3/15/2017

1

Acid-Base Properties

1

TAMMAR H. AliLecture 1Course No. 326Faculty of PharmacyUniversity Of Al-Muthanna

Physicochemical Principles of Drug Action

2

Physicochemical Principles of Drug Action

To design better drugs:

Molecular Mechanism.

Functional group

contributions to the

physicochemical

properties.

3/15/2017

2

Physicochemical Principles of Drug Action

3

Physicochemical Principles of Drug Action

• The influence of the organic functional groups within adrug molecule on:

Water solubility.Lipid solubility.Acid-base properties.

Partition coefficient.Steric factors.

Stereochemistry.

Acid-Base Properties

• Most drugs used today can be classified as acids or bases.• A drug’s acid–base properties can greatly influence its biodistribution

and partitioning characteristics.• the acid-based definition have been developed, acid as a proton donor

and a base is defined as a proton acceptor.

4

3/15/2017

3

Acid-Base Properties

5

Acid-Base Properties• Absorption:

Un-ionized form (lipid soluble).• Distribution:

Ionized form (soluble in plasma).• Excretion.• Drug-Receptor interaction.• Drug-Drug incompatibility.

Acid-Base Properties

6

• Bronsted-Lowery theory.• Proton donor (acid).• Proton acceptor (base).

3/15/2017

4

Acid-Base Properties

7

• Ionized forms are water-soluble.• Unionized forms are lipid soluble.

Common Acid Base Conjugation

8

3/15/2017

5

Common Acid Base Conjugation

9

• Water can be either a weak base accepting a proton to form thestrongly acidic hydrated proton or hydronium ion H3O_ (reactions a,c, e, g, i, k, andm), or a weak acid donating a proton to form thestrongly basic (proton accepting) hydroxide anion OH_ (reactions b, d,f, h, j, l, and n).

• Hence, water is known as an amphoteric substance.

10

ACID-BASE PROPERTIES

3/15/2017

6

Acid-Base Properties

11

Acid-Base Properties

12

3/15/2017

7

Acid-Base Properties

13

Acid-Base Properties

14

• Ciprofloxacin, a fluoroquinolone antibiotic• Both acidic and basic properties (amphoteric).

3/15/2017

8

Acid-Base Properties

15

Electronic Effects of Substituents• The electronic effects of various substituentswill clearly have an effect on a drug’sionization or polarity.• This in turn may have an effect on how easily a drugcan pass through cell membranes or howstrongly it can bind to a receptor.• It is therefore useful to have some measure ofthe electronic effect a substituent can have ona molecule.

Acid Base Conjugation

How to predict which direction an acid–base reaction lies?What extent does the reaction goes to completion?

16

pKa’s are modified equilibrium constants that indicate theextent to which the acid (proton donor) reacts with water to

form conjugate acid and conjugate base.

3/15/2017

9

Acid-Base Properties

17

Acid-Base Properties

18

3/15/2017

10

Weak acid vs Strong acid

19

A general rule for determining whether a chemical is strong orweak acid or base is:-•pKa < 2: strong acid; conjugate base has no meaningfulbasic properties in water•pKa 4 to 6: weak acid; weak conjugate base•pKa 8 to 10: very weak acid; conjugate base getting stronger•pKa >12: essentially no acidic properties in water; strongconjugate base.

This delineation is only approximate. Other properties also become important whenconsidering cautions in handling acids and bases. Phenol has a pKa of 9.9, slightlyless than that of ephedrine HCl. Why is phenol considered corrosive to the skin,whereas ephedrine HCl or free ephedrine is considered innocuous when applied tothe skin? Phenol has the ability to partition through the normally protective lipidlayers of the skin. Because of this property, this extremely weak acid has carried thename carbolic acid. Thus, the pKa simply tells a person the acid properties of theprotonated form of the chemical. It does not represent anything else concerningother potential toxicities.

Acid-Base Properties

20

Drugs pass through membranes in anunionized form.

•Drugs act as ions (if ionizations is apossibility).

•Ideal pKa (6-8; weak acid or weak base).

•Assumption passive diffusion.

3/15/2017

11

Acid-Base Properties

21

Calculations:

22

3/15/2017

12

Calculations:

23

Acid-Base Properties

24

Aspirin•An orally administered drug(pKa=3.5).•Acidic stomach. Partial absorption(un-ionizedform).•Basic intestinal tract. Ionized form. Microvilli. Huge surface area. Absorption.

3/15/2017

13

Acid-Base Properties

25

Acid-Base Properties

26

BH+ is not absorbed (stomach).• Alkaline intestinal tract (pH ≈ 8).• Equilibrium.• B and BH+ are absorbed.

Amines (pKa 9-10).

3/15/2017

14

Acid-Base Properties

27

• K+/H+ ATPase inhibitor.• Used for treatment of peptic ulcer.• PKa≈ 4 (not protonated in the stomach).• Can be absorbed into the parietal cells.• Is protonated inside the parietal cells (pH < 1).

Acid-Base Properties

28

3/15/2017

15

Acid-Base Properties

29

Acid-Base Properties

30

3/15/2017

16

Percent Ionization

Using the drug’s pKa, the formulation or compounding pharmacistcan Adjust the pH to ensure maximum water solubility (ionic formof the drug) or maximum solubility in nonpolar media (un-ionicform).

31

Calculations

32

Acids can be divided into two types, HA andBH+, on the basis of the ionic form of the acid(or conjugate base). HA acids go from un-ionized acids to ionized conjugate bases (Rx.2.4). In contrast, BH+ acids go from ionized(polar) acids to un-ionized (nonpolar) conjugatebases (Rx. 2.5). In general, pharmaceuticallyimportant HA acids include the inorganic acids(e.g., HCl, H2SO4), enols (e.g., barbiturates,hydantoins), carboxylic acids (e.g., low–molecular-weight organic acids, arylaceticacids, N-aryl anthranilic acids, salicylic acids),and amides and imides (e.g., sulfonamides andsaccharin, respectively). The chemistry issimpler for the pharmaceutically importantBH+ acids: They are all protonated amines. Apolyfunctional drug can have several pKa’s(e.g., amoxicillin).

3/15/2017

17

A polyfunctional drug can have several pKa’s (e.g., amoxicillin). The latter’s ionicstate is based on amoxicillin’s ionic state at physiological pH 7.4.

The percent ionization of a drug is calculated by using Equation 2.3 for HA acidsand Equation 2.4 for BH+ acids.

(Eq. 2.3)

(Eq. 2.4)

Calculations

33

Knowledge of percent ionization makes it easier to explain and predict why theuse of some preparations can cause problems and discomfort as a result of pHextremes.

Calculations

34

3/15/2017

18

Calculations

35

Interpretation

• First, note that when pH = pKa, the compound is 50% ionized (or 50%un-ionized).

When the pKa is equal to the pH, the molar concentration of the acidequals the molar concentration of its conjugate base.

36

3/15/2017

19

Application

• Phenytoin (HA acid; pKa 8.3) injection must be adjusted to pH 12 withsodium hydroxide to ensure complete ionization and maximize watersolubility.

37

Application

38

In the ionized form. Even then, a cosolventsystem of 40% propylene glycol, 10% ethylalcohol, and 50% water for injection is used toensure complete solution. This highly alkalinesolution is irritating to the patient and generallycannot be administered as an admixture withother intravenous fluids that are buffered moreclosely at physiological pH 7.4. This decrease inpH would result in the parent unionizedphenytoin precipitating out of solution.

3/15/2017

20

Application

• Tropicamide is an anticholinergic drug administered as eye drops forits mydriatic response during eye examinations.

• With a pKa of 5.2, the drug has to be buffered near pH 4 to obtainmore than 90% ionization.

39

Adjustments in pH to maintain water solubility cansometimes lead to chemical stability problems. Anexample is indomethacin (HA acid; pKa 4.5),which is unstable in alkaline media. Therefore, thepreferred oral liquid dosage form is a suspensionbuffered at pH 4 to 5. Because this is near the drug’spKa, only 50% will be in the water-soluble form.There is a medical indication requiring intravenousadministration of indomethacin to premature infants.The intravenous dosage form is the lyophilized(freeze-dried) sodium salt, which is reconstitutedjust prior to use.

Application

40

3/15/2017

21

Drug Distribution and pKa

• The pKa can have a pronounced effect on the pharmacokinetics of thedrug.

• For HA acids, it is the parent acid that will readily cross thesemembranes

• For BH acids, the unionized conjugate base (free amine) is the speciesmost readily crossing the non-polar membranes

41

Drug Distribution and pKa

The drug first encounter the acidic stomach

HA acids with pKa’s of 4 to 5 will tend to be nonionic and be absorbedpartially through the gastric mucosa.

42

3/15/2017

22

Drug Distribution and pKa

The drug first encounter the acidic stomach

Amines (pKa 9–10) will be protonated (BH acids) in the acidic stomachand usually

will not be absorbed until reaching the mildly alkaline intestinal tract(pH 8).

43