Module Test Flashcards
Define solubility
The maximum amount of solute that will dissolve in a given quantity of solvent at a given temperature
State the three types of solvents
- Polar solvents
- Non-polar solvents
- Semi-polar solvents
Describe what chemical features on a polar solvent increase solubility
- Presence of polar groups
- More branches
- Ratio of polar groups to non-polar groups on molecule
Explain the dielectric constant and state whether polar or non-polar solvents have a greater dielectric constant
The dielectric constant is the extent to which a material can store electrical charge.
Polar solvents have a higher dielectric constant.
Explain hydrogen bonding
Interaction between a molecule containing a hydrogen atom and an electro-negative atom on the other molecule
Water is a polar solvent that is amphiprotic. Explain what this means.
Amphiprotic means that the solvent can act as a proton acceptor or donor.
Explain Le Chatteliers principle of equilibrium
In an acid + water reaction, adding more acid will cause the equilibrium to shift towards reducing the amount of acid being produced
In an acid + water reaction, adding more base will cause the equilibrium to shift towards increasing the amount of acid produced (as the base reacts with H3O+)
State the three types of ‘solutions’
- Gas in liquid
- Liquid in liquid
- Solid in liquid
Temperature has an effect on the miscibility of liquid-liquid solutions. State and explain the 4 types of ‘critical’ temperatures,
- Upper critical temperature (temperature @ full miscibility)
- Lower critical temperature (temperature @ no miscibility)
- Upper & lower critical temperature
- No critical temperature (partial miscibility at all temperatures)
State the 4 solvation mechanisms
- DIelectric constant
- Dipole formation
- Hydrogen bonding
- Acid-base reaction
Define ‘rheology’
The study of ‘flow’ and the deformation of matter.
Flow = The tendency of a material to deform following the application of force
Discuss the resistance of flow in pharmaceutical applications
Water flows readily when poured = low resistance
- Good in certain medication for swallowing/digesting
Honey flows slowly when poured = high resistance
- Good for ointments and gels to stay on skin
Explain newtonian flow
Shear stress increases in a linear fashion upon increasing shear rate
Explain dilatant flow
Shear stress increases exponentially upon increasing the shear rate. This is because dilatant fluids are comprised of a high concentration of undissolved fluids. Therefore, when shear displaces the liquid, solid particles clump together and produce more resistance.
Explain pseudo-plastic flow
Shear stress decreases the shear rate. This is because when pseudoplastic fluids are shaken or stirred, the bonds in the molecules are broken. As a result, viscosity decreases as ‘networks’ are broken.
Pseudoplastic fluids are capable of thixotropy.
Explain thixotropy
The regain of structural integrity after shearing has stopped. Substances that have experience greater deformity will experience a slower rate of thixotropy.
Explain Bingham plastics
Bingham plastics act as newtonian fluids (i.e. linear) beyond a certain yield stress. Therefore, before this yield stress, they are fairly solid.
State and explain how rheology affect pharmaceutic
Formulation stability: more viscous means slower sedimentation of undissolved particles
Biological activity: more viscous means slower movement of drug out of formulation
Patient acceptability: less viscous means easier to pour and swallow
Explain viscometry
The testing of viscosity. Machine involves immersing a spindle in fluid that can be rotated at different speeds to give a reading of viscosity.
Define diffusion and explain its importance to pharmaceutics.
The net movement of molecules from a region of high concentration to a region of low concentration.
Important for drug movement and permeation around the body.
Diffusion is measured through quantifying molecular flux (f). State the components of molecular flux.
Mass (M) over cross sectional area of a barrier (S) and time (t).
Measures how many molecules are travelling through a cross-sectional area per second.
(Note: ‘S’ is the area of the ‘barrier’, NOT the ‘door’ meaning that a bigger barrier will mean a smaller door for the molecules to diffuse through meaning less molecules pass through per second meaning lower ‘f’)
Compare and contrast steady state and non-steady state diffusion.
Steady state diffusion is when the concentration gradient does not change over time. Non-steady state diffusion is when the concentration gradient changes over time, meaning that molecular flux will also change over time.
Describe the distribution of solutes in two immiscible liquids
If a solute is added to a mixture of two immiscible liquids, it will distribute itself amongst both phases. The solute will distribute more towards the liquid that is less dense and less polar.
State the distribution law and the relevant assumptions made
Distribution law: concentration of X in A at equilibrium/concentration of X in B at equilibrium = partition coefficient
Assumptions: temperature remains constant, solute X is below saturation concentration
Discuss diffusion (ALL OF IT :L)
- Lipophilicity and passive diffusion
- Lipophilic molecules are better absorbed/diffuse through biological membranes
- At a certain point, increasing lipid solubility will decrease drug activity due to:
- Binding to lipids and only lipids
- Won’t migrate towards site of action through fluids
- Functions of biological membrane
- Separate the aqueous contents of the cell from the external aqueous phase
- Allow exchange of materials between inside and outside of a cell
- As a result, biological membranes are lipid in nature, yet have selective permeability properties
- Transport across biological membranes
- Cross from one hydrophilic region to another through the lipophilic phospholipid membrane
- Passive diffusion
- Dependent on concentration gradient
- Does not require energy
- Passive diffusion
- Or exploit carriers/aqueous pores in the membrane to get across:
- Facilitated diffusion
- Process involving a specialised carrier
- No energy required
- Dependent on concentration gradient
- Active transport
- Energy is required
- Can go against concentration gradient
- Facilitated diffusion
- Cross from one hydrophilic region to another through the lipophilic phospholipid membrane
- Factors affecting biological diffusion
- Drugs are usually absorbed through passive diffusion
- Which is affected by:
- Lipophilicity of the drug
- Water solubility of drug
- Fraction of unionised form of drug
- Microenvironments of the biological compartments and the membranes involved
Compare and contrast LogP and LogD
LogP is the partition coefficient.
LogD is the distribution coefficient.
LogP is the equilibrium ratio of unionized drugs
LogD is the equilibrium ratio of un/ionized drugs
LogP remains constant
LogD changes with pH (fx degree of ionisation)
Explain why the pH-partition hypothesis (and hence, LogD) cannot be applied to GI absorption
Variability in pH conditions.
pH at membrane surface is lower than that in the bulk
Convective flow refers to the movement of water into and out of the GI tract, which will affect the absorption rate of small molecules.
Explain how ionised molecules can pass through the lipid membrane in the GI tract
The lipid membrane in the GI tract is negatively charged, meaning that it can attract cations (+) near the membrane. As a result, negatively charged molecules can pick up a cation or positively charged molecules can donate their positive charge to the membrane so that they can pass through.
Explain the difference between solubility and dissolution
Solubility is the extent to which a solute can dissolve in a solvent.
Dissolution is the rate at which a solute can dissolve in a solvent.
E.g. a drug can fully dissolve (high solubility) at a slow rate (low dissolution)
State the 4 classes of drugs in the Biopharmaceutical Classification System
Class 1 - high permeability, high solubility
Class 2 - high permeability, low solubility
Class 3 - low permeability, high solubility
Class 4 - low permeability, low solubility
State the properties required of a formulation to be eligible for a biowaiver and which class of drug is most likely to be eligible.
Rapid dissolution
High solubility
High permeability
Wide therapeutic window
Class I drugs.
Explain what is meant by ‘sink conditions’
‘Sink condition’ is when the concentration of a drug/solute in the receptor region is significantly lower than in the donor region.
Explain why solute concentration in receptor region is not considered in the equation, J = DKC(d)/h
J = molecular flux D = diffusion coefficient K = partition coefficient Cd = solute concentration in donor region h = thickness of membrane
Because under ‘sink conditions’, ideally, the lowest possible solute concentration in the receptor region is approximately zero, meaning that it is negligible.
Explain the difference between steady-state and non-steady-state diffusion
Steady-state diffusion follows Fick’s first law and assumes that the concentration gradient remains constant over time. Therefore, the rate of diffusion is dependent on the concentration gradient.
Non-steady-state diffusion follows Fick’s second law and states that the rate of diffusion is proportional to the rate of change of the concentration gradient.
Describe what a biowaiver is and the properties that a formulation must possess to be eligible for a biowaiver.
A biowaiver is an exemption from conducting human bioequivalence studies.
Properties:
- Rapid and similar dissolution
- High solubility
- High permeability
- Wide therapeutic window
- FDA approved “immediate release” excipients
What is meant by a ‘dispersed system’? (provide 2 examples)
A system containing a dispersed phase (internal phase) and a continuous phase (dispersion medium).
Suspension - solid in liquid dispersion
Emulsion - liquid in liquid (immiscible) dispersion
State the 3 classes of dispersion. Compare and contrast their properties.
- Molecular (diffuses fast, invisible under an electron microscope, passes through ultrafilter)
- Colloidal (diffuses slowly, visible under electron microscope but not light microscope)
- Coarse (does not diffuse, visible under light microscope, does not pass through normal filter)
A suspension is a coarse dispersion in which insoluble particles are dispersed in a liquid medium. Explain the applications of a suspension in terms of routes of administrations.
Oral route - can deliver water-insoluble drugs in an aqueous vehicle, taste masking, reduce hydrolysis
Topical route - slow drug release due to formulation needing to dissolve to produce an effect
Parenteral route - administer through IM or SC but not IV (due to risk of blocking vessels)
Describe the disadvantages of suspensions
- Sedimentation (caking)
- Dose precision
- Microbial contamination
- Bulky packaging (bottles)
Describe the changes you can make to the formulation of a suspension to increase or prolong the rate of drug release.
Increase - in order to increase the rate of dissolution which results in high initial concentrations, the active component can be converted to a salt.
Prolong - to decrease the rate of dissolution and therefore have a prolonged release, the active component can be converted to a polymorph.
Describe the effect of wetting agents on suspensions
The high interfacial tension between the solid water-insoluble drug and the liquid medium may cause the solid drug molecules to clump up and aggregate in order to reduce the surface area exposed to the liquid.
Adding a wetting agent that decreases interfacial tension will prevent the drug molecules from aggregating
In terms of particle size control, Stoke’s law states that the force required to move a sphere through a given viscous fluid is proportional to the velocity and radius of the sphere. State a limitation of this law.
Stoke’s law does not apply when there is an excessive amount of the suspended material due to collisions that influence the velocity.
State 3 advantages and 1 disadvantage of a smaller particle size
+ Slower rate of sedimentation
+ Less mechanical irritation
+ Ease of administration (no blocking of injection needle)
- Does not allow slow drug release
Viscosity modifiers can be used to alter the physical properties of suspensions. State 4 physical properties of a well-formulated suspension.
- Slow sedimentation
- Easy re-dispersion
- Homogenous
- Easily transferable
Explain the ideal rheological properties in terms of standing, shaking and leaving with reference to viscosity
Standing - High apparent viscosity at low rates of shear so that on storage the suspended particles would either settle very slowly or preferably remain permanently suspended
Shaking - At moderate shear rates, the apparent viscosity should fall sufficiently to allow the suspension to be easily poured
Leaving - Original apparent viscosity should be regained after a relatively short time to maintain adequate levels of physical stability
Provide examples of viscosity modifiers
- Polysaccharides
- Acacia
- Tragacath
- Alginates
- Starch
- Xantham gum
- Water-soluble celluloses
- Methylcellulose
- Hydroxy methylcellulose
- Hydrated silicates
- Bentonite
- Magnesium aluminium silicate
- Hectorite
- Carbomers
- Carboxy polymethylene
- Colloidal silicon dioxide
- Aerosil
Explain the difference between flocculated and deflocculated systems
Flocculated - loose sediments held together by weak van der Waals forces with a small amount of liquid medium in between, easily re-dispersible and fast sedimentation which can lead to inaccurate dosing
Deflocculated - a slower rate of sedimentation, therefore, more uniform dosing but prone to caking
Explain why flocculated particles sediment faster
Flocculated particles are particles that are loosely connected together. As a result, due to Stoke’s law, the particles are now ‘bigger’ which means that the velocity at which they sediment increases.
Discuss how flocculation can be controlled using electrostatic stabilisation
Electrostatic stabilisation refers to the electrostatic charge of the particle surface and its ability to attract oppositely charged ions. Since particles of the same charge exert repulsive forces on each other, the attraction of these ions (and hence, the neutralisation of the particle) means that these repulsive forces are reduced. As a result, the particles are able to flocculate.
Electrolytes can be used to add ions to the suspension.
Define ‘zeta potential’
Zeta potential is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle.
Define an emulsion and state the two types
Two-phase systems in which one phase is dispersed as fine droplets into another phase.
Coarse emulsions and microemulsions.
Explain the pharmaceutical relevance of emulsions
Emulsions allow us to entrap oil soluble drugs in dissolved form within an aqueous system and vice-versa.
Additionally, by designing a formulation that requires a drug to partition through different phases to reach its target, we can achieve sustained release.
Explain why an emulsion may be appropriate for oral and topical route formulations
Oral route - easy to swallow (oily drug in aqueous medium), allows for taste masking
Topical route - can be made more viscous (ointments), pseudo-plastic properties for ease of administration
Describe the role of an emulsifier and provide examples
Emulsifiers coat the dispersed phase droplets to reduce the interfacial tension between the droplets with the medium.
Examples:
- Surfactants
- High molecular weight alcohols
- Protein substances
State and explain 4 processes that must be avoided for an emulsion to be stable with reference to reversibility and irreversibility.
Flocculation - droplets loosely aggregate into loose clusters (reversible with shaking)
Creaming - higher concentration of drug in one region leads to lack of uniformity in distribution (reversible with shaking)
Coalescence - dispersed droplets flow together to gain energy, surfactant layer in the interface is broken down (irreversible with shaking)
Breaking - phase separation (irreversible with shaking)
Explain how flocculation can be reduced in emulsions
- Adding charged emulsifiers (cationic surfactant) but can be toxic
- Adding electrolytes to reduce charge
Explain how creaming can be reduced in emulsions
- Reduce droplet size
- Increase viscosity
- Reduce density difference between 2 phases
Explain how coalescence can be reduced in emulsions
- Reduce interfacial tension by adding surfactant
- Add mechanical barrier by adding hydrocolloid
- Increase droplet charge to induce repulsion
Explain why microemulsions are more efficient than emulsions using Neoral and Sandimmune as examples.
Sandimmune is an o/w emulsion that requires further emulsification by bile salts and digestion by pancreatic enzymes prior to absorption.
Neoral is a preconcentrate that forms a homogenous microemulsion immediately on contact with GI fluids (i.e. less dependent on bile salts for absorption).
Neoral has a more consistent PK behaviour, less inter and intrapatient variation, and a more consistent bioavailability when administered with food.
Define ‘dosage form’ and provide a reason why biologically active entities are not usually administered as pure chemical substances.
Dosage forms are clinical packages in which a drug is presented to a patient.
Before biologically active entities are administered, we must consider patient acceptability, therapeutic issues, toxicity, stability, etc. As a result, we instead administer formulate preparations.
State the criteria that are considered when making a drug
- Stability
- Reliability
- Convenience
- Palatability
- Effectiveness
Explain excipients
Chemical substances that aid in the formulation of a drug into the desired dosage form. Excipients are inner and physically and chemically stable.
Numerous functions include to solubilize, flavour, preserve, emulsify, suspend, etc.
Explain the Pulsincap release
The Pulsincap delivery system is a time-dependent release formulation comprised of:
- Enteric coat
- Capsule cap
- Hydrogel plus
- Drug wafer
- Ghost capsule body
Define bioavailability
The relative amount of an administered dose of a drug that reaches the systemic circulation unchanged.
The difference in bioavailability can vary with different routes of administrations, dosage forms or formulations.
Define bioequivalence
The comparison of the bioavailability of a drug to a recognised standard dosage form. BE determines if the rate and extent of absorption are equivalent in test and standard drug.
Explain how particle size affects the effectiveness of a drug
Smaller particles have a greater surface area. As a result, they have increased contact with the dissolution medium and will dissolve faster, leading to greater absorption.
Explain the Noyes-Whitney’s equation
dm/dt=kA(Cs-C)
dm/dt = the dissolution rate k = dissolution rate constant A = surface area of drug Cs = solubility of the drug C = concentration of solute in bulk solution at a time
