Drug Solubility Flashcards
definition of solution
dispersion formed by two or more compounds which form a homogenous system
definition of solvent
component that determines the phase of the solution - usually the largest proportion
definitions of solutes
other components of the solution and are dispersed as molecules or ions throughout the solvent
definition of saturated solution
solute is in equilibrium with solute
definition of solubility
concentration of a solute in saturated solution at a certain temperature that dissolves to form a homogenous phase
definition of unsaturates/subsaturated solution
the dissolved solute is in concentration below that necessary for complete saturation at a definite temperature
definition of supersaturated solution
contains more dissolved solute than normal
semi quantative expressions of solubility
very soluble (<1part) freely soluble (1-10 parts) soluble (10-30 parts) sparingly soluble (30-100 parts) slightly soluble (100-1000 parts) very slightly soluble (1000-10000 parts) insoluble (>10000 parts)
quantative expressions of solubility
molarity % w/w % w/v mg/ml g/100ml
what is a diffusion layer
when molecules in surface layer of drug dissolve to form a saturated solution around particles
dissolved drug molecules pass through dissolving fluid to contact absorbing mucosa
replenishment of diffusing layer by further drug dissolution
Factors affecting dissolution rate
surface area of undissolved particles solubility in dissolution medium conc in bulk of solution diffusion coefficient thickness of boundary layer
Reduction in particle size
inclreases dissolution rate - exposure of increasing amounts of solute to the solvent
solubility increased with decreasing particle size
to increase solubility
salt form of drug used
aqueous solubility can be reduced by esterification of prent drug
effect of esterification
masks the taste and protects from degredation in GI
can facilitate absorption in GI tract
polymorphism
crystallisation conditions -> molecules/ions arrange differently in lattice -> stable polymorph (less soluble) or metastable polymorph (more soluble, less stabe)
counterions used in salt formations
HCl, sulphate, mesylate, phosphate, maleate, salicylate, tartrate, lactate, citrate, succinate, acetate, sodium, potassium, calcium, lithium, magnesium, inc, choline, aluminium
weak bases in GI tract
high dissolution rate in stomach
dissolution rate falls as pH of GI tract rises
weak acids in GI tract
minimal dissolution in the stomach
dissolution rate increases down the gut
salt dissolution
dissolution of the salt form is greater than the free form
effect on use of salt form
modifies pH of diffusion layer
salt of weak acid increases pH of diffusion layer
salt of weak base decreases pH of diffusion layer
salt is preferable to acid as dissolution is better controlled
salt form controls pH of diffusion layer indepentdly of position of GI tract, this improves dissolution rates
co-solvent advantage
increases solubility
when does precipitation occur
when pH of solution is adjusted to produce mostly unionised molecules, exceeding solubility of their form
how to improve solubility of weak electrolytes or non-polar compounds
adding water-miscible solvents in which the compound is soluble
what are co-solvents
vehicles used in combination with water to increase solubility
the solubility in mixed systems is greater than that of individual solvents
Cosolvency
obtains aqueous-based systems in which the drug solubility is higher than aqueous solubility; it formulates higher concentrations of the drug
it improves stability of formulation
cosolvents
organic compounds
miscible with water
better solvents than water for a drug(H-bond acceptors/donors, small hydrocarbon regions)
most cosolvents are liquids (ethanol, glycerol, propylene glycol)
some are solids that are highly soluble in water (urea, PEG, PVP)
effect of cosolvents decreasing H-bond density of aqueous systems
reduces cohesive interactions of water, which reduces polarity of solutions, so the solution is less effective than water in squeezing out nonpolar structures solubilisation by cosolvency
cosolvency
water-ethanol has more cosolvency than water-glycerin with non-polar drugs
cosolvents increase solubility of non-polar and semipolar solute in water
as solutes become more polar, cosolvency becomes less efficient; it will decrease solubility of a polar solute in water
what are cyclodextrins
inclusion compounds that enhance solubility of drugs that are poorly soluble in water
they are enzymatically modified starches with a ring of glycopyranase units
the centre of the ring accommodates lipophilic molecules (outer ring is hydrophlic and inner is non-polar)
what are surfactants
surface active agents that enhance solubility
what do cyclodextrins do
they incorporate the non-polar portion of one polar molecule into the non-polar cavity of another molecule or group of molecules that is water soluble
driving force is similar to micellar solubilisation - it reduces the non-polar water interfacial area by inserting the solute into the complexing agent
the complex formed increases solubility initially but decrease in solubility as drug is released
beta cyclodextrins
useful solubilisers used in the controlled release of drugs
use of surfactants
have the ability to reduce surface tension at an interface without requiring large concentrations
lower conc required = better surfactant
highest reduction of interfacial tension obtained with solutes that combine in their molecular structure, one element having a high afinity for the solvent and one having minimal affinity for a solvent
role of surfactants
resolves interfacial tension between two immiscible liquids
more surface tension = less thermodynamically stable
structure of surfactants
polar head group and lipophilic/non-polar chain
can be presented in different proportions, which determines the surfactant solubility in water or oil
what is HLB
hydrophile/lipophile balance
solutions of surfactants
unusual properties at dilute solutions
act as normal solutes and normal electrolytes
amiphiles exist separately and are of such a size to be sub-colloidal
as concentrated solutions, they aggregate to form a micelle
what is critical micelle concentration
the narrow concentration range which causes surfactants to aggregate to form a micelle
what is micellisation
alternative mechanism to adsorption
permits strong water-water interations that would be prevented if the surfactant molecules were in solution as single molecules (hydrophobic effect)
physical properties that change with CMC
osmotic pressure, tubidity, electrical conductivity, surface tension
CMC can increase with increase of polarity of surfactant head group
CMC can decrease with temp, pH, additional surfactants or electrolytes
what is Kraft point
temp/time where solubility is equal to CMC
when kraft point is larger than temperature, the CMC is larger than solubility and micelles cannot form
when temp is larger than kraft point, the surfactant forms micelles (self solubilisation)
what is the cloud point
for non-ionic surfactants
increase in temp causes dehydration of POE chains, decreased solubility, formation of large micelles so the solution becomes cloudy
reversing cloudiness of non-ionic surfactants
by cooling
this forms small micelles - called clarification
what is critical micelle pH
ionised form of a compound is surface active and unionised form is surface inactive (or has lower CMC than ionised form), a change in pH can cause micellisation
geometric properties of micelles
at high conc of surfactants, high viscosity systems may occur
cylindrical rods, flattened discs, liquid crystals
lamella phase
bilayers
vesicles
groups on non-ionic surfactants
hydroxy
ether
less polar than ioninsed groups
what is a POE number
number of monomeric polyoxyethylene groups in the molecule
polyoxyethylene
chains with 20+ ether groups linked to non-polar moiety
several chains then linked to cyclic sugar and alkyl group
surfactant applications
anionic: cheap, toxic so only used externally
cationic: disinfectant/preservatice properties, o/w emulsifiers
nonionic: o/w, w/o emulsifiers, low toxicity and low irritancy, parenteral use
parenteral applicaitons for ionic surfactants
haemolysis of RBC and desrtuction of T-cells
parenteral applications for non-ionic surfactants
phospholipids, polysorbates, cremophor EL anaphylactic shock, toxicity related to ethylene oxide
what is solubilisation
process by which water=-insoluble or patially soluble substances are brought into aqueous solution by incorporation into micelles
solubilisation with micelles
site of solubilisation depends on chemical nature of solubilisate
more polar solute, more likely to be solubilised closer to the surface
polar region of non-ioninc micelle larger than polar region of ioninc micelle
what is solubilisation capacity
quantifies solubilisation
measure the ability of a surfactant to solubilise a solute
molar solubilisation capacity (k)is the number of moles of solute that can be solubilised by one mole of micellar surfactant
to decrease CMC
increase hydrocarbon chain length
introduce polar region on molecule or double bond
branched surfactants will produce smaller micelles
semipolar solutes
surface and palisade region largely unaffected by nonpolar region
factors of surfactant selection
amount of surfactant required
ability to solubilise a solute
increased chain length for reduced CMC and reduced solubility
Lundelieu’s rule
any factors that decreases solubility of surfactant promotes surface activity
HLB values
higher HLB = more hydrophilic
100% lipophilic = HLB1
100% hydrophilic = HLB20
what is phase intervention temperature (PIT)
HLB varies with temp because relative solubilities of lipophile and hydrophile parts vary with temperature
this is more pronounced with non-ionic surfactants becuase their solubility depends on H-bonding
temperature on H-bonding
higher temps weaken H-bonds and emulsifiers are less soluble in water
common non-ionic emulsifiers are water soluble at low temps to stabalise o/w emulsions
oil soluble at high temps to stabalise w/o emulsions
PIT of emulsifier
temp at which it changes from o/w to w/o
hydrophilic and lipophilic nature balance
