drug solubility and dissolution rates

Question 1

during dissolution the drug molecules in the surface layer dissolve to form a saturated solution arounf the particles - whats this called?

Answer 1

the diffusion layer

Question 2

whats the next step of drug dissolution after the diffusion layer has formed?

Answer 2

the dissolved drug molecules pass through the dissolving fluid to reach the absorbing mucosa for absorption to occur. further drug dissolution then replenishes the diffusing layer so absorption continues.

Question 3

the BCS classifies drug into 4 classes, if in class 1 theyre highly soluble and highly permeable hence they can be given as a simple solid oral dosage form. what if the drug is class 2?

Answer 3

class 2 drugs have low solubility and high permeability - they are therefore improved by reducing particle sixze to increase the surface area and often given in solutions using solvents or surfactants.

Question 4

the BCS classifies drug into 4 classes, if in class 1 theyre highly soluble and highly permeable hence they can be given as a simple solid oral dosage form. what if the drug is class 3?

Answer 4

class 3 drugs have high solubility but low permeabilityhence fromulations often incorptorate permeability enhancers and maximise local lumenal concentration

Question 5

the BCS classifies drug into 4 classes, if in class 1 theyre highly soluble and highly permeable hence they can be given as a simple solid oral dosage form, what if the drug is class 4?

Answer 5

class 4 drugs have both low solubility and low permeability - they try to improve these drugs using the same solutions as for class 2 and class 3.

Question 6

what happens when a new entity is discovered and has undergone toxicity testing?

Answer 6

preformulation tests are carried out and the most suitable salt is selected. common pharmaceutical counter ions are hydrochloride, sulphate phosphate and salicylate.

Question 7

what is the disolution of a weak base like?

Answer 7

a weak base has a high dissolution rate in the stomach but the dissolution rate falls as the pH of the GI tract rises.

Question 8

whats the dissolution of a weak acid like?

how can this be improved?

Answer 8

a weak acid has minimal dissolution in the stomach but its dissolution rate increases down the gut.

Question 9

the use of the salt form modifies the pH of the diffusion layer. how does this work for a weak acid and a weak base?

Answer 9

the salt of a weak acid will increase the pH of the diffusion layer.
the salt of a weak base will decrease the pH of the diffusion layer.

Question 10

what is the dissolution of the salt form like/how is it different?

Answer 10

dissolution of the salt form will usually be greater than that of the free form.

Question 11

what is the pH of the diffusion layer for a free acid?

Answer 11

the pH of the diffusion layer will be that of the bulk solution if the free acid is used.

Question 12

what is the pH of the diffusion layer if the salt is used?

Answer 12

the pH of the diffusion layer will be that of the salt when the salt form is used.

Question 13

chlordiazepoxide is a weak base, what can be done to alter the solubility?

Answer 13

by making a salt of the weak base chlordiazepoxide with an acid as this will create a salt with a lower pH diffusion layer hence the solubility will increase. the stronger the acid used to make the salt, the lower the pH will be and therefore the greater the solubility will be.

Question 14

what does the use of the salt form control?

Answer 14

by using the salt form of the drug we get a controlled pH of the diffusion layer, independent of the position in the GI tract. this is because the diffusion layer will have the pH of the salt rather than the bulk solution. we can therefore alter pH to optimise the dissolution rate. for example, for a weak base we can creat a salt with a strong acid, the salt will therefore have a low pH hence the diffusion layer will also have a low pH. this means the weak base will difffuse out better as we know weak bases diffuse better in the low pH conditions, early in the GI tract. however by altering the diffusion layer the weak base would now diffuse just as easily in the small intestine as it does in the stomach.

Question 15

when at a given ph of solutin the drug is in ionic form hence it behaves as a solution of strong electrolytes and the solubility is not an issue. however what happens when the ph is adjusted?

Answer 15

adjusting the pH of the solution could produce mainly unionised molecules therefore exceeding solubility so precipitation occurs.

Question 16

how can the solubility of weak electrolytes/non-polar compounds in water be improved?

Answer 16

by addition of a water miscible solvent in which the compound is soluble - vehicles used in combination with water to increase the solubility of a drug are called cosolvents - the solubility in this mixed system is greater than that of individual solvents.

Question 17

what is cosolvency?

Answer 17

often compounds are more soluble in a mixture of solvents rather than one alone.

Question 18

why might cosolvents be used in pharmaceutical preparations?

Answer 18

• to obtain aquous based systems in which the drug solubility is higher than the aquoes solubility.
• to formulate higher concentrations of the drug.
• to improve stability of the formulation.

Question 19

what are cosolvents?

Answer 19

organic compounds that are miscible with water and better solvents for the drug than water. there is no unique structural featurebut often have hydrogen bond donor and acceptor groups and small hydrocarbon regions.

Question 20

what are some examples of cosolvents?

Answer 20

most cosolcents are liquids like ethanol, glycerol and propylene glycol. however you also get some solid cosolvents that are highly soluble in water, these include PEG, PVP and urea.

Question 21

how do cosolvents work?

Answer 21

cosolvents decrease the hydrogen bond density of aquoeus systems hence reducing the cohesive interactions of water in turn reducing the polarity of the solution, the solution is therefore less effective than water in squeezing out non-polar solutes.

Question 22

whats a drug that is influenced by cosolvency?

Answer 22

phenobarbitone solubility increases exponentially with increasing cosolvent concentration.

Question 23

whats the solubilization model for coselvency?

Answer 23

if you plot a graph of log solute concentration against cosolvent concentration you should see a linear relationship.
the gradient of the line represents solubilization - this is the effectivenessof a cosolvent as a solubilizer for a particular solute.
the y intercept is the logSwater.
you can calculate logSmixture by using values obtained from the graph and fc - this is the volume fraction of the cosolvent.

Question 24

cosolvents are used to increase the solubility of a non polar and semi polar solute in water - how will it affect the solubility of a polar solute?

Answer 24

cosolvents will reduce the solubility of a polar solute in water.

Question 25

how is ethanol a good cosolvent?

Answer 25

ethanol is less polar than water and therefore lowers waters dielectric constant in solution making it a good cosolvent as it helps non polar molecules mix with water.

Question 26

cyclodextrins form inclusion compunds, what is an inclusion compound?

Answer 26

an inclusion compound results from the incorporation of the non polar portion of one molecule into the non polar cavity of another molecule that is water soluble.

Question 27

whats the driving force behind inclusion compounds?

Answer 27

the drivoing force is similar to that of micellar solubilization - it aims to reduce the non polar - water interfacial area by inserting the solute into the complexing agent?

Question 28

cyclodextrins are enzymatically modified starches - their glycopyranose units form a ring. how does the cyclodextrin work to mix drugs with water?

Answer 28

the cyclodextrin is cyclindrical with a hydrophilic outer surface and a non polar internal surface cavity. appropriately sized lipophilic molecules can be accomodated wholly or partially in the complex in which the host to guest ratio is usually 1 to 1. although other ratios may exist, e.g. multiple cyclodextrins could form inclusion complexes with 1 or more drugs.

Question 29

poorly soluble hydrophobic drugs will form an inclusion complex with cyclodextrin dissolved in water - this can then be isolated into a crystalline complex. what do the steps dissolution-dissociation-recrystallisation of the crystalline complex involve?

Answer 29

the crystalline complex can be dissolved in water and it will start to dissociate. after 60 minutes youll get the recrystallised cyclodextrin and the isolated drug.

Question 30

what do dissolution tests of ibuprofen involve and confirm? | what does comparison of the dissolution profiles show?

Answer 30

dissolution tests confirmed the increase in the ibuprofen dissolution rate when using b-cyclodextrin. this is due to the formation of a complex between the CD and ibuprofen when placed in a water bath. comparing the dissolution profiles show that the effect of the complex on the release of ibuprofen was more evident at low pH. there was fast and complete release of the drug in 30 minutes when a cyclodextrin was used - it took much longer in the absence of a cyclodextrin.

Question 31

di-o-methyl-b-cyclodextrin is one of the best solubilisers, whats bad about it?

Answer 31

it has a strong affinity for cholesterol and is haemolytic.

Question 32

what is a surfactant?

Answer 32

a surfactant is a solute with the ability to reduce the surface tension at an interface without requiring large concentrations hence it remains as a solute rather than becoming a solvent. a surfactant is a solute which reduces the interfacial tension between water and a hydrocarbon by 50mN/m when its at a concentration of less than 0.1%. surfactants are also called surface active agents.

Question 33

what must a solute combine in their molecular structure in order to acheive the highest reduction in interfacial tension?

Answer 33

a solute must have both a region with high affinity for the solvent and a region with low affinity for the solvent.

Question 34

where does a surfactant molecule have its lowest potential energy?

Answer 34

the lowest potential energy will be at the phase boundary.

Question 35

whats the structure of most surfactants?

Answer 35

most surfactats have a hydrophilic/polar head grou and a lipophilic/non-polar chain - these two regions can be presented in different proportions.

Question 36

what does the balance of the two regions of the surfactant determine?

Answer 36

the balance of the hydrophilic and hydrophobic part detremnine the surfactant solubility in water and oil, its applications and its place on the scale of hydrophile-lipophile balance (HLB).

Question 37

whats the properties of the polar region?

Answer 37

the polar region has an affinity for water, is capable of pulling long hydrocarbon chains in water. the polar head must be sufficiently polar to hold the non-polar region of the surfactant in colution. the charge carried by the polar head classifies the surfactant - it may be anionic, cationic, nonionic or zwitterionic.

Question 38

how do surfactants form micelles?

Answer 38

surfactants form micelles so all the hydrophobic tails point inwards whilst hydrophilic heads point outwards.

Question 39

solutions of surfactants show unusual physical properties at dilute solutions - what are these?

Answer 39

at low concentrations the surfactants act as normal solutes and normal electrolytes. the amphiphiles exist separately and are of such size to be sub colloidal.

Question 40

what unusual properties do surfactants show at high concentrations?

Answer 40

at high concentrations surfactants aggregate over a narrow concentration range - these are called micelles

Question 41

whats the critical micelle concentration?

Answer 41

the critical micelle concentration is the concentration of monomer at which micelles form.

Question 42

whats the aggregation nuber?

Answer 42

the aggregation number is the the number of monomers that aggregate to form a micelle.

Question 43

what is micellisation?

Answer 43

micellisation is an alternative mechanism to adsorption- it permits strong water-water interactions that would otherwise be prevented if the surfactant molecules were in solution as single molecules between water molecules - this is known as the hydrophobic effect. hence if the surfactant molecules were individual in water they would experience repulsion dure to the hydrophobic tails, by forming micellese they minimise the repulsion so that they can have strong water interactions.

Question 44

what are the abrupt changes in the physical properties of surfactants once CMC is reached?

Answer 44

- osmotic pressure increases as surfactant concemtration increases but once cmc is reached it becomes constant. - turbidity increases as surfactant concentration increases but once cmc is reached it increases more rapidly - electrical conductance decreases as surfactant concentration increases, once CMC is reached it will drop more rapidly - surface tension reduces as surfactant concentration increases but once cmc is reached it becomes constant.

Question 45

what may cmc increase with?

Answer 45

the critical micelle concentration may increase with increase in polarity of the head group.

Question 46

what may cmc decrease with?

Answer 46

the critical micelle concentration may decrease with temperature, pH, a second surfactant and the addition of electrolytes and organic matter.

Question 47

what is the kraft point?

Answer 47

the temperature at which solubility is equal to the critical micelle concentration - kraft noticed an abrupt increase of the solubility of sodium soaps in water with temperature. kraft point is the minimum temperature at which micelles can form.

Question 48

at temperature below kraft point what occurs?

Answer 48

when temperatures are below the kraft point the cmc is greater than the solubility and micelles cannot form.

Question 49

at temperatures above the kraft point what happens?

Answer 49

when temperatures are above the kraft point the surfactant forms micelles and self solubilization occurs

Question 50

whats the cloud point?

Answer 50

cloud point occurs to non ionic surfactants when the temperature is increased causing dehydration of POE chains, decreased water solubility and formation of very large micelles so the solution becomes cloudy. this is a reversible process - upon cooling smaller micelles form so clarification occurs.

Question 51

what would cause a change in ph to induce micellisation?

Answer 51

if the ionised form of th compound is surface active and the unionised form is surface inactive a change in ph could induce micellisation.

Question 52

at high concentrations of surfactants higher viscosity systems may occur. what geometric molecules may form?

Answer 52

cylindrical rods, liquid crystals, lamellar phase, bilayers and vesicles may form at a high concentration of surfactant.

Question 53

non ionic surfactants are less polar than ionised groups- we therefore need more units to produce an effective polar moeity. what can be done about this?

Answer 53

POE = polyoxyethylene is a common unit added to increase polarity. we can add POE chains with 20 or more ether groups linked to the non polar moeity. it involves several poe chains linked to a cyclic sugar sorbitan linked to an alkyl group.

Question 54

whats the poe nukmber?

Answer 54

the poe number is the number of monomeric polyoxyethylene groups in the molecule.

Question 55

how are anionic surfactants used?

Answer 55

anionic surfactants are cheap but due to toxicity they can only be used for external applications. anionic surfactants are good for oil nin water emulsifiers.

Question 56

how are cationic surfactants used?

Answer 56

cationic surfactants are also highly toxic but have disinfectant and preservative properties. they are good oil in water emulsifiers.

Question 57

how are non ionic surfactants used?

Answer 57

non ionic surfactants are good for oral and parenteral use due to their low toxicity and low irritancy. they are good for both oil in water and water in oil emulsifiers.

Question 58

what would happen if ionic surfactants were administered parenterally?

Answer 58

the ionic surfactant would cause hemolysis of red blood cells and destruction of T lymphocyte cells.

Question 59

why is the use of the nonionic surfactant cremophor EL limited?

Answer 59

it can cause anaphylactic shock

Question 60

what are some surfactants in which the hydrophobic portion is part of an aromatic or heterocyclic ring system?

Answer 60

chlorpromazine, imipramine, dipenhdramine and penicillin G.

Question 61

what happens when surfactants are in water?

Answer 61

when surfactants are in water its a hostile environment with poor thermodynamicsdue to the repulsion of the water molecules to the non polar region. this causes them to aggregate to the surface, reducing the surface tension. as surfactant concentration increases the surface will soon become saturated - this is the CMC and at this point micelles will start to form in order to stabilise the mixture/reduce surface tension.

Question 62

whats the structure of the micelle?

Answer 62

the micelle consists of: - palisade layer - hydrocarbon and polar moeities - core - hydrocarbon moeities - surface/mantle - polar head groups

Question 63

how does solubilisation occur with micelles?

Answer 63

solubilisation is the process by which water insoluble or partly soluble substances are bought int aqueous solution by incorporation into micelles.

Question 64

the site of solubilisation depends on the chemical nature of the solute. how ?

Answer 64

the more polar the solute the more likely to be solubilised close to the surface. the polar region of a non-ionic micelle is significanly larger than that of an ionic micelle.

Question 65

how does drug solubility change with surfactant concentration?

Answer 65

initiallly drug solubility will be constant, once cmc is reached micelles will begin to form so drug solubility will increase drastically as the micelles can accomodate a hydrophobic drug with their core to improve the solubility.

Question 66

whats the solubilization capacity?

Answer 66

k measures the ability of a surfactant to solubilise a solute.

Question 67

whats the molar solubilization capacity?

Answer 67

the number of moles of solute that can be solubilised by 1 mole of micellar surfactant. k is the gradient of the line of solute concentration against surfactant concentration once cmc has been reached.

Question 68

the non polar region of the surfactant directly relates with solubilization capacity of low polarity solutes - how?

Answer 68

increasing the hydrocarbon chain will create a longer core that can accomodate a larger/ more non polar molecules hence it will solubilize more solute and decrease the CMC. introducing a polar group to the chain is equivalent to decreasing the length of the chain hence it wil solubilise less solute. branched surfactants will form smaller micelles so it will solubilise less solute.

Question 69

what must you consider when choosing a surfactant?

Answer 69

- the amount of surfactant that can be placed in water as very long chains are nott effective surfactants as the have low solubility - the ability to solubilise a solute - very short chains have very high CMC so a lot of surfactant is required.

Question 70

increasing the chain length will decrease CMC, it also reduces solubility which reduces the amount of surfactant that can be used. in practice a balance is required - what is the ideal balance?

Answer 70

12-16 carbons or 18 with a double bond will provide a low CMC and sufficient water solubilityhence a sufficient concentration of micellar surfactant in water can be obtained.

Question 71

how does the lipophilic part of the surfactant affect it?

Answer 71

the lipophilic part is hydrophobic so will limit the surfactants solubility in water - the hydrophile must therefore provide enough interaction with water to bring the insoluble lipophile into solution.

Question 72

what happens as chain length of the lipophilic region increases?

Answer 72

the solubility will decrease and surface activity becomes more pronounced. the longer the hydrocarbon chain, the greater the tendency of the surfactant molecules to adsorb at the surface and lower the surface tension.

Question 73

whats lundeliuss rule?

Answer 73

any factor that decreases solubility of the surfactant promotes surface activity.

Question 74

what do high hlb numbers indicate?

Answer 74

if hlb is high it suggests the surfactant mainly exhibits polar or hydrophilic properties

Question 75

what do low hlb numbers indicate?

Answer 75

low hlb suggests the surfactant mainly exhibits lipophilic/nonpolar properties.

Question 76

pharmaceutical formulations often require a specific HLB for a given application - how can this be obtained?

Answer 76

use a micture of high and low hlb surfactants as this may give greater stability than single surfactants and enables you to reach and ideal hlb.

Question 77

surfactants can be added to reduce interfacial tension between oil and water. what is required to ensure a stable emulsion?

Answer 77

each type of oil requires an emulgent of a particular HLB number in order to ensure a stable emulsion

Question 78

how does temperature effect emulsifying agents?

Answer 78

the solubilities of the lipophile and hydrophile parts of a surfactant vary with temperature hence the overall hlb of an emulsifier will vary with temperature. this is more pronounced for non ionic surfactants as their solubility in water depends on hydrogen bonding. at higher temperatures the hydrogen bonds are weakened by thermal forces and the emulsifier is less stable in water.

Question 79

what emulsifiers work for what solutions?

Answer 79

- water soluble emulsifiers will solubilise oil in water emulsions at low temperature - oil soluble emulsifiers will stabilise water in oil emulsions at high temperature.

Question 80

what is the phase inversion temperature?

Answer 80

PIT is the temperature at which the emulsifier changes from baing an oil in water emulsifier to a water in oil emulsifier. at the pit the hydrophilic and lipophilic nature balance.