Pharmacology, Medicinal Chemistry, and Toxicology I - Acids, Bases, and Salts

This set explores the medicinal chemistry related to the acidity, basicity, and salt forms of drugs, including pKa values for specific functional groups, solubility calculations, and the therapeutic utility of different salt types.

Acidic functional groups

Functional groups that can lose a proton ($H^+$).

Basic functional groups

Functional groups that can accept a proton ($H^+$); the more reactive they are, the stronger the base.

Carboxylic acids

An acidic functional group with a $pK_a$ approximately between $2.5$ and $5$.

$\beta$-dicarbonyl groups

Acidic functional groups with a $pK_a$ between $4$ and $6$; they can undergo tautomerization between keto and enol forms.

Imide

An acidic functional group with a $pK_a$ approximately between $7$ and $8$, capable of resonance after dissociation.

Sulfonamides and Sulfonylureas

Acidic functional groups with a $pK_a$ between $5$ and $7$, stabilized by resonance.

Tetrazole

An acidic functional group with a $pK_a$ between $4.5$ and $6$.

Phenol

An acidic functional group with a $pK_a$ between $9$ and $10$.

Thiols

Acidic functional groups where aliphatic versions have a $pK_a$ of $10-11$ (weak) and aromatic versions have a $pK_a$ of $6$ (stronger).

Sulfates

Strongly acidic functional groups with a $pK_a$ approximately between $1$ and $2$.

Phosphonates and Phosphates

Acidic groups where the first hydrogen has a $pK_a$ of $1.5-2.5$ and the second hydrogen has a $pK_a$ of $6.5-7.5$.

Aliphatic and Alicyclic Amines

Basic functional groups with a $pK_a$ approximately between $9$ and $11$; the higher the $pK_a$, the stronger the base.

Aromatic Amines

Basic functional groups with a significantly lower $pK_a$ than aliphatic amines, typically between $2$ and $5$.

Imines and Hydrazines

Basic functional groups with a $pK_a$ approximately between $3$ and $5$.

Guanidines

Strongly basic functional groups with a $pK_a$ approximately between $11$ and $12$.

Aromatic Heterocycles

Nitrogen-containing rings with $pK_a$ values typically between $1$ and $5$ (e.g., Pyridine $pK_a = 5.3$, Pyrrole $pK_a = 0.4$).

Neutral functional groups

Functional groups that do not ionize under physiological conditions, including alkyl alcohols, ethers, amides, ketones, esters, and nitriles.

Acidic drug

A drug that contains one or more acidic functional groups.

Basic drug

A drug that contains one or more basic functional groups.

Amphoteric drug

A drug containing at least one acidic and at least one basic functional group; it is least soluble at the isoelectric pH ($pI$).

Neutral drug

A drug that contains zero ionizable functional groups.

Partition Coefficient ($P$)

A ratio calculated as $P = \frac{\text{Drug in lipid environment}}{\text{Drug in aqueous environment}}$; if $P > 1$, the compound is more lipid-soluble.

$\log P$ solubility thresholds

$\log P > +0.5$ is considered water-insoluble; $\log P < +0.5$ is considered water-soluble.

$$\text{LogD}$$

The log partition coefficient at a specific $pH$, which accounts for the ionization of the molecule (e.g., Ibuprofen's $\text{LogP}$ is $3.7$, but its $\text{LogD}$ at $pH=10$ is $0.1$).

$$\text{LogP}_{calc}$$

The sum of the hydrophilic and lipophilic values ($\boldsymbol{\text{π}}$ values) for all functional groups in a molecule.

Water-soluble inorganic salts

Salts made without carbon; acidic drugs react with bases like $NaOH$ or $KOH$, while basic drugs react with acids like $HCl$, $H_2SO_4$, or $H_3PO_4$.

Lipid-soluble organic salts

Carbon-containing salts that increase lipid solubility and decrease water solubility; used for IM depot injections or to increase oral palatability.

Henderson-Hasselbalch equation

$pH = pK_a + \text{log}\frac{[\text{Base Form}]}{[\text{Acid Form}]}$.

Rule of Nines

A shortcut for calculating ionization levels where a $1$ log unit difference between $pK_a$ and $pH$ equals $90\%$, $2$ units equal $99\%$, and $3$ units equal $99.9\%$.

IV Incompatibility

Chemical reactions (precipitation) that occur when mixing acidic and basic drugs or when diluting organic drug salts into a $pH$ that favors the unionized form.