Effect of ionization on drug lipophilicity Flashcards
When a drug becomes ionized, this will _______ its solubility in water.
Why?
Increase solubility in water
B/C there will be a better solvation by ionic-dipole interaction between the ionized drug and water molecule.
Drug can better interact with water through hydrogen bonds, ionic interactions, etc.
If a protein is dissolved in water and salt is added, what occurs?
Salting out. The protein precipitates out of solution.
This is because the salt takes out water molecules surrounding the compound
Because most drugs are ionizable at different body pH ranges, the _________ must be taken into consideration when we are about to synthesize or develop certain drugs.
% ionization
__________ will determine from where the drug will be absorbed and what target tissue it will reach.
Lipophilicity
Unionized –> no _____ –> more _______ –> can ______ across the membrane
charge
lipophilic
partition
How does lipophilicity affect what target tissue the drug will reach?
In some tissues, the lipid bilayer will have different porosity and will further determine where the drug is absorbed.
The unionized form of an acid is also called the ______ form.
The unionized form of a base is also called the ________.
protonated
unprotonated
Solubility:
The property of a _____, ______ or ________ chemical substance called a _______ to dissolve in a solid, liquid, or gaseous solvent to form a __________ solution of the solute in the solvent.
liquid, solid, gaseous
solute
homogeneous
Solubility is a _______ property of the compound.
physical
The _______ of the solubility of a substance in a specific solvent is measured as the ________ __________ where adding more solute does not increase the concentration of the solution.
extent
saturation concentration
What are the most common ways to express solubility?
grams of solute per liter of solvent
Molarity - moles of solute per litre of solution
How can the formulation of biological compounds that are not dissolved well, particularly in water, be improved?
- Create (form) a salt
- Reduce particle sizes
- Find and use a better solvent
Why does a reduction in particle sizes increase solubility?
Related to surface area.
Hydrogen bonds can be formed much more easily.
Why is changing the solvent not always a viable option for increasing solubility?
Food and drugs go hand in hand. So, needs to be safe, cannot always add alcohol, acetone or chloroform.
When changing the pH to increase solubility, what must be taken into account?
The drug needs to not be too corrosive.
Penicilin, in the free acid form, is not very soluble. How was this remedied?
Increased the solubility by changing it to the salt form - potassium form to be exact.
Other than simple solubility, for a drug to be effective in the body, what is important?
The drug has to be in a high enough plasma concentration.
The drug needs to not only be soluble, but able to partition well.
The most effective form of a drug will be both _______ and have a high _______ _________.
soluble
plasma concentration
If solubility needs to be increased for a drug. What is the first thing that a pharmaceutical company will do?
Grind the drug into smaller particles
What is tween?
Compound that acts as a detergent - allows a powder to wet easier.
Tween acts as a detergent to make the fine particles interact with water more efficiently.
Different brands may have different onsets of action. Why?
Due to the particle size of the different drugs/addition of tween.
They are the same formulation but different particle size.
The partition coefficient is expressed as what?
P or logP (if large)
What is the partition coefficient?
The ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium.
What does immiscible mean (referring to liquids)?
Liquids not forming a homogeneous mixture when added together.
What are the two immiscible solvents in pharmaceutical sciences, to determine P?
water and n-octanol
What does n-octanol represent?
the lipid bi-layer of a cell memrbane
Why is the partition coefficient based on two immiscible liquids? Why not more?
Because this is the simplest formulation.
One partition between two compartments.
How is the partition coefficient determined?
Place drug in beaker containing both a buffer (aqueous phase) and n-octanol (organic phase).
Shake and leave it.
Drug redistributes in both.
Take sample from organic and aqueous phase.
Use mass spec and determine P.
How is P calculated?
P = [Co]/[Cw]
or
LogP = Log [Co]/[Cw]
The partition equation does not determine the effect of _____ on the lipophilicity of drugs.
ionization
If P is _____ than 1 it partitions well into the lipid.
Conversely, if P is ______ than 1, it likes to stay in the aqueous phase.
larger
smaller
A higher P value means higher ________.
We would expect to have a higher ______ _________ in that case.
lipophilicity
plasma concentration
_____ can be used to predict the behaviour of a compound at all pH values, as long as we know ____.
Papp
P
For acids, at pH values below _____, Papp = ___?
pka
P
At pH values above the pKa, the value of Papp _______. Why?
decreases
Because the species is ionizing and moving into the aqueous layer
What is the equation to calculate Papp?
Papp = P/ 1 + 10^(pH-pKa)
For the Papp equation, if pH = pKa, what is the bottom term equal to?
2
If the pH is above pKa, the Papp will be ______, the drug will be ______ and move to the _______ phase.
decreased
ionized
aqueous
What is the Papp equation for bases?
Papp = P/1+10^(pKa-pH)
For the acidic drug, RCOOH, which has a pKa of 4 and a P value of 200, what would Papp be in the stomach (pH - 2) and intestine (pH - 8)?
Where is the drug absorbed better?
Refer to notes
Oral administration and absorption:
If a drug is to be absorbed through the ______ membranes that line the gut, then it must be in its ________ or ________ form to partition out of the aqueous medium.
mucosal
lipophilic or unionized
The _______ ________ of the unionized form will also determined how much is absorbed.
Partition coefficient (P)
The absorption phase of the dose-response curve is heavily influenced by the ____ and ____ of a drug.
pKa
logP
What are Lipinski’s rule of five?
Orally administered drugs must have: - logP < 5 - No more than 10 hydrogen bond acceptors - no more than 5 hydrogen bond donors - A molecular weight less than 500 Da (not more than 7 rotatable bonds)
What is an addition to Lipinski’s rule of five?
An orally administered drug must have no more than 7 rotatable bonds.
Why must an orally administered drug be less than 500 Da?
Can’t be too bulky, else it wont partition
Why should there be no more than 7 rotatable bonds for an orally administered drug?
More constrained, better for receptor interaction
For acids:
A high pKa means the species is predominantly _____, is a ____ proton donor, and a _____ acid.
A low pKa means the species is predominantly ______, is a _____ proton donor, and a _____ acid.
unionized, bad, weak
ionized, good, strong
For acids:
pH < pKa by 2 units –> ___% unionized
pH > pKa by 2 units –> ___% unionized
99
0.99
For bases:
A high pKa means the species is predominantly _____, is a ____ proton acceptor, and a _____ base.
A low pKa means the species is predominantly ______, is a _____ proton acceptor, and a _____ base.
ionized, good, strong
unionized, bad, weak
For bases:
pH < pKa by 2 units –> ___% unionized
pH > pKa by 2 units –> ___% unionized
0.99
99
