Post on 30-Jan-2021
transcript
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