air fluid interface when the constact angle is less than max
what is the contact angle equal to in neutrally buoyant agglomerates?
it is zero
what is dependent on thetha max?
spontaneous liquid inhibition into pores of agglomerates
how can the rate of agglomerate enflugment and liquid inhibition through pores be altered?
by the use of dispersant
what are the two modes of agglomerate breakage and describe them?
cohesive failure
- occurs in agglomerates in which fluid infiltration does not change packing structure of agglomerate and tensile strength applied by shear field is transmitted to both regions
Adhesive failure
- occurs in agglomerates in which fluid infiltration changes packing structure
- if primary particle packing is changes the interparticle forces at the boundary are dusmissed
- tensile strength is transmitted only in filtrated region and agglomerate can break due to weak wet region
what is single particle dissolution
rate at which powder dissolves is sum of rates at which each particle dissolves and can be calculated for stagnant and non zero velocity conditions
assumptions
- spherical particles
- dissolution is mass transfer controlled
factors affecting dissolution
- Properties of API: solubility, wettability, particle size, surface area
formulation characterstics: excipents, hardness, manufacturing process
dissolution method: appratus, medium and sampling
what are the 4 types of dissoluttion appratus
- rotating basket
- padd;e
- reciprocating cylinder
- flow through cell
how does a rotating basket work describe its characterstics?
advantages and disadvantages?
made of glass with a semi hemispherical bottom and a cylindrical basket attatched at low part of the stirrer.
used for capsules and tablets
full ph change
easily automated
basket can get clogged
hydrodynamic deadzone under the basket
degasifcation of medium
mesh can get corroded
what is a paddle basket and the advantages and disadvantages?
same as basket
paddle is formed from blade and a shaflt is used for stirring, sinkers may be used for dosage forms
easy to use
ph change is possible
easily automated
sinkers are needed
hydrodynamics are complex
what is a recipracting cylinder and the advantages and disadvantages?
set of cylindrical flat bottom glass and insert fittingd snd screens at top and bottom, Motor and drive assemmbly used to reciprocated the cylinders vertically and is used for tablets and beads
easy to change Ph
hydrodynamics can be directly influenced by dip rate
different ph profiles can be developed
small volume
limited experience
what is a recipracting cylinder and the advantages and disadvantages?
set of cylindrical flat bottom glass and insert fittingd snd screens at top and bottom, Motor and drive assemmbly used to reciprocated the cylinders vertically and is used for tablets and beads
easy to change Ph
hydrodynamics can be directly influenced by dip rate
different ph profiles can be developed
small volume
limited experience
what is a flow through cell and the advantages and disadvantages?
for dissolution medium
forces medium through cell
laminar flow
used for low solubility drugs
sink condtions are maintained
can operate in closed and open systems
can develop different ph profiles
deaeration neccassary
what is a flow through cell and the advantages and disadvantages?
for dissolution medium
forces medium through cell
laminar flow
used for low solubility drugs
sink condtions are maintained
can operate in closed and open systems
can develop different ph profiles
deaeration neccassary
immediate relase?
release drug immediately or as quick as possible after administration
modified release?
deliver drug with a delay after adminstration
delayed release?
systems which are formulated to release the active at a time other than immedatly after
extended release
allows for drug to be released over a prolonged period can be acheived using sustained or controlled dosage forms
sustained release
drug release over a sustained period
controlled release
to lead to predictability constant drug concentrations
what should the dissolution media meet?
should meet sink conditions and be biologically relevant for the site dissolution in vivo
sink conditions ensure the ammount of drug dissolved in the mdeia does not open affect dissolutionn
describe offline analystics in dissolution?
sample aquilots are withdrawn from dissolution vessel and filtered conc of API is measured
common techniques
- UV spectroscopy
- HPLC
describe rela time analytics for dissolution?
more frequent data points and gives more accurate dissolution profile.
common techniques
- UV fibre optic dip probes
- imaging: NMR, raman
- particle size analysis
- turbidity probes
- conductivity probes
- refractometry
choice of appratus
conformanace to dimensions and tolerance of dissolution appratus
crtical parameters
rotating basket and paddle: volume and temp of dissolution media and rotation speed
recipracoating cylinder: Dip rate
Flow through cell: flow rate of media
immediate release testing (performance verification test)
Q is the amount of dissolved active expressed as % of labelled content of dosage unit
S1 -> 6 units -> <Q+5%
S2 -> 6 units -> (S1+S2) for 12 units >Q and not unit less that Q-15%
extended release performance verication test
L corresponds to amount dissolved at each dosing interval
6 units -> no value lies outside range
L2 -> 6 units -> average 12 (l1+l2) lies within range
look at notes
delayed release performance verifcation test
stage 1
A1 -> 6 units -> no individual value exceeds 10% dissolved
A2-> 6 units -> 12 units (A1+A2) no more than 10% dissolved
no individual unit >25%
stage 2
B1 unit not less than Q+5%
B2 - (B1+B2)>Q
no unit less than 15%
What is crystalisation?
refers to the phase transformation of a compound from a fluid or an amphorus solid to a crystalline solid state
What is crystaliisation employed as?
A separation and purification technique in order to obtain pure crystals of a substance from an impure mixture or from solvent.
can also be used fir concentration, particulate product formation and analysis
what industries is crystallisation used and %?
- 80% of pharmaceuticals
- 60% of fine chemicals
- 30% food products
Examples of crystallisation application?
- Absorbic acid (Vitamin C)
- Caprolactam (used in polymer industry)
- Sucrose (from sugar cane or beet)
examples of food in crystalline form?
Salts, vitamins, organic acids, polyols and lipids
examples of food in amorphous soilds?
polysacharides, proteins, fibres and cocoa
examples of food in crystal and amorphous form?
refined sugars and thermoplastics
what is semi crystalline and example?
region where some crystal and some amorphous, complex structures like starch
What is a crystal?
A solid in which its building units are packed in regularly ordered, repeated patterns extending 3D. Crystalline solids can exist in several subphases such as polymorphs, solvates, hydrates and cocrystals
how can the molecular organisation of amorphous and crystalline materials be assessed?
Using polarised light, no brighrtness it is amorphous and if it appears bright it is crystal
Alternative approach to assess the molecular organisation of crystalline materials
X ray diffraction
What is a phase diagram?
Displays all the possible thermodynamic states of a system the proportion and the composition of each coexisting phase
WHat are thermodynamic states described by?
A set of independently fixed variables such as pressure, temperature and mass fraction of components
WHat is the eutectic point in a phase diagram?
two pure crystalline components and a solution of eutectic composition Xb are all in equilbrium
What is the liquidus line?
gives all possible compositions of liquids in equilbrium with a solid (above line system is liquid)
WHat is solidus line
below line solid phases are present at all compositions in equilbrium
what are the 5 types of binary phase diagrams?
- Eutectic systems: where only solid phases are pure components
- Mixed solid phase:
- solid azeotrope
- eutectic and solid solution behaviour
- Miscible systems without melting temperature minimum
Examples of phase diagrams for fat binary mixtures?
Miscible - everything mixed
Eutectic - random mixed
molecular compound forming - creating a new compound
WHat is the liquidus line equal to when looking at melting or solution for components A and B
Melting: SOlubility curve of A in B
SOlution: Solubility curve of A in the solvent
How can solubility curves be established?
Through microscopy
starting with a saturated solution and increasing temperature as you cross solubility line image disappears
Phase diagram (lever rule) -> what can it calculate?
it is used to calculate yield of crystalisation
fraction of saturated solid below liquidus line
fraction of crystalline material
What is glass transition temperature?
exist in crystal and amorphous corresponds to transition from rubbery state to glassy
Phase diagrams become state diagrams when glass transition temperature is incldued
describe different crystallisation pathers through state diagrams?
- From solution
- From Amorphous
From solution
1. Spontaneous below crystalisation line
2. grow from seeds between solubility line and crrystaline line
- increase T abd decrease C
From Amorphous solids
- spontaneous above glass transition line
- decrease conc and increase T
look at slide 30
desrcibe crystallisation from amorphous solids?
A rubbery to solid transition that may occur spontaneously upon hesting above glass transition temperature.
what is primary nucleation
occurs spontaneously when driving force is large enough
What is secondary nucleation
takes place in the precense of larger crystals
Gribs free energy
needs to be minimised
ctritical gibbs free energy needs to be passed to create clusters
r* critical radius of nucleation
what happens to gibbs free energy when the driving force is increased
delta G will be higher so more favourable to trigger crystalisation
If lower delta G is favoured for nucleation what is the ideal driving force and interfacial free energy?
low interfacial free energy and high driving force
What is a homogenous reaction?
when there is no impurities
At high driving force homogenous nucleation is dominant
What is a heterogeneous reaction?
When foreign particles exist which affect free energy and attatchment rate therefore affect nucleation
at low driving force heterogenous nucleation is dominant
desrcibe three regions in a constant pressure phase diagram to form crystals
region 1: Metastable region (between equilbium solubility and SNT)
seeds present: they will grow
seeds absent: no crystalisation
Region 2: secondary nucleation region (between SNT and PNT)
seeds present: nucleation will occur
Seeds absent: No nucleation will occur
Region 3: Primary nucleation region (Below PNT)
nucleation occurs with or without seeds both homo and hetreo
crystal growth on surface
the ability of a crystal tp capture and intergrate growth units into a crystal lattice depends on the strength and number of interactions that can form between the surface and the growth unit
smooth or layer growth on crystal surface
growth units attatch to kinks in the steps which propgate along the crystal and form growth layers
rough growth on crystal surface
growth units attatch anywhere to the surface and the energy for the formation of a step is low inducing creation of surface with many kink and step sites
diffusion is the limiting step since every unit reaching the surface will find a growth site
what are the benefits of direct compression compared to granulation?
reduced complexity, typically reduced costs, reduced stress on API
how can segregation occur (3 ways)
from elutriation and fluidisation, sifting and trajectory
What are the benefits of coninuous direct compression
- reduces the inherent risk of scale up
- reduction in material handling
- reduction in process steps
- more streamlined manufacturing platform
- enhanced product quality assurance
- robust scalability and demand driven supply
describe the process of contunuous direct compression?
- continous flow of formulation ingridents using loss in weight feeders
- passed through a comill to deagglomerate and improve distribution of products
- continuous mixing to produced a homogenous blend
- compression
- coating
what are the process sewlection paramters in CDC
- Bulk density
- Dose
- API flowability
- API sticking propensity
Describe feeder fundamentals
hopper, agitator and conveying screw
as the screw rotates a volume is swept out based on the screw geometry (free volume of screw bitch Vs)
Describe gravimentric and volumetric feeding?
loss in weight feeders use data from load cell to monitor the mass of material. When the feeder is operating in gravimetric mode the rate of weight loss os controlled by manipulating the screw speed.
when the data from the load cell is unreliable unintentional disturbances can occur such as knocks/bumps and variability in powder flow and intentional disturbances such as refilling the feeder hopper.
in this case the ffeder should operate in volumetric modebased on the expected feed factor
By using a simple moving average filter to compare data from external balance and feeder what considerations need to be accounted for?
feeder noise: screw agitator motion, material movement
Balance noise: material impact and heap motion
what are the three typical CDC powder mixing equipments
GEA: inclined linear blender with internal paddles
Gericke: Horizontal linear blender with internal paddles and weir
GEA CMT mixer
describe the three powder mixing mechanisms
Convective mixing
- macroscopic transport of parts of the mixture which reduces the scale of segregation
- occurs when blades or paddles move through materials
Diffusive mixing
- Induced by random motion of individual particles and is required fro microscopic mixing and to reduce intensity of segregation
Shear mixing
- required for cohesive particles
- occurs when a layer of material flows over another layer resulting in mixing at the interface
WHat happens in a continuous powder mixer?
At steady state there will be a consistent quantity of powder in the mixer which will dpened on operating conditions and material properties
particles will be conveyed axially and experience back mixing, shearing and radial transport
what two tests can be completed to measure residence time distributions
Spike test
- A known quantity of powder added to the inlet and concentration is measured of the component leaving
Step change test
- increaase feeder set point for once component and do a step increease/decrease, then measure conc at outlet
Residence time distribution concepts for continupus direct compression
RTD in downstream equipment filters out feeder fluctutations and perturbations, can preduct the mean downstream conc if RTD is known.
A high frequency variability in the inlet conc due to the feeders is smoothed out after the blender due to the axial mixing. RTD in the blender can be used to understand the level of acceptance variability from feeders
can be visualised using a funnel plot where tablet concs are plotted as a function of magnitude and duration of a conc pertubation from the feeder.
key process parameters in a horizontal linear mixer
- impeller speed
- throughput
- blade configuration
key process parameters in a horizontal mixer
- impeller speed
- throughput
- blade configuation
- weir angle
key process parameters in CMT
impeller speed
mass hold up
throughput
desribe tabletting processes and key requirements?
force is applied to compact powder.
filling -> lower punch is lowered to create space to fill powder
metering -> powder is leveled off to get a controlled volume
precompression -> top punch is lowered to apply force
compression -> intented force is applied to compact
ejection
HAs to be strong enough to withhold packaging and transport but weak enough to diintergrate.
what are the mechanical properties of a powder
compressiability, tabletability, compactability
we can get elasric, plastic or brittle tablets formed
what tablet defects can occur
pre capping/lamination -> splits and cracks on the side due to excessive compression and ejection forces, air entrapment, poor compactability
capping -> separation of tablet face
Picking -> removal of material from the tablet face and poor lubrication on punches
types of mixture formed due to differeneces in tensile strength in binary mixtures
- 5050 mixutre
- deviations from ideal behaviour
- perculation behaviour
- hogh/low tensile strength
In process measurements of tablets
tablet tester - dimensions, weight, breaking force
at line spectroscopy - identity, assay, content uniformity
soft sensor - assay, content uniformity
What is PAT?
PAT is a system for designing, analysisng and controlling manufacturing through timely measurements of crtical quality and performance attributes of raw and in process materials and processes with the goal of ensuring final product quality
Wha is a common CDC in line measurement?
blend uniformity using spectroscopic techniques
what are the challenges of inline measurement of powder streams?
- fouling of measurement probe
- diffcult to define sample size
- ensuring location of probe does not influence the process and collects a representative sample
what are the challenges of inline measurement of powder streams?
- fouling of measurement probe
- diffcult to define sample size
- ensuring location of probe does not influence the process and collects a representative sample
list a. few common areas of regulatory scrutiny for CDC
batch definition/scale
process description
material attributed
material traceability
state of control
automated control
RTRT
models
process validation
describe batch definition
quantatity of material required to be prodiced will be a project descion
batch size must be defined prior to the initation of each production run
batch definition should be based on the production period time operating at define mass flow
need to account for material that is diverted to quarantine during run
describe batch definition
quantatity of material required to be prodiced will be a project descion
batch size must be defined prior to the initation of each production run
batch definition should be based on the production period time operating at define mass flow
need to account for material that is diverted to quarantine during run
what is state of control
A condition in which a set of controls consistently provide assurance of continued process performance and product quality
crticial for continuous operation as there could be transient disturbances
increased need for process control strategy elements to:
Maintain the process in a state of control
detect temporary process diturbances
segregate resultant non conforming material from the system
control strategy implementation in CDC?
Level 3 -> conventional approach, establised IPC control limits based on established ranges for CMAs and CPPS. system monitors CPPs and activates diversion to quarantune if outside limits. product release based on end quality testing
level 2 -> real time quality assurance, system monitors CQAs and activates quarantine if product quality is out of range. product release based o end product testing
Level 1 -> active process control, same as level 2 but also uses active process control to automatically adjust the process to maintain quality in range. Combination of end product testing and RTRT for product release
Why do we use film coating?
Appearance and Image
- masks unpleasant taste of drugs and eases swallowing
- masks discoloration and improves surface asthetics
Performance and stability
- delayed or modified drug release
- provide stability to oxygen, moisture and light
Robustness safety and efficiency
- eliminate dust hazard
- tablet flow
what is the formulation of a film coat and what is each ingreident used for?
- Polymer used for strength and elasticity
- Plasticiser -> used to reduce film brittlness
- color
- solvent
- wetting agents
what is the mechanism and transformation of film coating?
Atomisation -> wetting and spreading -> water evaporation and packing -> polymer deformation -> coelscence into mechanically coherent dry film -> continuous polymer film -> water diffusion
What are the common defects in film coating?
Due to process equipment, tablet cose and coating formulation
logo infilling
colour variation
sticking
edge wear
breakage
cracking
erosion
peeling
scruffing
what are the main considerations for tablet core/excipients in film coating?
tablet tensile strength
stability
moisture and temperature sensitivity
What are the 3 elements of film coating
spraying, drying and mixing
describe the drum drying process in film coating?
consists of; air duct, perfrated pan, spray dryer and tablet bed
operates in laminar flow
avoid turbulent eddies as they impact droplet flight path which contributes to spray drying of film coat
describe the mixing process in film coating (types and parameters)?
Types: slipping, slumpingm rolling, cascading and centrifuging
Parameters: pan size, baffle design, pan load, pan speed, tablet size and tablet shape
what are the spray gun considerations in film coating
spray loaction:2/3 bed length
gun to bed distance: 15-25cm
gun to gun distance: 15-20cm
spray set up considerations in film coating
gun to gun distance impact
- spray overlap causing overwetting
- spray separate causing color variation
atomising pressure impact
- atomising pressure: 1-2.5 bar
- spray width pressure: atomising 0 to 1 bar
what is the basis of film coat model?
thermodynamic conditions such as temp and RH provided in film coating process which impact film coat formation and product quality
film coating process cycle
load -> warm -> Spray (30% RH and 20-70oC) -> Dry (10% RH) -> cool (RH<60% 35oC)
modellling application in film coating
the purpose is to predict steady state inlet temp and help to get stabilty on transition from warm to spray
what are the limitations of adiabatic film coating
max spray rate compatible with film coat formation
ever increasing sensitivity variation in spray rate and exhaust temperature
impact of control system capability
process imposed boundary deviation
can distinguish response at 25%RH and 40-45oC
can distinguish two types of operation dependent on temperature
exhaust T>45oC
- suitable for moisture sensitive products
- limits choice of exipients
exhaust T<40oC
-suitable for products with core instability
- requires dehumidification
- need for increased core strength
Why do we mix?
For an even distrubution of the active and to achievee a desired release of the drug
What is mixing?
A unit operation that aims to treat two or more components initally in an unmixed or partially mixed state so that each unit of the components lies nearly as possible in contact with a unit of each of the other components
What is the scale of scrutiny?
Is the amount of material within which the quality of mixing is important known as the weight/volume
The number of particles contained in the scale of scrutiny depend on what?
Sample weight, particle size and particle density and will increase as sample weight increases and particle size and density decreases
How do I acheive an acceptable deviation of active content in a mix?
- A lower active proportion in the content a higher deviation in the content
SD= (p(1-p)/n)^0.5
list 5 types of powder mixing equipment and the typical scale?
cone mixer, IBC, high shear mixer granulator, ribbon agitator, planetary mixer
100-1000L
Describe three types of powder segregation?
Percolation - smaller particles fall through the voids and move to the bottom of the mass
Trajectory - Differences in kinetic energy imparted to particles during mixing
Elutriation - dust formation by very small particles by turbulent air during.mixing which sediment and form a layer on top of coarser particles
WHat are the reasons for segregation
Particle size effects - larger particles have higher kinetic energy
particle density effects - dneser particles tend to move downwards
particle shape effects - round particles tend to have better flowability
What is a CSTR
A system with a steady state continuous flow of feed and product streams. The feed entering the reactor immediateley assumes a final uniform composition throughout the reactor because of perfect mixing.
residence time distributions in CSTRs
the moRE CSTRs the RTD becomes very narrow and acts like plug flow which has no mixing
CSTR with bypass is when a fraction of material leaves the tank early with a short res time
CSTR with a dead zone there is a fraction of material that never leaves the tank
describe the tracer spike methodology for RTD measurement
A purple tracer is added at t=0 and mixes. The blend potency is proportional to the conc. Over time conc decreases. and the change in outlet overtime is measured
what does a variant reduction ratio of high frequency signal result in?
dampening of a high frequency noise with a signal period smaller than the mean residence time is very effective resulting output signal with low variation
what does a variant reduction ratio of low frequency signal result in?
dampening of low frequency noise with signal period equivalent to mean residence time is not effective resulting output signal with same variability
what does a variant reduction ratio of random frequency signal result in?
dampening of low frequency noise with signal period equivalent to mean residence time is not effective resulting output signal with same variability
what are the key parameters in a horizontal mixer that impact RTDs
- hold up mass
impeller rotational speed
overall process throughput
mixing blades configuration
What are the key parameters in a vertical mixer that impact RTDs
- mass hold up
overall process throughput
what can extensive mixing impacg and why
tensile strength, dissolution and sticking because the hydrophobic lubricant is much better distributed and can further inhibit particle adheison and wetting
what parameters does the extent of powder lubrication effect?
- decreases strength
- increases flow
increases density - decreases wetability
- decreases powder sticking
increasing the shear applied to a powder results in what
weaker tablets, slower dissolution snd lower sticking and vice versa for low shear
process development for continuous mixing
minimise feeder variability at targer flow
select: impeller RPM, hold up mass and throughput
to acheive CSTR RTD and dampen feeder fluctuations and acheive Min and max extent of lubrication.
What is quality by design?
A systematic approach to development that begins with predefined objectives and emphaizes product and process understanding based on sound science and quality risk management
The outcome of QbD is a well designed and understood quality product that consistently delivers the continuous performance
What is process analytical technology (L11)
A system for designing, analysisng and controlling manufacturing through timely measurements of crtical performace attributes with the goal of ensuring final product quality
what is required to gain robust reproducible processes
high process understanding and process control
WHat can PAT do
flexible, adpatable, data rich, specific, empowers, misleads and consumers
WHat is the PAT strategy
identify snf understand all critical sources of variability -> consider how to control them -> predict variability over the design space
process parameters to be monitored and control strategy apporach taken can be decided according to prior knowledge, safety, quality and scientfic understanding
What can process analysers measure and examples
relative differences in materials before and during processing and provide useful info for process control
particle size and shape: laser diffraction, image analysis, FBRM
chemical composition: NIR, IR, raman, chromatography and mass spectroscopy
physical properties
crystalinity: raman and NIR
what is spectroscopy?
describe the two types
the study of the interaction between electromagnetic radiation and matter the matter can be atoms ions or molecules
atomic - isolated ions where the transition of electrons between electronic energy levels in isolated atoms (optical and mass)
molecular - atoms and molecules, transition on molecules with two or more atoms e.g. NMR, IR, UV
what does electromaghnetic radiation display?
properties of both particles and waves
what is a photon
A particle component where the energy component of a photon is proportional to the wave frequency
term photon is implied to mean small, massless particle that contains a small wave packet of EM radiation/light
describe three spectroscopic methods
absorption/transmittance spectroscopy - uses a range of EM spectra in which a substance absorbs
Emission spectroscopy - uses the range of the EM spectra in which a substance radiates and emits the substance must first absorb energy
Scattering spectroscopy - it measures the amount of light that a substance scatters at a certain wavelength and incident angles. fastest process
what are the typical components of spectroscopic instruments
- source of radiation
- wavelength slector to isolate a restricted region of the spectrum for measurement
sample holder
a radiation detector to greate a usable electrical signal
a signal processor
what are the two sources of radiation
continuum - emits radiation that changes in intensity only slowly as a function of wavelength widely used in absorption and fluorescence
line sources - emit a few discrete lines find wide use in atomic absorption
what are the two types of wavelength selectors
filters (absorption and interference)
monochromators(Prism and grating)
what are radiation transducers
most modern detectors in use convert radiant energy into electrical signal (MV units)
types: photon and thermal
photon transducers
used for UV visible radiation
not applicable in infared because photons in this region lack the energy to cause photoemission of electrons
Thermal Transducers
used for measurement of IR radiation
the radiation impinges on and is absorbed by a small blackbody and the temperature rise is measured
types: thermocouples
Infared spectrometry
deals with the infared region of the EM that is light and works exclusively on samples with covalent bonds
the infared spectrum of a sample is recorded by passing a beam of infared light through a sample and when the frequency of the IR is the same as the vibrational frequency of a bond absorption occurs
three regions
NIR
mid IR
far IR
analysis of the position, shape and intensity of peaks in this spectrum reveal details about the molecular structure of the sample
IR spectroscopy follows the energy conservation law….(which is?)
when the IR beam reaches the matter, the intensity of the incident beam Io must be equal to the sum of intensity of the reflected and transmitted beams
desribe the two measrement modes in IR spectroscopy and equations on how they are measured?
Transmission
allows to measure the light through a sample. Transmittance T is defined by the light fraction crossing the entire sample
it is represented by
T=IT/Io
The absorbance
A=log(1/T)
in general the amount of absorbance or transmission of incident radiation has a linear relationship with amount of concentration of sample under measurement
what is raman spectroscopy
Light scattering technique whereby a mlecule scatters the incident monochromatic light from a laser in the visible near infared range
most scattered light is at the same wavelength as the laser siurce and does not provide useful information, however a samll amount is inelastically scattered
what is mass spectroscopy
an analystical technique to helpnidnetify the amount and type of chemicals present in a sample
A sample is ionised causing some of the samples molecules to break into charged fragments which are then spearated according to their mass to charge ratio and results are displayed as spectra of the relative abundance of detected ions as a function of the mass to charge ratio
WHat is chromatography
important bipphysical technique that enables the separation, identification and purification of the components of a mixture for qualiative and quantative analysis
based on the principle where a solute in a solvent (mobile phase) is passed through or around an outside matrix (stationary phase) and interactions occur
between two phases
separation of compounds is based on their molecular weight and element composition
two categories of image analysis
static: measures samples that typically rest on a slide moved by an automated stage
Dynamic: measures samples that flow through a cell or infront of optics which collect an image of particles with a strobe.
Steps in image analysis process
Image segmentation -> image transformation and feature extraction-> immage classifcation
light scattering
particles scatter light and the angle of light scatter, the frequency of the light scattering and the intensity of said scatter can be measured to determinne the size and the molecular weight of materials
laser diffraction
relationship between light and surface particles
measures particle size distrbutions by measuring angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample
multivariate analysis tools for PAT
pharmaceutical processes are complex multifactorial processes and one factor at a time experiemnts do not address interactions among product and process variables
using multivariate apporaches we can enable idetification and evaluation of produxt and process variables that are critical to quality
what is chemometrics
multivariate chemistry discpline to design or select optimal measurement procedures and experiemnts and to provide max chemical info by analysis chemical data
continuous improvement PAT tools
can contribute to justifying proposals for post approval changes.
PAT Implementation elements
- building science (Understnading of scientific principles)
- process monitoring (understanding interactions between process and product is the basis for the design of the monitoring)
- validation of system
- regulatory strategies
the validation plant of PAT system includes validation of:
- software packages
- process analysers
- pprocess control software IT systems for the management and storage
discuss two types of regulatory strategies in PAT implementation
risk based approach
- an inverse relationship between the level of process understanding and the risk of producing a poor quality product is expected
for processes that are well understood can be less restrictive in regulatory approaches
real time release
- ability to evaluate and ensure the acceptable quantity of in process based on process data
benefits of PAT
- better understanding the chemical and physical mechanisms
- improves process robustness
- prevents reject batches
- reduces production cycle times
- reduction in sampling
- improved hygiene
- increased automation
- facilitates continuous processing
PAT applications in primary manufacturing
identifying raw material: NIR/MIR or Raman used to idnetify raw
synthesis step: immersion transmission probes are typically used with NIR spectrometers to measure concentration during synthesis
Crystalisation: use of NIR and MIR to determine the optimum concentrations for addtion of seeding crystals
Drying: monitoring the vapor stream in the vaccum line(headspace) and direct measurement of residual solvent in powder
Milling: particle size
final API: NIR,Raman or MIR to check chemical composition
PAT Applications: secondary manufacturing
Blend uniformity: critical for quality dosage form, homogenity can be monitored using NIR
Drug content uniformity
- NIR used for tablet assay and content uniformity testing
