MedChem Notes

When identifying a salt, focus on the smaller molecule, such as hydrochloric acid.
Recognize that salt formation involves an acid reacting with a base.
If reacting with an acid, the drug molecule needs to have a base.

In the context of drug molecules, a basic functional group will react with an acid to form a salt.
Amides are neither acidic nor basic.

Generally, hydroxyl groups (OH) are neither acidic nor basic.
A key exception is phenol, which is an acidic group.
The enolic form of a beta-dicarbonyl is acidic due to keto-enol tautomerism.
Beta-dicarbonyls, when deprotonated, can strongly bind calcium, as seen in tetracycline.

Salt forms and acid-base reactions are crucial due to potential drug-drug interactions and incompatibilities, especially in hospital pharmacies when creating IV solutions.
Compatibility charts are used to determine if drugs can be mixed in the same syringe.
Incompatibilities often occur due to acid-base reactions leading to salt formation, where the resulting high molecular weight causes precipitation.
Incompatibilities can also arise from differing pH levels in solutions, affecting whether a drug is in its ionized (soluble) or unionized (insoluble) form.

Y-sites refer to configurations where two drugs enter tubing and mix in a Y-shaped junction. Compatibility must be assessed at Y-sites and in syringes.
Syringe compatibility is more critical due to higher drug concentrations, increasing the likelihood of reactions. What may be compatible in IV mixtures might be incompatible in syringes.

Furosemide and dobutamine are incompatible due to an acid-base reaction. Furosemide contains a carboxylic acid (acid), while dobutamine contains an amine group (base).

Ketorolac and morphine are incompatible in a syringe due to an acid-base interaction where the carboxylic acid of ketorolac reacts with the tertiary nitrogen of morphine.

Ketamine (a base) should not be mixed with phenobarbital (an acid) in the same syringe.
Phenobarbital contains acidic protons next to two carbonyl groups.
Morphine has a phenolic hydroxyl group, which is a weak base and will not be ionized in solution at physiological pH.

Drugs need both water solubility (hydrophilicity) and lipid solubility (lipophilicity) to move through the body and across cell membranes.
Halogens are generally lipophilic though fluorine can sometimes act as a hydrogen bond acceptor, adding some hydrophilicity.
Adding fluorine to drug molecules often increases lipophilicity.

Solubility is determined using a separatory funnel containing octanol (representing fat) and water (representing the hydrophilic part), measuring drug concentration in each.
The partition coefficient is the ratio of drug concentrations in octanol and water.
Logarithms are used to simplify the understanding of concentration values, converting them to log P values.

$log P$ : Is a unitless value representing the logarithm of the partition coefficient of the neutral (unionized) compound.
$log D$ : Represents distribution coefficient and takes pH into account, reflecting both ionized and unionized forms of the drug.
$log D$ values must always specify the pH at which they were measured.
A $log P$ value greater than 1 indicates higher solubility in lipids, while a higher number indicates greater lipid solubility.

Ibuprofen has a $log P$ of 3.7, indicating it is lipid-soluble but its $log P$ never changes.
The $log D$ of ibuprofen varies with pH. At pH 1, the $log D$ is 3.7, mirroring the $log P$ because the carboxylic acid is protonated.
At pH 10, the $log D$ is lower due to the carboxylic acid being ionized (O-), making it more water-soluble.

$log P$ can be calculated by summing the pi values of each functional group in the molecule. : $Log P = \sum{\pi}$
Positive pi values indicate lipophilic contributions.
Negative pi values indicate hydrophilic contributions.

The calculated $log P$ for procaine is 2.3, predicting insolubility in water. $log P$ values greater than 5 indicate insolubility in water, while values less than 0.5 suggest water solubility.

Pharmacists use $log P$ to select drugs with desired characteristics like speed of onset. For instance, a more lipophilic drug crosses the blood brain barrier faster.
Lorazepam, with an extra chlorine atom (halogen), is more lipophilic than oxazepam and has a quicker onset of action.

A drug with greater water solubility (more negative $log P$ ) may only be available intravenously (IV) due to poor oral absorption.
Highly water-soluble IV drugs may not be effective if given orally as they won't be absorbed.

Understanding pH and pKa is critical in medicinal chemistry. It influences solubility, absorption, distribution, elimination, and binding of drugs.

As a drug moves through the GI tract, it encounters varying pH levels, affecting its ionization state and absorption.
The unionized form of a drug is absorbed.

pH: Is a property of the solution, can be measured, and varies based on the solution.
pKa: Is a constant property of a functional group and does not change.

Step 1: Draw the dissociation equation of the functional group, independent of the question’s pH. Use resources like “Foye’s Principles of Medicinal Chemistry” or “Boy’s medicinal chemistry” for reference.
Step 2: Compare the pKa to the pH, noting whether the environment is more acidic or basic.
Strep 3: For acidic conditions, draw protons (H+) everywhere. For basic conditions, draw nothing.
Step 4: Identify the “happy side” – the side with the proton in acidic conditions, or without the proton in basic conditions.
Step 5: Determine how “happy” the side is based on log units:
- One log unit: 90% happy
- Two log units: 99% happy
- Three log units: 99.9% happy
Step 6: Answer the specific question asked.