Colloids and Formulations Flashcards
What is a solution?
A dispersion of molecules of material in a liquid medium and is clear
What is a suspension?
A dispersion of solid particles of material in a liquid medium and it’s generally cloudy
What are the size of particles in a colloidal suspension?
Between 1-100nm
What are the size of particles in a normal suspension?
More then 100nm
Why are suspensions good?
Many drugs aren’t water-soluble but can be suspended in an aqueous phase
What is a surface?
An interface between two phases, where one phase is solid
What do unsettling interactions mean for suspensions in terms of the DLVO theory?
Leads to instability, coalescence and settling
What do settling interactions mean for suspensions in terms of the DLVO theory?
Means the particles remain suspended
Give the equation and annotate for attractive interactions in the DLVO theory:
VA = - Aa/12H
* A = Hamaker constant for the
particle material and medium (~10-20J)
* a = particle radius (~10-9-10-7m)
* H = interparticle distance (~10-9m)
* R=2a+H
* VA= attractive energy
What forces dominate attractive interactions?
Van der Waals
Give the equation and annotate for repulsive interactions in the DLVO theory:
VR= 2 π ε, εo aΨδ x exp(-κH)/(1+H/2a)
- ε, εo = permittivities of the medium and vacuum
- a = particle radius (~10-9-10-7m)
- Ψδ = surface potential (would normally use ζ potential instead as more
easily measured) (~0-50mV) - κ = Debye-Huckel parameter ~109m-1, (1/κ = double layer thickness)
- H = interparticle distance (~10-9m)
Remove bottom part if k <10^5
What is the equation to calculate the total energy of interaction (VT)?
VT= VA+VR
What does a positive peak mean on a potential energy diagram?
Repulsion
Primary maximum
Repulsive barrier, will keep particles apart when close together
What does a negative dip mean on a potential energy diagram?
Attraction
Primary minimum
Attraction between two particles, if it goes far down, the particles are irreversibly aggragated
What is the secondary minimum on a potential energy diagram?
Where the repulsive and attractive lines on the graph come together horizontally in the centre
This means particles are attracted to each other but not strongly, so can easily be dispersed (forms flocks)
What will high temperatures do to particles in a suspension?
At high temperatures will promote primary minimum as more kinetic energy
Describe the electric double layer:
Any particle in an aqueous medium will have a charge on a surface
Stern layer, counter ions totally held to the charge in the middle
Diffuse layer, an imbalance of mobile co-ions
Sheer surface, the boundary between the fix layer and diffusive layer (electrical potential here called the zeta potential)
What is double layer thickness?
The distance between the stern layer and which charge is screened
1/ Debye huckel parameter (k)
Name two ways in how particles are stabilised:
- Steric stabilisation
- Electrostatic stabilisation
What is steric stabilisation?
Involving adsorption of an inert polymer on the surface of the particles
The surface prevents the particles to approach each other and Van der waals are too weak therefore easily separated
What is electrostatic stabilisation?
Involving a surface charge on the surface of the particles with the same charge will repel each other using Zeta potential
Zeta> +30mv = stable
Zeta< -30mv = unstable so can coagulate
What is the Zeta potential dependent on?
Stern potential and ionic strength of medium
Can govern sedimentation
What is a stern potential dependent on?
Presence of adsorbent material
What are two ways and how you can control particle behaviour?
Debye Huckel length parameter, k, dependant on ionic strength of medium so can be easily controlled, decrease ionic strength better
Stern potential, surface can be modified, large stern potential is better
What type of movement do particles always have?
Brownian motion
What are deflocculated systems?
Behave as small individual particles
What are flocculated systems?
Behave as individual large particles with a porous structure, loosely attracted to eachother
How can particle movement in a suspension be reduced?
By increasing the viscosity of the medium
Why is diffusion good in suspensions and which system is this more likely to happen and why?
Acts to improve mixing
Depends on particle and medium property
Seen more in deflocculated systems as individual small particles can move more rapidly
Give and annotate the Stokes- Einstein diffusion equation:
D= kBT/ 6πηa
D
=
diffusion
coefficient
kB= Boltzmann’s
constant
T= temp in kelvin
η= viscosity of the medium
a= particle radius
When will sedimentation occur in a suspension and why?
Due to gravity
Affects particles with a radius larger than 0.5μm and above
In both flocculated and deflocculated systems
Flocculated- fast
Deflocculated- slow
Which system is better for sedimentation occurring?
Flocculated
Although the deflocculated system will happen slower as they are lighter, they are individual particles so can layer over each other better and more mechanical force is applied
This means deflocculated go from primary max to primary min and therefor irreversible
Flocculated, they sediment loosely and go to secondary min which is reversible
State the Stokes sedimentation equation and annotate it:
v=2a^2g(p-pº)/9η
v= sedimentation
velocity
a= particle radius
g= acceleration due to gravity
p= density of particles
pº= density of the medium
η= viscosity of the medium
Why do diffusion and sedimentation have opposing effects?
More chance of particulate interaction with more diffusion
What is the effect of reducing particle size in a suspension?
It will:
Increase diffusion, decrease sedimentation, will affect dissolution area, difficult to make particles this size
Beneficial for suspensions
What is the effect of increasing viscosity in a suspension?
Decrease diffusion, decreases sedimentation
Beneficial for most pharmaceutical suspensions
What is the effect of increasing density in a suspension?
No affect on diffusion, decrease sedimentation
Beneficial for most pharmaceutical suspensions
The equation for sedimentation volume ratio (F):
F= Vf/Vo
Vf= volume of sediment at equilibrium
Vo= total volume of solution
Explain sedimentation in deflocculated systems:
Because they are individual particles, they are not loosely held together and so can compact and densely sediment, reaching the primary minimum
Vf values are low e.g. 0.1 because they occupy smaller volume as more compact
Sedimentation is irreversible as solvent can’t penetrate the sediment
Explain sedimentation in flocculated systems:
As floccule is a large and porous, the sediment is loose and fluffy with incorporated solvent
Vf values are high e.g. 0.6 as less compact so more volume
Sedimentation is reversible by shaking
State and describe two aggregation of sediments:
Coalescence: two particles intertwine and become one large particle
Otswald ripening: larger particles get smaller particle in it, happens again and again
What are surfactants?
Surface acting agents, amphiphiles
Likes being in both oil and water
Have two regions:
Hydrophobic tail, hydrophilic head
How are surfactants classified?
According to nature of the hydrophilic head group
State for type of surfactants:
Anionic
Cationic
Zwitterionic
Non ionic
Describe anionic surfactants:
Negatively charged head
Most widely used class
Common: carboxylates, sultanates, sulphates
Describe catatonic surfactants:
Positively charged head
Less commonly used
Compatible with non-ionic and zwitterionic surfactants, but not anionic ones
Describe zwitterionic surfactants:
Have both negative and positive charge in head
Describe non-ionic surfactants:
Non-charged head groups – have ability to form H bonds
What are HBL values?
Hydrophile-lipophile balance
To measure the relative contributions of the lipophilic and hydrophobic regions of surfactant molecules
What is the average HBL value for non ionic surfactants?
0-20
0 being extremely hydrophobic
20 being extremely hydrophilic
What is the average HBL value for ionic surfactants?
Can excess of 20
How do surfactants work?
Adsorption at the air/water interface boundary
Intermolecular bonding between water molecules (cohesive forces) is disrupted and weakened by the presence of the surfactant lowers surface tension
What is surface tension?
The energy required to increase the surface isothermally and reversibly by unit amount
Give an annotate the equation for surface tension:
γ = (dG/dA)n,P,T,
y= surface tension
G= energy
A= surface
What effect does temperature have on the surface tension of water?
An increase in temperature decreases ST
What does CMC stand for?
Critical micelle concentration
What is the CMC?
The conc which micelles begin to form
How do micelles form?
Once surfactant has formed a complete monolayer at the liquid air interface, any additional surfactant must remain in solution
Extra surfactant molecules self assemble into micelles which have around 50-100 surfacant molecules
Give examples of physical properties that can change the CMC:
Light scattering, osmotic pressure, drug solubility
Give an annotate the equation as to why micelles form:
ΔGmic =ΔHmic – TΔSmic
* ΔGmic is negative, ∴ reaction occurs spontaneously
* ΔHmic is close to zero, ∴ system is fairly stable
* ΔSmic is large and positive, ∴ there is an increase in disorder
Why is there an increase in disorder when micelles form?
Due to water
Water is highly structured due to H bonds
Nonpolar groups do not form H bonds so disruptions are not compensated for
So water molecules forced into contact with the nonpolar groups to form a structure around them
So stressed water molecules
How do surfactants increase disorder?
The hydrophobic groups withdraw from the aq phase, releasing water back into the bulk medium and thus increasing entropy
When a micelles forms this happens again so more disorder in water, as release stress trapped water molecules
Do ionic or non-ionic surfacants have a lower CMC?
Non ionic
For ionic micelles, going up or down groups increase molecular size?
Going down
Which surfactant are affected by temperature and why?
Non-ionic, have lower CMC is when higher temp
Surfactant begins to precipitate into very large structures, cloud point
Ionic surfactants are relatively unaffected by temp
Which surfactant are affected by electrolytes and why?
Ionic surfactants, electrolytes decrease CMC and increase micelular size due to the reduction in repulsion and charged groups
Non-ionic surfactant are unaffected by electrolytes
The equation to calculate the total CMC mixture and annotate:
1/CMCmix = x1/CMC1 + x2/CMC2
x1 + x2 =1
x= mole fraction of each surfactant
What is the packing parameter (P)?
Comparing size of tailgroup to size of head group
State and annotate the packing parameter equation:
P= Vº/(ae x Iº)
Vº= surfactant tail volume
ae= eq area per molecule at the aggregate interface
Iº= tail length
State three things surfactants are used for:
Aid solubilisation
Emulsifiers
Cleaning agents
What is a emulsion and their phases?
Two immiscible liquids, one finely subdivided in the other
Continuous and dispersed phase
What are the two main types of emulsions?
Oil in water, o/w
Water in oil, w/o
Why are emulsions unstable?
Due to the high interfacial tensions at the water and oil interphase
How does destabilisation act in order to reduce the SA of the interface?
Larger droplets
Gravity will begin to act
Separation
What are emulsifying agents?
Reduce the interfacial tension and slow the instability
Describe the purpose for the two types of emulsions:
O/W- to deliver oil soluble drugs
W/O- for sustained release of water soluble drugs
State and describe two ways to distinguish between the two types of emulsions:
Conductivity testing- water will conduct electricity, oil won’t. If conducts electricity water is continuous phase
Dye solubility test- if you have a water soluble dye then the dye will take the whole liquid
What is interfacial tension?
Work required to increase the area of contact between two phases, same as surface tension
What is the relationship between stability and interfacial tension?
A lower interfacial tension, a higher stability
State and annotate the equation for free energy of emulsification:
△G= Ni π ri ^2 σ
Ni= number of droplets in population
r= radius
σ= interfacial tension
Why is △G of emulsification always positive?
Not a spontaneous process
For a system to go from separated to dispersed phase, need to put in energy e.g shaking
Name 4 types of emulsifying agents:
- Surfactants (SAA)
- Interfacial complexes
- Hydrophillic colloids
- Solid particles
Describe surfactants as emulsifying agents:
Decrease interfacial tension via adsorption onto droplet surface
Not all SAA all good emulsifying agents, depends on type of film formed as can cause electrostatic repulsion due to nature of the head group
Name two types of surfactants as emulsifying agents and describe them:
Span 20- hydrophobic, steric
Tween 80- hydrophilic, entropic, has a longer chain as has an ester PEG chain, fatty acid chain
Describe interfacial complexes as emulsifying agents:
A long chain alcohol, tail groups driving this by interacting with each other
Mixture of two surfactants to a surfactant and a molecule which forms complexes at the w-o surface
A film is formed at the surface which has a high viscosity, high flexibility and lowers IT far more than an individual component can
Describe hydrophilic colloids as emulsifying agents:
Many long chain hydrophilic polymers such as proteins and polysaccharides are very effective
They adsorb onto surface and form multi layers which are strong and flexible
Have steric and entropic properties as large and hydrophilic, not interacting with each other
Describe solid particles as emulsifying agents:
Finely divided solid will remain at interface with correct balance between hydrophobic and hydrophilic groups
If solid particles are preferentially whetted by oil, a W/O emulsion is formed and vice versa
Aluminium and MgOH’s clay are readily wetted by water in o/w
Carbon black and talc are readily wetted by oil in w/o
What is the Bancroft rule?
Applies to any type of emulsifying agent
The phase in which the emulsifier is more soluble is likely to be the continuous phase
How do you calculate the HLB value:
(Sum of hydrophilic group numbers)- (sum of lipophilic group numbers) +7
How do you calculate the HLB for a mixture of surfactants?
f HLAa + (1-f) HLBb
f= fraction
Name 5 ways in how emulsions can present instability:
Flocculation
Coalescence
Phase inversion
Creaming
Cracking
Describe flocculation in instability:
Occurs when emulsion droplets approach each other closely
Due to it being a liquid, there is a flexible interface so more particles coming together and flocculate, leads to coalescence due to film rupture
Describe creaming in instability:
Disperse phase rises or sinks to form concentrated layer
O/W face upwards, W/O face downwards
Doesn’t indicate coalescence as shaking may re-disperse
State and annotate the rate of creaming (sedimentation) equation:
v= 2a^2 g (p2-p1)/9n
depends on viscosity of medium
Describe cracking in instability and how does it occur?
Complete phase separation
Occurs if:
- emulsifier incompatible
- chemical or microbial decomposition
- increase or decrease in temp or pH
- changing ionic strength
Describe coalescence in instability:
Particles become one
Describe phase inversion in instability, how is this reduced?
At high concentrations, and emulsion may phase invert
O/W becomes W/O and vice versa
Reduced by keeping the conc of the dispersed phase in the range of 30-60%
What are multiple emulsions?
Disperse phases containing droplets of another phase
e.g o/w/o
Used for controlled release of drugs and taste masking
What are micro emulsions?
Contain high % of oil, water and surfactants
All small droplets so high SA
Swollen micelles rather than emulsions
What are Self Emulsifying Drug Delivery systems, SEDDs?
Not micro emulsions
Mixture of oils and surfactants and drugs
In the body, it is rapidly emulsified and dispersed into gut and forms droplets
Why would a suspension be used?
Drug isn’t water soluble
Stability of drug is poor
Name 6 types of excipients:
Flavours/ colours
Antimicrobial preservatives
Buffers and stabilisers
Density/ viscosity modifiers
Wetting agents
Flocculation modifiers
Describe the purpose for flavours/ colourants:
Increase patient adherence
Give examples of antimicrobial preservative:
Benzoic acid, chloroform, sucrose
Describe the purpose for viscosity modifiers:
Reduce settling of particles
e.g alginates, acacia, silicates
Increase viscosity also reduces evaporation of water- humectant effect
Describe the purpose for wetting agents:
Decrease interfacial tension, improve distribution
Describe the purpose for flocculation modifiers:
Changing ionic strength of medium
e.g NaCl
What are the skins main function?
-protect internal body structures
-limit entry into body of noxious chemicals, allergens
-stabilise body temp
-sensory organ
What does the skin do when in contact with a noxious agent?
Some may pass across the top layer (stratum corneum)
Some may be metabolised in lower layers (viable epidermis)
Sensing of a reaction to chemical damage in epidermis
Removal of chemical by blood flow through vessel
What is the epidermis is made up of?
Stratum Corneum (SC), non viable epidermis, 200-800microns thick
Melanocytes produce skin pigment which is taken up by keratinocytes
SC a keratin rich dead cell layer and is metabolically inactive
Viable epidermis contains a number of metabolic enzymes
What is the dermis made up of?
Middle skin layer, 1-5 mm, fibrous and elastic tissue
Supportive and cushioning tissue composed mainly of collagen (70%), elastin and fibrillin
Sparce cellular population E.G vessels, follicles, glands
Describe eccrine sweat glands as skin appendages:
Body temp homeostasis and emotional response
Sympathetic cholinergic innervation – controlled by CNS
Different sweat emotion, spice, body temp
Describe apocrine sweat glands as skin appendages:
Present in axillae, auditory canal, genitals
Produce viscous, milky secretion under hormonal control
Emulsified to stop sweat dripping, pheromones
Describe hair follicles as skin appendages:
All over body except lips, palms, soles of feet and part of genitals
Describe sabaceous glands as skin appendages:
Together with hair follicles forms pilosebaceous unit
Halocrine gland that produces lipid rich secretion called sebum
Over activity, especially during puberty causes common acne
Describe subcutaneous tissue as skin appendages:
Fat layer acts as: mechanical protecter, energy store, thermal insulator, heat regulation
Thickness depends on whole body but needs a min
What is topical delivery?
Delivery of a medicament to skin or mucus membrane
Describe local treatment:
Skin softening- emollient
Delivery of active agent to skin tissue
Describe systemic treatment:
Delivery of drug across skin into dermal blood vessels for SC
Potent drugs e.g nicotine, hormones etc
Name three examples of skin surface treatments:
Suncreams
Surface antiseptics
Deoderants
Name three examples of stratum corneum treatments:
Anti- perspirants
Antibacterials
Antifungals
Name an example for viable epidermis treatment:
Steroids for psoriasis
Where must a drug cross to have an effect on the body?
The stratum corneum
What are the two types of cell routes and describe them:
Intracellular route- between cells, hydrophobic
Transcellular route- through cells, hydrophilic
Describe stratum corneum lipids:
20% of total volume of SC
Form lamellar sheets in intracellular spaces
Composition- ceramides, cholesterol, fatty acids
100-150mg produced per day to replace lost ones
Describe Ficks law in the absorption of drug across the skin:
Increase the conc gradient across the SC so more diffusion so higher partition coefficient
What is the rate limiting step in the diffusion of drug across the skin?
Drug must partition into SC before diffusing across epidermis
The SC is the absorption rate limiting step, except when the SC is damaged where the drug released from formation will be the rate limiting
State and annotate the equation for the prediction of rate transport of drug across skin:
J= (DP/δ) ΔCv
J= flux (cm/s)
D= diffusion coefficient in SC
P= partition coefficient between formulation and skin
δ= thickness of stratum corneum
ΔCv= conc difference between formulation and skin
How would you increase the rate of drug across the skin:
Increase ΔCv, high conc of drug
Increase D, make drug more lipophilic
How would you measure the rate of drug transport across skin:
Franz diffusion cell
Place skin tissue between two glass places
Apply drug
Take sample through side arm
Measure drug levels
How to predict skin penetration from drug physio chemical properties:
Potts Guy equation
Predicts drug transport rate from drug molecular size and logk
How do you calculate Kp?
Hydrophobicity= logKoctanol/water- molecular weight
Which factors are suitable to identify candidates for transdermal delivery:
Physiochemical nature
Potency of drug- low pot has low effective conc
Timescale of drug exposure
Site and condition of skin
Formulation
Alteration of skin barrier by formualtion
Skin hydration
Which factors effect the rate of transdermal delivery?
Timescale of drug exposure
Site and condition of skin
Formulation factors
Alteration of skin barrier
Skin hydration state, more hydrated= more permeable as looser packing of SC phospholipids
What is a transdermal therapeutic system (TTS)?
Designed to release drug at a rate below the max rate for controlled systemic release
What are 4 advantages of TTS?
Avoid first pass metabolism by liver
Consistent site of adsorption
Consistent drug input rate
Can stop dosing by removing patch
What are two types of transdermal skin patches?
Monolith (matrix) system
Rate limiting membrane system
Describe monolith system patch:
Drug present as suspension
Impermeable backing layer
Dissolved drug and dissolved crystal- drug matrix
Adhesive layer
Protective strippable film
Describe rate limiting membrane system patch:
Drug present as suspension
Impermeable backing layer
Dissolved drug and dissolved crystal- drug matrix
CONTROLLING MEMBRANE
Adhesive layer
Protective strippable film
Why are is the drug dissolved and in crystal solution in the matrix of a transdermal patch?
The dissolved drug will diffuse and be released first, then the drug crystals will eventually dissolve so can keep driving thermodynamic system, as saturated solution
Are creams/ ointments hydrophobic or hydrophilic?
Creams- water bases- hydrophilic
Ointments- oily- hydrophobic
Why would a hydrophobic drug be moved out of a cream faster than an ointment?
A cream is water based and the drug doesn’t favour this condition so will partition
What does a negative logP mean?
hydrophilic so +ve = hydrophobic
What does a close to zero but on the positive range mean of a logP?
Lipophilic
What are the four classes of drugs?
Highly soluble/ highly permeable
Highly soluble/ low permeability
Low solubility/ low permeability
Low solubility/ highly permeable
Describe micro needle delivery for therapeutic macromolecules:
Large drug molecules are too large/hydrophilic to diffuse through skin
Peptide/proteins are rapidly degraded in GI tract, skin has much lower enzymatic activity
SC defence can be breached by micro needles, these are tiny needles that can penetrate into a epidermis but not as far as nerve fibres
Describe iontophoresis as a from of drug delivery across the skin:
Driving charged molecules through skin using low electrical currents
