Acids, Bases, and Ionization in pharmaceutical science

• Many chemical molecules are acids or bases and can exist as ions or uncharged molecules.
• The properties of ions and non-ions differ and can be used to predict the properties of a molecule, including:
• How it reacts with other compounds/receptors
• Stability
• Solubility in different solvents like water
• Capability to pass across lipid membranes to reach the site of action.
• 75% of drugs are basic, 20% are acidic, and 5% are neither.
• Medications for sensitive areas like skin should not cause irritation, thus formulations may need adjustment.
• Drug degradation in contact with moisture depends on pH.
• A 2014 study found that most drugs have ionizable groups and dissociate within a biological system.
• According to the Brönsted-Lowry definition:
• An acid donates a proton in a reaction.
• A base accepts a proton in a reaction.
• Hydrochloric acid donates a proton to water, acting as a base, thereby behaving as a Brönsted-Lowry acid.
• Sodium hydroxide dissociates in water, and the formed OH- ions function as a Brönsted-Lowry base by accepting a proton.
• An acid or base's strength is determined by its extent of dissociation.
• Greater dissociation means a stronger acid or base.
• Hydrochloric acid fully dissociates in aqueous solution.
• Acetic acid is a weak acid that only partially dissociates.
• Acids and bases in aqueous solutions produce conjugate pairs, consisting of ionized and non-ionized species.
• HCl fully dissociates, and Cl- ions do not readily accept a proton.
• HCl is a strong acid, and its conjugate ion (Cl-) is a weak base.
• Acetic acid does not dissociate much, therefore CH3COOH will not readily donate a proton to produce CH3COO-.
• Acetic acid is a weak acid, and its conjugate ion (CH3COO-) is a strong base.
• A general rule: a weak acid is associated with a strong conjugate base, and vice versa.
• Water can act as an acid or a base and is called an amphiprotic solvent.
• In the presence of an acid (HA) water acts as a base and when a base is present water acts as an acid.
• Mineral acids like HCl and H2SO4, and common bases like NaOH and Ca(OH)2 are generally considered "STRONG".
• Strong acids and bases are fully ionized.
• Most drugs with acidic or basic functional groups are "weak" acids/bases.

Acidic and Basic Drugs

• Fusidic acid, a topical antibiotic with pKₐ 5.35, shows that charged species are ionized or dissociated.
• Strong acids have weak conjugate bases.
• Weak acids have strong conjugate bases.
• Pethidine is an opioid analgesic with a pKa of 8.7 that is used for moderate to severe pain and commonly used in obstetrics.
• A strong base has a weak conjugate acid.
• A weak base has a strong conjugate acid.
• Unprotonated bases are often called a "free base".
• Water functions as a weak acid and a weak base.

Acidity Constant

• Kₐ is the acidity constant, defined as Kₐ = [H3O+][A-]/[HA] for acid HA.
• Acids are proton donors, and in aqueous solution, they are hydrated.
• Stronger acids have higher Kₐ values.
• Benzylpenicillin has a Kₐ of 1.6 x 10⁻³, with the equilibrium lying to the left.
• pKₐ is a convenient measure of acidity because Kₐ ranges can be large.
• pKₐ = -log Kₐ.
• For benzylpenicillin, pKₐ = -log (1.6 x 10⁻³) = 2.80.
• Amides (CONR₂) are NEUTRAL functional groups.

Basicity Constant

• K is the basicity constant, defined as K = [BH₂+][OH-]/[BH] for base BH.
• Bases accept protons and stronger bases have higher K .
• pK is used to measure basicity, with ranges of K being very large.
• pK is rarely used to measure base strength, it is helpful to compare ALL drugs on the same scale.
• The pK of a basic drug is calculated as pKₐ + pK = pK = 14, where pK is the ionization constant of water.
• pK can also be thought of as the pK of the conjugate acid (pKaH).
• In the equilibrium BH₂⁺ + H₂O ⇌ BH + H₃O⁺, Kₐ = [H₃O⁺][BH]/[BH₂⁺], so pKₐ or pKaH = -log Kₐ.
• The pKₐ of pethidine is 8.7 as found the scientific literature.
• The chemical structure of pethidine contains an amine basic functional group, not any acidic functional groups.
• The quoted value "pKₐ = 8.7" is the pK of the conjugate acid.

Base Strength

• To find the base strength (pK_b) of the ‘free base’, use the equation: pKₐ + pK_b = pKw.
• Given that pKₐ for benzocaine is 2.8, the pK_b is calculated as:
• 2.8 + pK_b = 14, therefore pK_b = 11.2.
• Pethidine is approximately 1 million (10⁶) times more basic than benzocaine on a log scale.
• Basicity reflects the ability to accept a proton, explained by the nucleophilicity of amines.
• Aromatic rings reduce nucleophilicity because electrons are shared with the π-cloud.
• Aliphatic groups increase nucleophilicity donating electron density to the lone pair.
• Drugs can have multiple acidic and/or basic functional groups.
• Fusidic acid has three pKₐ values in theory while only the initial is measured.
• The totally ionized form of fusidic acid, has three negative charges which makes it unstable.
• Second and third pK values differ from the expected value and become less acidic because the conjugate base is disfavored.

Salt Formation

• Acids and bases can form salts.
• Salts are ionic with greater aqueous solubility.
• Salts have higher melting points than the original acid or free base (often 50-100 °C higher).
• They offer better pharmaceutical properties for milling the powders.
• Stable salt formation needs a pKₐ difference of three units to ensure that the equilibrium lies to the right.
• Hydrochloride salts are a common formulation for basic drugs and are very acidic.
• Methanesulfonic acid is a strong acid (Kₐ = 1 x 10², pKₐ = -2).
• It's used as a counter-ion in drug salts and offers alternative properties to HCl.
• Imatinib has basic functional groups, and no acidic functional groups.
• The pKₐ values of the conjugate acid are 5.93, 10.27, 11.44, and 12.48.
• Methansufonic acid salt is recognized as mesylate or mesilate
• "Mesilate" means "methanesulfonate."
• A large pKₐ difference makes it a pharmaceutical counter-ion.
• Many basic sites mean lots are ionized, which means the remaining groups become hard to ionize as the molecule charges up.
• There is less than 100mg of imatinib in 100mg of imatinib mesylate.
• LogP measures drug polarity, helping predict drug solubility and membrane permeation.
• The distribution coefficient D, is better for ionizable drugs and it's better at predicting absorption and membrane permeability than logP.
• D = [HX]lipid phase / ([HX]aq + [X-]aq), where HX is an acidic drug
• LogD is harder to measure in practice than logP.
• LogP is used more widely and it's easier to compare to non-ionizable drugs.