Medicinal Chemistry/ CHEM 458/658

Chapter 2- Drug Structure and Solubility

Bela TorokDepartment of Chemistry

University of Massachusetts BostonBoston, MA

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Structure

• Overall chemical structure

- possible binding groups

- size

- shape

- stereochemical features (flexibility, conformation, configuration)

- electronic features

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• The Thalidomide Failure

Stereochemistry and Drug Design

N

O

O

O

O

N

O

O

O

O

Racemate

physiological conditions

(S)-Thalidomide(sedative + teratogenic)

(R)-Thalidomide(sedative)

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• Structurally Rigid Groups

Stereochemistry and Drug Design

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• Conformation

Stereochemistry and Drug Design

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Stereochemistry and Drug Design

• Conformation

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Stereochemistry and Drug Design

• Configuration- almost identical activities, but significantly different potencies- completely different activities (one maybe only inactive)- the behavior of enantiomers will be different to that of theracemate

Effect on ADME propertiesAbsorption

O

OH

(-)-NorgestrelO

OH

(+)-Norgestrel

COOHH NH2

CH2

OHOH

D-Dopa

COOHH2N H

CH2

OHOH

L-Dopa7

Stereochemistry and Drug Design• Configuration

Effect on ADME propertiesDistribution little influenceMetabolism

Excretion little influence 8

Solubility

• Physical Nature of the Solute

Solubility product (CxAy)

Henry’s Law

Ksp = [C+]x [A-]y

Cg = Kg Pg

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• SolubilitySolvation - lipophilic vs. hydrophilic character of the solute

polar – hydrophilic; non-polar – lipophilic like dissolves like

Solutions

• Importance of Water Solubility

cells (65% water!), gastric fluid10

• Role of polar and non-polar groups

Solubility and Structure of the Solute

water solubility lipid solubility

salt formationincorporation of water solubilizing groupsspecial dosage forms

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Salt Formation

Most common sources:Anions: (H)Cl-, (H2)SO4

2-, HSO4-

Cations: Na+, Ca2+, Zn2+, diethanolamine, N-methylglucamine

water solubility taste

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Incorporation of Water Solubilizing Groups

• The type of grouppolar groups: alcohol, amine, amide, acid, sulfonic acid, etc.

• Reversible and irreversible groupsirreversible: C-C, C-N, C-O reversible: ester, amide phosphate, sulfate, glycosidic links

• The position of the water solubilizing groupdepends on the reactivity and the position of the pharmacophore(e.g. aromatic groups, or aldehyde etc.)

We should avoid modifying the part that is responsible for the drug-receptor interaction.

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• Methods of introductionCarboxylic acid by alkylation

Incorporation of Water Solubilizing Groups

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• Methods of introductionCarboxylic acid by acylation

Incorporation of Water Solubilizing Groups

O2N CH

OH OH

NHCOCHCl2

O

O

O

NaOHO2N C

H

OH OCOCH2CH2COONa

NHCOCHCl2

Chloramphenicol (antibacterial) Chloramphenicol succinate (antibacterial)

S

NNHSO2 NH2

O

O

O

EtOH S

NNHSO2 NHCOCH2CH2COOH

Sulfathiazole (antibacterial) Succinyl Sulfathiazole (antibacterial)

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Incorporation of Water Solubilizing Groups

• Methods of introductionPhosphate groups

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Incorporation of Water Solubilizing Groups

• Methods of introductionSulfate groups

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8-hydroxyquinoline 8-hydroxy-7-iodo-5-quinolinesulfonic acid(topical antiseptic)

NOH

H2SO4N

OH

several

steps

SO3H

NOH

SO3H

I

CH

CH

CH

N SO2NH2NaHSO3

CH

C C N SO2NH2

SO3Na

H HSO3Na

N4-cinnamylidenesulfanilamide noprylsulfamide (antibacterial)

Incorporation of Basic Groups

• Methods of introduction

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Polyhydroxy and Ether Residues

• Methods of introduction

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Polyhydroxy and Ether Residues

• Methods of introduction

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Microwave Irradiation – Synthetic Applications

• Introduction of

- methyl, alkyl;- fluoro, trifluoro- chloro

groups

Improving Lipid Solubility

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Formulation Methods of Improving Water Solubility

• Cosolventsnon-toxic, inert (toward the drug), water-soluble(ethanol, isopropanol, glycerol, sorbitol, etc.)

• Colloid “Solution” (L/S systems)Preparation of colloid particles (1-1000 nm); sols or hydrosols

• Emulsions (L/L systems)o/w or w/o emulsions; surfactants

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The pH of the system will either enhance or reduce solubility

• Acidic drugs

pH is important but not exclusive

The Effect of pH on the Solubility of Drugs

pKa = pH + log[Non-ionized from]

[Ionized form]

• Basic drugs

pKa = pH + log[Ionized from]

[Non-ionized form]

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• Dual function molecules – amino acids, peptides

The Effect of pH on the Solubility of Drugs

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Partition

• Partition coefficient

normally: 25 °C or 37 °Coctanol as organic solvent

Partition coefficient (P) = [Drug in the organic phase][Drug in an aqueous phase]

Partition coefficient (P) = [Non-ionized drug in the organic phase][Non-ionized drug in an aqueous phase]

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Practical Determination of P

• Mutual saturation by shaking at constant temperature(traditional)

• HPLC method

• Buffer model (octanol/aqueous)

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• Producing database by measuring the P of many compounds -

statistical analysis

Rekker and Hansch comtributions from the fragments

• Extrapolation from known Porganic/H2O data to other solvents

Theoretical Determination of P

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• Amphiphiles – molecules with fragment that likes to dissolvein opposite solvents

• Surfactants – compounds that lower surface tension

Cationic surfactants:-Sodium stearate (CH3(CH2)16COO- Na+)

Anionic surfactants- dodecylpyridinium hydrochloride (C12H25C5H5N+ Cl-)- dodecylamine hydrochloride (CH3(CH2)11NH3

+ Cl-)Ampholytic surfactants

- dodecyl betaine (C12H25N+(CH3)2CH2COO-)Non-ionic surfactants

- heptaoxyethylene monohexyldecyl ether - polyoxyethylene sorbitan monolaurate

Surfactants and Amphiphiles

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• Biological systems – at interfaces of the target cell – cell death

• Natural surfactants and surfactant drugs

Surfactants and Amphiphiles

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• Micelles – cmc (critical micelle concentration)

Surfactants and Amphiphiles

• Effect of micelle

formation

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Drug Solubilization

• Micelles can help solubilize drugs

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Drug Solubilization

• Micelles can help delay metabolitic degradation

• Micelles are also important in the digestion of triglyceridesin mammals.

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Mixed Micelles as Drug Delivery Systems

• Mixed micelles – mixture of surfactants

e.g. Diazepam is stabilized by micelles formed by lechitin and sodium cholate

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Vesicles and Liposomes

• Vesicles – aggregates formed from spherical bilayers ofamphiphiles

• Liposomes – vesicles formed from lipids

• Importance in drug delivery – e.g. amphotericin B.or doxorubicin daunorubicin

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