Week 8 solutions Flashcards
Dissolution pharmaceutical relevance
Absorption -> in order for drugs to work they need to be absorbed by the body, drugs usually need to be in (aqueous) solution to be absorbed, aqueous solubility is important as the body is mostly water
Solubility in formulations
Biopharmaceutical classification system (BCS) -> a way of categorising drug substances into 4 different groups depending on aqueous solubility and intestinal membrane permeability
Atm, 40% of drugs are considered to be poorly soluble and drugs in development 90% are poorly soluble
Solubility - medicine incompatibilities
Intravenous infusion -> mostly solutions and sometimes emulsions, but carefully formulated that the emulsion particles are very small
If a patient is very ill we dont want to keep injecting them with needles, if they have a intravenous line open we can add the drug into that
Can lead to a precipitation reaction -> what you add to the solution bag alters the solubility of something that is already in there / if solubility is lower we say that it has come out of solution or salts out
Before you had a perfect solution where everything had individual molecular dispersion, you now have solid particles - can be dangerous
BNF warns about this
Dissolution - crystalline structure
-Most drugs are crystalline in structure
Regardless of molecular weight you will have very different drug substances that will form very different crystalline structures
Very ordered arrangement
Molecule is the individual substance not the large crystal - that is a particle
A solution is a molecular dispersion -> f such a drug is to enter solution then the individual molecules must leave the crystalline particles
Dissolution - what happens
Dissolution (in order for a crystalline structure to enter solution)
The crystalline structure needs to move apart, the solvent molecules are able to get closer into the crystal as these individual molecules start to leave
Cavities created in the solvent allow a drug molecule to leave
The drug crystal gets smaller and smaller
Dissolution can only happen if the attractive forces between the drug molecules and solvent molecule is greater than the forces between the two individual drug molecules
Solute-solvent interactions
Attractive forces between solute and solvent are governed by the molecular structure of the solid and the nature of the solvent
“like dissolves like” -> a solvent that is polar is more likely to dissolve polar drugs and vise versa
Effects of solute structure
-A small change in molecular structure, e.g. addition/removal of a functional group, can have a marked effect on solubility (aqueous solubility)
e.g.,
Effects of solute structure - salt formation
Acid + Base -> Salt + Water
Most drugs are week acids / weak bases
The acid is only slightly soluble in water but the salt is freely soluble in water -> converting the weak acid to a base increases solubility
Effects of solute structure - molecular shape
Isomerism, can play a part in determining solubility
Solubility can be measured as molality -> moles per kilo
Despite the molecular formula, branching differences in the structure can lead to differences in solubility
Typically, branching leads to an increase in aqueous solubility
Effects of solute structure - molecular shape 2
Substituent position on a ring can also impact upon solubility
->Positioning of the functional group on the ring
-Para isomers tend to have slightly lower solubility, this is because the slightly better symmetry of the molecule means that the crystalline structure tends to be more stable -> less likely to break up and dissolve
Effects of solute structure - substituents
Solute substituents alter solubility
Hydrophobic / hydrophilic
Ionisation -> e.g., COOH when it is in its unionised state is it more on an intermediate, but when it has lost its proton its now charged and left with a negative charge - more polar and so more hydrophilic
->Charged functional groups are more hydrophilic and therefore more soluble
Polar solvents
Polar solvents, e.g. water, methanol, acetic acid, have a
high relative permittivity εr (formerly known as the
dielectric constant)
Measure of polarisability in response to current being added
Non-polar solvents have a much
lower relative permittivity
Polar solvents dissolve ionic solutes by reducing the force
of attraction between oppositely charged ions in crystalline solids
Polar solvents can even break covalent bonds
Semi-polar solvents
->Can dissolve polar and non-polar substances
Solvent molecule dipole moment or H-bonding groups enable polar solutes to be dissolved
Semi-polar solvents can induce a degree of polarity in non-polar molecules
Non-polar solvents
->Low relative permittivity εr dielectric constant and lack of
H-bonding groups prevent these solvents from dissolving ionic or polar solutes
->Unable to break covalent bonds
->Dissolve non-polar compounds only
->Non-polar solutes are held in solution through van der waals interactions with the solvent
Other factors that determine solubility
-Temperature-> Dissolution is usually an endothermic process (heat absorbed) so increase in temperature leads to an increase in solubility
If exothermic then the reverse occurs
-Polymorphism / solvates / hydrates -> Crystalline solids can exist as different polymorphs depending on how the constituent molecules are arranged
Structure also altered by incorporation of solvent molecules (solvates & hydrates)
Less stable polymorphs (metastable) will be more soluble
-Particle size
-pH
