lecture 20: drug solubility and dissolution rate 3.1

• our main interest is how to increase the solubility of class 2 drugs with low solubility in water but high permeability

• class 2 can be used oraly or topically

what are the easiest ways to change solubility?

to use a drugs salt form

what are inclusion compounds?

• also known as cyclodextrins

• a way to bring a molecule into solution by inglobing it into its structure

• results from the incorporation of the non-polar portion of one molecule into the non-polar cavity of another molecule that is water soluble

• similar to micelles

• reduce non-polar water interfacial area by inserting the solute(guest) into the complex agent(H2O)

what are the structures of cyclodextrins?

• enzymatically modified starches

• less toxicity therefore large range of use in the pharmaceuticals and delivery

• composed of alpha beta or gamma rings (alpha-CD)

• the outershell of all cyclodextrins is hydrophilic so can easily be dissolved in aqueous solution

• inner circle in ring is non-polar/lipophilic, can accomodate non-polar molecules

cyclodextrins in practice:

• placed in water and come into contact with cyclodextrins

• form an inclusion complex as the non-polar molecules dont like the hostile environment

• now isolated and used for solubilisation

how is the crystaline complex solubilised in water?

• overall faster and more complete release of drug when compared to mixtures without CD

• have major advantages

what are some disadvantages of cyclodextrins?

• di-o-methyl beta CD has strong affinity for cholesterol and is haemolytic(destuction of rbc) but is one of the best solubilisers for non-polar molecules

• beta CD also find a way to be used as controlled-release of drugs

what is a surface active solute(surfactant)?

• need to reduce surface tension without using large concentrations

• in interface( when 2 different faces are touching eachother) there is a lot of surface tension

• they increase miscibility between 2 faces therefore they can mix and get solubilized

• reduces ST

what identifies as a surfactant?

• highly polar head: important as it pulls aliphatic chain into the water

• highly non-polar tail: aliphatic chains

• hydrophilic/polar head: ionic or nonionic

• lipophilic/ nonpolar chain

why is the polarity of the head important?

the bigger the difference in the polarity between the polar head and non-polar tail, the better the surfactant

• if polarity isnt high, it will have to be improved

how can the hydrophilic lipophilic balance be observed in different regions and what does it determine?

• surfactant solubility in water and oil

• its applications

• its place on the scale of hydrophile-lipophile balance also known as the HLB

hydrophilic and lipophilic moieties:

what is polyethylene oxide used for?

used to increase polarity of non-ionic surfactants by preparing a chain

• its hydrophilic

what are features of the polar region?

• affinity for water

• capable of pulling long hydrocarbon chains into water

• polar group must be sufficiently polar to hold the nonpolar region of the surfactant in solution

what are the classifications of surfactants: the charges carried by polar heads

• anionic

• cationic

• non-ionic

• zwitterion

• different characteristics in terms of polarity

what are the properties of surfactants: micellisation?

• surfactants at very dilute concentrations in water, act as normal solutes and disperse as a sub-colloidal solution(no reaction)

• surfactants at concentrated solutions will self-aggregate and form micelles which contain 50+ monomers

• their typical size is about 50 angstroms

• depending on the size range theyre usually defines as colloidal

what is CMC?

critical micelle concentration- the concentration at which cells self aggregate(micelles form)

what is the aggregation number?

the number of monomers/surfactants that aggregate to form a micelle

what is the process of micellisation?

• surfactants can adsorb at interface of water and air. bcs if you add surfactants to water there is no hindrance with the molecules of water due to similar properties

• lipophilic non-polar tail(hydrophobic) will experience hindrance from water molecules. so waters around aliphatic chains pull out and create a void around aliphatic chain making the system very unstable

• to stabilise the system, surfactants start adsorbing to the surface to excape aliphatic chain into the air to escape hostile environment

• therefore are low conc theres no instability, but if you increase they will adsorb at the surface

• if you add more surfactants, the phenomena of adsorption will not be enough to stabilise the system, so molecules try to self aggregate( this conc is called CMC)

• place polar heads outside in contact with water and hide aliphatic chains inside, stabilising system

what are the several changes of the properties of the surfactants at CMC?

• osmotic pressure

• turbidity

• electrical conductance

• surface tension: once micelles form, surface tension wont change anymore as they have thermodynamically the most stable structure

CMC graph:

what are the factors that increase the CMC?

increases with increase in polarity of head group

what are the factors that decrease the CMC?

• temperature - cloud point

• pH(surfactants are weak electrolytes)

• a second surfactant

• addition of electrolytes and organic matter

how does the length of carbon chain affect the CMC?

longer chain= stick together easier =system is thermodynamically unstable much faster= micellisation concentration occuring is smaller

what are the critical values for micelles?

• CMC

• kraft point( critical micelle temperature)

• cloud point

• critical micelle pH

what is the kraft point?

• below kraft point, cant form micelles

• above kraft point, forms micelles

what happens when temperature is less than kraft point and when temperature is more than kraft point?

• at t< kraft point, CMC is less than solubility therefore micelle cannot form

• at T> kraft point, CMC is higher than solubility therefore micelles can form, self solubilization

• unassociated surfactant has limited solubility

• micelles= highly soluble= accomodate large amount of surfactant

what are key points about the kraft point graph?

• increasing temperature increases solubility of surfactants

• if you have micelle form, its a way of increasing solubilization

• if you have surfactaants, they make a solution clear

• when they become micelles, the solution becomes turbid

what is cloud point and what are its features?

• RS between temperature and non-ionic surfactants

  for nonionic, at the beginning if you increase temperature:

• lower than cloud point = clear, cant form micelles

• forms large micelles so the solution becomes cloudy, also known as cloud point

  reversible:

• if cooled down, small micelles form, the solution becomes clear

what is critical micelle pH?

• some surfactants act as weak electrolytes therefor can be ionised as a function of pH

• ionised form= surface active

• unionised form=surface inactive(lower CMC)

• change in pH induces micellisation

diagram of a micelle in polar environment:

• n. of surfactants that make a micelle is aggregation number approx 50-100 monomers

what are the geometric properties of micelles?

At a high conc of surfactants:

• Cylindrical rods, flattened disks

• Liquid crystals (hexagonal phase, middle phase)

• Lamellar phase (neat phase)

• Bilayers

• Vesicles

what are the different shapes of micelles?