Summary of the last lecture - c12-06-07-380-123-4567...

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Summary of the last lecture A. Buffer capacity

It is always higher when the pH of your solution is close to the pKa of

the buffer system you choose.

B. Water solubility and drug design

Chemical bonds

Functional groups (Tables from textbook)

Salt formation

C. Measurement of drug solubility

Partition coefficient (P, whole molecule)

% ionization: Ionized = conjugate base [A-] or conjugate acid [BH+]

(1) For weak acidic drugs, pKa-pH =log ([HA]/[A-]) or pH-pKa =log

([A-]/[HA]) or pH-pKa =log ([salt]/[acid]) or % ionization

=100/[1+10(pKa-pH)]

(2) For weak basic drugs, pKa-pH =log ([BH+/[B]) or pKa-pH =log

([salt]/[base]) or % ionization =100/[1+10(pH-pKa)]

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Co (Conc. in octanol)

Drug in octanol

Unionized molecules in water

2. Log P and Log D(a) Log P

The log of the partition coefficient (P)

(The whole molecule)

For acidic drugs

For basic drugs

Generally

[B]o

[B]wP =

[HA]o

[HA]wP =

[B]o

[B]w

[HA]o [HA]w

LogP = Log

LogP = Log

[Drug]o

[Drug]wP = [Drug]o

[Drug]wLogP = Log

Cw (Conc. in water)

2

(2) Log D

The log of the distribution coefficient (generally between 1-octanol and

aqueous buffer) for ionizable compounds at a particular pH.

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Cw (Conc. in water) =Ci (ionized in H2O) + Cu (unionized in H2O)

Drug in octanol


Ionized molecules in water

e.g., Change in log D as a function of pH

for metoprolol (Nilsson and Fjellstrom)

pH Log D

2.0 -1.31

3.0 -1.31

4.0 -1.31

5.0 -1.28

5.5 -1.21

6.0 -1.05

6.5 -0.75

7.0 -0.34

7.5 0.12

8.0 0.59

8.5 1.03

9.0 1.39

10.0 1.73

Generally

For acidic drugs

For basic drugs

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Cw (Conc. in water) =Ci (ionized in H2O) + Cu (unionized in H2O)

Drug in octanol


Ionized molecules in water

=[HA]o

[HA]w + [A-]w

Log D =[HA]o

[HA]w + [A-]w

=[B]o

[B]w + [BH+]w

[B]o [B]w + [BH+]w

Log

Log D =Log

[Drug]o

[Drugionized]w(Compare to Papp =

LogD =Log

[Drugunionized]w+

[Drug]o

[Drugionized]w [Drugunionized]w+

)

)

)

(Compare to Papp

(Compare to Papp

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3. Predicting the drug water solubility by empiric approach (from Foye�s)

Based on the carbon-solubilizing potential of organic functional groups

If the potential of the functional groups exceeds the total number of

carbon atoms, then the compound is considered water-soluble

Otherwise water insoluble.

One functional group-monofunctional molecule

More than one functional group-polyfunctional molecule

Functional group Monofunctional molecule Polyfunctional molecule

Alcohol 5 to 6 carbons 3 to 4 carbons

Phenol 6 to 7 carbons 3 to 4 carbons

Ether 4 to 5 carbons 2 carbons

Aldehyde 4 to 5 carbons 2 carbons

Ketone 5 to 6 carbons 2 carbons

Amine 6 to 7 carbons 3 carbons

Carboxylic acid 5 to 6 carbons 3 carbons

Ester 6 carbons 3 carbons

Amide 6 carbons 2 to 3 carbons

Urea, carbonate, carbamate 2 carbons

Charge (cationic and anionic) 20-30 carbons




Polyfunctional

Two functional groups of six carbons

Total carbon content = 9

6<9

Conclusion

6<9, Insoluble (solubilizing potential less than carbon content,

C9H8O4)

Homework-Please find the data of water solubility for Aspirin

from the USP

Practice Problem #8

Aspirin solubility (From Foye�s)

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Term Parts of solvent required for one part of solute

Very soluble Less than 1 part (1:1)

Freely soluble 1 to 10 part (1:1-10)

Soluble 10 to 30 part (1:10-30)

Sparingly Soluble 30 to 100 part (1:30-100)

Slightly Soluble 100 to 1000 part (1:100-1000)

Very slightly Soluble 1000 to 10000 part (1:1000-10000)

Practically insoluble More than 10000 part (1:>10000)

Definition of approximate drug solubility by US pharmacopoeia

The Craig plot (slide #2 on page 4, Handout #2; page 73, The Organic Chemistry of

Drug Design and Drug Action by Richard B. Silverman, 2nd edition, Elsevier Academic

Press)

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Practice problem #9 (from Foye�s)

Q1: Is anileridine (an opioid agonist) water soluble? (Predict the water

solubility of anileridine)

Fig. 2.13. (From Foye�s) Identification of functional groups in anileridine. Polyfunctional Three functional groups of nine carbons Total carbon content = 16 (error in textbook/handout) 9<16 Therefore the prediction is anileridine is water insoluble In reality, based on the report in the U.S. Pharmacopoeia (USP) the

solubility of anileridine is 1 g/10,000 mL, or 0.01%, or 1: 10,000. According to the USP: �Practically insoluble = >1:10,000�

O

N

H2N

OCH2 CH3

Anileridine




Q2. How to improve the water solubility of anileridine?

O

N

H2N

OCH2 CH3

HCl

Anileridine HCl

O

N

H2N

OCH2 CH3

Anileridine


Alcohol 5 to 6 carbons 3 to 4 carbons

Phenol 6 to 7 carbons 3 to 4 carbons

Ether 4 to 5 carbons 2 carbons

Aldehyde 4 to 5 carbons 2 carbons

Ketone 5 to 6 carbons 2 carbons




Amide 6 carbons 2 to 3 carbons

Urea, carbonate, carbamate 2 carbons

Charge (cationic and anionic) 20-30 carbons

O

H2N

OCH2 CH3

N

HCl

Three functional groups of 9 carbons and one charge of 20-30 carbons. Total carbon number = 16 (Error in handout/textbook) 20-30 + 9 = 29-39 >16 The prediction is that anileridine HCl is water soluble

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According to the USP, the water solubility of anileridine HCl is 0.2

g/ml, or 20% or 1:5.

By USP, Freely soluble = 1:1-10

Problem 6, Chapter 2, Foye�s has more practice questions to use the

empiric method of Lemke to predict water solubility.

Solubility data for these compounds can be found in the USP.

Rationalize any discrepancies between the predicted results and

the USP data.

Problem #10

-The water solubility of tyrosine

CH2

NH2HO

CHC

O

OH

Tyrosine(Solubility in H2O is 0.45g/100mL@25oC)

CH2

HO

CHC

O

O

NH3

CH2

NH2HO

CHC

O

O

Na

CH2

NH3HO

CHC

O

OH

Cl

Zwitterionic form Hydrogen bond formed intramolecularly

Very soluble Very soluble

HCl/H2ONaOH/H2O

mailto:0.45g/100mL@25

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Fig. 2.10. (Foye�s) Water solubilities of different salt forms of selective drugs.

Practice problem #11:

Evaluate the solubility of the drugs on the right:

Term Parts of solvent required for one part of solute

Very soluble Less than 1 part (1:1)

Freely soluble 1 to 10 part (1:1-10)

Soluble 10 to 30 part (1:10-30)

Sparingly Soluble 30 to 100 part (1:30-100)

Slightly Soluble 100 to 1000 part (1:100-1000)

Very slightly Soluble 1000 to 10000 part (1:1000-10000)

Practically insoluble More than 10000 part (1:>10000)

D. Specific issues1. Ion trap

a. Ion trap and pH partition

It is a physiochemical process

Does not require an active drug transport system

Need a lipid membrane preferentially permeable to the weak

acid or weak base drug molecules that are unionized

A pH gradient across the membrane

Unionized drugs

Permeable Lipoprotein membrane

Ionized drugs

Unionized drugs

Ionized drugs

Blood stream

PlasmaGastrointestinal tract

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b. The pH partition hypothesis

Unionized drugs

Permeable Lipoprotein membrane

Ionized drugs

Unionized drugs

Ionized drugs

Blood stream

PlasmaGastrointestinal tract

At steady state, an acidic drug will accumulate on the more basic side

of the membrane

A basic drug will accumulate on the more acidic side of the membrane

Asp

irin r

elat

ive

conc

entr

ation

100

<0.1

400

Aspirin (weak acid pKa 3.5)

Gastric juicepH 3

PlasmapH 7.4

Aspirin

UrinepH 8

Anion A-

Undisolved AH

Peth

idine

(typ

o)

relative

co

ncen

trat

ion

100

30

106

Protonated base BH+

Free base B

Pethidine(weak base pKa 8.6)

Pethidine(Meperidine)

Problem #12

Protonated base BH+

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c. Some physiological consequences of pH partition:

Urinary acidification

Accelerates excretion of weak bases and retards that of weak

acids

Urinary alkalinization

Reduce excretion of weak bases and increase excretion of weak

acids)

Increasing plasma pH (e.g. by administration of sodium bicarbonate)

Causes weak acidic drugs to be extracted from the CNS into the

plasma.

In class break (4 min) In class break (4 min)

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d. Ion trap and drug overdose

Practice problem #14-Treatment of barbiturate overdose

Pentobarbital (weak acid pKa 7.4)Plasma pH 7.4

PentobarbitalUrine pH ranges from 4-8


PentobarbitalUrine > pH 8

O

O

CH2CH3

ONH

HN

Permeable membrane

Pentobarbital (weak acid pKa 7.4)

Plasma pH 7.4

Pentobarbital

Brain pH 7.4


Plasma pH 7.4

PentobarbitalBrain pH 7.4

Drug treatment of barbiturate overdose

Increase excretion by adjusting urinary pH

Treatment #1: Pentobarbital (and other barbiturates) are weak acid

and excretion can be increased with alkalinized urine (sodium bicarb).

Alkalining urine in treating phenobarbital (pKa7.4) overdose.





O

O

CH2CH3

ONH

HN

Permeable membrane

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Treatment #2: Reducing plasma pH (e.g. by administration of NH4Cl,

or a carbonic anhydrase inhibitor such as acetazolamide causes

phenobarbital to become more concentrated in CNS.





O

O

CH2CH3

ONH

HN

Permeable membrane


Plasma pH 7.4

Pentobarbital

Brain pH 7.4


Plasma pH 7.4

PentobarbitalBrain pH 7.4

Lumen of the distal convoluted tubule of the

kidney

Interstitial spaceBlood circulation

CO2H2O + CO2 CO2

H2O +

Excretion in urine

H2CO3

HCO3-

NaHCO3Na+

AntiporterH+

Na+

H+

NaHCO3

HCO3-

H2CO3 Carbonic anhydrase

Carbonic anhydrase inhibitorscan cause the pH of blood becomes more acidic

Carbonic anhydrase inhibitorscan cause the pH of urine becomes more alkaline

Mechanism of action of carbonic

anhydrase inhibitors

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e. Problem #13

Separation of the �over-the-counter� analgesic mixture APC (Aspirin,

Acetaminophen (Paracetamol) , and Codeine)

Aspirin, an acidic drug with pKa= 3.5

Acetaminophen, an acidic drug with pKa = 9.5

Codeine with bitter taste has a pKa of 8.2

Solvents:

H2O

Toluene (Organic solvent)

HCl (pKa=-7)

NaHCO3 (pKa=6.4)

Aspirin, acetaminophen codeine

H2O, Toluene and ?

Aqueous phase

Toluene

H2O and ?

TolueneAqueous phase

Outline (Handout #3)

Stereochemistry in drug design

A. Importance of stereochemistry in drug design

B. Overview

C. Enantiomerism

D. Geometrical isomerism

E. Conformational isomerism

F. Possible pharmacological differences between stereoisomers

G. Review

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A. Importance of stereochemistry in drug design and development

(a) Affecting drug pharmacological activity

(S)-(-)-thyroxinebiologically active

O CH2

CCO2H

HH2NI I

II

HO

(R)-(+)-thyroxineinactive

O CH2HO

I

I I

IC

CO2H

NH2

H

Fig. 2.18. (Foye�s) Optical isomers. Only in compound 6 do the functional groups A, B, and C align with the corresponding sites of binding on the asymmetric surface.

(b) Affecting drug (ligand) /receptor binding affinity

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(R)-(�)-epinephrine

All three points of interaction with the receptor sites (required for receptor

activation):

1. A substituted aromatic ring with two hydroxyl groups

2. A â-hydroxyl group

3. A protonated secondary ammonium group

(S)-(+)-epinephrine

Only two interactions are provided

1. The protonated secondary ammonium and the substituted aromatic ring

2. The â-hydroxyl group occupies the wrong region of space and,

therefore, cannot interact properly with the receptor.

N-methyldopamine

Achieve the same interactions with the receptor as (S)-(+)-epinephrine

Its vasopressor response is the same as that of (S)-(+)-epinephrine and less

than that of (R)-(�)-epinephrine.

Fig. 2.19., Foye�s

Fig. 2.20. (Foye�s) Selective phases to which optical isomers may be subjected before biological response.

(c) Other mechanisms of enantiomer selectivity

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Summary of the last lecture - c12-06-07-380-123-4567...

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