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Acids and Bases Moore, T. (2016). Acids and Bases. Lecture presented at PHAR 422 Lecture in UIC College of Pharmacy,

Chicago.

• Drug dissolution can impact buffering capacity of the body

• Most enzymes require drug to be charged to bind

• Drug must be neutral to pass through cell membranes / blood brain barrier (BBB)

• Charged drug = specific binding = more soluble

• Ex) Memantine clearance = organic base. When urine more basic, the molecule

becomes charged and can’t be reabsorbed. Drug build up in body, can become toxic

• pKa = measure of acidity

o Topical drugs have amount of drug that exceeds the physiologic buffer – the pKa

and state of the drug can impact the buffer pH

o Ionization state usually determined by pKa of the drug in buffer when the drug

does not exceed the buffer capacity

o Ionization state of the drug determines its absorption, solubility, and binding to

albumin

• Bronsted acid – any molecule that can donate a proton

• Bronsted base – any molecule that can accept a proton

• A Bronsted acid will have a conjugate base and vice versa

** Another way of thinking of an acid and base is that an acid accepts a pair of electrons while a base

donates a pair of electrons. This might make it easier to predict why certain electron

withdrawing/donating groups make things more or less acidic/basic.

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• A base in solution will increase the pH of the solution

• An acid in solution will decrease the pH of the solution

• Amphoteric molecules can act as acids and bases = buffers

o main example is bicarbonate in the blood

• Strong acid means it dissociates in water easily

o Relative strength based on ability to donate a proton

o Equilibrium favors the weaker acid

• Ka is a quantitative way of measuring the strength of an acid

o Higher Ka, more acidic

o pKa = -log(Ka)

*** Remember that knowing how a drug will dissociate in solution is all dependent on

RELATIVE acidity and basicity. The majority of the time the solution is going to be water, with

a pKa around 16. If the molecule is more acidic (lower pKa), it will act as an acid. If the

molecule is more basic (higher pKa), it will act as a base.

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• HCl (hydrochloric acid)

• HNO3 (nitric acid)

• H2SO4 (sulfuric acid)

• HBr (hydrobromic acid)

• HI (hydroiodic acid)

• HClO4 (perchloric acid)

• HClO3 (chloric acid)

Strong Acids

• H3PO4 (phosphoric acid)

• HNO2- (nitrous acid)

• C6H5COOH (benzoic acid)

• CH3COOH (acetic acid)

• HCOOH (formic acid)

• HsS (hydrogen sulfide)

• HCN (hydrogen cyanide)

Weak Acids

• LiOH (lithium hydroxide)

• NaOH (sodium hydroxide)

• KOH (potassium hydroxide)

• RbOH (rubidium hydroxide)

• Sr(OH)2 (strontium hydroxide)

• Ba(OH)2 (barium hydroxide)

Strong Bases

• CO32- (carbonate ion)

• CH3NH2(methyl amine)

• NH3 (ammonia)

• HCO3- (bicarbonate)

• C5H5N (pyridine)

• C6H5NH2 (aniline)

• Ca(OH)2 (calcium hydroxide)

• Zn(OH)2 (zinc hydroxide)

Weak Bases

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STUDY TIP: Have a good idea of what are strong acids and bases. If you know these, you will automatically know if something is a weak acid or base. This will make it easier to predict equilibrium

• Strong base + strong acid in water give neutral solution

• Weak acid + strong base in water give slightly basic solution (pH>7) b/c increases

hydroxyl ion concentration (-OH)

• Strong acid + weak base in water gives slightly acidic solution (pH<7) b/c increases

hydronium ion concentration (H3O+)

• Salts of a strong acid + a weak base gives an acidic solution

o Examples of salts of strong acids: ZnCl2, Ca(NO3)2, Zn(ClO4)2, CaSO4, Ca3(PO4)2

• Salts of a strong base + a weak acid gives a basic solution

o Examples of salts of strong bases: Na2CO3, KCN, Na2S

Keq – gives concentrations of components at equilibrium

A + B C + D

Keq = [C][D] [A][B]

Ka – acid dissociation constant

HX + H2O X- + H3O+

Ka = Keq * [H2O] = [X-][ H3O+] [HX]

Larger Ka means stronger acid

pKa = -log(Ka)

pKa < 2 = strong acid pKa 4-6 = weak acid

pka 8-10 = weak conjugate base pKa >12 = strong conjugate base

• Equilibrium favors the side of the weaker acid and weaker base

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• Water participates in acid/base equilibrium

o Strong acids dissociate completely, so the hydronium ion then becomes the

strongest acid in solution = leveling effect

o Strong bases dissociate completely, so the hydroxide ion then becomes the

strongest base in solution

• Basic amine groups are used to neutralize a drug to allow it to pass through BBB

Henderson-Hasselbalch Equation – gives idea of how many

groups are ionized

pH = pKa + log [conjugate base] acid

pH = -log[H+]

REMEMBER: Ionized just means

CHARGED. Doesn’t necessarily mean

proton vs. no proton. For example,

with H2O and H3O+ the ionized form is

the positively charged hydronium

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Buffers

• Buffer = a solution that resists changes in pH even when acids and bases are added

o Titration curve will look flat where pH = pKa

o Ex) Tris, MES, HEPES, MOPS, PIPES

• Alcohol functional groups are found in 20% of drugs

o Have pKa around 16

o Are more acidic when near electronegative groups b/c the negative charge it

gets when it loses the proton (when it becomes an alkoxide) can be stabilized by

induction

• The reason branched alcohols are less acidic is because there is steric hinderance that

blocks the negative charge (if it loses a proton) from being stabilized by hydrogen

bonding with water

• Normally, alcohols, thiols, and ethers are considered weak Bronsted Lowery bases and

exist undissociated in water

• Phenols

o When electron withdrawing group is on the ring, it increases the acidity because

they help to stabilize the negative charge when the proton is lost

▪ Ex) Nitrate group para to the hydroxyl

o When electron donating group is on the ring, it decreases the acidity

▪ Ex.) CH3 group on the ring

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• Amines

o Has unshared pair of electrons so acts as a base

o The order of basicity is usually secondary > tertiary > primary. Tertiary is more

than primary because the methyl groups act as electron donors and stabilize the

added proton. The secondary is more than tertiary because there is less steric

hinderance to accept the proton

o When attached to an aromatic ring, the aromatic ring draws electrons in and

decreases the basicity of the amine group b/c it’s harder for the amine to give up

the electrons now

• Carboxylic acids

o Similar to phenols. When attached to electron withdrawing group, acidity

increases. When attached to electron donating group, acidity decreases.

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pKa of Amino Acids → MEMORIZE

• Amino acids act as natural buffers

• Many drugs formulated as salts to help with absorption and delivery

• Solubility is pH dependent

o At some point, salt stops dissolving = equilibrium solubility

Asp/Glu

pKa: 4-4.5

Cys

pKa: 8.5-9

Tyr

pKa: 9.5-10

Ser/Thr

pKa: 13.5-14

His

pKa: 6-6.5

Lys

pKa: 10-10.5

Arg

pKa: 12-13

Partition Coefficient: LogP

P = [drug]octanol [drug]water

Higher logP means the drug is more lipophilic

pH must be at a value where the drug is unionized to use this equation

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Distribution Coefficient: LogD

P = [drug]ionized octanol + [drug]unionized octanol

[drug]ionized aq + [drug]unionized aq

LogD takes into account ionization state of the drug

With higher pH, the drug becomes ionized and moves out of the octanol phase into the aqueous phase

The higher pH, the lower logD value. Lower logD value means more

hydrophilic drug