Pharmaceutics test 2 : Ionization

pharmaceutical conceptualization of pH

- extent of ionization of a weak acid or a weak base is dependent on the INTRINSIC acidity/basicity (pKa) of the molecule and the pH of the environment

- the extent of ionization determines MANY important pharmaceutical properties of a drug***

pH changes the

solubility of the drug by changing the chemical nature of the conditions

Weak acids

- donate H+

- HA <> H+ + A-

Weak bases

- accept H+

- B + H+ <> BH+

H+

A hydrogen atom that has lost an electron

Weak acids and bases are

partially ionized

Conjugate acid

The particle formed when a base gains a hydrogen ion, it can donate the H+

Conjugate base

the particle that remains when an acid has donated a hydrogen ion, it can now accept a H+

Conjugate acids and conjugate bases are

ionized species

At equilbrium

HA <> H+ + A-

B+ H+ <> BH+ + OH-

<=> (K1= K2)

Ka

dissociation constant for a weak acid

Ka for weak base

conjugate acid??

The Henderson-Hasselbach equation provides a means to

determine the impact of the solution/ environment pH and the drug pKa on the degree of ionization

What are the two critical parameters for determining the degree of ionization?

- solution/ environment pH

- drug pKa

pKa

The pH at which 50% is ionized and 50% is unionized

Base in low pH

BH+, ionized, high concentration of H+ so the base will accept a H+ to become ionized, Higher percent ionized

Acid in low pH

HA, unionized, high concentration of H+ so the acid does not need to donate it's proton, it will remain as HA and nonionized

Base in high pH

B, nonionized, low concentration of H+, so the base does not need to take them on, base remains unionized

Acid in high pH

A-, ionized, low H+ concentration, so the acid will donate it's H+

pKb

14-pKa

Lower pKa

relatively stronger acid, more readily gives H+ up

Higher pKa

relatively stronger base, accepts protons more readily in water (does not readily donate)

pKa does not mean.....

weak acid! must look at the chemical structure

smaller pKa

- greater H+ dissociation from the HA form

- less H+ attracting strength of the A-form

larger pKa

- less H+ dissociation from the BH+ form

- greater the H+ attracting strength of B form

Acidic function groups (by name)

- sulfonic acid

- sulfonamide

- carboxylic acid

- imide

- enol

- phenol

Basic functional groups (by name)

- aliphatic amine

- alicylic amine

- imidazole

- heterocyclic amine

- aromatic amine

Non-ionizable groups

- aliphatic alcohols

- ester

- nitro, nitrate

- aldehyde

- ether

- halogen (Cl, F)

- amide

- ketone

How to make a drug salt?

- ionize the drug

- ionize the counter ion

- ionic interactions between charges

- drug salt if formed

Why do we make drug salts?

to form a permanent ion/ charge to have an ion-dipole interaction with water and increase solubility

salt formation combinations

- strong acid + strong base

- weak acid + strong base

- weak base + strong acid

How to make a drug salt of a weak acid drug?

add a strong base, this way the base will take the proton from the acid and the ion will form a salt with the acid

HA+ NaOH > Na+A- +H2O

How to make a drug salt of a weak base drug?

add a strong acid, this way the acid will donate it's H+ to the base and form a charge to interact with ion.

B+ HCl > BH+Cl +H2O

Weak acid naming trends

- single name followed by the word acid

- -ium suffix

- esters then -ium -ate

Weak base naming trends

- two words salt of the conjugate acid

- -ate suffix

- -ide suffix

Partition hypothesis

For ionizable drugs, the absorbed dose is determined by the extent of the unionized form at a given pH

A more lipid-soluble form of a drug can permeate the cell membrane (charge/ionization is a barrier to crossing the cell membrane)

What form of drugs can readily pass the cell membrane?

only relatively nonpolar/ low water solubility

cell membrane

- composed of phospholipids and cholesterol

- lipophilic

- hydrophobic

"like dissolves like"

drugs that are unionized or relatively non-polar can be "dissolved" in the hydrophobic cell membrane

pH effect on the absorption of acidic drugs: low pH

H+ is high, HA increases, and drug absorption increases

pH effect on the absorption of acidic drugs: high pH

H+ is low, A- increases, and drug absorption decreases

pH effect on the absorption of basic drugs: low pH

H+ is high, BH+ increases, and drug absorption decreases

pH effect on the absorption of basic drugs: high pH

H+ is low, B increases, and drug absorption increases

pH impact on solubility

- A drug in its ionic form is more readily soluble in polar solvents compared to it's unionized form

- the extent of drug ionization of a weak base or weak acid is dependent on the pH of the solution and the pKa of the drug

- thu aqeuous solubility will be affected by the pH of the solution and pKa of drug

Solubility of an acidic drug in a low pH

decreased, more in non-ionized

Solubility of a basic drug in a low pH

increased, more in ionized form

Solubility of an acidic drug in a high pH

increased, more in ionized form

Solubility of a basic drug in a high pH

decreased, more in non-ionized form

S0

solubility of the unionized form (intrinsic solubility)

Si

solubility of the ionized form

S

S0+Si, total dissolved

As pH increased, the solubility of an acidic drug

increases

Solubility equation for weak acids

pH= pKa + Log (S-S0/S0)

If we exceed the solubility vakue of the unionized species ....

start shifting equilibrium to be more nonionized, then we must change pH to get more ionized and dissolve

As pH increased, the solubility of a basic drug

decreases

Basic drug solubility equation

pH= pKa + log (S0/S-S0)

What is our goal as pharmacists?

- to avoid mixing potentially incompatible drugs

- to avoid pH that may precipitate non-ionized forms (solubility)

-ide and -ate drugs may interact with

- ium

- ium -ate

-ide and -ate drugs in what pH is bad?

increasing or higher pH

-ium and -ium -ate drugs in what pH is bad?

decreasing or lower pH

What do we add to weak electrolyte drug solutions to lower the pH?

- strong acid

- HCl

- H2SO4

What do we add to weak electrolyte drug solutions to increase the pH?

- strong base

- NaOH

- KOH

Weak acid + strong base

- Forms weak electrolyte salts that ionize

- Equal molar species and dissolution of salt form yields pH > 7.0 solution

KEY: salt forms of weak acids will form BASIC solutions in water

Why do salt forms of weak acids form basic solutions?

salt form will ionize and A- conjugate base will accept H+ from water, forming OH- (basic)

What happens if you add acid to the solution of weak acid solution?

A- conjugate will accept H+ to a greater extent shifting equilibrium to form HA --> precipitate

Weak base + strong acid

- Forms weak electrolyte salts that ionize

- Equal molar species and dissolution of salt form yields pH< 7.0 solution

KEY: salt forms of weak bases will form ACIDIC solutions in water

Why do salt forms of weak bases form acidic solutions?

salt form will ionize and BH+ conjugate acid will donate H+ to water to a low extent to form H3O+ (acid)

What happens if base is added to the solution of weak base solution?

BH+ conjugate acid will donate H+ to OH to form H2O, more B (preciptate)

Weak acid + weak base

can form ionic complexes with low solubility, resulting in precipitation

Salt of the weak acid and base will ionize then the A- and BH+ will form BH-A

If you accidentally mix a weak acid and a weak base, how can you fix it?

You can't, if you add base, it will precipitate the bas,e and if you add acid, it will precipitate the acid

BH+A- + OH- > B + A- +H2O

BH+A- + H+ > BH+ HA