Chapter 5 Salts and Solubility Flashcards
What are the effects of drug solubility on drug development and disposition?
-Formulation of the drug and appropriate dosage form: a drug that is not soluble is not appropriate for an oral dosage form bc it needs to dissolve to get absorbed
-Biodisposition after administration: What happens after being absorbed and showing its effect, is it excreted in the urine? does it require metabolism by the liver to make it more water-soluble? water-soluble drugs are getting absorbed faster
BIOAVAILABILITY depends on both SOLUBILITY (Dissolution in GI tract) and LIPOPHILICITY (Penetration through the membrane)
Advantages of high water solubility
-Quickly solubilized in the gut
-Suitable for IV and ophthalmic solutions (drugs with low solubility cant be given via IV (risk of penetration) or ophthalmic (the eye is very sensible)
-Ideal for drugs that work in the urinary tract (needs SOLUBILITY)
-Less likely to undergo extensive metabolism (through the liver)
Why is the metabolism through the liver relevant when choosing a drug?
Because for patients whose liver is impaired, a water-soluble drug would be the better choice VICE VERSA for patients with kidney impairments we would not choose a very water-soluble drug
Characteristics of lipid-soluble drugs:
-slowly solubilized in the gut (that’s fine as long as gets into solution)
-Better for transdermal or pulmonary absorption bc no dissolution step needed
-more extensively distributed in the CNS, bc it can cross the blood-brain -barrier (f.e. Fluoxetine -> lipophilic, nice and small)
-suitable for IM administration
-more highly plasma protein-bound (#1 Albumin (basic), #2 alpha-1-glycoprotein (acidic) -> also acid-basic factor involved)
Which proteins are most likely to bind #1 plasma protein: Albumin
Why is it so relevant?
Lipophilic, acidic drugs
-it is important bc only unbound drugs can bind to their target (the drug is slowly released from Albumin to act on the target
How can the Lipophilicity be quantitive expressed?
-Funnel with octanol and water -> put the drug in it and shake and observe to which phase it goes -> lipophilic goes more to the octanol phase, lipophilic to the water phase -> this ratio is expressed by log P
Lipinskis Rule:
90% probability that a drug has low Bioavailability if more than one rule meets
Too lipophilic: log P > 5, MW > 500
Too hydrophilic: Greater than 5 hydrogen bond donors, greater than 10 hydrogen bond acceptors
Why can be H-donor also be an H-acceptor?
F.e. O-H -> it donates the H, but it can accept donors at O too
for NH2 there is not enough dipole to make another H-bond ?? or to donate its second H
RECOGNIZE H-donors and acceptors
What are strategies to optimize solubility?
-Change drug structure
-Convert drug to salt
-Convert drug to a prodrug
What is a salt?
-Formed between an acidic and basic functional group
-Acidic (negative), Bases (positives) needs counterions
How do salts improve solubility?
-Salts improve water-solubility bc salts dissociate to produce hydrated ions -> f.e. Na+ will be surrounded with O of H2O (no hydrogen bonds)
if no hydrogen bonds are formed, what happens with a negatively charged ion? Doesn’t H bind with the negative ion??
So to be surrounded by water molecules (hydrated) the salt has to come apart -> so the rate of dissociation can be used to control how quickly the drug gets delivered
Types of salts involved in a solubility increase:
-Inorganic: Na+, Ca2+, Zn2+, SO4(-2), Cl-, NO3- (most often, they dissociate very quickly, often used to enhance solubility)
-Organic: for acidic (with the amino group - positively charged), for basics (carboxylic acid - negatively charged)
Characteristics of inorganic salts:
-always increase water-solubility
-quickly dissociate in solution -> non-covalent interaction so easy to break
f.e. Penicliin V with K+
Characteristics of organic salts:
(water-soluble)
.counter-ion is a carbon -> solubility can be increased when the counterion is small or decreased when it is big
-May increase water-solubility
-slower dissociation in solution than inorganic salts
-can involve some covalent binding (contributes to slow dissolution)
f.e. Timolol maleate (basic) with Carboncontaining counterion (carboxylic acid) Malic acid
can be used to slow down the dissolution to protect the drug from the acidic environment
Water insoluble example of an organic salt
-water-insoluble organic salt
Erythromycin (basic drug) + steric acid = Erythromycin stearate
-> Erythromycin goes into solution slowly because the ester group is prone to degradation -> making it unstable in the gut (acidic)
-> the idea is to delay the dissolution until the drug gets further in the GI tract where pH is higher
