Physicochemical Properties III Flashcards
What happens when a drug is too hydrophilic?
Good water solubility
Poor membrane penetration
What happens when a drug is too lipophilic?
Good membrane penetration
Poor water solubility
How can solubility issues be fixed?
Salt formation
Chemical modification by adding polar groups like -OH, NH2, etc.
How can lipophilicity issues be fixed?
Chemical modification by addition of lipophilic groups
Masking of polar groups by nonpolar groups.
What is a dipole bond?
Results from unequal sharing of electrons between atoms within a covalent bond.
Generally the greater number of hydrogen bonds a molecule has the greater the solubility except when?
Except when there are intramolecular hydrogen bonds. Intramolecular hydrogen bonds decrease solubility and increase lipid solubility.
Compounds capable of intramolecular ionic interactions have very high or low solubility? What is an example of this?
Low solubility
Tyrosine
Strong acids and strong bases make what when they interact?
salt and water
What happens when weak acids interact with strong bases?
A molecular salt may be formed.
What are some examples of weekly acidic drugs?
Carboxylic acids, sulfonamides, imides, phenols
What are some examples of strong bases?
Sodium hydroxide (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca(OH)2)
What is the original acidic drug and identify the base:
Sodium sulfisoxazole
NaOH
sulfisoxazole
What is the original acidic drug and identify the base:
aluminum aspirin
Aluminum Hydroxide
aspirin
What is the original acidic drug and identify the base:
phenobarbital sodium
NaOH
phenobarbital
What is the original acidic drug and identify the base:
Penicillin V Potassium
KOH
Penicillin
What makes up a salt of molecular bases?
Weakly basic drugs with a strong acid.
Basic drugs with organic acids
What are weakly basic drugs?
Amines
What are strong acids?
Hydrochloric acid (HCl), Hydrobromic acid (HBr), Sulfuric acid (H2SO4), Nitric acid (HNO3)
What is the original basic drug and identify the acid:
Pseduoephedrine Hydrochloride
HCl
Pesudoephedrine
What are examples of organic acids?
Maleic, fumaric, tartaric, succinic, and citric acid
Low molecular weight salts are more or less water soluble than high molecular weight salts?
More water soluble
Therapeutic salts marketed for aqueous injection are commonly:
Weak organic acidic drugs with strong bases (e.g. a metal hydroxide)
Weak organic basic drugs with strong acids (e.g. mineral acids)
Ionized acids and bases if added together in water, have the capacity to interact in?
proton transfer reaction.
Why can proton transfer be dangerous?
The unionized species would be water insoluble and precipitate out in the syringe or in the IV line.
No drug will be delivered
Risk of injecting particulate matter into the bloodstream if the drugs were being given IV.
What are some reasons predicted incompatibility may not occur in practice?
The unionized conjugates have many polar functional groups capable of hydrogen bonding with water, which would allow the unionized forms to remain soluble.
The concentration of the drugs in solution is very dilute.
The solution is buffered to maintain a pH that allows the agents to remain in ionized, water soluble form.
Predict whether this pair of water soluble drugs would be chemically compatible or incompatible:
Alfentanil hydrochloride and Morphine Sulfate
Compatible
Predict whether this pair of water soluble drugs would be chemically compatible or incompatible:
Acyclovir Sodium and Morphine Sulfate
Incompatible
Predict whether this pair of water soluble drugs would be chemically compatible or incompatible:
Butorphanol Tartrate and Morphine Sulfate
Compatible
Predict whether this pair of water soluble drugs would be chemically compatible or incompatible:
Pantoprazole Sodium and Morphine Sulfate
Incompatible
What are the two approaches to water solubility predictions?
Empiric Approach
Analytical Approach
What is the empiric approach?
Molecule is considered to be water soluble when:
the solubilizing potential of the functional groups is greater then the total number of carbon atoms presents.
Salt forms increases solubilizing potential by difficult to quantitate 20 to 30 carbons.
What is the analytical approach?
Lipophilicity and LogP(partition coefficient for a molecule)
What does the LogP mean?
The molecules affinity for octanol over water. The higher the LogP the more lipophilic it is.
What is the LogP range to penetrate the Blood Brain Barrier (BBB)?
1.5 to 2.7 with an average of 2.1
What are examples of drugs that are common CNS targeted therapeutic agents?
Carbamazepine(Tegretol)
Phenobarbital(Luminal)
What beta blocker penetrates the BBB and may induce disturbing CNS side effects?
propranolol(ClogP 2.65) not atenolol (ClogP 0.5)
What are the effects of lipophilicity on drug absorption as shown in Enalaprilat (Vasotec IV) and Enalapril (Vasotec)?
Enalaprilat has a ClogP value of 1.17, oral bioavailability of 30-40%, and is administered by IV route.
Enalapril has a ClogP value of 1.77, oral bioavailability of 50-70%, and is administered orally. Also a Prodrug.
What enzyme is enalapril activated by?
hepatic esterases, ester turns into carboxylic acid
What drug was made into a sustained-release using increased lipophilicity?
Haloperidol (ClogP 3.49) was made into Haloperidol deconate (ClogP 7.3) which was taken into fatty tissues and slowly released over time. Haloperidol deconate is a prodrug.
